Bacterial checkpoints, analogous to those proposed to exist in eukaryotic cells, offer insights into the definition of a checkpoint. Examination of bacterial “checkpoint” or arrest phenomena illustrate problems with a too‐casual application of the checkpoint idea to eukaryotic phenomena. The question raised here is whether there are cellular processes that “check” whether a cellular process is completed. It is possible that many eukaryotic “checkpoints” may not have “checking” functions. Some of the ubiquitous checkpoint phenomena widely described (...) may be merely the result of the inherent incompleteness of earlier events preventing the initiation of subsequent events. BioEssays 28: 1035–1039, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

How chromatin bridges are detected by the abscission checkpoint during mammalian cell division is unknown. Here, we discuss recent findings from our lab showing that the DNA topoisomerase IIα (Top2α) enzyme binds to catenated (“knotted”) DNA next to the midbody and forms abortive Top2‐DNA cleavage complexes (Top2ccs) on chromatin bridges. Top2ccs are then processed by the proteasome to promote localization of the DNA damage sensor protein Rad17 to Top2‐generated double‐strand DNA ends on DNA knots. In turn, Rad17 promotes local (...) recruitment of the MRN protein complex and downstream ATM‐Chk2‐INCENP signaling to delay abscission and prevent chromatin bridge breakage in cytokinesis. (shrink)

In nature, cells face a variety of stresses that cause physical damage to the plasma membrane and cell wall. It is well established that evolutionarily conserved cell cycle checkpoints monitor various cellular perturbations, including DNA damage and spindle misalignment. However, the ability of these cell cycle checkpoints to sense a damaged plasma membrane/cell wall is poorly understood. To the best of our knowledge, our recent paper described the first example of such a checkpoint, using budding yeast as a model. (...) In this review, we will discuss this important question as well as provide hypothetical explanations to be tested in the future. (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)

The ATM protein kinase is centrally involved in the cellular response to ionizing radiation (IR) and other DNA double‐strand‐break‐inducing insults. Although it has been well established that IR exposure activates the ATM kinase domain, the actual mechanism by which ATM responds to damaged DNA has remained enigmatic. Now, a landmark paper provides strong evidence that DNA‐strand breaks trigger widespread activation of ATM through changes in chromatin structure.1 This review discusses a checkpoint activation model in which chromatin perturbations lead to (...) the conversion of inactive ATM domains to phosphorylated, active ATM monomers. The new findings underscore the critical importance of epigenetic events in genome function and surveillance in mammalian cells. BioEssays 25:627–630, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Dependency relationships within the cell cycle allow cells to arrest the cycle reversibly in response to agents or conditions that interfere with specific aspects of its normal progression. In addition, overlapping pathways exist which also arrest the cell cycle in response to DNA damage. Collectively, these control mechanisms have become known as checkpoints. Analysis of checkpoints is facilitated by the fact that dependency relationships within the cell cycle, such as the dependency of mitosis on the completion of DNA synthesis, and (...) the DNA damage checkpoint can be separated genetically. In fission yeast, Schizosaccharomyces pombe, the dependency of mitosis on prior completion of DNA synthesis is mediated through tyrosine‐15 phosphorylation of the ubiquitous mitotic regulator p34cdc2. In contrast, the arrest of mitosis caused by DNA damage acts through a separate mechanism that appears to be independent of tyrosine‐15 phosphorylation. Despite these distinct interactions with the mitotic machinery, the majority of fission yeast mutants that are deficient in mitotic arrest after DNA damage are also unable to respond to inhibition of DNA synthesis. In this essay we survey the current knowledge concerning feedback controls and checkpoints within fission yeast and relate this to information derived from other systems. (shrink)

Cell cycle arrest in M phase can be induced by the failure of a single chromosome to attach properly to the mitotic spindle. The same cell cycle checkpoint mediates M phase arrest when cells are treated with drugs that either disrupt or hyperstabilize spindle microtubules. Study of yeast mutants that fail to arrest in the presence of microtubule disruptors identified a set of genes important in this checkpoint pathway. Two recent papers report the cloning of human and Xenopus (...) homologues of one of these yeast genes, called MAD2 (for mitotic arrest deficient‐2)(1,2). Introduction of antibodies to the MAD2 protein into living mammalian cells or Xenopus egg extracts abrogates the M phase arrest induced by microtubule inhibitors. This and other recent developments suggest a model for the M phase checkpoint in which unattached kinetochores inhibit the ubiquitination of proteins whose proteolysis is necessary for chromatid separation and exit from mitosis. (shrink)

