The TRIM/RBCC proteins are defined by the presence of the tripartite motif composed of a RING domain, one or two B‐box motifs and a coiled‐coil region. These proteins are involved in a plethora of cellular processes such as apoptosis, cell cycle regulation and viral response. Consistently, their alteration results in many diverse pathological conditions. The highly conserved modular structure of these proteins suggests that a common biochemical function may underlie their assorted cellular roles. Here, we review recent data indicating that (...) some TRIM/RBCC proteins are implicated in ubiquitination and propose that this large protein family represents a novel class of ‘single protein RING finger’ ubiquitin E3 ligases. BioEssays 27:1147–1157, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

The dynamic structure and composition of lipid membranes need to be tightly regulated to control the vast array of cellular processes from cell and organelle morphology to protein‐protein interactions and signal transduction pathways. To maintain membrane integrity, sense‐and‐response systems monitor and adjust membrane lipid composition to the ever‐changing cellular environment, but only a relatively small number of control systems have been described. Here, we explore the emerging role of the ubiquitin‐proteasome system in monitoring and maintaining membrane lipid composition. We focus (...) on the ER‐resident RNF145 E3 ubiquitin ligase, its role in regulating adiponectin receptor 2 (ADIPOR2), its lipid hydrolase substrate, and the broader implications for understanding the homeostatic processes that fine‐tune cellular membrane composition. (shrink)

Notch is a mechanosensitive receptor that requires direct cell–cell contact for its activation. Both the strength and the range of notch signaling depend on the size and geometry of the contact sites between cells. These properties of cell–cell contacts in turn depend on cell shape and polarity. At the molecular level, the E3 ubiquitin ligase Neuralized links receptor activation with epithelial cell remodeling. Neur regulates the endocytosis of the Notch ligand Delta, hence Notch activation. It also targets the apical (...) polarity protein Stardust to promote the endocytosis of the Crumbs complex, thereby contributing to epithelium remodeling. Here, we review the interplay between Notch signaling and cell polarity and discuss the possible significance of linking Notch signaling with epithelial cell polarity via a common regulator. Notch receptor activation depends on direct cell–cell contacts that in turn depends on cell shape and cellular polarity. The size and geometry of cell–cell contacts have an impact on the strength and range of signaling. The E3 ubiquitin ligase Neuralized regulates the endocytosis and signaling activity of Delta. The activity of Neuralized is tightly regulated during development. Neuralized also modulates epithelial cell polarity by targeting the apical polarity protein Stardust and by promoting the endocytosis of Crumbs. Thus, the cell-specific expression of Neuralized couples Notch receptor activation with cell polarity regulation in epithelia. (shrink)

Notch is a mechanosensitive receptor that requires direct cell–cell contact for its activation. Both the strength and the range of notch signaling depend on the size and geometry of the contact sites between cells. These properties of cell–cell contacts in turn depend on cell shape and polarity. At the molecular level, the E3 ubiquitin ligase Neuralized links receptor activation with epithelial cell remodeling. Neur regulates the endocytosis of the Notch ligand Delta, hence Notch activation. It also targets the apical (...) polarity protein Stardust to promote the endocytosis of the Crumbs complex, thereby contributing to epithelium remodeling. Here, we review the interplay between Notch signaling and cell polarity and discuss the possible significance of linking Notch signaling with epithelial cell polarity via a common regulator. Notch receptor activation depends on direct cell–cell contacts that in turn depends on cell shape and cellular polarity. The size and geometry of cell–cell contacts have an impact on the strength and range of signaling. The E3 ubiquitin ligase Neuralized regulates the endocytosis and signaling activity of Delta. The activity of Neuralized is tightly regulated during development. Neuralized also modulates epithelial cell polarity by targeting the apical polarity protein Stardust and by promoting the endocytosis of Crumbs. Thus, the cell-specific expression of Neuralized couples Notch receptor activation with cell polarity regulation in epithelia. (shrink)

Protein ubiquitination constitutes a post‐translational modification mediated by ubiquitin ligases whereby ubiquitinated substrates are degraded through the proteasomal or lysosomal pathways, or acquire novel molecular functions according to their “ubiquitin codes.” Dysfunction of the ubiquitination process in cells causes various diseases such as cancers along with neurodegenerative, auto‐immune/inflammatory, and metabolic diseases. KCTD10 functions as a substrate recognition receptor for cullin‐3 (CUL3), a scaffold protein in RING‐type ubiquitin ligase complexes. Recently, studies by ourselves and others have identified new substrates that (...) are ubiquitinated by the CUL3/KCTD10 ubiquitin ligase complex. Moreover, the type of polyubiquitination (e.g., K27‐, K48‐, or K63‐chain) of various substrates (e.g., RhoB, CEP97, EIF3D, and TRIF) mediated by KCTD10 underlies its divergent roles in endothelial barrier formation, primary cilium formation, plasma membrane dynamics, cell proliferation, and immune response. Here, the physiological functions of KCTD10 are summarized and potential mechanisms are proposed. (shrink)

The RNA-binding protein, UPF1, is best known for its central role in the nonsense-mediated RNA decay pathway. Feng et al. now report a new function for UPF1—it is an E3 ubiquitin ligase that specifically promotes the decay of a key pro-muscle transcription factor: MYOD. UPF1 achieves this through its RING-like domain, which confers ubiquitin E3 ligase activity. Feng et al. provide evidence that the ability of UPF1 to destabilize MYOD represses myogenesis. In the future, it will be important (...) to define other protein substrates of UPF1-driven ubiquitination and to determine whether this biochemical activity is responsible for some of UPF1's previously defined biological functions, including in development and stress responses. The exciting findings presented by Feng et al. open up the possibility that protein turnover and RNA turnover are coupled processes. The RNA-binding protein, UPF1, is best known for its central role in the nonsense-mediated RNA decay pathway. Here we discuss a new role for UPF1—it is directly involved in protein decay. This hidden talent raises the possibility that protein turnover and RNA turnover are coupled processes. (shrink)

The RNA-binding protein, UPF1, is best known for its central role in the nonsense-mediated RNA decay pathway. Feng et al. now report a new function for UPF1—it is an E3 ubiquitin ligase that specifically promotes the decay of a key pro-muscle transcription factor: MYOD. UPF1 achieves this through its RING-like domain, which confers ubiquitin E3 ligase activity. Feng et al. provide evidence that the ability of UPF1 to destabilize MYOD represses myogenesis. In the future, it will be important (...) to define other protein substrates of UPF1-driven ubiquitination and to determine whether this biochemical activity is responsible for some of UPF1's previously defined biological functions, including in development and stress responses. The exciting findings presented by Feng et al. open up the possibility that protein turnover and RNA turnover are coupled processes. The RNA-binding protein, UPF1, is best known for its central role in the nonsense-mediated RNA decay pathway. Here we discuss a new role for UPF1—it is directly involved in protein decay. This hidden talent raises the possibility that protein turnover and RNA turnover are coupled processes. (shrink)

Proteolysis-targeting chimeric molecules represent an emerging technique that is receiving much attention for therapeutic intervention. The mechanism is based on the inhibition of protein function by hijacking a ubiquitin E3 ligase for protein degradation. The hetero-bifunctional PROTACs contain a ligand for recruiting an E3 ligase, a linker, and another ligand to bind with the protein targeted for degradation. Thus, PROTACs have profound potential to eliminate “undruggable” protein targets, such as transcription factors and non-enzymatic proteins, which are not limited (...) to physiological substrates of the ubiquitin-proteasome system. These findings indicate great prospects for PROTACs in the development of therapeutics. However, there are several limitations related to poor stability, biodistribution, and penetrability in vivo. This review provides an overview of the main PROTAC-based approaches that have been developed and discusses the promising opportunities and considerations for the application of this technology in therapies and drug discovery. The hetero-bifunctional PROTAC molecules contain a ligand for recruiting an E3 ligase linked with a ligand to bind with the protein targeted for degradation. Thus, PROTACs have profound potential to eliminate “undruggable” disease-causing proteins, which are not limited to physiological substrates of the ubiquitin-protease system, suggesting great prospects for therapeutic development. (shrink)

Neddylation, a ubiquitylation‐like post‐translational modification, is catalyzed by a cascade composed of three enzymes: E1 activating enzyme, E2 conjugating enzyme, and E3 ligase with cullins as physiological substrates. Specifically, neddylation E2 UBE2M couples with E3 RBX1 to neddylate cullins 1–4, whereas neddylation E2 UBE2F couples with E3 RBX2/SAG to neddylate cullin 5, leading to activation of CRL1‐4 (Cullin‐RING ligases 1–4) and CRL5, respectively. While over‐activation of the neddylation‐CRLs axis occurs frequently in many human cancers, how neddylation‐CRLs regulate the function (...) of immune cells, particularly Treg cells was previously unknown. To this end, we recently performed Treg selective knockout of two neddylation E2s and two E3s, individually, driven by Foxp3‐Cre, and found that while the Ube2f‐Sag E2/E3 pair plays a minimal role, if any, the Ube2m‐Rbx1 pair is essential for the maintenance of Treg functionality, since their deletion triggers robust inflammatory response with autoimmune phenotypes. Milder phenotype severity upon Treg KO of upstream Ube2m than that of downstream Rbx1 strongly suggested that Rbx1 regulates Treg function in a manner dependent and independent of neddylation. (shrink)

The fate of eukaryotic proteins, from their synthesis to destruction, is supervised by the ubiquitin–proteasome system (UPS). The UPS is the primary pathway responsible for selective proteolysis of intracellular proteins, which is guided by covalent attachment of ubiquitin to target proteins by E1 (activating), E2 (conjugating), and E3 (ligating) enzymes in a process known as ubiquitylation. The UPS can also regulate protein synthesis by influencing multiple steps of RNA (ribonucleic acid) metabolism. Here, recent publications concerning the interplay between the UPS (...) and different types of RNA are reviewed. This interplay mainly involves specific RNA‐binding E3 ligases that link RNA‐dependent processes with protein ubiquitylation. The emerging understanding of their modes of RNA binding, their RNA targets, and their molecular and cellular functions are primarily focused on. It is discussed how the UPS adapted to interact with different types of RNA and how RNA molecules influence the ubiquitin signaling components. (shrink)

The pore‐forming BCL‐2 family proteins are effectors of mitochondrial poration in apoptosis initiation. Two atypical effectors—BOK and truncated BID (tBID)—join the canonical effectors BAK and BAX. Gene knockout revealed developmental phenotypes in the absence the effectors, supporting their roles in vivo. During apoptosis effectors are activated and change shape from dormant monomers to dynamic oligomers that associate with and permeabilize mitochondria. BID is activated by proteolysis, BOK accumulates on inhibition of its degradation by the E3 ligase gp78, while BAK (...) and BAX undergo direct activation by BH3‐only initiators, autoactivation, and crossactivation. Except tBID, effector oligomers on the mitochondria appear as arcs and rings in super‐resolution microscopy images. The BH3‐in‐groove dimers of BAK and BAX, the tBID monomers, and uncharacterized BOK species are the putative building blocks of apoptotic pores. Effectors interact with lipids and bilayers but the mechanism of membrane poration remains elusive. I discuss effector‐mediated mitochondrial poration. (shrink)

Ubiquitination is essential in mediating diverse cellular functions including protein degradation and trafficking. Ubiquitin‐protein (E3) ligases determine the substrate specificity of the ubiquitination process. The Nedd4 family of E3 ligases is an evolutionarily conserved family of proteins required for the ubiquitination of a large number of cellular targets. As a result, this family regulates a wide variety of cellular processes including transcription, stability and trafficking of plasma membrane proteins, and the degradation of misfolded proteins. The modular architecture of the proteins, (...) comprising a C2 domain, multiple WW domains and a catalytic domain, enables diverse intermolecular interactions and recruitment to various subcellular locations. The WW domains commonly mediate interaction with substrate proteins; however, an increasing number of Nedd4 targets do not contain obvious WW domain‐interaction motifs suggesting the involvement of accessory proteins. This review discusses recent insights into how accessory and adaptor proteins modulate the activities of Nedd4 family members, including recruitment of novel substrates, alteration of subcellular localisation and effects on ubiquitination. BioEssays 28: 617–628, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

