Transport of macromolecules from the nucleus to the cytoplasm is essential for nearly all cellular and developmental events, and when mis‐regulated, is associated with diseases, tumor formation/growth, and cancer progression. Nuclear Envelope (NE)‐budding is a newly appreciated nuclear export pathway for large macromolecular machineries, including those assembled to allow co‐regulation of functionally related components, that bypasses canonical nuclear export through nuclear pores. In this pathway, large macromolecular complexes are enveloped by the inner nuclear membrane, (...) transverse the perinuclear space, and then exit through the outer nuclear membrane to release its contents into the cytoplasm. NE‐budding is a conserved process and shares many features with nuclear egress mechanisms used by herpesviruses. Despite its biological importance and clinical relevance, little is yet known about the regulatory and structural machineries that allow NE‐budding to occur in any system. Here we summarize what is currently known or proposed for this intriguing nuclear export process. (shrink)

Mammalian telomeres have evolved safeguards to prevent their recognition as DNA double‐stranded breaks by suppressing the activation of various DNA sensing and repair proteins. We have shown that the telomere‐binding proteins TRF2 and RAP1 cooperate to prevent telomeres from undergoing aberrant homology‐directed recombination by mediating t‐loop protection. Our recent findings also suggest that mammalian telomere‐binding proteins interact with the nuclear envelope to maintain chromosome stability. RAP1 interacts with nuclear lamins through KU70/KU80, and disruption of RAP1 and TRF2 (...) function result in nuclear envelope rupture, promoting telomere‐telomere recombination to form structures termed ultrabright telomeres. In this review, we discuss the importance of the interactions between shelterin components and the nuclear envelope to maintain telomere homeostasis and genome stability. (shrink)

The nuclear envelope shapes the functional organization of the nucleus. Increasing evidence indicates that one of its main components, the nuclear lamina, dynamically interacts with the genome, including the promoter region of specific genes. This seems to occur in a manner that accords developmental significance to these interactions. This essay addresses key issues raised by recent data on the association of nuclear lamins with the genome. We discuss how lamins interact with large chromatin domains and with (...) spatially restricted regions on gene promoters. We address the relationship between these interactions, chromatin modifications and gene expression outcomes. Lamin‐genome contacts are redistributed after cell division and during stem cell differentiation, with evidence of lineage specificity. Thus, we also speculate on a developmental role of lamin interactions with specific genes. Finally, we highlight how concepts arising from this recent work lay the foundations of future challenges and investigations. (shrink)

Chromosome segregation requires the ordered separation of the newly replicated chromosomes between the two daughter cells. In most cells, this requires nuclear envelope (NE) disassembly during mitotic entry and its reformation at mitotic exit. Nuclear envelope breakdown (NEB) results in the mixture of two cellular compartments. This process is controlled through phosphorylation of multiple targets by cyclin‐dependent kinase 1 (Cdk1)‐cyclin B complexes as well as other mitotic enzymes. Experimental evidence also suggests that nucleo‐cytoplasmic transport of critical (...) cell cycle regulators such as Cdk1‐cyclin B complexes or Greatwall, a kinase responsible for the inactivation of PP2A phosphatases, plays a major role in maintaining the boost of mitotic phosphorylation thus preventing the potential mitotic collapse derived from NEB. These data suggest the relevance of nucleo‐cytoplasmic transport not only to communicate cytoplasmic and nuclear compartments during interphase, but also to prepare cells for the mixture of these two compartments during mitosis. (shrink)

The export of processed RNA molecules from the nucleus is an intricately regulated process, subject to various developmental and physiological controls. The structural and biochemical properties of the nuclear envelope that are involved in this process are described here.

The transport of molecules across the nuclear envelope plays a central role in the metabolism of the cell. Significant advances hi three major areas highlight the limits of our current knowledge and point to the prospect of exciting future developments. Firstly, findings that ions and small proteins do not diffuse freely into the nucleus call into question the current views of nuclear envelope permeability. Secondly, indications that nuclear protein import can be regulated in conjunction with (...) the cell cycle and development have been confirmed by the clear demonstration of regulated nuclear entry of specific transcription factors and morphogens. Thirdly, identification and characterisation of candidate receptor proteins indicates that the recognition of the nuclear targeting sequence occurs in the cytoplasm, suggesting that a different recognition event occurs at the nuclear pore. (shrink)

Chromosomes are not only carriers of the genetic material, but also actively regulate the assembly of complex intracellular architectures. During mitosis, chromosome‐induced microtubule polymerisation ensures spindle assembly in cells without centrosomes and plays a supportive role in centrosome‐containing cells. Chromosomal signals also mediate post‐mitotic nuclear envelope (NE) re‐formation. Recent studies using novel approaches to manipulate histones in oocytes, where functions can be analysed in the absence of transcription, have established that nucleosomes, but not DNA alone, mediate the chromosomal (...) regulation of spindle assembly and NE formation. Both processes require the generation of RanGTP by RCC1 recruited to nucleosomes but nucleosomes also acquire cell cycle stage specific regulators, Aurora B in mitosis and ELYS, the initiator of nuclear pore complex assembly, at mitotic exit. Here, we review the mechanisms by which nucleosomes control assembly and functions of the spindle and the NE, and discuss their implications for genome maintenance. (shrink)