Three major aspects of G1 regulation acting at START in fission yeast are discussed in this review. Firstly, progression towards S phase in the mitotic cycle. This is controlled by the activation of transcription complexes at START which cause cell cycle‐dependent activation of genes required for DNA synthesis. The second aspect is the regulation of developmental fate occurring during G1. Passage through START appears to inhibit sexual differentiation because the meiotic and mitotic pathways are mutually exclusive. This is brought about (...) because the meiotic pathway is inhibited by the same gene functions that are required for S phase onset. Thirdly, distinct checkpoint, or dependency, controls operate both pre‐ and post‐START in the mitotic cycle to inhibit mitosis in the absence of replicated DNA, and also to limit rounds of DNA replication to one per cell cycle. (shrink)

The concept of regulatory ‘checkpoints’ in the eukaryotic cycle has proved to be a fruitful one. Here, its applicability to the bacterial cell cycle is examined. A primitive DNA damage checkpoint operates in E. coli such that, after exposure to ultraviolet light, while excision repair occurs, chromosome replication continues very slowly with the production of discontinuous daughter strands. The slower the rate of excision of photoproducts, the greater the delay before the normal rate of DNA replication is restored, the (...) additional time for repair ensuring that normal survival is maintained. A model is proposed in which replication rate is controlled by the ratio of RecAcoated to uncoated single stranded regions of DNA in the replication fork. There are also two cell division inhibitors SulA (=SfiA) and SfiC under the control of the SOS system and sensitive to DNA damage, but they are irrelevant to the survival of wild‐type bacteria under normal conditions. In strains where SulA and SfiC do not operate, inhibition is not influenced by the rate of excision repair and so fails one of the criteria for a DNA damage checkpoint, namely the monitoring of the DNA for the level of residual damage. (shrink)

T cells, which are derived from hematopoietic stem cells (HSCs), are the most important components of adaptive immune system. Based on the expression of αβ and γδ receptors, T cells are mainly divided into αβ and γδ T cells. In the thymus, they share common progenitor cells, while undergoing a series of well‐characterized and different developmental processes. N6‐Methyladenosine (m6A), one of the most abundant modifications in mRNAs, plays critical roles in cell development and maintenance of function. Recently, we have demonstrated (...) that the depletion of m6A demethylase ALKBH5 in lymphocytes specifically induces an expansion of γδ T cells through the regulation of Jag1/Notch2 signaling, but not αβ T cells, indicating a checkpoint role of ALKBH5 and m6A modification in the early development of γδ T cells. Based on previous studies, many key pathway molecules, which exert dominant roles in γδ T cell fate determination, have been identified as the targets regulated by m6A modification. In this review, we mainly summarize the potential regulation between m6A modification and these key signaling molecules in the γδ T cell lineage commitment, to provide new perspectives in the checkpoint of γδ T cell development. (shrink)

This article examines the Israeli women’s movement, Checkpoint Watch, as a case from which to argue that the strategic use of the politics of care can challenge existing social and political orders. The conscious decision of activists to direct the practice of care toward the ‘wrong’ subject – toward Palestinians rather than Israeli soldiers – challenges the dehumanisation of Palestinians in Israeli society. While the politics of care may call the political order into question, the service of a behaviour (...) that is considered essentialist may paradoxically reinforce the existing social order. I argue that the politics of care has the potential to challenge both the political and the social order, though not simultaneously. (shrink)