The insulin/insulin‐like growth factor‐1 (IGF‐1) signaling (IIS) pathway is a pivotal genetic program regulating cell growth, tissue development, metabolic physiology, and longevity of multicellular organisms. IIS integrates a fine‐tuned cascade of signaling events induced by insulin/IGF‐1, which is precisely controlled by post‐translational modifications. The ubiquitin/proteasome‐system (UPS) influences the functionality of IIS through inducible ubiquitylation pathways that regulate internalization of the insulin/IGF‐1 receptor, the stability of downstream insulin/IGF‐1 signaling targets, and activity of nuclear receptors for control of gene expression. An age‐related (...) decline in UPS activity is often associated with an impairment of IIS, contributing to pathologies such as cancer, diabetes, cardiovascular, and neurodegenerative disorders. Recent findings identified a key role of diverse ubiquitin modifications in insulin signaling decisions, which governs dynamic adaption upon environmental and physiological changes. In this review, we discuss the mutual crosstalk between ubiquitin and insulin signaling pathways in the context of cellular and organismal homeostasis. (shrink)

PTEN‐induced kinase 1 (PINK1) is a Parkinson's disease gene that acts as a sensor for mitochondrial damage. Its best understood role involves phosphorylating ubiquitin and the E3 ligase Parkin (PRKN) to trigger a ubiquitylation cascade that results in selective clearance of damaged mitochondria through mitophagy. Here we focus on other physiological roles of PINK1. Some of these also lie upstream of Parkin but others represent autonomous functions, for which alternative substrates have been identified. We argue that PINK1 orchestrates a (...) multi‐arm response to mitochondrial damage that impacts on mitochondrial architecture and biogenesis, calcium handling, transcription and translation. We further discuss a role for PINK1 in immune signalling co‐ordinated at mitochondria and consider the significance of a freely diffusible cleavage product, that is constitutively generated and degraded under basal conditions. (shrink)

Ubiquitination plays a central role in the regulation of stem cell self‐renewal, propagation, and differentiation. In this review, the functions of ubiquitin dynamics in a myriad of cellular processes, acting along side the pluripotency network, to regulate embryonic stem cell identity are highlighted. The implication of deubiquitinases (DUBs) and E3 Ubiquitin (Ub) ligases in cellular functions beyond protein degradation is reported, including key functions in the regulation of mRNA stability, protein translation, and intra‐cellular trafficking; and how it affects cell metabolism, (...) the micro‐environment, and chromatin organization is discussed. Finally, unsolved issues in the field are emphasized and will need to be tackled in order to fully understand the contribution of ubiquitin dynamics to stem cell self‐renewal and differentiation. (shrink)

In this review, we discuss a novel on‐site remodeling function that is mediated by the H2A‐ubiquitin binding protein ZRF1. ZRF1 facilitates the remodeling of multiprotein complexes at chromatin and lies at the heart of signaling processes that occur at DNA damage sites and during transcriptional activation. In nucleotide excision repair ZRF1 remodels E3 ubiquitin ligase complexes at the damage site. During embryonic stem cell differentiation, it contributes to retinoic acid‐mediated gene activation by altering the subunit composition of the Mediator (...) complex. We postulate that ZRF1 operates in conjunction with cellular remodeling machines and suggest that on‐site remodeling might be a hallmark of many chromatin‐associated signaling pathways. We discuss yet unexplored functions of ZRF1‐mediated remodeling in replication and double strand break repair. In conclusion, we postulate that on‐site remodeling of multiprotein complexes is essential for the timing of chromatin signaling processes. (shrink)

Ubiquitination of protein species in regulating signal transduction pathways is universally accepted as of fundamental importance for normal development, and defects in this process have been implicated in the progression of many human diseases. One pathway that has received much attention in this context is transforming growth factor‐beta (TGF‐β) signalling, particularly during the regulation of epithelial‐mesenchymal transition (EMT) and tumour progression. While E3‐ubiquitin ligases offer themselves as potential therapeutic targets, much remains to be unveiled regarding mechanisms that culminate in their (...) regulation. With this in mind, the focus of this review highlights the regulation of the ubiquitination pathway and the significance of a recently described group of NEDD4 E3‐ubiquitin ligase isoforms in the context of TGF‐β pathway regulation. Moreover, we now broaden these observations to incorporate a growing number of protein isoforms within the ubiquitin ligase superfamily as a whole, and discuss their relevance in defining a new ‘iso‐ubiquitinome’. (shrink)

The BTB domain is a protein–protein interaction motif that is found throughout eukaryotes. It determines a unique tri‐dimensional fold with a large interaction surface. The exposed residues are highly variable and can permit dimerization and oligomerization, as well as interaction with a number of other proteins. BTB‐containing proteins are numerous and control cellular processes that range from actin dynamics to cell‐cycle regulation. Here, we review findings in the field of transcriptional regulation to illustrate how the high variability of the BTB (...) has allowed related transcription factors to evolve different functional abilities. We then report how recent work has showed that, in spite of their high sequence divergence and apparently unrelated functions, many BTB‐containing proteins have at least one shared role: the recruitment of degradation targets to E3 ubiquitin ligase complexes. Taken together, these findings illustrate diverse and convergent functions of a versatile protein–protein interaction domain. BioEssays 28: 1194–1202, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

In eukaryotic cells terminally misfolded proteins of the secretory pathway are retarded in the endoplasmic reticulum (ER) and subsequently degraded in a ubiquitin‐proteasome‐dependent manner. This highly conserved process termed ER‐associated protein degradation (ERAD) ensures homeostasis in the secretory pathway by disposing faulty polypeptides and preventing their deleterious accumulation and eventual aggregation in the cell. The focus of this paper is the functional description of membrane‐bound ubiquitin ligases, which are involved in all critical steps of ERAD. In the end we want (...) to speculate on how the modular architecture of these entities ensures the specificity of substrate selection and possibly accomplishes the transport of misfolded polypeptides from the ER into the cytoplasm. (shrink)

DNA joining enzymes play an essential role in the maintenance of genomic integrity and stability. Three mammalian genes encoding DNA ligases, LIG1, LIG3 and LIG4, have been identified. Since DNA ligase II appears to be derived from DNA ligase III by a proteolytic mechanism, the three LIG genes can account for the four biochemically distinct DNA ligase activities, DNA ligases I, II, III and IV, that have been purified from mammalian cell extracts. It is probable that the (...) specific cellular roles of these enzymes are determined by the proteins with which they interact. The specific involvement of DNA ligase I in DNA replication is mediated by the non‐catalytic amino‐terminal domain of this enzyme. Furthermore, DNA ligase I participates in DNA base excision repair as a component of a multiprotein complex. Two forms of DNA ligase III are produced by an alternative splicing mechanism. The ubiqitously expressed DNA ligase III‐α forms a complex with the DNA single‐strand break repair protein XRCC1. In contrast, DNA ligase III‐β, which does not interact with XRCC1, is only expressed in male meiotic germ cells, suggesting a role for this isoform in meiotic recombination. At present, there is very little information about the cellular functions of DNA ligase IV. (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)

Here I interpret a central passage in Plato's Sophist by focusing on understudied elements that provide insight into the fit of the dialogue's parts and the Sophist-Statesman diptych as a whole. I argue that the Eleatic Stranger's account of what the dialectician "adequately views" at Sophist 253d1-e3 involves both division and the communion of ontological kinds, not just one or the other as has been typically argued. I also consider other key passages and the turn throughout the dialogue from imagistic (...) opining toward noetic understanding. (shrink)

BackgroundCORE (Clarity and Openness in Reporting: E3-based) Reference (released May 2016 by the European Medical Writers Association [EMWA] and the American Medical Writers Association [AMWA]) is a complete and authoritative open-access user’s guide to support the authoring of clinical study reports (CSRs) for current industry-standard-design interventional studies. CORE Reference is a content guidance resource and is not a CSR Template.TransCelerate Biopharma Inc., an alliance of biopharmaceutical companies, released a CSR Template in November 2018 and recognised CORE Reference as one of (...) two principal sources used in its development.MethodsThe regulatory medical writing and statistical professionals who developed CORE Reference conducted a critical review of the TransCelerate CSR Template. We summarise our major findings and recommendations in this communication. We also re-examined and edited the Version 1 CORE Reference Terminology Table that we first published in 2016, and we present this as Version 2 in this communication.ResultsOur major critical review findings indicate that opportunities remain to refine the CSR Template structure and instructional text, enhance content clarity, add web links to referenced guidance documents, improve transparency to support the broad readership of CSRs, and develop supporting resources.The CORE Reference ‘Terminology Table’ Version 2 includes estimand as a defined term and an adaptation of the original ‘worked study example’ to incorporate the recently evolved concept of ‘estimands’.ConclusionsAs TransCelerate’s CSR Template represents an important milestone in authoring CSRs, we offer CSR authors advice and recommendations on its use, similarities, and differences with CORE Reference and advise them to consider shared interpretations between the two.RegistrationCORE Reference is registered with the EQUATOR Network. The TransCelerate CSR Template is not registered with any external organisation to the knowledge of the authors of this paper. (shrink)

Numerous eukaryotic DNA processing enzymes, such as DNA polymerases and ligases, bind the processivity factor PCNA, which acts as a platform to recruit and regulate the binding of enzymes to their DNA substrate. Multiple PCNA‐interacting motifs (PIPs) are present in these enzymes, but their individual structural and functional role has been a matter of debate. Recent cryo‐EM reconstructions of high‐fidelity DNA polymerase Pol δ (Pol δ), translesion synthesis DNA polymerase κ (Pol κ) and Ligase 1 (Lig1) bound to a (...) DNA substrate and PCNA demonstrate that the critical interaction with PCNA involves the internal PIP proximal to the catalytic domain. The ancillary PIPs, located in long disordered regions, are instead invisible in the reconstructions, and appear to function as flexible tethers when the enzymes fall off the DNA. In this review, we discuss the recent structural advancements and propose a functional hierarchy for the PIPs in Pol δ, Pol κ, and Lig1. (shrink)

Deciphering how DCAFs (DDB1‐CUL4 Associated Factors) modulate a broad spectrum of cellular processes, including cell cycle progression and maintenance of genomic integrity is critical to better understand cellular homeostasis and diseases. Cells contain more than 100 DCAFs that associate with the Cullin‐Ring Ubiquitin Ligase 4 (CRL4) complex that target specific protein substrates for degradation. DCAFs are thought to act as substrate receptors that dictate the specificity of the ubiquitination machinery (“catalytic DCAFs”). However, recent studies have suggested that some DCAFs (...) might play a different role by targeting CRL4 complexes to distinct cellular compartments (“structural DCAFs”). Once localized to their correct cellular domains, these CRLs dissociate from the structural DCAFs prior to their association with other, substrate‐specific catalytic DCAFs. Thus, we propose that DCAF switches can provide a mechanistic basis for the degradation of proteins that regulate cell growth and proliferation at precise points in space and time. (shrink)