The nuclear envelope has recently become the object of intense scrutiny because it is the site of nuclear transport and is possibly involved in the organization of the interphase genome, thereby affecting gene expression. The major structural support for the nuclear envelope is the nuclear lamina, composed of the nuclear lamin proteins. They lie on the surface of the inner nuclear membrane and are in direct contact with the chromatin at the edge (...) of the nucleus. The structure of the nuclear lamin proteins has recently been deduced from their cDNAs and shown to have remarkable homologies to the family of cytoplasmic intermediate filaments. However, the lamin proteins have been found to depolymerize in response to metaphase‐specific phosphorylation events, and reassemble around daughter chromosomes at the completion of cell division. Little is known of the mechanisms of these dynamics, nor of other post‐translational modifications evident in these proteins. In addition, we have as yet no concrete idea of the function of these highly conserved proteins in the cell. This review will summarize our present knowledge of nuclear lamin structure and the new experimental approaches designed to elucidate their function. (shrink)

During mitosis, cells comprehensively restructure their interior to promote the faithful inheritance of DNA and cytoplasmic contents. In metazoans, this restructuring entails disassembly of the nuclear envelope, redistribution of its components into the endoplasmic reticulum (ER) and eventually nuclear envelope reassembly around the segregated chromosomes. The microtubule cytoskeleton has recently emerged as a critical regulator of mitotic nuclear envelope and ER dynamics. Microtubules and associated molecular motors tear open the nuclear envelope in (...) prophase and remove nuclear envelope remnants from chromatin. Additionally, two distinct mechanisms of microtubule‐based regulation of ER dynamics operate later in mitosis. First, association of the ER with microtubules is reduced, preventing invasion of ER into the spindle area, and second, organelle membrane is actively cleared from metaphase chromosomes. However, we are only beginning to understand the role of microtubules in shaping and distributing ER and other organelles during mitosis. (shrink)

After viral entry into the cell, the nuclear envelope poses a major cellular barrier that needs to be overcome upon adaptation of highly pathogenic avian influenza viruses (HPAIV) to the new host. To ensure efficient viral transcription and replication in the nucleus of the host cell, the viral polymerase complex of avian influenza viruses needs to switch from recognition of avian to mammalian components of the nuclear import machinery. Recent evidence suggests that influenza viruses have evolved different (...) mechanisms to utilize importin‐α isoforms as components of this machinery, bridging pre‐ and post‐nuclear import on both sides of the nuclear envelope. (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)

Sad1 and UNC84 (SUN) and Klarsicht, ANC‐1, and Syne homology (KASH) proteins interact at the nuclear periphery to form the linker of nucleoskeleton and cytoskeleton (LINC) complex, spanning the nuclear envelope (NE) and connecting the cytoskeleton with the nuclear interior. It is now well‐documented that several cellular functions depend on LINC complex formation, including cell differentiation and migration. Intriguingly, recent studies suggest that SUN proteins participate in cellular processes where their association with KASH proteins may not (...) be required. Building on this recent research, we elaborate on the hypothesis that SUN proteins may perform LINC‐independent functions and discuss the modalities that may allow SUN proteins to function at the INM when they are not forming LINC complex. (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)

Here we discuss a “chromosome separation checkpoint” that might regulate the anaphase‐telophase transition. The concept of cell cycle checkpoints was originally proposed to account for extrinsic control mechanisms that ensure the order of cell cycle events. Several checkpoints have been shown to regulate major cell cycle transitions, namely at G1‐S and G2‐M. At the onset of mitosis, the prophase‐prometaphase transition is controlled by several potential checkpoints, including the antephase checkpoint, while the spindle assembly checkpoint guards the metaphase‐anaphase transition. Our hypothesis (...) is based on the recently uncovered feedback control mechanism that delays chromosome decondensation and nuclear envelope reassembly until effective separation of sister chromatids during anaphase is achieved. A central player in this potential checkpoint is the establishment of a constitutive, midzone‐based Aurora B phosphorylation gradient that monitors the position of chromosomes along the spindle axis. We propose that this surveillance mechanism represents an additional step towards ensuring mitotic fidelity. (shrink)

Does the three‐dimensional (3D) conformation of interphase chromosomes merely reflect their function or does it actively contribute to gene regulation? The analysis of sex chromosomes that are subject to chromosome‐wide dosage compensation processes promises new insight into this question. Chromosome conformations are dynamic and largely determined by association of distant chromosomal loci in the nuclear space or by their anchoring to the nuclear envelope, effectively generating chromatin loops. The type and extent of such interactions depend on chromatin‐bound (...) transcription regulators and therefore reflects function. Dosage compensation adjusts the overall transcription activity of X chromosomes to assure balanced expression in the two sexes. Initial analyses of mammalian and Drosophila X chromosomes have led to the hypothesis that their conformations may not only reflect their functional state but may in turn contribute to the coordination of chromosome‐wide tuning of transcription. (shrink)

