:Many writers have expressed scepticism about the explanatory power of transformational generative grammar, but little of this scepticism has been aimed towards formal semantics for natural languages. To a large extent, this neglect is a consequence, not of widespread agreement, but of a lack of clarity, about the aims of philosophers and linguists who construct these semantic theories. Here I hope to make clear a sense in which these theories are explanatory. In short, I argue that the importance and legitimacy (...) of semantics rests on its contribution to epistemology. First, I argue that what distinguishes someone who understands a language from someone who does not is not any linguistic or non‐linguistic behavior but rather the capacity to acquire certain justified beliefs upon hearing another's utterances. It is this justificatory element which is the chief mark of understanding. Second, I argue that in order for someone to have this capacity to acquire certain justified beliefs he must have knowledge of the meanings of the sentences in question. (shrink)

DBS Think Tank IX was held on August 25–27, 2021 in Orlando FL with US based participants largely in person and overseas participants joining by video conferencing technology. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers and researchers can freely discuss current and emerging deep brain stimulation technologies as well as the logistical and ethical issues facing the field. The consensus among the DBS Think Tank IX speakers was that DBS expanded in (...) its scope and has been applied to multiple brain disorders in an effort to modulate neural circuitry. After collectively sharing our experiences, it was estimated that globally more than 230,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. As such, this year’s meeting was focused on advances in the following areas: neuromodulation in Europe, Asia and Australia; cutting-edge technologies, neuroethics, interventional psychiatry, adaptive DBS, neuromodulation for pain, network neuromodulation for epilepsy and neuromodulation for traumatic brain injury. (shrink)

This paper is truly a joint effort and it could not have been written without the contribution of both authors. Garson, though, deserves credit (or blame) for first seeing the need for two kinds of quantifier scope, and also for devising essentials of the positive theory.

The notions of “narrated time” and “narrative identity” have become, in less than three decades, commonplaces, not only for philosophers, but also for psychologists and ethicists. This would be welcomed, if only it were not used nowadays in what must be called a new dogmatic way. Now, Paul Ricœur indeed asserted, in various ways, the wealth of the notion of narrative; but he also readily acknowleged its limits – aren’t these limits those of hermeneutics itself? Normal 0 false false false (...) EN-US JA X-NONE. (shrink)

L’ontologie heideggérienne de l’être-pour-la-mort a souvent servi de référence négative à Paul Ricœur. Il lui a très tôt opposé trois thèses qu’il n’aurait peut-être pas formulées s’il n’avait pas croisé la philosophie de Jaspers : a) « La naissance signifie plus que la mort » ; b) « la rencontre décisive avec la mort est la mort de l’être aimé » ; c) « la mortalité elle-même doit être pensée sub specie vitae et non sub specie mortis ». La première (...) thèse conditionne les deux suivantes. Elle introduit une phénoménologie de l’ « être-en-vie » qui en appelle de la vie reçue à la vie transmise. On objectera peut-être que la phénoménologie de l’être-en-vie suppose l’ontologie de l’être-pour-la-mort. Mais, même si c’était le cas, elle n’en transformerait pas moins profondément la signification. La compréhension de l’existence est affectée elle-même par les phénomènes de la vie reçue et transmise. C’est ce que veut dire cette expression : « exister vivant ». L’angoisse de la fin n’annule pas la joie des commencements. Peut-être même reçoit-elle de celle-ci son sens.Paul Ricoeur has often referred to Heidegger’s ontology of being-towards-death to oppose it. He early set against it three thesis that he might have formulated differently had he not studied Jasper’s philosophy : a) « birth means more than death » ; b) « the decisive encounter with death is the death of the loved one » ; c) « mortality itself must be thought sub specie vitae, not sub specie mortis ». From the first thesis, can be inferred the two others. It brings in a phenomenology of being-alive. One may raise the objection that the phenomenology of being-alive presupposes the ontology of being-towards-death. But even so it would be necessarily transform its meaning. The understanding of existence is itself affected by the phenomena of life as given and received. Such is the meaning of the phrase : « existing alive ». The distress of the end never cancels the joy of the beginnings. It may even get its sense from it. (shrink)