Stress associated proteins (SAPs), novel A20/AN1 zinc‐finger domain‐containing proteins, are fast emerging as potential candidates for biotechnological approaches in order to improve abiotic stress tolerance in plants – the ultimate aim of which is crop‐yield protection. Until relatively recently, such proteins had only been identified in humans, where they had been shown to be key regulators of innate immunity. Their phylogenetic relationship and recruitment of diverse protein domains reflect an architectural and mechanistic diversity. Emerging evidence suggests that SAPs may act (...) as ubiquitin ligase, redox sensor, and regulator of gene expression during stress. Here, we evaluate the new knowledge on SAPs with a view to understand their mechanism of action. Furthermore, we set an agenda for investigating hitherto unexplored roles of these proteins. (shrink)

In this paper, an evolutionary multiverse argument against naturalism (EMAAN) is presented: E1. In an evolutionary multiverse, phenomena have variable evolutionary ages. E2. After some time T, the development of the empirical sciences will be evolutionarily conserved. E3. The phenomena with an evolutionary age above T are methodologically supernatural. Entities are classified according to whether they are (1) physical and spatiotemporal, (2) causally efficacious, and (3) either observed by or explanatorily necessary for the empirical sciences. While the conjunction of (1) (...) and (2) is taken to be sufficient for existence in reality, the negation of (3) defines methodological supernaturalness. EMAAN uses a generalization of evolutionary theory, namely cosmological natural selection, to argue that phenomena evolve that fulfill conditions (1) and (2), but not (3). This shows that methodologically supernatural phenomena have a clear epistemology according to a theory that is grounded in the commitments of naturalism. Supernatural phenomena are not observed by the empirical sciences because the empirical sciences themselves are supernaturally guided and predestined to develop according to an evolutionarily conserved plan. In spite of this scientific plan, there is room for afterlives and supernaturality in the everyday experience. (shrink)

In this paper we exploit the notions of conjoined and iterated conditionals, which are defined in the setting of coherence by means of suitable conditional random quantities with values in the interval [0,1]. We examine the iterated conditional (B|K)|(A|H), by showing that A|H p-entails B|K if and only if (B|K)|(A|H) = 1. Then, we show that a p-consistent family F={E1|H1, E2|H2} p-entails a conditional event E3|H3 if and only if E3|H3= 1, or (E3|H3)|QC(S) = 1 for some nonempty subset S (...) of F, where QC(S) is the quasi conjunction of the conditional events in S. Then, we examine the inference rules And, Cut, Cautious Monotonicity, and Or of System P and other well known inference rules (Modus Ponens, Modus Tollens, Bayes). We also show that QC(F)|C(F) = 1, where C(F) is the conjunction of the conditional events in F. We characterize p-entailment by showing that F p-entails E3|H3 if and only if (E3|H3)|C(F) = 1. Finally, we examine Denial of the antecedent and Affirmation of the consequent, where the p-entailment of (E3|H3) from F does not hold, by showing that (E3|H3)|C(F) is not equal to 1. (shrink)

At first glance the three eukaryotic protein translocation machineries – the ER‐associated degradation (ERAD) transport apparatus of the endoplasmic reticulum, the peroxisomal importomer and SELMA, the pre‐protein translocator of complex plastids – appear quite different. However, mechanistic comparisons and phylogenetic analyses presented here suggest that all three translocation machineries share a common ancestral origin, which highlights the recycling of pre‐existing components as an effective evolutionary driving force.Editor's suggested further reading in BioEssays ERAD ubiquitin ligases Abstract.

In lieu of an abstract, here is a brief excerpt of the content:Plato on Knowledge as a Power1Nicholas D. SmithAt 471C4 in Plato’s Republic, the argument takes a sudden turn when Glaucon becomes impatient with all of the specific prescriptions Socrates has been making, and asks to return to the issue Socrates had earlier set aside—whether or not the city he was describing could ever be brought into being. In response to Glaucon’s impatient question, Socrates articulates his “third wave of (...) paradox” (472ag–7), namely, that the ills of the cities will never be ended until either philosophers become rulers or rulers become philosophers (473c11–d6). Glaucon immediately responds that such a view is likely to be greeted with violence and scorn (473e6–474a4), and so Socrates must hasten to explain his odd claim. His explanation, it turns out, is that true philosophers have an enormous cognitive advantage over non-philosophers—philosophers have and use knowledge (ἐπιστήμη), whereas non-philosophers have and use only opinion (δόξα).2 This distinction, between επιστήμη and δόξα, turns out: to be a distinction between two different cognitive powers (δυνάμεις—477d7–e3). And different powers, Plato clearly tells us, apply to or take as their objects (Plato says they are “ἐπί”) different things (477dl).In this paper, I shall argue that the relationship between the cognitive powers and their various objects has been fundamentally misunderstood, which has led scholars into one or more misinterpretations of important and explicit features of the text. At the heart of these misunderstandings, I claim, is [End Page 145] their shared misconception of the relation between the cognitive power and its objects as interpretable in terms of the relationship between a cognitive stale and what the content of that state is of or about.3 One consequence of the view for which I shall argue is that what has come to be known as the “two-worlds theory”4 of Plato’s epistemology is seriously mistaken, but no less mistaken than the alternatives given by its recent critics. Another consequence that I shall draw from my argument is that Plato should be understood neither as a kind of foundationalist with regard to knowledge and warrant, as some have supposed him to be,5 nor as a coherentist, as others have supposed,6 but, rather, as a kind of causal reliabilist. [End Page 146]1. KNOWLEDGE AS A POWERScholarly interpretations of Plato’s epistemology have routinely sought to understand the relationships between each cognitive power of Republic Book V and the objects of the ἐφ’ ᾦ (“what it is related to”) condition by which it is differentiated from other δυνάμεις as Plato’s way of telling us what each sort of cognition is of or aboul. 7 So, for example, we find Gail Fine using the expressions “belief [δόξα] is set over [Fine’s translation of Plato’s ἐπί] …” and “knowledge is set over …” interchangeably with “belief is of …” or “belief is about…” and “knowledge is of …” or “knowledge is about …”8 Against the “two-worlds theory,” Fine argues that, for Plato, there can be knowledge of sensibles and beliefs about Forms. Accordingly, since she assimilates the power-ἐπί-object set of relations to the cognilion-of/about-object relation, she concludes—in order to account for knowledge of sensibles and beliefs about Forms—that the objects of knowledge and opinion must be propositions. Plato’s claims that knowledge is ἐπί what is, whereas opinion is ἐπί what is and is not, Fine understands as, “One can only know true propositions; one can believe both true and false propositions.”9 We shall see later that this “veridical” understanding of what Plato means to identify as “what is,” and “what is and is not” fails to account for important and explicit elements of Plato’s exposition of the epistemological and metaphysical distinctions he is making. For now, it is enough to note that Fine understands the ἐφ’ᾦ) relation in terms of our cognition-of/about-object relation. One finds the same assimilation made by those who advance existential readings of Plato’s “is” and “is not,”10 as [End Page 147] well as those who have urged that we adopt predicative readings of “is” and “is not.”11But I think there are very serious problems with this assimilation. Plato is very... (shrink)

In this paper I argue that, despite what many commentators have concluded, Plato’s division of three psychological “causes” of criminal behavior at Laws 863b1-e3 (anger, pleasure, and ignorance) is not intended to invoke the tripartite theory of the soul. I suggest that the focus of the division is on an alternative moral psychological picture, one which is better suited to the criminal penology of Book 9. However, I argue, this alternative picture is nonetheless consistent with tripartite theory.

The premise-fact confusion in Aristotle’s PRIOR ANALYTICS. -/- The premise-fact fallacy is talking about premises when the facts are what matters or talking about facts when the premises are what matters. It is not useful to put too fine a point on this pencil. -/- In one form it is thinking that the truth-values of premises are relevant to what their consequences in fact are, or relevant to determining what their consequences are. Thus, e.g., someone commits the premise-fact fallacy if (...) they think that a proposition has different consequences were it true than it would have if false. C. I. Lewis said that confusing logical consequence with material consequence leads to this fallacy. See Corcoran’s 1973 “Meanings of implication” [available on Academia. edu]. -/- The premise-fact confusion occurs in a written passage that implies the premise-fact fallacy or that suggests that the writer isn’t clear about the issues involved in the premise-fact fallacy. Here are some examples. -/- E1: If Abe is Ben and Ben swims, then it would follow that Abe swims. -/- Comment: The truth is that from “Abe is Ben and Ben swims”, the proposition “Abe swims” follows. Whether in fact Abe is Ben and Ben swims is irrelevant to whether “Abe swims” follows from “Abe is Ben and Ben swims”. -/- E1 suggests that maybe “Abe swims” wouldn’t follow from “Abe is Ben and Ben swims” if the latter were false. -/- E2: The truth of “Abe is Ben and Ben swims” implies that Abe swims. -/- E3: Indirect deduction requires assuming something false. -/- Comment: If the premises of an indirect deduction are true the conclusion is true and thus the “reductio” assumption is false. But deduction, whether direct or indirect, does not require true premises. In fact, indirect deduction is often used to determine that the premises are not all true. -/- Anyway, the one-page paper accompanying this abstract reports one of dozens of premise-fact errors in PRIOR ANALYTICS. In the session, people can add their own examples and comment on them. For example, is the one at 25b32 the first? What is the next premise-fact error after 25b32? Which translators or commentators discuss this? -/- . (shrink)

Ward Blondé ABSTRACT: In this paper, an evolutionary multiverse argument against naturalism is presented: E1. In an evolutionary multiverse, phenomena have variable evolutionary ages. E2. After some time T, the development of the empirical sciences will be evolutionarily conserved. E3. The phenomena with an evolutionary age above T are methodologically supernatural. Entities are classified ….

This review discusses the possible role of α‐tubulin detyrosination, a reversible post‐translational modification that occurs at the protein's C‐terminus, in cellular morphogenesis. Higher eukaryotic cells possess a cyclic post‐translational mechanism by which dynamic microtubules are differentiated from their more stable counterparts; a tubulin‐specific carboxypeptidase detyrosinates tubulin protomers within microtubules, while the reverse reaction, tyrosination, is performed on the soluble protomer by a second tubulin‐specific enzyme, tubulin tyrosine ligase. In general, the turnover of microtubules in undifferentiated, proliferating cells is so (...) rapid that the microtubules accumulate very little detyrosinated tubulin; that is, they are enriched in tyrosinated tubulin. However, an early event common to at least three well‐studied morphogenetic events myogenesis, neuritogenesis, and directed cell motility is the elaboration of a polarized array of stable microtubules that become enriched in detyrosinated tubulin. The formation of this specialized array of microtubules in specific locations in cells undergoing morphogenesis suggests that it plays an important role in generating cellular asymmetries. (shrink)

Much recent scholarship on Plato’ Crito has revolved around the controversy about the relationship and possible compatibility between the arguments Socrates gives in his own person (SocratesS) and those he gives in the person of the Laws (SocratesL). By contrast, the relation between the arguments given by SocratesL and those given by Crito continues to be seen as uncontroversial: by the end of the dialogue, commentators agree, Crito has no choice but to concede to the force of SocratesL’s arguments. Against (...) this traditional reading, this paper will argue not only that SocratesL’s arguments fail to secure Crito’s agreement, but also that two characters’ attempts to communicate end at an impasse that seems to leave little room for meaningful shared discourse –and may even undermine Crito’s belief in the possibility of meaningful speech. My interpretation is informed by Socrates’ account (at 49c9-e3) of the need for and nature of a “common ground” as a prerequisite for genuine dialogue. This passage, I argue, challenges the traditional analysis of Crito as the representative of a particular value system or a particular “type”, demanding, instead, a consideration of the effect of Socrates’ arguments upon Crito in light of a more robust view of the latter’s perspective. Such a reconsideration has consequences not only for our appreciation of the dramatic structure of the dialogue, but also for how we understand one of the dialogue’s central, if underexplored, themes: the belief in a shared logos and the psychagogic necessity and perils of testing that belief. (shrink)