Mitotic entry and exit are switch‐like transitions that are driven by the activation and inactivation of Cdk1 and mitotic cyclins. This simple on/off reaction turns out to be a complex interplay of various reversible reactions, feedback loops, and thresholds that involve both the direct regulators of Cdk1 and its counteracting phosphatases. In this review, we summarize the interplay of the major components of the system and discuss how they work together to generate robustness, bistability, and irreversibility. We propose that it (...) may be beneficial to regard the entry and exit reactions as two separate reversible switches that are distinguished by differences in the state of phosphatase activity, mitotic proteolysis, and a dramatic rearrangement of cellular components after nuclear envelope breakdown, and discuss how the major Cdk1 activity thresholds could be determined for these transitions. (shrink)

The origin of mitosis and the nuclear envelope were the pivotal processes in the evolutionary origin of the nucleus; they probably occurred in a wall‐less mutant bacterium that evolved a cytoskeleton and phagocytosis about 1500 million years ago. Principles of intracellular coevolution clarify their origin, as well as that of nucleosomes, spliceosomes, and the evolution of genome size.

Within the last decade, the study of mitosis has evolved into a multidisciplinary science in which findings from fields as diverse as chromosome biology and cytoskeletal architecture have converged to present a more cohesive understanding of the complex events that occur when cells divide. The largest strides have been made in the identification and characterization of regulatory enzymes (kinases and phosphatases) that modulate mitotic activity, as well as a number of the proteins and structural components (spindle, chromosomes, nuclear (...) class='Hi'>envelope) which carry out the mitotic instructions. One emerging theme appears to be that molecular signalling, which can involve modification of components (such as phosphorylation) or even their specific destruction, monitors the state of the mitotic cell at all stages. One of the major challenges for the future will be the identification of addititonal targets of the signalling machinery, as well as new regulatory components and their targets on the chromosomes, on the spindle, and at the cleavage furrow. (shrink)

A diverse family of proteins has been discovered with a small C‐terminal KASH domain in common. KASH domain proteins are localized uniquely to the outer nuclear envelope, enabling their cytoplasmic extensions to tether the nucleus to actin filaments or microtubules. KASH domains are targeted to the outer nuclear envelope by SUN domains of inner nuclear envelope proteins. Several KASH protein genes were discovered as mutant alleles in model organisms with defects in developmentally regulated (...) class='Hi'>nuclear positioning. Recently, KASH‐less isoforms have been found that connect the cytoskeleton to organelles other than the nucleus. A widened view of these proteins is now emerging, where KASH proteins and their KASH‐less counterparts are cargo‐specific adaptors that not only link organelles to the cytoskeleton but also regulate developmentally specific organelle movements. BioEssays 27:1136–1146, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Proteins and RNAs move between the nucleus and cytoplasm by translocation through nuclear pore complexes in the nuclear envelope. To do this, they require specific targeting signals, energy, and a cellular apparatus that catalyzes their transport. Several of the factors involved in nucleocytoplasmic trafficking of proteins have been identified and characterized in some detail. The emerging picture for nuclear transport proposes a central role for the small GTPase Ran and proteins with which it interacts. In particular, (...) asymmetric distribution of these proteins between nucleus and cytoplasm appears to be responsible for the vectorial nature of nucleocytoplasmic transport. Here, we summarize the role of Ran and Ran-binding proteins in nuclear trafficking of proteins with classical nuclear localisation signals. We also discuss examples of the growing number of alternative pathways that are involved in transport of proteins across the nuclear envelope. BioEssays 21:579–589, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

A complex structure, visible by electron microscopy, surrounds each chromosome during mitosis. The organization of this structure is distinct from that of the chromosomes and the cytoplasm. It forms a perichromosomal layer that can be isolated together with the chromosomes. This layer covers the chromosomes except in centromeric regions. The perichromosomal layer includes nuclear and nucleolar proteins as well as ribonucleoproteins (RNPs). The list of proteins and RNAs identified includes nuclear matrix proteins (perichromin, peripherin), nucleolar proteins (perichro‐monucleolin, Ki‐67 (...) antigen, B23 protein, fibrillarin, p103, p52), ribosomal proteins (S1) and snRNAs (U3 RNAs). Only limited information is available about how and when the perichromosomal layer is formed. During early prophase, the proteins extend from the nucleoli towards the periphery of the nucleus. Thin cordon‐like structures reach the nuclear envelope delimiting areas in which chromosomes condense. At telophase, the proteins are associated with the part of the chromosomes remaining condensed and accumulate in newly formed nucleoli in regions where chromatin is already decondensed. The perichromosomal layer contains several different classes of proteins and RNPs and it has been attributed various roles: (1) in chromosome organization, (2) as a barrier around the chromosomes, (3) involvement in compartmentation of the cells in prophase and telophase and (4) a binding site for chromosomal passenger proteins necessary to the early process of nuclear assembly. (shrink)