In most of the more lively fields of physical enquiry in the first three decades of the seventeenth century, a striking contrast may be observed between the antiquity of the problems attacked, and the innovatory procedures applied to solve them. None of these questions, inherited from a past now remote, seemed more pressing than the time-honoured controversy of the plenum versus the vacuum, especially as the concept of the atomic structure of matter was so closely associated with the existence of (...) the void. The more one studies the arguments produced at that time, the more one will be impressed with the value and importance, for the vacuists and the atomists, of the Pneumatics of Hero of Alexandria. When we read Galileo's explanation of combustion, “the extremely fine particles of fire, penetrating the narrow pores of the metal would fill the minute intervening vacuum, and would set free these minute particles from the forced attraction which these same vacua exert’, we can hear clear echoes of Hero's account of disseminated micro-vacua. Now Hero's work is clearly divided into two sections: a theoretical preface and a collection of 78 “pneumatic devices”. One might be tempted to claim that he, rather than his fellow-atomist Lucretius, inspired the first tentative syntheses of seventeenth-century atomism but it would still be necessary to agree that his chief contributions to the achievements of that generation lie in the experimental techniques which they derived from his instrumentation. Were it not for the popularity of his pneumatic demonstrations, he could never have won such a great reputation as a natural philosopher. Without that reputation, his opinions on this topic would not have been valued as almost equal to those of the mighty Aristotle, especially since he was so decidedly in the minority. (shrink)

The double membrane of the nuclear envelope is a formidable barrier separating the nucleus and cytoplasm of eukaryotic cells. However, movement of specific macromolecules across the nuclear envelope is critical for embryonic development, cell growth and differentiation. Transfer of molecules between the nucleus and cytoplasm occurs through the aqueous channel formed by the nuclear pore complex (NPC)Abbreviations: NPC, nuclear pore complex; GlcNac, N‐acetylglucosamine; WGA, wheat germ agglutinin. Although small molecules may simply diffuse across the NPC, transport of large proteins and (...) RNA requires specific transport signals and is energy dependent. A family of pore glycoproteins modified by O‐linked N‐acetylglucosamine moieties are essential for transport through the NPC. Recent evidence suggests that the regulation of nuclear transport may also involve the inteaction of RNA and nuclear proteins with specific binding proteins that recognize these transport signals. Are these nuclear pore glycoproteins and signal binding proteins the ‘gatekeepers’ that control access to the genetic material? Recent evidence obtained from a combination of biochemical and genetic approaches suggests – perhaps. (shrink)

In a number of membrane-bound viruses, ion channels are formed by integral membrane proteins. These channel proteins include M2 from influenza A, NB from influenza B, and, possibly, Vpu from HIV-1. M2 is important in facilitating uncoating of the influenza A viral genome and is the target of amantadine, an anti-influenza drug. The biological roles of NB and Vpu are less certain. In all cases, the protein contains a single transmembrane α-helix close to its N-terminus. Channels can be formed by (...) homo-oligomerization of these proteins, yielding bundles of transmembrane helices that span the membrane and surround a central ion-permeable pore. Molecular modeling may be used to integrate and interpret available experimental data concerning the structure of such transmembrane pores. This has proved successful for the M2 channel domain, where two independently derived models are in agreement with one another, and with solid-state nuclear magnetic resonance (NMR) data. Simulations based on channel models may yield insights into possible ion conduction and selectivity mechanisms. BioEssays 20:992–1000, 1998. © 1998 John Wiley & Sons, Inc. (shrink)

This specimen of a forthcoming book on the void in ancient natural philosophy by using an example illustrates the problems that confront the scholar. The term εὐτονία, used by Chrysippus, occurs in the Pneumatics of Hero of Alexandria in connection with empty pores. Has he borrowed the notion from Stoic philosophy, or was Strato of Lampsacus, older than Chrysippus, the first to use it? In all probability it was Ctesibius who independently of Stoic philosophy applied the term to account for (...) the kinetic qualities of the material used for his inventions, and Philo Byzantius took over the notion from him. Hero may have derived it from Ctesibius either directly or via Philo. (shrink)

