The Structure and Function of GLFGs in the Nuclear Pore Complex of Yeast

The nuclear pore complex (NPC) is a large multiprotein complex which perforates the nuclear envelope. The NPC is made up of nuclear pore proteins (Nups), one third of which are phenylalanine-glycine (FG) containing. The NPC has a role in controlling movement of molecules between the nucleus and the cytoplasm. The FG Nups fill the NPC’s centre and regulate translocation. There are many different proposed models of how FG Nups may regulate translocation from them reeling cargo complexes into the NPC to inter FG repeats binding to create a gel-like meshwork into which specific cargo can enter and translocate. Using transmission electron microscopy the glycine-leucine-phenylalanine-glycine (GLFG) domains of Nups are mapped, showing a cytoplasmic bias within the wild type (WT) NPC and also in FG domain deletion mutants. FG deletion mutants have higher percentages of GLFG labelling towards the NPC edge than WT and lower percentages towards the middle than WT. GLFG domain labelling is also observed ‘reaching’ to membrane structures from the NPC. Serial sectioning of individual NPCs confirmed that individual NPCs had different distributions of GLFG labelling, which was on the nucleoplasmic or cytoplasmic side, or on both sides. Mutants which are defective in the nucleotide exchange activity of the RanGEF, Prp20, have a deficiency of the active RanGTP molecular switch. This causes a shift in the GLFG labelling from the cytoplasmic side towards the nucleoplasmic side. Similarly the import of Kap121-dependant import cargo causes a shift from cytoplasmic to nucleoplasmic labelling. This is observed as the cargo reaches the midplane of the NPC. Field emission scanning electron microscopy shows GLFG labelling to be associated with filaments (cytoplasmic, internal and nucleoplasmic) and possibly also the transporter. Finally, a model based on the shift in GLFG labelling is developed. This model suggests that there is a collapse and ‘reel in’ of import cargo as in the reversible collapse model, there is then a restructure of GLFG domains into the nucleoplasm due to potentially passing cargo on

Jahresbericht 2008 zur kooperativen DV-Versorgung

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Neurobiological explanation of consciousness

Glavni cilj ovog rada jeste formulisanje modela svesti koji bi uspeo da prevaziđe prigovore i probleme sa kojim su se suočavali svi dosadašnji neurobiološki modeli. Najveći izazov je odgovor na pitanje kako je moguće da neki materijalni sistem, poput mozga, proizvede subjektivno iskustvo. Kao što ću pokazati, odgovor se nalazi u načinu na koji je mozak organizovan i njegovoj sposobnosti da proizvede posebnu vrstu kauzalnih interakcija (neprekidnu kauzalnu samoreferencu). Model svesti koji predlažem se oslanja na dinamičke modele prema kojima je svest globalno sistemsko svojstvo. Prema hipotezi neprekidne kauzalne samoreference koju ću zastupati, organizacija ima nesvodivu ulogu u stvaranju novih svojstava. Svest se ne može u potpunosti objasniti svođenjem na osnovne materijalne konstituente, već je ona suštinski relaciono svojstvo tih konstituenata. Objašnjenje svesti ne možemo naći u pojedinačnim gradivnim jedinicama mozga, neuronima, već u načinu na koji su oni organizovani. Istraživanja (Bressler and Kelso, 2016) (Tognoli and Kelso, 2014) (Kelso, 2012) pokazuju da postoje svojstva koja se nalaze na nivou celog sistema, koja proizilaze iz relacija među konstituentima a koja se ne mogu pronaći na nivou bazičnih konstituenata. Svest je dinamički proces, neprekidno menjajuća struktura kauzalnih relacija među konstituentima sistema. U skladu sa tim pokušaću da pokažem da se svest kao svojstvo pojavljuje u slučajevima kada materija i relacije između njenih elemenata imaju posebnu kauzalnu konfiguraciju. Kao glavnu teorijsku i empirijsku podršku toj hipotezi koristiću modele i eksperimentalnu evidenciju različitih autora koji zastupaju dinamičke teorije svesti poput Tononija, Edelmana, Spornsa i drugih. Navedeni autori implicitno podržavaju ontologiju u kojoj relacije spadaju u osnovna primitivna svojstva stvarnosti. (Sporns, Chialvo, Kaiser and Hilgetag, 2004) (Edelman and Tononi, 2000) (Olaf Sporns, 2010) (Tononi and Koch, 2015). U prvom poglavlju ću pokazati kakav je uticaj teorija dinamičkih sistema imala na druge nauke i koliko je uticala na promenu ontoloških pretpostavki. Ukazaću na važnost teorije dinamičkih sistema u argumentima u debati između redukcionizma i emergentizma. Kroz debatu između dva suprotstavljena stanovišta videćemo kako se fokus u razumevanju fizičkog sveta, pre svega funkcionisanja sistema, pomerio sa delova (mikro nivo) na celinu (makro nivo). U ovom poglavlju ćemo kroz različite teorijske hipoteze i empirijske primere videti da je teorija dinamičkih sistema osnov za prihvatanje savremene forme emergentizma, koja je od suštinske važnosti za uspostavljanje i odbranu teze prema kojoj je svest emergentno svojstvo u dinamičkim sistemima. Drugo poglavlje će fokus istraživanja staviti na teorijske okvire i osnovne pojmove teorije dinamičkih sistema. Pojmovi kojima raspolaže teorija dinamičkih sistema poput samoorganizujuće kritičnosti, metastabilnosti, tranzicije faza, emergencije, integracije i informacije su od suštinske važnosti za objašnjenje ponašanja kompleksnih