continent. 2.2 (2012): 60–63 Translated by Rodrigo Maltez Novaes. From the forthcoming book Post-History , Minneapolis: Univocal Publishing, 2013. It is not necessary to have a keen ear in order to find out that the steps we take towards the future sound hollow. But it is necessary to have concentrated hearing if one wishes to find out which type of vacuity resonates with our progress. There are several types of vacuity, and ours must be compared to others, if the aim (...) is to understand it. The incomparable is incomprehensible. If we affirm that our situation is incomparable, we give up the effort to grasp it. The comparison that imposes itself is to the vacuity of the Baroque. There are innumerable traces in the present that evoke the Baroque. We bear the mark of the same somber rationalism (logics, informatics, cybernetics), and of the same magic and fanatic irrationalism (mass media, phantastic ideologies). But there is a decisive difference. Humanity advanced over a stage during the Baroque. All of its gestures, even the most sincere, were marked by theatricality. The vacuity that resonated under its feet was of the void under the stage. Baroque man represented. 1 For example he represented faith in waging religious wars. Baroque vacuity was the consequence of a medieval loss of faith in dogmas . Our vacuity is different. We do not represent anything. Our world is not a stage. We are not actors, and if we act, it is not to represent a drama, but to divert the audience's attention and our own from the subjects that really matter. We act like criminals that try to hide their tracks. We pretend. Our progress is a farce. The vacuity under our feet is not Baroque. We have not lost our faith in dogmas: we have lost faith in ourselves . We are as counter-reformists as was the Baroque (we want to cover up the recent revolution with warm cloths), but for different reasons. Although comparable with the Baroque, in certain aspects, our situation is in fact incomparable to any other. That is because an incomparable, unheard of, never before seen event happened recently, which emptied the ground we tread. Auschwitz . Other posterior events; Hiroshima, the Gulags, are nothing but variations of the first. Therefore every attempt to grasp the present leads to the following questions: how was Auschwitz possible? How can we live after this? Such questions relate not only to the ones directly or indirectly responsible, and not only to those who were directly or indirectly hit by it: they relate to everyone who takes part in our culture. Because what is so incomparable, unheard of, never before seen and therefore incomprehensible in Auschwitz, is that it was there that Western culture revealed one of its inherent virtualities. Auschwitz is a characteristic realization of our culture. It is neither the product of a particular Western ideology, nor of specific “advanced” industrial techniques. It springs directly from the depths of culture and of its concepts and values. The possibility to realize Auschwitzes is implicit within our culture from the very start: the Western “project” already harbored it, although as a remote possibility. Auschwitz lies within the initial program of the West, which progressively realizes all of its virtualities as history unfolds. That is why the question that Auschwitz poses before us is not: how did it happen? It serves no purpose to “explain” Auschwitz. The fundamental question is: how was it possible? Because what is being questioned is not the extermination camp, but the West. Thus one other question: how to live within a culture henceforth unmasked? Everything that happened afterwards resonates with such a question, with such vacuity. Every economic, social, political, technical, scientific, artistic, philosophic event is corroded by such an undigested question. The distance that separates us from the event does not mitigate the abyss, it erodes it even deeper. Because the distance progressively dissolves the aura of the horror that envelops the event, and it progressively opens up a vision of the scene. It progressively reveals that there all of our categories, all of our “models”, suffered an irreparable shipwreck. Auschwitz was a revolutionary event, in the sense that it overthrew our culture. Insofar as we seek ways to cover up such revolution with trips to the moon or with genetic manipulations, we are counter-revolutionaries: we are inverting the course of history in order to cover up the past. The unspoken in Auschwitz is not the mass murder, it is not the crime . It is the ultimate reification of people into amorphous objects, into ashes. The Western tendency towards objectification was finally realized and it was done so in the shape of an apparatus . The SS were functionaries of an extermination apparatus, and their victims functioned in function of their own annihilation. The extermination camp's program, once it started functioning, developed in an automatic fashion, autonomous from the decisions of the initial programmers, even if, as it effectively did, it contributed to the defeat of the programmers. The SS and the Jews functioned one in function of the other like cogwheels. The models for such functionality were provided by the highest of Western values: the SS behaved like “heroes” and the Jews like “martyrs”. This is an apparatus that functions at a borderline situation: objective even beyond death. What has just been said is intolerable. We cannot accept it and so we mobilize arguments against it. Good arguments. The SS behaved like criminals: they removed the gold teeth from the cadavers. The Jews behaved like victims: they rose up in the Warsaw ghetto. Such arguments are true, but they do not reach the nucleus, the “ eidos ” of the phenomenon: they do not grasp it. Although there was “normal” behavior: (theft, murder, revolt, heroism), there was also “abnormal” behavior: functionality during a borderline situation. And this is what counts. There, for the first time in the history of humanity, an apparatus was put into operation that was programmed with the most advanced techniques available, which realized the objectification of man, together with the functional collaboration of man. The previous