Membrane damage induced by haemolytic agents does not necessarily lead to lysis: the pores that are formed at low concentration of agent are formed at low concentration of agent are not large enough to allow leakage of cytoplasmic proteins, and in many instances the lesions become repaired with time. Quite different agents induce a similar type of lesion: in each case leakage is reduced at low ionic strenth, and is prevented by divalent cations such as Ca2+ or Zn2+, suggesting a (...) possible therapeutic approach to the containment of several membrane‐damaging diseases. (shrink)

Many pigmented heterokonts are able to synthesize elements of their cell walls (the frustules) of dense biogenic silica. These include diatom algae, which occupy a significant place in the biosphere. The siliceous frustules of diatoms have species‐specific patterns of surface structures between 10 and a few hundred nanometers. The present review considers possible mechanisms of uptake of silicic acid from the aquatic environment, its transport across the plasmalemma, and intracellular transport and deposition of silica inside the specialized Silica Deposition Vesicle (...) (SDV) where elements of the new frustule are formed. It is proposed that a complex of silicic acid with positively charged proteins silaffins and polypropylamines remains a homogeneous solution during the intracellular transport to SDV, where biogenic silica precipitates. The high density of the deposited biogenic silica may be due to removal of water from the SDV by aquaporins followed by syneresis—a process during which pore water is expelled from the network of the contracting gel. The pattern of aquaporins in the silicalemma, the membrane embracing the SDV, can determine the pattern of species‐specific siliceous nanostructures. BioEssays 30:328–337, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

© 2015 Elsevier Inc.Toxoplasma gondii is a protozoan pathogen in the phylum Apicomplexa that resides within an intracellular parasitophorous vacuole that is selectively permeable to small molecules through unidentified mechanisms. We have identified GRA17 as a Toxoplasma-secreted protein that localizes to the parasitophorous vacuole membrane and mediates passive transport of small molecules across the PVM. GRA17 is related to the putative Plasmodium translocon protein EXP2 and conserved across PV-residing Apicomplexa. The PVs of GRA17-deficient parasites have aberrant morphology, reduced permeability to (...) small molecules, and structural instability. GRA17-deficient parasites proliferate slowly and are avirulent in mice. These GRA17-deficient phenotypes are rescued by complementation with Plasmodium EXP2. GRA17 functions synergistically with a related protein, GRA23. Exogenous expression of GRA17 or GRA23 alters the membrane conductance properties of Xenopus oocytes in a manner consistent with a large non-selective pore. Thus, GRA17 and GRA23 provide a molecular basis for PVM permeability and nutrient access. (shrink)

The crystal δ‐endotoxins of Bacillus thuringiensis (Bt) are a family of insecticidal proteins which have been known for some time to kill insects by lysing their gut epithelial cells, but the precise molecular mechanism of toxicity has remained elusive. The recent publication of the crystal structure of a Bt δ‐endotoxin has made it possible for us to model the molecular events that occur as the toxin binds to its receptor and inserts into the membrane to form a pore. Using our (...) knowledge of insect gut physiology, we can also predict the effect on the insect of the formation of a toxic pore. We present a new model to explain the events that occur in the insect gut during toxin action. (shrink)

The human immune system can directly lyse invading micro‐organisms and aberrant host cells by generating pores in the cell envelope, called membrane attack complexes (MACs). Recent studies using single‐particle cryoelectron microscopy have revealed that the MAC is an asymmetric, flexible pore and have provided a structural basis on how the MAC ruptures single lipid membranes. Despite these insights, it remains unclear how the MAC ruptures the composite cell envelope of Gram‐negative bacteria. Recent functional studies on Gram‐negative bacteria elucidate that local (...) assembly of MAC pores by surface‐bound C5 convertase enzymes is essential to stably insert these pores into the bacterial outer membrane (OM). These convertase‐generated MAC pores can subsequently efficiently damage the bacterial inner membrane (IM), which is essential for bacterial killing. This review summarizes these recent insights of MAC assembly and discusses how MAC pores kill Gram‐negative bacteria. Furthermore, this review elaborates on how MAC‐dependent OM damage could lead to IM destabilization, which is currently not well understood. A better understanding on how MAC pores kill bacteria could facilitate the future development of novel strategies to treat infections with Gram‐negative bacteria. (shrink)