sistema u koje spada i mozak. Kakva je empirijska primena ovih pojmova biće predstavljeno kroz analizu ponašanja gomile peska, zemljotresa, feromagnetnih materijala i kompjuterski model „Game of Life“. Navedeni primeri će imati poseban doprinos u odgovoru na pitanje kako jedan fizički sistem može da poseduje emergentno svojstvo koje prevazilazi ponašanje njegovih pojedinačnih elemenata. U ovom poglavlju načiniću i korak dalje pa ću pokazati koje su osobine mozga koje mu omogućavaju da proizvede emergentno svojstvo (svest). Kroz mnogobrojne primere iz kliničke prakse i simulacije pokazaću koliko je svesno iskustvo povezano sa sposobnošću sistema da integriše velike količine informacije. Kao što ćemo videti, sposobnost integracije velike količine informacije je posledica posebne arhitekture i funkcionalne dinamike mozga i upravo zahvaljujući njima mozak može da proizvede svesno iskustvo. U trećem poglavlju predstaviću najvažnije modele svesti koje se oslanjaju na teoriju dinamičkih sistema. Prvo ćemo videti modele koje svoje hipoteze zasnivaju na procesu integracije informacije (teorija dinamičkog jezgra, teorija integrisane informacije). Nakon toga ćemo videti kako se kompleksna dinamika polja može dovesti u vezu sa svesnim iskustvom. U okviru teorije polja će biti prikazani i modeli koji koriste pojam informacije da bi objasnili svesno iskustvo, ali treba imati na umu da takvi modeli informaciju koriste u kontekstu teorije polja. Na kraju ovog poglavlja će biti predstavljena teza proširene svesti koja dovodi u pitanje prostorno vremenske okvire u kojima se realizuje svesno iskustvo. U četvrtom poglavlju ću izložiti slabosti predloženih modela, pokazati njihovu nepotpunost i izložiti dodatne argumente kojima bi se otklonili problemi i dao potpuniji dinamički model svesti. Pokazaću da nijedan od navedenih dinamičkih modela svesti nije uzeo u obzir fundamentalnu osobinu fenomenalnog iskustva, usmerenost na samu sebe (samoreferentnost). Izložiću svoju osnovnu hipotezu koju sam nazvao „neprekidna kauzalna samoreferenca“ a koja se zasniva na procesu cirkularne kauzalnosti. Prema modelu koji ja zastupam subjektivno iskustvo je proces u kome dolazi do balansa kauzalnog uticaja između top down kauzalnosti koju sprovode elektromagnetna polja unutar mozga i bottom up kauzalnosti koju sprovode pojedinačni neuroni kroz svoje pražnjenje. Pokazaću da je glavni mehanizam svesti cirkularna kauzalna petlja koja se ostvaruje u talamokortikalnom sistemu gde dolazi do uspostavljanja kauzalne samoreference. Na samom kraju ćemo kroz nekoliko empirijskih primera testirati predviđanja HNKS i pokazati da ona bolje od ostalih prikazanih modela odgovara na svakodnevno shvatanje pojma svesti. Dakle, da bismo objasnili svest potrebno je da objasnimo kako je moguće da materijalni sistem proizvede fenomenalnu svest, egzistenciju doživljenu iz perspektive prvog lica. U pokušaju da odgovorim na ovo pitanje pošao sam od fenomenološke činjenice, da je svest uvek usmerena na samu sebe, da je subjektivno iskustvo uvek „zaključano“. Mi nikada ne možemo izaći van njega i pristupiti objektivnoj stvarnosti. Svesno iskustvo je uvek usmereno na sopstvene sadržaje. Pojam samoreferentnosti sam iskoristio za formulisanje hipoteze „neprekidne kauzalne samoreference“ koja nam pruža objašnjenje moždanih kauzalnih mehanizama koji stoje u osnovi svesti. Kako nijedan dinamički model do sada nije na zadovoljavajući način iskoristio tu činjenicu, smatram da predložena hipoteza predstavlja unapređenu verziju dosadašnjih dinamičih modelaThe main goal of this paper is to formulate a model of consciousness that would overcome the objections and problems faced by all neurobiological models to date. The biggest challenge is answering the question of how it is possible for a material system, such as the brain, to produce subjective experience. As I will show, the answer lies in the way the brain is organized and its ability to produce a special kind of causal interactions (continuous causal self-reference). The model of consciousness I propose relies on the dynamic models according to which consciousness is a global property of the system. According to the hypothesis of continuous causal self-reference that I will present, organization plays an irreducible role in creating new properties. Consciousness cannot be fully explained by reduction to basic material constituents, but it is rather essentially a relational property of those constituents. We cannot find an explanation of consciousness in the individual building blocks of the brain, neurons. It is in the way they are organized. Research (Bressler and Kelso, 2016) (Tognoli and Kelso, 2014) (Kelso, 2012) shows that there are properties that can be found on the level of the system as a whole, that arise from relationships among constituents, but that cannot be found at the level of basic constituents. Consciousness is a dynamic process, a constantly changing structure of causal relations between the constituents of a system. Accordingly, I will try to show that consciousness as a property occurs in cases where matter and the relations between its elements have a special causal configuration. As the main theoretical and empirical support for this hypothesis, I will use models and experimental record of various authors representing dynamic theories of consciousness such as Tononi, Edelman, Sporns