horrors committed by Western society against other societies and against itself (and there are many) were crimes . They were violations of Western models of behavior: anti-Christian, anti-human, irrational. So that it is possible to condemn them and continue to be Western, even if the horror is so colossal, such as the enslavement of Africans. However, it is not possible to condemn Auschwitz and continue to adhere consciously to the West. Auschwitz is not a violation of Western models of behavior, it is, on the contrary, the result of the application of such models. Our culture allowed its mystifying mask to fall and must be rejected in toto if we admit that the purpose of every culture is to allow for the convivial existence of men that recognize each other mutually as subjects. However: it is not possible to reject one's own culture. It is the ground we tread . Those who seek to reject their own culture (as Nietzsche did in rejecting Judeo-Christianity), fall victim to madness. Those who reject their culture's models, are incapable of grasping the world in which they live. Cultural models are traps to catch the world. Those who seek to substitute their own models for other's (for example by shouting “Hare Krishna”) will find that such exotic models have already been caught by the very models to be substituted. There is no exit: we are condemned to use our models and to serve such models, even after they have been unmasked, if we wish to continue living. The only alternative would be to commit suicide. That is: we must continue our economic, political, scientific, artistic, philosophic activities despite Auschwitz. We must continue progressing despite everything . That is why there are those who recommend that we should seek to forget what happened, that we should repress the event. They sustain that enough has already been said and written about the subject and that it is time to “overcome” it. But such an ostrich strategy reveals itself disastrous. Because the result is that Auschwitz transfers itself from Poland of the 1940s to the post-industrial society of the future. What characterizes the extermination camp is precisely that it is not an event that can be “overcome”, because it is the first realization of an inherent virtuality within the Western project, which will repeat itself in other formats unless we become totally conscious of it. The advantage (if this is an appropriate term) that Auschwitz offers us, is to give us a concrete example of the West’s tendency towards the apparatus. For the first time in our history it is possible for us to experience concretely the utopia inherent in our culture. For the first time in our history we have the experience that utopia, no matter in what form, towards which we progress, is the extermination camp. Everywhere we can observe, as of now, the emergence of variations on the theme “Auschwitz”. Everywhere apparatus spring, just like mushrooms after a Nazi rain, from the ground that has become rotten. Certainly: such new apparatus are not externally similar to the Nazi extermination camps. Their labels are different, as are the ideologies that pretend to inspire them. Even the apparatus that admittedly envision extermination, such as the Gulags, the ones of a future nuclear war, or the ones that functioned in Vietnam, claim to be different from Auschwitz. Others claim to be “friends of mankind”, such as the scientific, technical and administrative apparatus. But such labels and such ideologies are deceptive and serve only to cover up the essence of apparatus. They are all just like Auschwitz, black boxes that function with complex inner-workings in order to realize a program. They all function according to an inertia that is inherent to them and such functionality escapes , from a certain point, the control of their initial programmers. In a final analysis such apparatuses function, all of them, towards the annihilation of all their functionaries, including their programmers. Exactly because they objectify and dehumanize man. Thus Western culture reveals itself as a project that seeks to transform itself into an apparatus. What characterizes the West is its capacity for an objectifying transcendence. Such transcendence allows for the transformation of all phenomena, including the human phenomenon, into an object of knowledge and manipulation. The space for such transcendence opened up thanks to Judeo-Christianity and resulted, in the course of our history, in science, technique and recently, in Auschwitz. The ultimate objectification of the Jews into ashes is the ultimate victory of the spirit of the West. It is social technique taken to the extreme. Certainly: the transformation of men into ashes is primitive, incipient social technique that progressively refines itself. It will be followed by less brutal objectifications, such as the robotization of society. But it does not matter which form it will assume: it will always be an objectifying manipulation of mankind. Although the apparatus of the immediate future are not necessarily incineration ovens, all will be, and not only the nuclear ones, apparatus for the annihilation of man. The Western program contains several virtualities, not only apparatus. Numerous virtualities have not yet been realized. In this sense the “history of the West” has not ended yet, the Western game continues. But all not-yet realized virtualities are infected by apparatus. That is why it has become currently impossible to engage ourselves in the “ progress of culture .” As it would be to engage ourselves in our own annihilation. We have lost our faith in our culture, in the ground we tread. That is: we have lost faith in ourselves. It is this hollow vibration that follows our steps towards the future. What remains is for us to analyze the event “Auschwitz” in all its details in order to discover the fundamental project that realized itself there for the first time, so that we may nurture the hope to project ourselves out of that project. Out of the history of the West. This is the “post- historical” climate in which we are condemned to live from hereon. NOTES 1. In Portuguese representar (to represent) also means “to act” or “to play a role.&rdquo. (shrink)