In many animals, early development of the embryo is characterized by synchronous, biphasic cell divisions. These cell divisions are controlled by maternally inherited proteins and RNAs. A critical question in developmental biology is how the embryo transitions to a later pattern of asynchronous cell divisions and transfers the prior maternal control of development to the zygotic genome. The most‐common model regarding how this transition from maternal to zygotic control is regulated posits that this is a consequence of the limitation of (...) maternal gene products, due to their titration during early cell divisions. Here we discuss a recent article by Crest et al.1 that instead proposes that the balance of Cyclin‐dependent Kinase 1 and Cyclin B (Cdk1‐CycB) activity relative to that of the Drosophila checkpoint kinase Chk1 determines when asynchronous divisions begin. BioEssays 29:949–952, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Together, DNA repair and checkpoint responses ensure the integrity of the genome. Coordination of cell cycle checkpoints and DNA repair are especially important following genotoxic radiation or chemotherapy, during which unusually high loads of DNA damage are sustained. In mammalian cells, the checkpoint kinase, Cds1 (also known as Chk2) is activated by ATM in response to DNA damage. The role of Cds1 as a checkpoint kinase depends on its ability to phosphorylate cell cycle regulators such p53, Cdc25 (...) and Brca1. A role for Cds1 in repair is suggested by the finding that it interacts with the Holliday junction resolving activity Mus81. This review focuses on the many questions generated by recent progress in understanding the function and regulation of human Cds1. BioEssays 24:502–511, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Reviewed by:Consistently Pro-Life: The Ethics of Bloodshed in Ancient Christianity by Rob Arner, and: Christ at the Checkpoint: Theology in the Service of Justice and Peace ed. by Paul Alexander, and: Becoming Nonviolent Peacemakers: A Virtue Ethic for Catholic Social Teaching and US Policy by Eli Sarasan McCarthyBrian D. BerryReview of Consistently Pro-Life: The Ethics of Bloodshed in Ancient Christianity ROB ARNER Eugene, OR: Pickwick, 2010. 136 pp. (...) $15.56Review of Christ at the Checkpoint: Theology in the Service of Justice and Peace EDITED BY PAUL ALEXANDER Eugene, OR: Pickwick, 2012. 182 pp. $19.80Review of Becoming Nonviolent Peacemakers: A Virtue Ethic for Catholic Social Teaching and US Policy ELI SARASAN MCCARTHY Eugene, OR: Pickwick, 2012. 259 pp. $27.00In Consistently Pro-Life, Rob Arner (who teaches at Chestnut Hill College in Philadelphia) makes the case that Christians should not kill other human beings—regardless of the circumstances. Taking as his point of departure the vigilante killing of abortion doctor George Tiller in Wichita, Kansas, in 2009, he argues not only that abortion is always morally impermissible but so also is [End Page 217] the murder of abortion doctors and the use of the death penalty to punish those who murder them. In addition, he turns to the early church fathers to contend that, prior to Constantine, “without exception, the church strongly condemned the taking of human life in any form whatsoever”—thus rejecting abortion and infanticide, the blood sport of the Roman games, suicide, and killing in war (120). This was because the New Testament witness to Jesus and his death on the cross required early Christians to view “the means as just as important, if not more important, than the ends” (xiii).Arner supplements this deontological argument for Christian pacifism, which he learned from John Howard Yoder, with a brief consideration of the virtue of patience cultivated in the early churches, reflecting the influence of Stanley Hauerwas on his thought. This “cardinal virtue” connoting “longsuffering, forbearance, patient endurance”—as found in Jesus’s teaching in the Sermon on the Mount (Mt 5:38–48)—enabled early Christians to practice non-violent resistance “deferring personal revenge in favor of God’s vindicating justice” (98). If Christians were to adopt this same consistently pro-life ethic today, argues Arner, it would “lead to greater healing and peace in our blood-soaked world” (121). The book closes with three appendices—one of which is a chart of terminology that dehumanizes vulnerable victims, including unborn human beings. Unfortunately, the book does not have an index.Christ at the Checkpoint, edited by Paul Alexander (professor of Christian ethics and public policy at the Palmer Theological Seminary of Eastern University), includes thirteen plenary addresses delivered at a conference on the Arab-Israeli conflict organized by Palestinian Evangelical Christians at Bethlehem Bible College in March 2010. Almost all of the contributors to this volume—including biblical scholars, theologians, ethicists, pastors, activists, and others—criticize the ideology of Christian Zionism and its support of a theology of dispensationalism that, in their view, distorts the scriptures and fosters violence rather than reconciliation between the Israelis and the Palestinians. In his own presentation titled “What Can Pentecostals and Charismatics Do for Peace with Justice in Israel and Palestine?,” Alexander—who describes himself as a former “one-sided” Christian Zionist who later discovered the writings of Yoder and Hauerwas—appeals to Jesus’s teaching in the Sermon on the Mount and urges Pentecostals to create church communities “that cultivate persons of character and conviction, who through habits, practices, and action live out the core of our faith” (69). Along with being faithful to the “greater challenges” of love, mercy, compassion, and forgiveness, he argues that they should publicly declare that Jesus does not want Israel to continue the occupation of Palestine, and they should engage in the “easier tasks” of promoting human rights, lending support to United Nations Resolutions, and working toward a two-state solution (72). “The time has come in human history,” writes Alexander, “for Pentecostals to speak and act prophetically regarding this present injustice … [End Page 218] and to use every nonviolent weapon in our arsenal—stories, preaching... (shrink)