and others. Listed authors implicitly support the ontology in which relations belong to the basic primitive properties of reality. (Sporns, Chialvo, Kaiser and Hilgetag, 2004) (Edelman and Tononi, 2000) (Olaf Sporns, 2010) (Tononi and Koch, 2015). In the first chapter, I will show what impact the theory of dynamical systems has had on other sciences and how much it influenced the change in ontological assumptions. I will point out the importance of the theory of dynamic systems in the arguments from the debate between reductionism and emergentism. Through the debate between the two opposing viewpoints we will see how the focus has shifted from the parts... to the whole... in the understanding of the physical world, above all of the functioning of the system. In this chapter, through various theoretical hypotheses and empirical examples, we will see that the theory of dynamical systems is the basis for adopting the contemporary form of emergentism, which is essential for establishing and defending the thesis that consciousness is an emergent property in dynamic systems. The second chapter will focus on the research on theoretical frameworks and basic concepts of the dynamical systems theory. Concepts in the theory of dynamic systems such as self-organizing criticality, metastability, phase transition, emergence, integration and information are essential for explanation of the behavior of complex systems, including the brain. Empirical application of these terms will be presented through an analysis of the behavior of sand piles, earthquakes, ferromagnetic materials and the computer model of the “Game of Life“. The examples mentioned above will give a special contribution to answering the question of how a physical system can have an emergent property that goes beyond the behavior of its elements. In this chapter, I will make a step further and show what are the characteristics of the brain that enable it to produce an emergent property (consciousness). Through numerous examples from clinical practice and simulation, I will demonstrate how conscious experience is related to the ability of the system to integrate a large quantity of information. As we shall see, the ability to integrate a large quantity of information is a result of the unique architecture and functional dynamics of the brain and due precisely to them the brain can produce conscious experience. In the third chapter, I will present the most important models of consciousness that rely on the theory of dynamical systems. We will first see the models that base their hypotheses on the process of information integration (Dynamic Core Theory, Integrated Information Theory). We will then see how complex field dynamics can be related to conscious experience. Within the field theory, models that take the notion of information to explain conscious experience, but which use information in the context of field theory, will also be shown. Field theory will also include models that use the notion of information to explain conscious experience, but we should have in mind that such models use information in the context of field theory. At the end of this chapter, the theses of extended consciousness that question the spatio-temporal boundaries in which conscious experience is realized will be presented. In the fourth chapter, I will outline the weaknesses of the proposed models, demonstrate their incompleteness, and present additional arguments to solve the problems and provide a more complete dynamic model of consciousness. I will show that none of these dynamic models of consciousness have taken into account the fundamental feature of phenomenal experience, self-directedness (self-referentiality). I will present my basic hypothesis, which I have called "continuous causal self-reference", which is based on the process of circular causality. According to the model that I am presenting, subjective experience is a process in which there is a balance of causal influence between top-down causality carried out by electromagnetic fields inside of the brain and a bottom-up causality carried out by firing of the single neurons. I will show that the main mechanism of the consciousness is the circular causal loop which is realized inside of the thalamocortical system, where causal self-reference is established. At the very end, through several empirical examples, we will test the predictions of HCCS and show that it fits the everyday understanding of the notion of consciousness better than other models presented. Hence, in order to explain consciousness, we need to explain how it is possible for the material system to produce phenomenal consciousness, existence experienced from a first-person perspective. In an attempt to answer this question, I started from the phenomenological fact that consciousness is always self-directed, that subjective experience is always "locked". We can never go beyond it and approach objective reality. A conscious experience is always focused on its own content. I used the term self-referentiality to formulate the hypothesis of “continuous causal self-reference” that provides us with an explanation of the brain’s causal mechanisms underlying consciousness. As no dynamic model has satisfactorily exploited this fact, I believe that the proposed hypothesis represents an advanced version of the dynamic models so fa