Complex systems are difficult to manage, operate and maintain. This is why we see teams of highly specialised engineers in industries such as aerospace, nuclear and subsurface. Condition based monitoring is also employed to maximise the efficiency of extensive maintenance programmes instead of using periodic maintenance. A level of automation is often required in such complex engineering platforms in order to effectively and safely manage them. Advances in Artificial Intelligence related technologies have offered greater levels of automation but this (...) potentially pivots the weight of decision making away from the operator to the machine. Implementing AI or complex algorithms into a platform can mean that the Operators’ control over the system is diminished or removed altogether. For example, in the Boeing 737 Air Max Disaster, AI had been added to a platform and removed the operators’ control of the system. This meant that the operator could not then move outside the extremely reserved, algorithm defined, “envelope” of operation. This paper analyses the challenges of AI driven condition based monitoring where there is a potential to see similar consequences to those seen in control engineering. As the future of society becomes more about algorithm driven technology, it is prudent to ask, not only whether we should implement AI into complex systems, but how this can be achieved ethically and safely in order to reduce risk to life. (shrink)

Complex platforms are very difficult to manage and maintain. This iswhy we see teams of engineers, many highly specialised, that carry outthis role for industries such as aerospace, nuclear and subsurface. It is acritical undertaking to maintain the aforementioned systems, which oftenhave components at varying degrees of degradation. To maintain com-plex systems, Condition Based Monitoring (CBM) (a type of predictivemaintenance that uses sensors to measure the status of an asset over timewhile it is in operation) is most frequently used. (...) Artificial Intelligence(AI) models that have been developed in the area of CBM are currentlynot well explained, nor well understood by users or operators. When AIis brought into a complex system we observe varying degrees of success.The level of success rests on the complexity of the system, the trainingand understanding of the end operator as well as the maintenance pro-cesses around the system. Implementing AI or complex algorithms into aplatform can mean that the Operators control over the system is dimin-ished or removed altogether. For example, in the Boeing 737 Air MaxDisaster, AI had been added to a platform and removed the operators’control of the system. This meant that the operator could not then moveoutside the extremely reserved, algorithm defined, ‘envelope’ of opera-tion, leading to loss of life. Therefore, the implementation of AI leading toany removal of operator system management in complex systems, espe-cially related to aerospace and subsurface industries, has to be consideredcarefully. In this paper we analyse the risks of removing operator systemcontrol and implementing algorithms, or AI, in complex systems. (shrink)

Evidence has recently been obtained suggesting that the accumulation of specific endogenous proteins by the nucleus is due both to facilitated transport across the envelope and intranuclear binding. Using recombinant DNA methodology, polypeptide domains containing the signals required for nuclear accumulation have been identified in several karyophilic proteins.

SummaryA more careful delineation of the ideal‐typical marriage allows the flaws in Berger and Kellner's article to be examined. These flaws stem both from a rather too easy assumption that marriages are egalitarian relationships and that equality means sameness of experience between husbands and wives, and from the use of sexist language combined with a reliance on examples drawn primarily from the husband's experience. Their claim that marriage is a crucial nomic process where individuals gain a sense of identity and (...) of stability must be modified to say that individuals go into marriage with a clear commitment to being husbands and wives and without any realization, or perhaps even the ability to realise, that the current organisation of the nuclear family can be harmful for wives. The nomic processes which take place in marriage are central to a sense of identity and stability as Berger and Kellner claim, but they are only one of many other nomic processes, one of which is accessed only through the world of paid work. For the wife in the ideal‐typical family, to give up her access to nomic processes which have contributed to her sense of who she is and to envelop herself only in the marital conversation is to reduce her power, her sense of herself and her capacity to negotiate successfully within the marital conversation. Couples who may believe in and practise equality may find themselves caught up in a structure which makes equality non‐practicable without really realising how or why this has happened.I believe the foregoing analysis has demonstrated the way in which flawed theory is a probable outcome of reasoning based only on male experience. It is possible through attention to the experience in which the theory is grounded to extend that ground to include women and thus rewrite the theory such that it makes sense for women as well as for men.The implications for equality of educational opportunityThrough a reworking of the theories that make up the knowledge base of tertiary education, female students will not only gain access to theories which do not limit and distort their experience, but they will also gain access to a different form of negotiation within the educational process itself. Currently they learn through a multitude of explicit and implicit statements and through the process of education itself, that their role is to be passive and invisible.To engage them in the process of rewriting the theories themselves is to empower them, to give them a say in what constitutes the knowledge that they have currently been excluded from. In so doing they are learning to challenge one of the most basic foundations of the existing social order because they are asserting their power to question, to interpret men's words, to assert the validity of their experience outside masculine constructions of that experience, to theorize alongside men, not from a position of subordination , but from a position of equality. (shrink)

Various proposals have been made for solving The Two Envelope Problem. But even though the problem itself is easily stated and quite simple, the proposedsolutions have not been. Some involve calculus, some involve considerations about infinite values, and some are complicated in other ways. Moreover, there is not yet any one solution that is widely accepted as correct. In addition to being notable for its simplicity and its lack of a generally agreed-upon solution, The Two Envelope Problem is (...) also notable because it demonstrates that something that has been taken to be a fundamental principle of decision theory is false. The main purpose of this paper is to propose and defend a simple solution to The Two Envelope Problem. But I also want to make a start on the project of figuring out how the relevant fundamental principle of decision theory should be revised. (shrink)