A number of novel gene detection techniques all revolve around the ligation of synthetic nucleic acid probes. In such ligase‐assisted gene detection reactions, specific DNA or RNA sequences are investigated by using them as guides for the covalent joining of pairs of probe molecules. The probes are designed to hybridize immediately next to each other on the target nucleic acid strand. Demonstration of ligated probes results in highly specific detection of and efficient distinction between similar sequence variants under standard (...) reaction conditions. Accordingly, the principle has been applied in automated genetic screening procedures. Ligation reactions are also integral to a number of amplification procedures and they will be of value in an expanding range of genetic analyses. (shrink)

The development of new approaches is critical to gain further insights into biological processes that cannot be obtained by existing methods or technologies. The detection of protein–protein interaction is often challenging, especially for weak and transient interactions or for membrane proteins. Over the last decade, several proximity‐tagging methodologies have been developed to explore protein interactions in living cells. Among those, the most efficient are based on protein partner modification, such as biotinylation or pupylation. Such technologies are based on engineered variants (...) of enzymes like peroxidases or ligases that release reactive molecules, in the presence of specific substrates, that bind surrounding proteins. Fusing a protein of interest (POI) to these enzymes allows the definition of an unbiased “proxisome,” that is, all of the proteins in interaction or in close vicinity of the POI. Here, the different proximity‐labeling tools available are described and comprehensive comparison to discuss advantages and limitations is provided. (shrink)

THE ART OF CAUSAL CONJECTURE Glenn Shafer Table of Contents Chapter 1. Introduction........................................................................................ ...........1 1.1. Probability Trees..........................................................................................3 1.2. Many Observers, Many Stances, Many Natures..........................................8 1.3. Causal Relations as Relations in Nature’s Tree...........................................9 1.4. Evidence............................................................................................ ...........13 1.5. Measuring the Average Effect of a Cause....................................................17 1.6. Causal Diagrams..........................................................................................20 1.7. Humean Events............................................................................................23 1.8. Three Levels of Causal Language................................................................27 1.9. An Outline of the Book................................................................................27 Chapter 2. Event Trees............................................................................................... .....31 2.1. Situations and Events...................................................................................32 2.2. The Ordering of Situations and Moivrean Events.......................................35 2.3. Cuts................................................................................................ ..............39 2.4. Humean Events............................................................................................43 2.5. (...) Moivrean Variables......................................................................................49 2.6. Humean Variables........................................................................................53 2.7. Event Trees for Stochastic Processes...........................................................54 2.8. Timing in Event Trees.................................................................................56 2.9. Intersecting Event Trees...............................................................................60 2.10. Notes on the Literature...............................................................................61 Chapter 3. Probability Trees...........................................................................................63 3.1. Some Types of Probability Trees.................................................................64 ii 3.2. Axioms for the Probabilities of Moivrean Events.......................................68 3.3. Zero Probabilities....................................................................................... ..70 3.4. A Sample-Space Analysis of the Event-Tree Axioms.................................72 3.5. Probabilities and Expected Values for Variables.........................................74 3.6. Martingales......................................................................................... .........79 3.7. The Expectation of a Variable in a Cut........................................................83 3.8. Conditional Expected Value and Conditional Expectation.........................87 Chapter 4. The Meaning of Probability...........................................................................91 4.1. The Interpretation of Expected Value..........................................................92 4.2. The Interpretation of Expectation................................................................95 4.3. The Long Run..............................................................................................98 4.4. Changes in Belief.........................................................................................101 4.5. The Empirical Validation of Probability......................................................106 4.6. The Diversity of Uses of Probability...........................................................108 4.7. Notes on the Literature.................................................................................110 Chapter 5. Independent Events.......................................................................................113 5.1. Independence........................................................................................ .......114 5.2. Weak Independence.....................................................................................118 5.3. The Principle of the Common Cause...........................................................121 5.4. Conditional Independence............................................................................128 5.5. Notes on the Literature.................................................................................133 Chapter 6. Events Tracking Events.................................................................................135 6.1. Tracking............................................................................................ ...........137 6.2. Tracking and Conditional Independence.....................................................142 6.3. Stochastic Subsequence...............................................................................143 6.4. Singular Diagrams for Stochastic Subsequence...........................................147 6.5. Conjunctive and Interactive Forks...............................................................149 Chapter 7. Events as Signs of Events..............................................................................153 iii 7.1. Sign................................................................................................ ..............154 7.2. Weak Sign................................................................................................ ....159 7.3. The Ethics of Causal Talk............................................................................160 7.4. Screening Off...............................................................................................16 2 Chapter 8. Independent Variables...................................................................................167 8.1. Unconditional Independence........................................................................170 8.2. Conditional Independence............................................................................175 8.3. Independence for Partitions.........................................................................177 8.4. Independence for Families of Variables......................................................182 8.5. Individual Properties of the Independence Relations...................................186 Chapter 9. Variables Tracking Variables........................................................................189 9.1. Tracking and Conditional Independence: A Summary...............................190 9.2. Strong Tracking............................................................................................ 192 9.3. Strong Tracking and Conditional Independence..........................................198 9.4. Stochastic Subsequence...............................................................................201 9.5. Functional Dependence................................................................................203 9.6. Tracking in Mean.........................................................................................204 9.7. Linear Tracking............................................................................................ 207 9.8. Tracking by Partitions..................................................................................210 9.9. Tracking by Families of Variables...............................................................212 Chapter 10. Variables as Signs of Variables...................................................................215 10.1. Sign................................................................................................ ............219 10.2. Linear Sign................................................................................................ .222 10.3. Scored Sign................................................................................................ 225 10.4. Families of Variables.................................................................................227 Chapter 11. AnTheory of Event Trees.............................................................229 11.1. Event Trees as Sets of Sets........................................................................230 11.2. Event Trees as Partially Ordered Sets........................................................232 iv 11.3. Regular Event Trees...................................................................................240 11.4. The Resolution of Moivrean Variables......................................................244 11.5. Humean Events and Variables...................................................................246 Chapter 12. Martingale Trees..........................................................................................247 12.1. Examples of Decision Trees......................................................................249 12.2. The Meaning of Probability in a Decision Tree.........................................253 12.3. Martingales......................................................................................... .......257 12.4. The Structure of Martingale Trees.............................................................261 12.5. Probability and Causality...........................................................................265 12.6. Lower and Upper Probability.....................................................................269 12.7. The Law of Large Numbers.......................................................................272 12.8. Notes on the Literature...............................................................................274 Chapter 13. Refining............................................................................................ ...........275 13.1. Examples of Refinement............................................................................277 13.2. A Constructive Definition of Finite Refinement.......................................281 13.3. Axioms for Refinement..............................................................................282 13.4. Lifting Moivrean Events and Variables.....................................................288 13.5. Refining Martingale Trees.........................................................................288 13.6. Grounding........................................................................................... .......294 Chapter 14. Principles of Causal Conjecture..................................................................299 14.1. The Diversity of Causal Explanation.........................................................302 14.2. The Mean Effect of the Happening of a Moivrean Event..........................305 14.3. The Effect of a Humean Variable..............................................................311 14.4. Attribution and Generality.........................................................................316 14.5. The Statistical Measurement of the Effect of a Cause...............................319 14.6. Measurement by Experiment.....................................................................320 14.7. Using Our Knowledge of How Things Work............................................322 v 14.8. Sampling Error...........................................................................................329 14.9. The Sampling Frame..................................................................................329 14.10. Notes on the Literature.............................................................................330 Chapter 15. Causal Models.............................................................................................3 31 15.1. The Causal Interpretation of Statistical Prediction....................................333 15.2. Generalizing to a Family of Exogenous Variables....................................337 15.3 Some Joint Causal Diagrams......................................................................339 15.4. Causal Path Diagrams................................................................................342 15.5. Causal Relevance Diagrams.......................................................................346 15.6. The Meaning of Latent Variables..............................................................352 15.7. Notes on the Literature...............................................................................357 Chapter 16. Representing Probability Trees...................................................................359 16.1. Three Graphical Representations...............................................................361 16.2. Skeletal Simplifications.............................................................................368 16.3. Martingale Trees in Type Theory...............................................................371 Appendix A. Huygens’s Probability Trees.....................................................................379 Huygens’s Manuscript in Translation..................................................................380 Appendix B. Some Elements of Graph Theory..............................................................385 B1. Undirected Graphs........................................................................................385 B2. Directed Graphs............................................................................................38 6 Appendix C. Some Elements of Order Theory...............................................................393 C1. Partial and Quasi Orderings.........................................................................393 C2. Singular and Joint Diagrams for Binary Relations.......................................394 C3. Lattices............................................................................................ .............395 C4. The Lattice of Partitions of a Set..................................................................396 Appendix D. The Sample-Space Framework for Probability.........................................399 D1. Probability Measures....................................................................................399 D2. Variables........................................................................................... ...........400 vi D3. Families of Variables...................................................................................401 D4. Expected Value............................................................................................402 D5. The Law of Large Numbers.........................................................................405 D6. Conditional Probability................................................................................406 D7. Conditional Expected Value........................................................................407 Appendix E. Prediction in Probability Spaces................................................................409 E1. Conditional Distribution...............................................................................411 E2. Regression on a Single Variable...................................................................412 E3. Regression on a Partition or a Family of Variables......................................415 E4. Linear Regression on a Single Variable.......................................................418 E5. Linear Regression on a Family of Variables................................................422 Appendix F. Sample-Space Concepts of Independence.................................................425 F1. Overview............................................................................................ ...........426 F2. Independence Proper.....................................................................................432 F3. Unpredictability in Mean..............................................................................434 F4. Simple Uncorrelatedness..............................................................................437 F5. Mixed Uncorrelatedness...............................................................................438 F6. Partial Uncorrelatedness...............................................................................440 F7. Independence for Partitions..........................................................................442 F8. Independence for Families of Variables.......................................................445 F9. The Basic Role of Uncorrelatedness.............................................................448 F10. Dawid’s Axioms.........................................................................................449 Appendix G. Prediction Diagrams..................................................................................453 G1. Path Diagrams............................................................................................ ..454 G2. Generalized Path Diagrams..........................................................................462 G3. Relevance Diagrams.....................................................................................466 G4. Bubbled Relevance Diagrams......................................................................475 Appendix H. Abstract Stochastic Processes...................................................................479 vii H1. Probability Conditionals and Probability Distributions...............................477 H2. Abstract Stochastic Processes......................................................................479 H3. Embedding Variables and Processes in a Sample Space.............................480 References.......................................................................................... ..............................491. (shrink)