Graphical AbstractRecent evidence indicates that branched actin might control cell progression through G1 in addition to lamellipodium protrusion.

Factors affecting transcriptional elongation have been characterized extensively in in vitro, single cell (yeast) and cell culture systems; however, data from the context of multicellular organisms has been relatively scarce. While studies in homogeneous cell populations have been highly informative about the underlying molecular mechanisms and prevalence of polymerase pausing, they do not reveal the biological impact of perturbing this regulation in an animal. The core components regulating pausing are expressed in all animal cells and are recruited to the majority (...) of genes, however, disrupting their function often results in discrete phenotypic effects. Mutations in genes encoding key regulators of transcriptional pausing have been recovered from several genetic screens for specific phenotypes or interactions with specific factors in mice, zebrafish and flies. Analysis of these mutations has revealed that control of transcriptional pausing is critical for a diverse range of biological pathways essential for animal development and survival. (shrink)

Homologous recombination (HR) is required to protect and restart stressed replication forks. Paradoxically, the Mrc1 branch of the S phase checkpoints, which is activated by replicative stress, prevents HR repair at breaks and arrested forks. Indeed, the mechanisms underlying HR can threaten genome integrity if not properly regulated. Thus, understanding how cells avoid genetic instability associated with replicative stress, a hallmark of cancer, is still a challenge. Here I discuss recent results that support a model by which HR responds to (...) replication stress through replicative and repair activities that operate at different stages of the cell cycle (S and G2, respectively) and in distinct subnuclear structures. Remarkably, the replication checkpoint appears to control this scenario by inhibiting the assembly of HR repair centers at stressed forks during S phase, thereby avoiding genetic instability. (shrink)

Cancer cells seem to exploit mechanisms that evolve as part of physiological tolerance, which is a complementary and often beneficial form of defense. The study of physiological systems of tolerance can therefore provide insights into the development of a state of host tolerance of cancer, and how to break it. Analysis of these models has the potential to improve our understanding of existing immunological therapeutic targets, and help to identify future targets and rational therapeutic combinations. The treatment of cancer with (...) immune checkpoint inhibitors aims to reverse the progression to tolerance of cancer, and achieve an immunogenic, rather than tolerogenic, homeostasis. Broadening the efficacy and durability of checkpoint inhibitors focuses on reversing tolerance and stimulating immunogenicity in the cancer, host, and environment. Two examples of important physiological states of tolerance that may inform tolerance of cancer are microbial infection and placental reproduction. These states of tolerance result from bilateral shaping of host and non‐self, akin to immunoediting in cancer, and offer reliable models to study the immune tolerance paradigm. (shrink)

The human spindle and kinetochore associated complex is required for proper mitotic progression. Extensive studies have demonstrated its important functions in both stable kinetochore-microtubule interactions and spindle checkpoint silencing. We suggest a model to explain how various Ska functions might be fulfilled by distinct pools of Ska at kinetochores. The Ndc80-loop pool of Ska is recruited by the Ndc80 loop, or together with some of its flanking sequences, and the recruitment is also dependent on Cdk1-mediated Ska3 phosphorylation. This pool (...) seems to play a more important role in silencing the spindle checkpoint than stabilizing kinetochore-microtubule interactions. In contrast, the Ndc80-N-terminus pool of Ska is recruited by the N-terminal domains of Ndc80 and appears to be more important for stabilizing kinetochore-microtubule interactions. Here, we review and discuss the evidence that supports this model and suggest further experiments to test the functioning mechanisms of the Ska complex. The human spindle and kinetochore associated complex plays essential functions in proper mitotic progression by promoting stable kinetochore-microtubule interactions and spindle checkpoint silencing. We propose that “distinct pools” of Ska—the Ndc80-loop and Ndc80-N-terminus pools—might fulfill these various functions. (shrink)