Bribing doctors for preferential treatment is rampant in the healthcare system of developing countries like Vietnam. Although bribery raises the out-of-pocket expenditures of patients, it is so common to be deemed an “envelope culture.” Given the little understanding of the underlying mechanism of the culture, this study employed the mindsponge theory for reasoning the mental processes of both patients and doctors for why they embrace the “envelope culture” and used the Bayesian Mindsponge Framework (BMF) analytics to validate our (...) reasoning. Analyzing responses from 1042 Vietnamese patients, we discovered that bribing doctors can help patients reduce the destitution risk induced by treatment. Such effect of doctor bribery remains consistent among patients that have to pay high daily costs (e.g., accommodation and subsistence fees) regardless of their employment status. Nevertheless, for patients with no or unstable jobs, their risks of destitution increase if they have to pay more thank-you money. These findings suggest that doctor bribery is an adaptive strategy for patients in an environment where the healthcare supply cannot meet the actual demand. Moreover, healthcare equity is greatly exacerbated due to the envelope culture, as vulnerable individuals are exposed to a greater threat of poverty. At the same time, those with good economic conditions get preferential treatment by paying a higher amount of thank-you money. Healthcare workers’ ethics must be the top priority for an equitable and proper healthcare system. (shrink)

This paper describes a way of defending a modification of Eckhardt's [2013] solution to the Two Envelopes Paradox. The defence is based on ideas from Arntzenius, Elga, and Hawthorne [2004].

Four variations on Two Envelope Paradox are stated and compared. The variations are employed to provide a diagnosis and an explanation of what has gone awry in the paradoxical modeling of the decision problem that the paradox poses. The canonical formulation of the paradox underdescribes the ways in which one envelope can have twice the amount that is in the other. Some ways one envelope can have twice the amount that is in the other make it rational (...) to prefer the envelope that was originally rejected. Some do not, and it is a mistake to treat them alike. The nature of the mistake is diagnosed by the different roles that rigid designators and definite descriptions play in unproblematic and in untoward formulations of decision tables that are employed in setting out the decision problem that gives rise to the paradox. The decision maker’s knowledge or ignorance of how one envelope came to have twice the amount that is in the other determines which of the different ways of modeling his decision problem is correct. Under this diagnosis, the paradoxical modeling of the Two Envelope problem is incoherent. (shrink)

This paper discusses the finite version of the two envelope paradox. (That is, we treat the paradox against the background assumption that there is only a finite amount of money in the world.).

Nuclear deterrence requires objective ethical analysis. In providing it, the authors face realities - the Soviet threat, possible nuclear holocaust, strategic imperatives - but they also unmask moral evasions - deterrence cannot be bluff, pure counterforce, the lesser evil, or a step towards disarmament. They conclude that the deterrent is unjustifiable and examine the new question of conscience that this raises for everyone.

This study endorses the use of data envelopment analysis, which uses benefit-of-the-doubt weighting to evaluate the social, economic and overall performance of social enterprises. This methodology is especially useful for creating composite indicators based on multiple outputs expressed in different measurement units, and allows for enterprise-specific weighting of the different objectives. Applying this methodology on a unique longitudinal dataset of Flemish sheltered workshops suggests that social enterprises may face different types of mission drift. Further, our results show that top-performing social (...) enterprises are more economically and socially efficient than low performers. These top performers also have a stronger economic orientation, which sheds new light on the balance between social and economic orientations in social enterprises. (shrink)

Consider this situation: Here are two envelopes. You have one of them. Each envelope contains some quantity of money, which can be of any positive real magnitude. One contains twice the amount of money that the other contains, but you do not know which one. You can keep the money in your envelope, whose numerical value you do not know at this stage, or you can exchange envelopes and have the money in the other. You wish to maximise (...) your money. What should you do?1 Here are three forms of reasoning about this situation, which we shall call.. (shrink)

Invited media scholars and journalists examine the general issue of nuclear waste, risk and the sicentific promises that were made, but not kept, about safe disposal. The mass media uncovered and reported on nuclear waste problems at Rocky Flats in Colorado and Hanford in Washington. Two environmental journalists review efforts to expose problems at these sites, how secrecy hampered reporting, and the effects of media coverage on nearby residents. An environmental communications scholar evaluates media coverage, the role of (...) the U.S. Department of Energy, and the impact of secrecy on public risk perceptions and attitudes toward government nuclear waste policies. (shrink)

Previous claims to have resolved the two-envelope paradox have been premature. The paradoxical argument has been exposed as manifestly fallacious if there is an upper limit to the amount of money that may be put in an envelope; but the paradoxical cases which can be described if this limitation is removed do not involve mathematical error, nor can they be explained away in terms of the strangeness of infinity. Only by taking account of the partial sums of the (...) infinite series of expected gains can the paradox be resolved. (shrink)