There is a very simple way in which the safe/normal variable discipline of Bellantoni–Cook recursion [S. Bellantoni, S. Cook, A new recursion theoretic characterization of the polytime functions, Computational Complexity 2 97–110] can be imposed on arithmetical theories like PA: quantify over safes and induct on normals. This weakens the theory severely, so that the provably recursive functions become more realistically computable . Earlier results of D. Leivant [Intrinsic theories and computational complexity, in: D. Leivant , Logic and Computational Complexity, (...) Lecture Notes in Computer Science, vol. 960, Springer-Verlag, 1995, pp. 177–194] are re-worked and extended in this new context, giving proof-theoretic characterizations of complexity classes between Grzegorczyk’s E2 and E3. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:When Is Enough, Enough?Megan HomsyThis was a case that stuck with many members of our transplant team for a long time. The patient was a 44-year-old Caucasian male evaluated for a liver transplant with a diagnosis of hepatitis C virus (HCV), originally diagnosed 11 years before the transplant evaluation. The patient met the criteria for the following substance use diagnoses: alcohol use disorder moderate in sustained remission, in a (...) controlled environment, opioid use disorder, severe, in sustained remission, on maintenance therapy, in a controlled environment, stimulant use disorder, amphetamine-type, severe, in early remission, in a controlled environment and stimulant use disorder, cocaine-type, severe in early remission, in a controlled environment.The patient had been living in a sober living housing program for approximately ten months prior to his transplant evaluation with me, his social worker. He had also been diagnosed with depression and bipolar disorder. He had been intermittently linked with mental health services and had participated in numerous detox and substance abuse programs over the last ten years, with varying degrees of success. He was in dual diagnosis treatment (i.e., treatment for co-occurring substance use and mental health disorders) through his Suboxone clinic and was completing toxicology screenings on a biweekly basis.After concluding the minimum three months of drug and alcohol treatment set forth by the state's Organ Transplantation Consortium, the patient graduated from his sober living program, moved in with his sister, and was listed for a liver transplant.The patient was transplanted five months after his clinic evaluation. At the time of the surgery, the patient's Suboxone was abruptly discontinued and replaced with IV Dilaudid. Within days of his transplant, the patient frequently expressed concerns about his pain. Several medical services attempted to manage the pain medications, resulting in his pain management plan being changed repeatedly and much confusion over his current medication regimen. During his liver transplant hospitalization, the RN found the patient with a needle in his arm, and after a search of the patient's hospital room, the hospital police found drug paraphernalia and illicit substances. The patient was eventually discharged to an inpatient substance abuse program, which he left before completing the program and against medical advice.During his first year post-transplant, I attempted to arrange other various treatment programs for him (most of which he did not follow through with) and to find housing for him (as he had been forced to leave his sister's home after his relapse). Eventually, the patient was incarcerated on drug-related charges. Numerous times, the patient missed completing his labs and his post-transplant appointments. He did not refill his immunosuppressant medications, and for lengthy periods of time, he was unreachable by the transplant care team, which resulted in my team members and I calling the patient's family, other providers, and the police for safety checks.In the aftermath of these issues, my colleagues and I had to reckon with the realization that we had failed the patient. As a team, our transplant center created a task force to review this case and what to do in the future to prevent such breakdowns in patient care. We created protocols for managing patients who, at the time of their transplant, are on Medication Assisted Treatment (MAT) such as Suboxone and methadone. Staff across the multidisciplinary team attended trainings regarding addiction, pain management, and best practices for MAT services. Additionally, our transplant center collaborated with our hospital's addiction treatment program for a streamlined referral process for transplant patients to addiction services.This patient's case and its sensational nature resulted in many conversations, both professional and unprofessional. Members of the social worker department became aware that personnel within transplant, though not involved in patient care, were inappropriately discussing this patient's case and engaging in unprofessional behavior. Said actions led to the termination of a member of the transplant team. I was placed in the unenviable [End Page E3] position of having to report this behavior to hospital management and legal teams to protect a vulnerable patient.The ethical challenge behind this case really stems from the transplant team attempting to balance two... (shrink)

In lieu of an abstract, here is a brief excerpt of the content:A Chance to CutBruce H. CampbellMy gloved hand reaches for progressively sharper surgical instruments. The prior radiation therapy and recurrent cancer [End Page E3] have made his neck tissues as stiff and hard as an old block of wood; everything appears too dull and feels too dry under the bright operating room lights. I push, dissect, urge, divide, prod, and spread with little effect.The nursing staff keeps to its (...) routine—completing computer entries, retrieving supplies, counting sponges—only intermittently aware that things are not going well at the point of attack. Nondescript music plays softly and the anesthesia machine continues to emit its gentle sounds. The junior resident—assisting me with the first of many neck dissections she will see during her five years of training—grips the retractor as she has been told and dabs the wound periodically to clear any blood or fluid.I glance up to recheck the CT scan. It confirms that this man’s recurrent cancer is just below the next layer of neck muscles. There are also some large blood vessels and major nerves nearby. I am confident, though, that I will be able to expose the mass, protect all of the critical structures, and safely remove the cancer.Curing cancer with surgery is no small feat, mind you. Cancer is, after all, a molecular disease not easily confined to an obvious lump, even though we sometimes refer to a malignant mass being “like a walnut” or “as hard and round as a marble.” The actual disease rests deep inside each cancer cell where the genetic code—the DNA—makes mistake–after–mistake. If cancer is to be cured with a surgical procedure, the surgeon must remove every last cell that is capable of making the same nonsensical, life–threatening error. Given Science’s rudimentary knowledge of cancer cell dynamics and signaling, it’s a miracle that surgery ever works. Yet, we continue to try. And we succeed just often enough to keep on trying.I rearrange the retractors and alter my approach. My mentors would have known what to do next, I imagine. My training included time well–spent with brilliant and technically–gifted surgeons. How would they have approached this case? Their experience and instincts might have told them to open the wound more widely, work the lateral and deep margins first, or position the instruments differently.Perhaps, one of my mentors would have attacked this man’s tumor using the same approach I am attempting but would have known exactly where to exploit some area of weakness that I cannot locate. A few swift, confident moves and he would have held the mass in his hands. “That’s it. We’re done,” he would have said.I met this patient several months ago when his cancer was first discovered and have seen him throughout his course of treatment. Recently, his daughter had accompanied him to the office to review his options. “Treatment has been rugged, Doc,” he reminded me. “The cancer’s still there and they said I can’t get any more radiation. Chemo would only prolong things. I don’t really want surgery, but what choice do I have if I want to be cured?”“Supportive care is an option, but the only curative approach is surgery.”“Well, I’m not ready to quit yet, Doc. I got grand-kids, y’know. I want to watch them grow up.” He nodded to his daughter. “I’m in charge of spoiling her little boys.”The daughter smiled. We crowded around the computer screen to look at the scans. I showed them how the tumor was invading and destroying surrounding structures. I described the surgery and the risks.“There are many things I will not know about your tumor until we are actually in the operating room,” I explained. Surgery in the setting of recurrent disease involves a series of on–the–spot decisions and course corrections. The odds of success are unknowable. “Sometimes, the only way to find out if we can remove the cancer is simply to try.”He took a deep breath and looked at his daughter. “Well then, Doc, if surgery is the only... (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Spirituality in Nursing PracticeRegina Conway–PhillipsPersonally, I am a Christian and follow the principles of Unity, a new thought community that espouses that each individual creates their own reality and that God’s presence is within each individual. I am a spiritual being and I am sustained by my faith.Professionally, I have been a nurse for over 38 years in various capacities including clinical, administrative and academic. When I worked at (...) the bedside in the clinical capacity, I always believed that a person’s spirituality was most evident when dealing with an illness. In practice, I frequently prayed with and for patients that I was caring for regardless of their religion.In my administrative capacity I always encouraged my staff to feel free to incorporate their faith and belief into their practice. As an administrator I felt it important to be an example to my staff and allow them to see a professional practice in a spiritually faith–based capacity.Now, in my role as an academician, I stress to each of my students that it is important for them to get to know themselves. I challenge my students to know and understand what they believe about themselves and others, what they value and why. I encourage them to really reflect and be very honest with themselves about their worldview and what influences has shaped this worldview, their faith, beliefs and values. I explain that it is important for them to know themselves before they can help others. In the health care field it is important for my students to feel comfortable when they encounter a patient in need of spiritual support.Religion and spirituality are terms that are often used interchangeably in the health care setting. Although related, these terms have different meanings to health care practitioners, administrators, academicians and patients. Religion, religiousness, or religiosity is often referred to as membership and participation in the organizational structures, beliefs, rituals and dogma of religious faiths such as Judaism, Christianity, or Islam. While spirituality has been defined as believing in a Higher Power that guides ones life and is a source of unconditional love, peace and strength; as a result, one is able to cope with life’s situations and maintain a positive attitude and assurance that all is well.When presented with the opportunity to submit a story about how I, as a health care provider integrated faith into my practice, I jumped at the opportunity because I think it is an important factor in the care of others, be they patients, peers, students or oneself. One of the concepts I explored in my dissertation research was spirituality. I have always operated from a spiritual faith–based perspective both in my personal and professional life as a nurse and more recently as an academician. Personally, [End Page E3] I define myself as a spiritual being, governed by spiritual laws, guided by spiritual principles, living a human experience. I am a Christian and a beloved child of God, placed on this earth at this time to fulfill the divine potential and purpose I was sent to serve. I believe that every human being on the face of this earth is a spiritual being whether they acknowledge, believe it or accept it themselves. As such I believe we are all one with God and one with each other and I believe that everything in our lives happen for a reason and in due time. My faith and beliefs were never more clear to me than my experience in loosing my 84–year–old mother on January 18, 2013 after a four year battle with lung cancer.Professionally, I have been a nurse for over 38 years in various capacities including clinical, administrative and academic. When I worked at the bedside in the clinical capacity, I always believed that a person’s spirituality was most evident when dealing with an illness. In practice, I frequently prayed with and for patients that I was caring for regardless of their religion. I always felt it was a privilege to witness others resilience and faith. But it was as a cancer nurse navigator that I got to truly develop as a spiritual care... (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Navigating Intersex Healthcare: My OdysseyCynthiaI was born in 1965 with what the medical community called “ambiguous genitalia.” My initial announcement as a boy was called into question upon closer assessment of my atypical anatomy by medical specialists at a children’s hospital in Chicago. That team of medical experts included a pediatric urologist and a pediatric endocrinologist, as well as a prominent pediatric surgeon, who was at that time presiding (...) president of the relatively newly established American Pediatric Surgeons Association. I have wondered over the years whether, or to what extent, that status and position had any important impact on the unfolding of my medical case.Just over 100 days after my birth, I was surgically and socially reassigned female, and renamed Cynthia. My mother and physician father, ages 25 and 30, respectively, with two young sons at home, did the best they could to move ahead in life as a young family. Part of our family story is that my unusual birth contributed to my parents’ decision to move away from Chicago, where both of my parents had been raised and wanted to settle, and where my father had many professional opportunities. We relocated to Southern California to make a “fresh start” where no one would know the dark secret too terrible to be shared with any beyond a small circle of close friends and family. It would never be talked about openly.With the exception of the rare and dreaded occasions of medical appointments with my primary care physician, or maybe an endocrinologist to renew hormone prescriptions, my parents chose [End Page E3] to have me travel from our home in San Diego to a clinician in Los Angeles, away from my father’s medical colleagues. This decision was puzzling to me at the time, and maybe more so now. These trips were a source of considerable stress and anxiety, as I had no idea of what to expect; my mother told me only that treatment would “help me get my period started.” I was instructed to tell my friends and teachers that I was taking off school on a weekday to go on a “shopping trip” with my mother. As far as I know, these trips were never discussed at home with my older brothers. I heard years later that my parents disclosed some information about me with my brothers when my parents travelled outside the country. They felt that my brothers should know what had happened to me in the event of a catastrophic accident that might prevent my parents from telling me themselves. I suppose they believed that I wasn’t ready at the time to be told my own life and medical history. I can’t say for sure.I don’t want to judge my parents too harshly for how they handled my medical care. I know that it was an extremely stressful and uncertain time for them, and peer support, which I know now is so vitally important for both parents and young affected individuals like myself, was not made available to us. I never thought to ask about such help, or even consider the idea that anyone else would be in a similar situation like mine. I don’t think I would have been even remotely comfortable or willing to discuss it openly at that point.In my early twenties, I had to face another milestone in my journey and in my interactions with the medical community. I had yet to have the vaginoplasty I was told I “needed.” There was no discussion as to whether or not I wanted it or not. It just had to be done, and I was aware of the limitations I had at this vulnerable time in my life when my peer group was sexually active and I was not. My awareness of the obstacle posed by my difference made me avoid the topic of dating; it was difficult even to think about the possibility of a romantic relationship. I put it out of my mind, but I knew that it was a significant concern for my parents. My physician father did most of the prodding to get me to acknowledge the reality... (shrink)