The fate of cells arrested in mitosis by antimitotic compounds is complex but is influenced by competition between pathways promoting cell death and pathways promoting mitotic exit. As components of both of these pathways are regulated by Cdc20‐dependent degradation, I hypothesize that variations in Cdc20 protein levels, rather than mutations in checkpoint genes, could affect cell fate during prolonged mitotic arrest. This hypothesis is supported by experiments where manipulation of Cdc20 levels affects the response to antimitotic compounds. The observed (...) differences in Cdc20 levels between cell lines likely reflects differences in the rate of synthesis or degradation of the protein; therefore, understanding these pathways at a molecular level could pave the way for modulating the activity of Cdc20, in turn presenting novel therapeutic possibilities. (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)

Movement and positional control of mitochondria and other organelles are coordinated with cell cycle progression in the budding yeast, Saccharomyces cerevisiae. Recent studies have revealed a checkpoint that inhibits cytokinesis when there are severe defects in mitochondrial inheritance. An established checkpoint signaling pathway, the mitotic exit network (MEN), participates in this process. Here, we describe mitochondrial motility during inheritance in budding yeast, emerging evidence for mitochondrial quality control during inheritance, and organelle inheritance checkpoints for mitochondria and other organelles.

Vulnerability and resistance have often been seen as opposites, with the assumption that vulnerability requires protection and the strengthening of paternalistic power at the expense of collective resistance. Focusing on political movements and cultural practices in different global locations, including Turkey, Palestine, France, and the former Yugoslavia, the contributors to Vulnerability in Resistance articulate an understanding of the role of vulnerability in practices of resistance. They consider how vulnerability is constructed, invoked, and mobilized within neoliberal discourse, the politics of war, (...) resistance to authoritarian and securitarian power, in LGBTQI struggles, and in the resistance to occupation and colonial violence. The essays offer a feminist account of political agency by exploring occupy movements and street politics, informal groups at checkpoints and barricades, practices of self-defense, hunger strikes, transgressive enactments of solidarity and mourning, infrastructural mobilizations, and aesthetic and erotic interventions into public space that mobilize memory and expose forms of power. Pointing to possible strategies for a feminist politics of transversal engagements and suggesting a politics of bodily resistance that does not disavow forms of vulnerability, the contributors develop a new conception of embodiment and sociality within fields of contemporary power. -/- Contributors. Meltem Ahiska, Athena Athanasiou, Sarah Bracke, Judith Butler, Elsa Dorlin, Basak Ertür, Zeynep Gambetti, Rema Hammami, Marianne Hirsch, Elena Loizidou, Leticia Sabsay, Nükhet Sirman, Elena Tzelepis. (shrink)

The informativity of a computational model of language acquisition is directly related to how closely it approximates the actual acquisition task, sometimes referred to as the model's cognitive plausibility. We suggest that though every computational model necessarily idealizes the modeled task, an informative language acquisition model can aim to be cognitively plausible in multiple ways. We discuss these cognitive plausibility checkpoints generally and then apply them to a case study in word segmentation, investigating a promising Bayesian segmentation strategy. We incorporate (...) cognitive plausibility by using an age-appropriate unit of perceptual representation, evaluating the model output in terms of its utility, and incorporating cognitive constraints into the inference process. Our more cognitively plausible model shows a beneficial effect of cognitive constraints on segmentation performance. One interpretation of this effect is as a synergy between the naive theories of language structure that infants may have and the cognitive constraints that limit the fidelity of their inference processes, where less accurate inference approximations are better when the underlying assumptions about how words are generated are less accurate. More generally, these results highlight the utility of incorporating cognitive plausibility more fully into computational models of language acquisition. (shrink)