Nuclear power has never been free from the stifling involvement of government. Heavy regulation has reduced the ability of entrepreneurs to develop and provide new means for the generation of energy using nuclear fuel. The strict parameters dictated by government officials are based upon outdated technology, an improper regulatory philosophy, and preclude innovation in nuclear power generation. Anti-market environmentalists misunderstand the implications of a free market in nuclear power and argue against it based on problems that (...) are actually caused by government involvement. Our position is neither for nor against nuclear power. We advocate a hands-off policy where the nuclear industry is left to its own devices, free from governmental regulations and subsidies: free to succeed or fail on its own. Thus, our position is neither right-wing conservative (removing regulations), nor left-wing liberal (removing subsidies). Very much to the contrary of both positions, we propose a free-market in nuclear power. (shrink)

There has been much discussion on the two-envelope paradox. Clark and Shackel (2000) have proposed a solution to the paradox, which has been refuted by Meacham and Weisberg (2003). Surprisingly, however, the literature still contains no axiomatic justification for the claim that one should be indifferent between the two envelopes before opening one of them. According to Meacham and Weisberg, "decision theory does not rank swapping against sticking [before opening any envelope]" (p. 686). To fill this gap in (...) the literature, we present a simple axiomatic justification for indifference, avoiding any expectation reasoning, which is often considered problematic in infinite cases. Although the two-envelope paradox assumes an expectation-maximizing agent, we show that analogous paradoxes arise for agents using different decision principles such as maximin and maximax, and that our justification for indifference before opening applies here too. (shrink)

A well known theorem proved by J. Paris and H. Friedman states that BΣn +1 is a Πn +2-conservative extension of IΣn . In this paper, as a continuation of our previous work on collection schemes for Δn +1-formulas , we study a general version of this theorem and characterize theories T such that T + BΣn +1 is a Πn +2-conservative extension of T . We prove that this conservativeness property is equivalent to a model-theoretic property relating Πn-envelopes and (...) Πn-indicators for T . The analysis of Σn +1-collection we develop here is also applied to Σn +1-induction using Parsons' conservativeness theorem instead of Friedman-Paris' theorem.As a corollary, our work provides new model-theoretic proofs of two theorems of R. Kaye, J. Paris and C. Dimitracopoulos : BΣn +1 and IΣn +1 are Σn +3-conservative extensions of their parameter free versions, BΣ–n +1 and IΣ–n +1. (shrink)

A technique for the bilateral activation of neural nets that leads to a functional asymmetry of two simulated ''cerebral hemispheres'' is described. The simulation is designed to perform object recognition, while exhibiting characteristics typical of human consciousness-specifically, the unitary nature of conscious attention, together with a dual awareness corresponding to the ''nucleus'' and ''fringe'' described by William James (1890). Sensory neural nets self-organize on the basis of five sensory features. The system is then taught arbitrary symbolic labels for a small (...) number of similar stimuli. Finally, the trained network is exposed to nonverbal stimuli for object recognition, leading to Gaussian activation of the ''sensory'' maps-with a peak at the location most closely related to the features of the external stimulus. ''Verbal'' maps are activated most strongly at the labeled location that lies closest to the peak on homologous sensory maps. On the verbal maps activation is characterized by both excitatory and inhibitory Gaussians (a Mexican hat), the parameters of which are determined by the relative locations of the verbal labels. Mutual homotopic inhibition across the ''corpus callosum'' then produces functional cerebral asymmetries, i.e., complementary activation of homologous ''association'' and ''frontal'' maps within a common focus of attention-a nucleus in the left hemisphere and a fringe in the right hemisphere. An object is recognized as corresponding to a known label when the total activation of both hemispheres (nucleus plus fringe) is strongest for that label. The functional dualities of the cerebral hemispheres are discussed in light of the nucleus/fringe asymmetry. (shrink)

This chapter contains sections titled: Introduction Ethics and the Use of Nuclear Weapons Ethics and the Possession of Nuclear Weapons Toward a Theory of Justified Deterrence Applying Justified Deterrence Theory References and Further Reading.

In this article, I argue that there is no compelling therapeutic ‘need’ for human nuclear genome transfer to prevent mitochondrial diseases caused by mtDNA mutations. At most there is a strong interest in this technology on the part of some women and couples at risk of having children with mitochondrial disease, and perhaps also a ‘want’ on the part of some researchers who see the technology as a useful precedent – one that provides them with ‘a quiet way station’ (...) in which to refine the micromanipulations techniques essential for other human germline interventions and human cloning. In advance of this argument, I review basic information about mitochondrial disease and novel genetic strategies to prevent the transmission of mutated mitochondria. Next, I address common features of contemporary debates and discussions about so-called mitochondrial replacement. First, I contest the cliché that science-and-technology is fast outpacing ethics. Second, I dispute the accuracy of the term ‘mitochondrial replacement’. Third, I provide a sustained critique of the purported ‘need’ for genetically-related children. In closing, I call into question the mainly liberal defense of human nuclear genome transfer. I suggest an alternative frame of reference that pays particular attention to issues of social justice. I conclude that our limited resources should be carefully expended in pursuit of the common good, which does not include pandering to acquired desires. (shrink)