Probabilities are numbers between 0 and 1 that attach to events. Events always occur with respect to a reference class of possibilities. Consider a die with faces 1 through 6. The reference class of possibilities in this case can be represented by the set {1, 2, 3, 4, 5, 6}. Any subset of this reference class then represents an event. For instance, the event Eodd, i.e., “an odd number was tossed,” corresponds to {1, 3, 5}. Such an event is said (...) occur if any one of its outcomes occurs, i.e., if either a 1 is tossed or a 3 or a 5. Outcomes can therefore be represented as singleton sets, i.e., sets with only one element. Thus, the outcomes associated with Eodd = {1, 3, 5} are E1 = {1}, E3 = {3}, and E5 = {5}. Outcomes are sometimes also called elementary events. Events include not only outcomes but also composite events like Eodd that include more than one outcome. (shrink)

La frase sobre el logos escrito como “reflejo” del discurso vivo y animado del que sabe (cf. Fedro, 276a8-9) hay que referirla al diálogo platónico: “el que sabe” es el dialéctico, que gracias a los conocimientos a los que ha accedido por medio de la teoría de las Ideas, “sabe cómo es la verdad” (ibid., 278c4-5). Tres capacidades tiene, según Platón, solo el discurso vivo del “que sabe”: puede responder las preguntas que se le planteen, puede buscar el receptor adecuado (...) o quedar en silencio ante aquellos que no tienen que ver con filosofía y, en caso de un ataque, puede acudir en ayuda de su argumento con cuestiones que pertenecen a un nivel superior (cf. ibid., 275d4-276a9, 278c4-e3). El análisis de estas expresiones de Platón en su contexto muestra que la interpretación usual que, desde hace casi 200 años, le atribuye estas capacidades de “el que sabe” al diálogo escrito, no hace justicia al texto de la crítica de la escritura y va en contra de su sentido. Esta constatación exige una orientación radicalmente nueva de la hermenéutica de los diálogos platónicos. Hay que reconocer que Platón concibió sus diálogos (cada uno en particular y todos en conjunto) como unidades literarias y filosóficas que no tienen un carácter autárquico. Los diálogos apuntan consistentemente más allá de ellos mismos hacia la doctrina oral de Platón. --- “Reflection of the living discourse. ¿What is a Platonic dialogue and what does it pretend?”. Plato’s word in the Phaedrus about the written logos as an “image” of the living logos of the man who knows (cf. Phaedrus, 276a8-9) has to be referred to his own dialogues: the “man who knows” is the dialectician, who “knows the truth” (cf. ibid., 278c4-5) thanks to the insights he has gained by way of his use of the Theory of Ideas. There are three things, according to Plato, which can be achieved only by the living logos of “the man who knows”: his logoscan give answers to new questions, can choose the right sort of recipient and remain silent to those who have nothing to do with philosophy, and, in case it should be attacked, it can help its argument with “things of higher importance” (cf. ibid., 275d4-276a9, 278c4-e3). An analyse of these views and concepts of Plato in their context shows that the conventional interpretation, current since almost 200 years, according to which the written Platonic dialogue can do the same three things as the “man who knows”, is contrary to the wording of Plato’s “Criticism of Writing” and incompatible with its sense. This result leads to a new orientation regarding the hermeneutics of the Platonic dialogue. We have to acknowledge that Plato did not mean his dialogues (each one by itself, and their entirety as a whole) to be autarchic of self-sufficient literary entities. The dialogues point consistently beyond themselves to Plato’s oral teaching. (shrink)

Wnt signaling plays pivotal roles during our entire lives, from conception to death, through the regulation of morphogenesis in developing embryos and the maintenance of tissue homeostasis in adults. The regulation of Wnt signaling occurs on several levels: at the receptor level on the plasma membrane, at the β‐catenin protein level in the cytoplasm, and through transcriptional regulation in the nucleus. Several recent studies have focused on the mechanisms of Wnt receptor regulation, following the discovery that the Wnt receptor frizzled (...) (Fzd) is a target of the ubiquitin ligases, RNF43 and ZNRF3. RNF43 and ZNRF3 are homologous genes that are mutated in several cancers. The details underlying their mechanism of action continue to unfold, while at the same time raising many new questions. In this review, we discuss advances and controversies in our understanding of Wnt receptor regulation. (shrink)