The paper explores Quine's ?naturalized epistemology?, investigating whether its adoption would prevent the description or vindication of normative standards standardly employed in regulating beliefs and inquiries. Quine's defence of naturalized epistemology rejects traditional epistemological questions rather than using psychology to answer them. Although one could persuade those sensitive to the force of traditional epistemological problems only by employing the kind of argument whose philosophical relevance Quine is committed to denying, Quine can support his view by showing how scientific inquiry need (...) not confront any evaluative issues which cannot be addressed in naturalistic terms. A survey of Quine's own epistemological writings supports this account of his position: naturalized epistemology, it is argued, requires acceptance of the shallowness of epistemic reflection, and traditional epistemology employs general epistemic norms and principles which Quine endeavours to show that we can do without. The closing sections of the paper argue that Quine can consistently resist recent criticisms by Alvin Plantinga in spite of the fact that an unsympathetic reader could reasonably be unimpressed by this resistance. Finally, an attempt is made to understand the normative role of Quine's empiricism and of his claim that prediction is the checkpoint of inquiry. (shrink)

During tumor evolution, cancer cells use the tumor‐stroma crosstalk to reorganize the microenvironment for maximum robustness of the tumor. The success of immune checkpoint therapy foretells a new cancer therapy paradigm: an effective cancer treatment should not aim to influence the individual components of super complex intracellular interactomes (molecular targeting), but try to disrupt the intercellular interactions between cancer and stromal cells, thus breaking the tumor as a whole. Arguments are provided in favor of a hypothesis that such interactions (...) include formation of synapse‐like structures (interfaces) where the interacting cells are located at a distance of ∼10–15 nm. Within these interfaces, molecules initiating and strengthening the interaction are organized, and allow optimum cross‐signaling; a very confined intercellular space facilitates the concentration of secreted cytokines, enhancing the paracrine cross‐communication. These features of tumors form a druggable cancer hallmark the tumor‐stroma symbiotic crosstalk—which represents a new target for efficient cancer drug discovery. (shrink)

Looking at one site, the Israeli checkpoints in the occupied Palestinian territory, this article seeks to understand the mechanisms by which violence can present itself as justifiable (or justified), even when it materializes within frames presumably set to annul it. We look at the checkpoints as a condensed microcosmos operating within two such frames. One is the prolonged Israeli-Palestinian ‘peace process’ (the checkpoints became a primary technology of control in the period following the beginning of the peace process), and the (...) other is regulatory power (disciplinary and biopower), which in the Foucauldian framework presumably sidelines the violent form which sovereign power takes. We argue that the checkpoints, which dissect the Palestinian occupied territories into dozens of enclaves and which are one of the most effective and destructive means of control within the current stage of occupation, can be seen as more than obstacles in the way of Palestinian movement; we suggest that they also function as corrective technologies that are meant to fail. It is with this failure that violence can appear as justified. In order to show the operation of this embedded failure, we examine one mechanism operating within the checkpoints: ‘the imaginary line’. The imaginary line is both a component within, and an emblem of a mode of control that constantly undoes itself in order to summon violence. Since it is never visibly marked in the physical space, the imaginary line is bound to be unintentionally crossed, thereby randomly rendering Palestinians as ‘transgressors’ of the rule and thus facilitating eruptions of violence by the soldiers stationed at the checkpoints. This article proposes an analysis of this hidden demarcation of space in order to question the different relations between subjects and power which it both assumes and constitutes. (shrink)