Ion channels are transport proteins present in the lipid bilayers of biological membranes. They are involved in many physiological processes, such as the generation of nerve impulses, hormonal secretion, and heartbeat. Conformational changes in the ion channel-forming protein allow the opening or closing of pores to control the ionic flux through the cell membranes. The opening and closing of the ion channel have been classically treated as a random kinetic process, known as a Markov process. Here the time the channel (...) remains in a given state is assumed to be independent of the condition it had in the previous state. More recently, however, several studies have shown that this process is not random but a deterministic one, where both the open and closed dwell-times and the ionic current flowing through the channel are history-dependent. This property is called long memory or long-range correlation. However, there is still much controversy regarding how this memory originates, which region of the channel is responsible for this property, and which models could best reproduce the memory effect. In this article, we provide a review of what is, where it is, its possible origin, and the mathematical methods used to analyze the long-term memory present in the kinetic process of ion channels. (shrink)

The relationship between kinetochores and nuclear pore complexes (NPCs) is intimate but poorly understood. Several NPC components and associated proteins are relocated to mitotic kinetochores to assist in different activities that ensure faithful chromosome segregation. Such is the case of the Mad1‐c‐Mad2 complex, the catalytic core of the spindle assembly checkpoint (SAC), a surveillance pathway that delays anaphase until all kinetochores are attached to spindle microtubules. Mad1‐c‐Mad2 is recruited to discrete domains of unattached kinetochores from where it promotes the rate‐limiting (...) step in the assembly of anaphase‐inhibitory complexes. SAC proficiency further requires Mad1‐c‐Mad2 to be anchored at NPCs during interphase. However, the mechanistic relevance of this arrangement for SAC function remains ill‐defined. Recent studies uncover the molecular underpinnings that coordinate the release of Mad1‐c‐Mad2 from NPCs with its prompt recruitment to kinetochores. Here, current knowledge on Mad1‐c‐Mad2 function and spatiotemporal regulation is reviewed and the critical questions that remain unanswered are highlighted. (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)

Abstract This paper examines a fundamental, though relatively understudied, aspect of the physical theory of the physician Asclepiades of Bithynia, namely his doctrine of pores. My principal thesis is that this doctrine is dependent on a conception of void taken directly from Epicurean physics. The paper falls into two parts: the first half addresses the evidence for the presence of void in Asclepiades' theory, and concludes that his conception of void was basically that of Epicurus; the second half focuses on (...) the precise nature of Asclepiadean pores, and seeks to show that they represent void interstices between the primary particles of matter which are the constituents of the human body, and are thus exactly analogous to the void interstices between atoms within solid objects in Epicurus' theory. (shrink)

SummaryMuch excitement surrounded the proposal that a family of endo‐lysosomal channels, the two‐pore channels (TPCs) were the long sought after targets of the Ca2+‐mobilising messenger, nicotinic acid adenine dinucleotide phosphate (NAADP). However, the role of TPCs in NAADP signalling may be more complex than originally envisaged. First, NAADP may not bind directly to TPCs but via an accessory protein. Second, two papers recently challenged the notion that TPCs are NAADP‐regulated Ca2+ channels by suggesting that they are highly selective Na+ channels (...) regulated by the lipid phosphatidylinositol 3,5‐bisphosphate and by ATP. This paper aims critically to evaluate the evidence for TPCs as NAADP targets and to discuss how the new findings fit in with what we know about endo‐lysosomal Ca2+ stores. (shrink)

Transport through the nuclear pore complex (NPC), a keystone of the eukaryotic building plan, is known to involve a large channel and an abundance of phenylalanine–glycine (FG) protein domains serving as binding sites for soluble nuclear transport receptors and their cargo complexes. However, the conformation of the FG domains in vivo, their arrangement in relation to the transport channel and their function(s) in transport are still vividly debated. Here, we revisit a number of representative transport models—specifically Brownian affinity gating, selective (...) phase gating, reversible FG domain collapse, and reduction of dimensionality (ROD)—in the light of new data obtained by optical single transporter recording, optical superresolution microscopy, artificial nanopores, and many other techniques. The analysis suggests that a properly adapted, simplified version of the ROD model accounts well for the available data. This has implications for nucleocytoplasmic transport in general. (shrink)