This paper aims to suggest a new approach to Plato’s theory of being in Republic V and Sophist based on the notion of difference and the being of a copy. To understand Plato’s ontology in these two dialogues we are going to suggest a theory we call Pollachos Esti; a name we took from Aristotle’s pollachos legetai both to remind the similarities of the two structures and to reach a consistent view of Plato’s ontology. Based on this theory, when Plato (...) says that something both is and is not, he is applying difference on being which is interpreted here as saying, borrowing Aristotle’s terminology, 'is is (esti) in different senses'. I hope this paper can show how Pollachos Esti can bring forth not only a new approach to Plato’s ontology in Sophist and Republic but also a different approach to being in general. -/- Keywords Plato; being; difference; image; pollachos esti; pollachos legetai 1. Being, Not-Being and Difference The three dialogues where the notion of "difference" attaches to the notion of being, namely Parmenides II, Sophist and Timaeus,and specifically the first two we try to discuss here. In these dialogues, Plato is going to achieve a new and revolutionary understanding of being which is not anymore based on the notion of "same" as it was before in Greek ontology. It was his discovery, I think, that the notion of being in the Greek ontology is attached to the notion of the "same" and it is because of this attachment that there have always been many problems understanding being especially after Parmenides. That being has always been relying on the "same" can be found out from the way most of the Presocratics understood it. It was based on such a relationship between being and "same" that a later Ionian, Heraclitus of Ephesus, rejected Being by rejecting its sameness: unable to be the same, being cannot be being anymore but becoming. Heraclitus’ criticism of his predecessors’ understanding of being was due to his discovery that what they call being is not the same but different in every moment. The relation of being and sameness reaches to its highest point in Parmenides. What Plato does in using the "difference" is nothing but the establishment of a creative relation between being and "difference". In this new relation, although he is in agreement with Heraclitus that being is not the same but different, he does not do it by use of becoming. He disagrees, on the other hand, with Parmenides that such a relation between being and difference leads to not being. At Parmenides 142b5-6 it is said that if One is, it is not possible for it to be without partaking (μετέχειν) of being (οὐσίας), which leads to the distinction of being and one: -/- So there would be also the being of the one (ἡ οὐσία του̑ ἑνὸς) which is not the same (ταὐτὸν) as the one. Otherwise, it wouldn’t be its being, nor the one would partake of it. (142b7-c1) -/- The fact that what is (ἔστι) signifies (σημαῖνον) is other (ἀλλο) than what One signifies (c4-5), is being taken as a reason for their distinction. The conclusion is that when we say 'one is', we speak of two different things, one partaking of the other (c5-7). Having repeated these arguments of the otherness of being and one at 143a-b, Parmenides says that the cause of this otherness can be neither Being nor One but "difference": -/- So if being is something different (ἕτερον) and one something different (ἕτερον), it is not by being one that the one is different from being nor by its being being that being is other than one, but they are different from each other (ἕτερα ἀλλήλων) by difference (τῷ ἑτερῳ) and otherness (ἄλλῳ). (143b3-6) -/- The fifth hypothesis, 'one is not' (160b5ff.) is also linked with the notion of difference. When we say about two things, largeness and smallness, that they are not, it is clear that we are talking about not being of different (ἕτερον) things (160c2-4). When it is said that something is not, besides the fact that there must be knowledge of that thing, we can say that it entails also its difference: 'difference in kind pertains to it in addition to knowledge' (160d8). Parmenides explains the reason as such: -/- For someone doesn’t speak of the difference in kind of the others when he says that the one is different from the others, but of that thing’s own difference in kind. (160e1-2) -/- Although the theory of being as "difference" is not fulfilled yet, an exact look at what occurs in Sophist can make us sure that this was the launching step for "difference" to get its deserved role in Plato’s ontology. The notion of the "difference" is not yet well-functioned in Parmenides because we can see that being is still attached to the same: -/- For that which is the same is being (ὄν γὰρ ἐστι τὸ ταὐτόν) (162d2-3). -/- The notion of difference in Sophist is the key element based on which a new understanding of being is presented and the problem of not being is somehow resolved. The friends of Forms, the Stranger says, are those who distinguish between being and becoming (248a7-8) and believe that we deal with the latter with our body and through perception while with the former, the real being (ὄντως οὐσίαν) with our soul and through reasoning (a10-11). Being is then bound with the "same" by adding: -/- You say that being always stays the same and in the same state (ἣν ἀεὶ κατὰ ταὐτὰ ὡσαύτως ἔχειν) but becoming varies from one time to another (δὲ ἄλλοτε ἄλλως). (248a12-13) -/- That the theory of the relation of being and capacity (247d8f., 248c4-5) matches more with becoming than with being (248c7-9) must be rejected because being is also the subject of knowledge which is kind of doing something (248d-e). It does, however, confirm that 'both that which changes and also change have to be admitted as existing things (ὄντα) (249b2-3). I believe that this is what Socrates would incline to do at Theaetetus 180e-181a, that is, putting a fight between two parties of Parmenidean being and Heraclitean becoming and then escaping. The solution is that becoming is itself a kind of being and we ought to accept what changes as being. This is what must be done by a philosopher, namely, to refuse both the claim that 'everything is at rest' and that 'being changes in every way' and beg, like a child, for both and say being (τὸὄν) is both the unchanging and that which changes (249c10-d4). This kind of begging for both is obviously under the attack of contradiction (249e-250b). For both and each of rest and change similarly are (250a11-12) but it cannot be said either that both of them change or both of them rest, being must be considered as a third thing both of the rest and change associate with (250b7-10). The conclusion is that 'being is not both change and rest but different (ἕτερον) from them instead' (c3-4). The notion of difference helps Plato to take being departed from both rest and change because it was their sophisticated relation with being that made the opposition of being and becoming. Plato is now trying to separate being from rest and, thus, from "same" by "difference". Such a crucial change is great enough to need a 'fearless' decision (256d5-6). The possibility of being of not being is resulted (d11-12) comes as the answer to the question 'so it’s clear that change is not being and also is being (ἡ κίνησις ὄντως οὐκ ὄν ἐστι καὶ ὄν) since it partakes in being?' (d8-9). It is then by the notion of difference that becoming is considered as that which both is and is not. This coincidence of being and not being about change is apparently similar to Socrates’ paradoxical statement at Republic 477a about what both is and is not. -/- Introduction The Republic 476-477 has always been a matter of controversy mainly about two interwoven points. The first problem is the meaning of being here; that whether what he has in mind is a veridical, existential or propositional sense of being. The second problem is his distinction between the objects of knowledge and opinion which seems to lead, some believe, to the Two Worlds (TW) theory. The crucial point in Republic is that what is considered between knowledge (ἐπιστήμης) and ignorance (α͗γνοιας), namely opinion, must have a different object that leads Socrates to draw the distinction of knowledge and opinion between their objects. The problem of understanding being in the fifth book of the Republic is that when it is said that the Form of F is F but a particular participating in F, both is and is not F, it sounds too bizarre and unacceptable. It cannot be imaginable how a thing can be existent and non-existent at the same time. At the first sight, the only solution seems to be the degrees of existence which is called by Annas (1981, 197) a 'childish fallacy' and a 'silly argument'. Kirwan (1974, 118) thinks that Republic V does not attribute 'any doctrine about existence' to Plato and Kahn (1966, 250) claims that the most fundamental value of einai when used alone (without predicate) is not "to exist" but "to be so", "to be the case" or "to be true". The problems of understanding being in Republic and Sophist besides the difficulties of the existential reading led scholars to the other senses of being, mostly related to the well-known Aristotelian distinctions between different senses of being. In the predicative reading, Annas, for example, refers this difference to the qualified and unqualified application. Whereas the Form of F is unqualifiedly F, a particular instance of F can be F only qualifiedly (1981, 221). Vlastos’ well-known substitution of 'degrees of reality' for 'degrees of being/existence' must be categorized as a predicative reading. Kahn thinks that the basic sense of being for Plato is 'something like propositional structure, involving both predication and truth claims, together with existence for the subject of predication' (2013, 96). Believing that the complete-incomplete distinction terminology is misleading about Plato, he thinks that semantic functions are only second-order uses of the verb and it is the predicative or incomplete function which is fundamental. Suggesting a veridical reading, Fine (2003, 70 ff) thinks that while both existential and predicative readings separate the objects of knowledge and belief, it is only her reading which does not force such separation of the objects and thus does not imply TW. Stokes (1998, 266) thinks that though Fine is right saying that Plato does not endorse TW in book V, she is wrong in rejecting existential in favor of the veridical reading. The reception of existential reading can be seen more obviously in Calvert who thinks, in agreement with Runciman, that 'it would be safer to say that Plato’s gradational ontology is probably not entirely free from degrees of existence' (1970, 46). At Sophist 254d-e Plato singles out five most important kinds (or Forms!?) in which the same (ταὐτὸν) and difference (θάτερον) are regarded besides being, rest and change. They are, therefore, neither the same nor the difference but share in both (b3). Being (τὸ ὄν) cannot be the same also because if they 'do not signify distinct things' both change and rest will have the same label when we say they are (255b11-c1). We have then four distinct kinds, being, change, rest and same, none of them is the other. The case of difference is more complicated. When the stranger wants to assess the relation of being and difference, he can say simply neither that they are distinct nor that they are not. He has to make an important distinction inside being to get able to draw the relation of being and difference: -/- But I think you'll admit that some of the things that are (τῶν ὄντων) are said (λέγεσθαι) by themselves (αὐτὰ καθ’ αὑτά) but some [are said] always referring to (πρὸς) other things (ἄλλα) (255b12-13) -/- The difference is always said referring to other things (τὸδέγ’ ἕτερον ἀεὶ πρὸς ἕτερον) (255d1). It pervades all kinds because each of them should be different from the others and is so due to the difference and not its own nature (253e3f.) After asserting that change is different from being and therefore both is and is not (256d), the difference is described as what makes all the other kinds not be, by making each different from being. Given that all of them are by being, this association of being and difference is the cause of their being and not-being at the same time, the issue that its version at RepublicV made all those controversies we discussed above: -/- So in the case of change and all the kinds, not being necessarily is (Ἔστιν ἄρα ἐξ ἀναγκης τὸ μὴ ὄν). Τhat’s because as applied to all of them, the nature of the difference (ἡ θατέρον φύσις) makes each of them not be by making it different from being. And we’re going to be right if we say that all of them are not in the same way. And conversely [we’re also going to be right if we say] that they are because they partake in being. (Sophist 256d11-e3) -/- Plato’s new construction of five distinct kinds and the role he gives to thedifference among them is aimed to resolve the old problem of understanding being which has always been annoying from the time of Heraclitus and Parmenides. Both the ontological status of becoming and that of not being were, in Plato’s mind, based on the absolute domination of the notion of the Same over being. Now, not only becoming is understandable as being but also not being which is not the contrary of being anymore but only different (ἕτερον) (257b3-4). Though I agree partly with Frede that the account of not being which is needed for false statements is more complicated than just saying, as Cropsey (1995, 101) says, that Plato is substituting 'X is not Y' with 'X is different from Y', I totally disagree with him that when we say X is not beautiful, Plato could not have thought that it is not a matter of its being different from beautiful because 'it would be different from beauty even if it were beautiful by participation in beauty' (1992, 411). Conversely, as we will discuss, it is exactly the relation of the beautiful thing, X, and the beautiful itself, in which X shares that is to be solved by the notion of not being as difference. Though it is beautiful because of sharing in beauty, X is not beautiful because it is different from beautiful itself. What the difference is to do is to show how something can both be and not be the same thing. The difference is what makes one thing both be and not be a certain other thing. This equips the difference with the ability to explain a certain thing’s not-being when it is. Thanks to the notion of difference, it is now possible to explain not only not being but also the simultaneous being and not being of a thing: 'What we call "not-beautiful" is the thing that ἕτερόν ἐστιν from nothing other than του̑ καλου̑ φύσεως' (257d10-11). The result is that not beautiful happens to be (συμβέβηκεν εἶναι) one single thing among kinds of beings (τι τῶν ὄντων τινὸς ἑνὸς γένους) and at the same time set over against one of the beings (πρός τι τῶν ὄντων αὖ πάλιν ἀντιτεθὲν) (257e2-4) and thus be something that happens to be not beautiful (εἶναί τις συμβαίνει τὸ μὴ καλόν); a being set over against being (ὄντος δὴ πρὸς ὄν ἀντίθεσις) (e6-7). Neither the beautiful is more a being (μα̑λλον ... ἐστι τῶν ὄντων) nor not beautiful less (e9-10) and thus both the contraries similarly are (ὁμοίως εἶναι) (258a1). This conclusion, it is emphasized again (a7-9), owes to θατέρου φύσις now turned out as being. Therefore, each of the many things that are of the nature of the difference and set over each other in being (τῆς τοῦ ὄντος πρὸς ἄλληλα ἀντικειμένων ἀντίθεσις) is being as being itself is being (αὐτοῦ τοῦὄν τοςοὐσία ἐστιν) and not less. They are different from, and not the contrary of, each other (a11-b3). This is exactly τὸμὴὄν, the subject of the inquiry (b6-7). Hence, not being has its own nature (b10) and is one εἶδοςamong the many things that are (b9-c3). Such far departing from Parmenides’ ontological principle is done on the basis of the nature of the difference. It was the discovery of such a notion that made the stranger brave enough to say that not being is each part of the nature of the difference that is set over against being (258d7-e3, cf. 260b7-8). That the relation of being and difference is difference is the key element of the new ontology. The difference is, only because of its sharing in being, but it is not that which it shares in but different from it (259a6-8). Not being is exactly based on this difference: ἕτερον δὲ τοῦ ὄντος ὄν ἔστι σαφέστατα ἐξ ἀνάγκης εἶναι μὴ ὄν (a8-b1). 2. Difference and the Being of a Copy We discussed above that the sense of being of particulars in Republic V made so many debates that whether being is there used in an existential sense or not. Particulars in Republic are regarded as images in the allegories of Line and Cave. The being of an image/copy makes, thus, the same problem. Plato’s analogy of original -copy for the relation of Forms and their particulars in Republic has obviously a different attitude to being. The main question is that what is the ontological status of a copy in respect of its original? Are there two kinds of being, 'real being' versus 'being' as Ketchum says (1980, 140) or only one kind? What is the difference of being in an original and its copy? Is it a matter of degrees of being or reality as some commentators have suggested? Is it a matter of being relational? By reducing the ontological issue to an epistemological one, Vlastos’ suggestion of degrees of reality in an article with the same name does neither, I think, pay attention to the problem nor resolve it. He agrees that Plato never speaks of "degrees" or "grades" of reality (1998, 219). What allows him to entitle it as such are some of Plato’s words in Republic as well as Plato’s words in some other dialogues (1998, 219). When Plato states that the Forms only can completely, purely or perfectly be real he means, Vlastos says, they are cognitively reliable (1998, 229); an obvious reduction of the issue to an epistemological one. He thinks that when in Republic we are being said that a particular’s being F is less pure than its Form, it is because it is not exclusively F, but it is and is not F and this being adulterated by contrary characters is the reason of our confused and uncertain understanding of it (1998, 222). Ketchum rightly criticizes Vlastos’ doctrine in its disparting from ontology thinking that 'to understand Plato’s talk of being as talk of reality is to obscure the close relation that exists between "being" and the verb "to be"' (1980, 213). He thinks, therefore, that οὐσία must be understοοd as being rather than reality, τὸὄν as "that which is" and not "that which is real" and … (ibid). His conclusion is that degrees of reality cannot interpret Plato correctly and we must accept degrees of being. Allen believes that a 'purely epistemic' reading of the passage in Republic is patently at odds with Plato’s text (1961, 325). He thinks that not only degrees of reality but also degrees of reality must be maintained (1998, 67). What Cooper suggests gets close to this paper’s solution: -/- Plato does not I think wish to suggest that existence is a matter of degree in the way in which being pleasant or painful is a matter of degree. Rather there are different grades of ontological status. (1986, 241) -/- A more ontological solution for the problem of understanding the being of a copy and its relation with the being of its original is suggested by the theory of copy as a relational entity. Based on this interpretation, 'the very being of a reflection is relational, wholly dependent upon what is other than itself: the original…' (Allen, 1998, 62). As relational entities, particulars have no independent ontological status; they are purely relational entities which derive their whole character and existence from Forms (ibid, 67). Although these relational entities are and have a kind of existence, we must also say that 'they do not have existence in the way that Forms, things which are fully real, do' (ibid). Allen (1961, 331) extends his theory to Phaedo where it is said that particulars are deficient (74d5-7, 75a2-3, 75b4-8), 'wish' to be like (74d10) or desire to be of its nature (75a2); an extension that, like F.C. white (1977, 200), I cannot admit. He correctly states that Plato did not start out with a doctrine of particulars as images and semblances but come to such a view after Phaedo, or perhaps after Republic V (1977, 202). Though we may not agree with him about Republic V, if we have to consider its last pages also, we must agree with him that not only the ontology of Phaedo but also that of Republic II-V (except the last pages of the latter book) are somehow different from (but at the same time appealing to) the ontology of original-copy which should exclusively assign to Sophist, Timaeus and RepublicVI-VII besides the last pages of book V. The answer to the problem of Plato’s sense of being in RepublicV can be reached only if we read Republic V based on and as following Sophist. We can find out his meaning of that which both is and is not only by the ontological status he assigns to a copy in Sophist. The kind of being of a copy in Sophist reveals as Plato’s key for the lock of the problem of not being. Let’s see how the ontological status of a copy is the critical point of Plato’s ontology. In the earlier pages of Sophist, we are still in the same situation about not being. To think that that which is not is is called a rash assumption (237a3-4) and Parmenides’ principle of the impossibility of being of not being is still at work (a8-9). At 237c1-4, the problem of "not being" is noticed in a new way which shows some kinds of a more realistic position to the problem of not being. Nevertheless, not being is still unthinkable, unsayable, unutterable and unformulable in speech (238c10). Soon after mentioning that it is difficult even to refuse not being (238d), the solution to the problem appears: the being of a copy (εἴδωλον) (239d). A copy is, says Theaetetus, something that is made referring to a true thing (πρὸς τἀληθινὸν) but still is 'another such thing (ἕτεροντοιου̑τον)' (240a8). Nevertheless, this 'another such thing' cannot be another such real or true thing. In answer to the question of the Stranger that if this 'another such thing' is the true thing (240a9), Theaetetus answers: οὐδαμῶς ἀληθινόν γε, ἀλλ’ ἐοικὸςμὲν (240b2). A copy’s being 'another such thing' does not mean another true thing but only a resemblance of it. Not only is not a copy another true thing besides the original, but it is the opposite of the true thing (b5) because only its original is the thing genuinely and being a copy is being the thing only untruly. The word ἐοικὸς is opposed to ὄντως ὄν in the next line (240b7): 'So you are saying that that which is like (ἐοικὸς) is not really that which is (οὐκ ὄντως [οὐκ] ὄν)'. But still a copy 'is in a way (ἔστι γε μήν πως)' (b9). While it is not really what it is its resemblance, it has its own being and reality because it really is a likeness (εἰκων ὄντως) (b11). The Stranger asks: -/- So it is not really what is (οὐκ ὄν ἄρα [οὐκ] ὄντως ἐστὶν) but it really is what we call a likeness (ὄντως ἣν λέγομεν εἰκόνα)? (b12-13) -/- This is Plato’s innovative ontological solution to the problem of not being. Theaetetus’ answer confirms this: 'Maybe that which is not is woven together with that which is' (c1-2). Therefore, a copy neither is what really is nor is not-being but only is what in a way is. Thanks to the ontological status of a copy, the third status intermediate between being and not being is brought forth. The essence of an image, in Kohnke’s words, does not consist 'solely in the negation of what is genuine and has real being' because otherwise 'it would be an ὄντως οὐκ ὄν,essentially and really a not being' (1957, 37). The characteristics of a copy can be summed up as folows: i) A copy is a copy by referring to a true thing (πρὸς τἀληθινὸν). ii) A copy is different from that of which it is a copy (ἕτερον). iii) A copy is not itself a true thing (ἀληθινόν) as that of which it is a copy but only that which is like it (ἐοικὸς). iv) It is not really that which really is (ὄντως ὄν) but only really a likeness (εἰκων ὄντως). The conclusion is that: v) A copy in a way (πως) is that means it both is and in not, the product of interweaving being with not being. This leads to the refutation of father Parmenides’ principle, accepting that 'that which is not somehow is (τό τε μὴ ὄν ὡς ἔστι)' and 'that which is, somehow is not (τό ὄν ὡς οὐκ ἔστι) (241d5-7). Besides copies and likenesses (εἰκόνων), we have also imitations (μιμημάτων) and appearances (φαντασμάτων) as the subjects of this new kind of being and thus false belief (241e3). In Timaeus, the world of becoming which cannot correctly be called and thus we have to call it "what is such" (τὸ τοιου̑τον) (49e5) or "what is altogether such" (τὸ διἀ παντὸς τοιου̑τον) (e6-7), consists solely of imitations (μιμημάτα) (50c5) which are identifiable only by the things that they are their imitations. The word τοιου̑τον which had been used to determine the situation of a copy in respect of its original, now becomes the definition of the world of becoming in which everything is an image of another thing, a Being, that stays always the same and is different and separated from its image. Cherniss, in my view rightly, draws attention to the very important point about the ontological status of an image that can at the same time be considered a criticism of the relational theory. What we are being said in Timaeus, he thinks,cannot be explained by saying that an image is not self-related and making its being relational. What is crucial about an image is that it 'stands for something, refers to something, means something and this meaning the image has not independently as its own but only in reference to something else apart from it' (1998, 296). This function finds its best explanation in the theory we are to suggest in the following. 3. πολλαχῶς ἔστι The best way to understand the ontological status of an image in Plato is to see first how his most clever pupil, Aristotle, resolved the same problem that Plato brought his theory of image for its sake. Aristotle’s theory of pollachos legetai is a brilliant and, at the same time, deviated version of Plato’s theory that is able, however, to help us read Plato in a better way. We discuss Aristotle’s theory to reach to a full understanding of Plato’s theory because it is, firstly, constructed in Aristotle in a more clear way and, secondly, it can also be taken as an evidence that our reading of Plato is legitimate. The phrase τὸ ὄν πολλαχῶς λέγεται, a so much repeated phrase in Aristotle’s works, is his resolution for some of the ontological problems of his predecessors all treating being as if it has only one sense. Aristotle is right in his criticism of the philosophical tradition specially Heraclitus, Parmenides and Plato since all did presuppose only one sense for being and his theory is, thus, a creative and revolutionary solution for many problems that all the past philosophers were stuck in. But it is at the same time somehow a borrowed theory. As we will discuss, both the structure of the doctrine and the problems it tries to resolve are the same as Plato’s doctrine (and even is comparable in its phraseology) though it is in Aristotle, as can be expected, a more clear and better structured doctrine. 1) Associated with the theory of pros hen and the theory of substance, the theory of several senses of being provides a structure which, I insist, is the best guide to understand Plato’s theory of Being in Sophist, Timeaus and Republic. a) Although the theory of pollachos legetai is not necessarily based on the theory of pros hen, they become tightly interdependent about being: -/- Being is said in many ways/senses (τὸ δὲ ὄν λέγεται μὲν πολλαχῶς) but by reference to one (πρὸς ἕν) [way/sense] and one kind of nature (μίαν τινὰ φύσιν). (Metaphysics 1003a33-34) -/- The doctrine of pros hen which is Aristotle’s initiative third alternative besides the homonymous and synonymous application of words, is primarily a linguistic theory that tries to provide a new theory to explain the different implementations of the same word. The pros hen implementation of being is to provide an alternative for the theory of the synonymous (in Plato: homonymous) implementation of being which says being is said in one sense (kath hen) (1060b 32-33). That both the pros hen and the kath hen implementation of a word has one thing (hen) as what is common, makes them in opposition to the homonymous implementation which does not consider anything in common. Whereas both pros hen and kath hen assume a common nature, with which all the implementations of the word have some kind of relation, their difference is that while kath hen takes all the implementations of the word as the same with the common nature, pros hen makes them different. Substance is called πρῶτον ὄν because it is said to be primarily: -/- For as is (τὸ ἔστιν) is predicated of all things, not however in the same way (οὐχ ὁμοίως) but of one sort of thing primarily and of others in a secondary way. So too τὸτί ἐστιν belongs simply (ἁπλῶς) to substance but in a limited sense (πῶς) to the others [other categories] (1030a21-23). -/- The word ἁπλῶς standing against κατὰ συμβεβηκός tries to make substance different from the accidents. When we are being said that τὸ ὄν πολλαχῶς λέγεται, it means that only the substance that is simply (ἁπλῶς) the ἕν, the common nature, τὸὄν. When we use the word 'being' about a substance, the being is said differently from when we use 'being' about an accident. The distinction between the substance and the other categories is a distinction between what simply is said to be and what only with reference to (pros) the substance is said to be. The doctrine of pros hen, changing kath hen to pros hen in respect of to on, makes a distinction that wants to show that while there is a kind of implementing the word being that is simply being, there is another kind which is called being only by reference to that which is simply being. In the doctrine of pros hen it is not so that all the things that are said to be are only by reference to a common one thing, but that while one thing is called being because it is that thing itself, the other things are called so without being that thing itself but only by referring to it. At the very beginning of book Γ, it is said that: -/- Being is said in many senses but all refer to one arche. Some things are said to be because they are substances, others because they are affections of substances, others because they are a process towards substances or destructions or privations or qualities of substances … (1003b5-9, cf. 1028a18-20) -/- Substance is what really is said to be and all other things that are said to be are said only in favor of it. This difference of substance from all other senses of being is what is, I believe, primarily aimed in Aristotle’s interrelated theories of pollachos legetai,pros hen and the theory of substance. b) The difference of the implementation of being in the case of substance and the accidents goes so deep that while substance is considered as the real being, the accidents are almost not being. An accident is a mere name (Metaphysics 1026b13-14) and is obviously akin to not being (b21). Aristotle adds that Plato was 'in a sense not wrong' saying that sophists deal with not being (τὸ μὴ ὄν) because the arguments of sophists are, above all, about the accidental (1026b13-16). At the beginning of book , he says about quality and quantity (which look to be more of a being than other accidents) that they are not existent (οὐδ̕ ὄντα ὡς εἰπεῖν) in an unqualified sense (ἁπλῶς) (1069a21-22). The two above-mentioned points, Aristotle’s (a) interwoven theories of pollachos legetai, pros hen and the theory of substance and (b) taking accidents almost as not being, comparedwith substance, brings forth a structure that I shall call Pollachos Legetai (with capital first letters). What is of the highest importance in this structure for me is the difference of substance from accidents and the kind of relation which is settled between them. There is a substance that without any qualification is said to be and the accidents that are said to be only by reference (pros) to it. Adding Aristotle’s point about accidents that they are nearly not being to this relation and difference, we can obviously see how much this structure is close to Plato’s original-copy ontology. We spoke of the relation of being and difference in Plato’s model and the way Plato construes the being of a copy. A copy is a copy only by referring to (pros) a model; it is different from (ἕτερον) that of which it is a copy; it is not itself a true thing as its model and not really that which is (ὄντως ὄν) but only is in a way (πῶς). If we behold the difference of substance and accident in the context of the theory of pollachos legetai and pros hen, we can observe its fundamental similarity with Plato’s original-copy theory in its structure. Allen draws attention to the fact that the relation between Forms and particulars in Plato’s original-copy model is 'something intermediate between univocity and full equivocity' (1998, 70, n. 24) and the same as what Aristotle calls it pros hen (ibid). What made us compare the two structures was not, of course, the complete similarity of two structures (we have to agree with many possible differences of the two theories) but exactly the specific relation between an original and its copy on the one hand, and a substance and its accident on the other hand. As substance and accident do not share a common character and the substance -accident model hints that they stand in a certain relation, there is no common character between the original and copy in Plato’s model as well. Furthermore, their similarity is not confined to their structure only; they are also aimed to solve the same problem. The central point of the theory is that all the predecessors took being in one sense and this was their weakness point. Besides the mentioned above passages about the relation of pollachos legetai and presocratics’, as well as Plato’s, ontology, the relation of the theory with the problem of not being is clear in several passages. In Metaphysics, it is said: 'Being is then said in many senses… It is for this reason that we say even of not being that it is not being' (1003b5-10). Discussing the accidental sense of being, Aristotle points that it is in the accidental way that we say, for example, that not-white is because that of which it is an accident is (1017a18-19, cf. 1069a22-24). We mentioned that he thought Plato was right saying that sophistic deals with not being because sophistic deals with accidental, which is somehow not being (1026b14-16). Plato turned sophistic not-being to what both is and is not and Aristotle to what accidentally is said to be. What helps Aristotle to resolve the problem of not being is his distinction between ἁπλῶς and κατὰ σθμβεβηκός. Aristotle’s "qua" (ᾕ) which is directly linked with his distinction between καθ’ αὑτο λέγεται and κατὰ συμβεβηκός λέγεται, is used to resolve the old problem of coming to be out of not being (Physics 191b4-10). He strictly asserts that his predecessors could not solve the problem because they failed to observe the distinction of "qua itself" from "qua another thing" (b10-13). He then continues: -/- We ourselves are in agreement with them in holding that nothing can be said simply (ἁπλως) to come from not being (μὴὄντος). But nevertheless we maintain that a thing may come to be from not being in an accidental way (κατὰ συμβεβηκός). For from privation which ὅ ἐστι καθ’ αὑτο μὴ ὄν, nothing can become. (Phy. 191b13-16, cf. b19-25) . (shrink)

Non‐homologous end‐joining (NHEJ) is the dominant means of repairing chromosomal DNA double strand breaks (DSBs), and is essential in human cells. Fifteen or more proteins can be involved in the detection, signalling, synapsis, end‐processing and ligation events required to repair a DSB, and must be assembled in the confined space around the DNA ends. We review here a number of interaction points between the core NHEJ components (Ku70, Ku80, DNA‐PKcs, XRCC4 and Ligase IV) and accessory factors such as kinases, (...) phosphatases, polymerases and structural proteins. Conserved protein‐protein interaction sites such as Ku‐binding motifs (KBMs), XLF‐like motifs (XLMs), FHA and BRCT domains illustrate that different proteins compete for the same binding sites on the core machinery, and must be spatially and temporally regulated. We discuss how post‐translational modifications such as phosphorylation, ADP‐ribosylation and ubiquitinylation may regulate sequential steps in the NHEJ pathway or control repair at different types of DNA breaks. (shrink)