The nuclear pore complex (NPC) is emerging as a center for recruitment of a class of “difficult to repair” lesions such as double‐strand breaks without a repair template and eroded telomeres in telomerase‐deficient cells. In addition to such pathological situations, a recent study by Su and colleagues shows that also physiological threats to genome integrity such as DNA secondary structure‐forming triplet repeat sequences relocalize to the NPC during DNA replication. Mutants that fail to reposition the triplet repeat locus to the (...) NPC cause repeat instability. Here, we review the types of DNA lesions that relocalize to the NPC, the putative mechanisms of relocalization, and the types of recombinational repair that are stimulated by the NPC, and present a model for NPC‐facilitated repair. (shrink)

Six years ago, the Singer lab published a landmark paper which described how individual mRNA particles cross the nuclear pore complex in mammalian tissue culture cells. This involved the simultaneous imaging of mRNAs, each labeled by a large number of tethered fluorescent proteins and fluorescently tagged nuclear pore components. Now two groups have applied this technique to the budding yeast Saccharomyces cerevisiae. Their results indicate that in the course of nuclear export, mRNAs likely engage complexes that are present on either (...) side of the pore and that these interactions are modulated by proteins present in the messenger ribonucleoprotein (mRNP) complex. These findings lend support to the notion that just before and/or after the completion of nuclear export, mRNPs undergo one or more maturation steps that prepare the packaged mRNAs for translation. These results represent new and exciting insights into the mechanism of mRNA nuclear export. (shrink)

The nuclear export of mRNA through the nuclear pore complex (NPC) is a process required for the healthy functioning of human cells, making it a critical area of research. However, the geometries of mRNA and the NPC are well below the diffraction limit of light microscopy, thereby presenting significant challenges in evaluating the discrete interactions and dynamics involved in mRNA nuclear export through the native NPC. Recent advances in biotechnology and single‐molecule super‐resolution light microscopy have enabled researchers to gain granular (...) insight into the specific contributions made by discrete nucleoporins in the nuclear basket of the NPC to the export of mRNA. Specifically, by expanding upon the docking step facilitated by the protein TPR in the nuclear basket as well as identifying NUP153 as being the primary nuclear basket protein initiating export through the central channel of the NPC. (shrink)

In eukaryotic cells the nucleus and its contents are separated from the cytoplasm by the nuclear envelope. Macromolecules, as well as smaller molecules and ions, can cross the nuclear envelope through the nuclear pore complex. Molecules greater than approx. 60 kDa and containing a nuclear localization signal are actively transported across the nuclear membranes, but there has been little evidence for regulatory mechanisms for smaller molecules and ions. Recently, diffusion across the nuclear envelope has been observed to be regulated by (...) nuclear cisternal Ca2+ concentrations. Following depletion of Ca2+ from the nuclear store by inositol 1,4,5‐trisphosphate or Ca2+ chelators, a fluorescent 10 kDa marker molecule was no longer able to enter the nucleus. Distinct conformational states of the nuclear pore complexes depended on the Ca2+ filling state of the nuclear envelope, supporting the assumption that a switch in the conformation of the nuclear pore complex may control the transport of intermediate‐sized molecules across the nuclear envelope. Thus nuclear Ca2+ stores may regulate the conformational state of the nuclear pore complex, and thereby passive diffusion of molecules between the cytosol and the nucleoplasm. The physiological significance of this finding is currently unknown. (shrink)

Il n’est pas de discipline qui ait, autant que la psychanalyse, inquiété la philosophie de Paul Ricoeur. Elle accompagne tout son chemin de pensée et ne cesse d’en troubler le cours. On aurait tort cependant de croire que ce long compagnonnage soit marqué avant tout par l’hostilité ou la polémique. Même dans l’Essai sur Freud, où elle incarne l’«herméneutique du soupçon», la psychanalyse est rencontrée non comme une ennemie certaine mais comme une alliée possible. Elle est le miroir que la (...) philosophie se tend et où elle se voit elle-même comme une autre. C’est un véritable dialogue qui est ainsi noué entre elles. L’enjeu n’en est rien de moins que la compréhension de l’homme. (shrink)