Nowadays, the concepts of soldier and war have changed due to terrorism and the war on terrorism. According to the literature, to prevent terrorism, it is possible to use more violence, but how can we grant the safety of many versus the dignity of a few? In Israel, in order to protect civilians against possible terrorist attacks, Palestinian ambulances that would reach the Israeli hospitals (or the Palestinian hospitals in East Jerusalem) must be quickly controlled. However, many times, at the (...) checkpoint, patients have to wait for an Israeli vehicle that will take them to Israel. This procedure causes many delays in medical emergency. How to avoid that terrorists may receive better care than Palestinian civilians may just because they are already on the Israeli side of the Separation Wall? How is it possible to ensure the life and safety of many, without denying the right to healthcare to somebody? How to decide when the State requirements conflict with traditional medical duties? Is it acceptable to provide health care to a terrorist? What should be done when it is uncertain whether the ambulance transports weapons besides patients? These questions call upon the core role of the doctor and of the medical profession: taking care of all sick persons. The care is the starting point of ethics. If we do not care about other human beings we do not have a real moral comprehension of any human ideal or action. For this reason we can say that the care is the premise of morality. The rights of all citizens, including the claim to public security, grounds on the care for each individual who needs help. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Kennedy Institute of Ethics Journal 11.4 (2001) 391-400 [Access article in PDF] Bioethics Inside the Beltway A Shooting on Capitol Hill: "The Ruby Satellite System," Mental Illness, and Failure of the American Legal System Peter J. Cohen On 24 July 1998, Russell Eugene Weston, Jr., stormed the United States Capitol, forced his way through a security checkpoint, bypassed a metal detector, and entered the office complex of Representative (...) Tom DeLay (R-TX), the House Majority Whip (Weil 1998). During this period of terror, he shot and killed two officers of the Capitol Police and seriously wounded another as they attempted to end his foray. 1 Weston was severely wounded by several Capital police officers and taken into custody. After being treated for his injuries, he was incarcerated in the District of Columbia. 2On 5 May 1999, Weston was transferred to the Federal Correctional Institute in Butner, North Carolina (United States v. Weston, 69 F. Supp. 2d 99 (D.D.C. 1999), 103), where he remains to this day. He has neither been brought to trial nor received appropriate psychiatric therapy, but continues to be warehoused "in solitary confinement under constant observation... in a psychotic state (United States v. Weston, 255 F.3d 873; LEXIS 16851 (U.S. App. 2001b), 3-4 [LEXIS]). I will briefly detail the legal events responsible for this mad situation and suggest alternative actions that should have been taken at the very onset of the case. Early Chronology Although overtly the crime appeared to be senseless and without any conceivable motivation, Weston believed that his acts were justified and necessary. The story he told to the court-appointed forensic psychiatrist, Sally C. Johnson, M.D., 3 was that while working for NASA in the early 1980s, he had developed a "Ruby Satellite System," a powerful machine that could reverse time. With access to this system, nothing was permanent--the user could simply reverse time and exit from the current scene. However, the "System" was now controlled by cannibals who were developing and spreading "Black Heva," the deadliest disease known to [End Page 391] humankind, similar to HIV or the plague. It resulted from human corpses rotting and turning black. Time was running out, and Weston believed he had to return to override the "Ruby Satellite System" in the Capitol so that he could stem the spread of "Black Heva" and prevent world calamity. He believed that if he were tried, convicted, and even executed, he could simply time reverse himself, place himself in a safe within the Capitol, and subsequently resume his life at whatever point he chose (United States v. Weston, 206 F.3d 9 (D.C. Cir. 2000), 19-20).On 22 April 1999, the district court accepted Dr. Johnson's diagnosis that Weston suffered from paranoid schizophrenia, the symptoms of which were so severe that he would be incapable of understanding the proceedings against him and of assisting in his own defense. On this basis, the court had no difficulty in finding him incompetent to stand trial (U.S. v. Weston 1999, 102).At Weston's initial hearing, Dr. Johnson had testified that medication would be efficacious in treating Weston's delusions: [T]he standard of care in someone suffering from this type of symptom picture would be to treat them with medication.... [T]here is a good likelihood that he'll have a positive response, positive in the sense that his symptoms will diminish in response to treatment.... The potential benefits to treating the defendant far outweigh the risks.... (U.S. v. Weston 1999, 108) The defense presented no expert testimony refuting Dr. Johnson's presentation. The district court then ordered that Weston begin receiving medication in order to render him nondangerous and competent for trial (U.S. v. Weston 1999, 108-9). The Problem Weston refused to be medicated! 4 He has continued to claim that the administration of antipsychotic drugs against his will would violate his Fifth Amendment due process liberty interest in avoiding unwanted bodily intrusion and implicated... (shrink)

Abstractp53 is a multifunctional protein which plays a role in modulating gene transcription, policing cell cycle checkpoints, activating apoptosis, controlling DNA replication and repair, maintaining genomic stability and responding to genetic insults. Mutation of the p53 gene confers the single greatest known selective advantage favoring cancer formation. Point mutations result not only in the loss of tumor suppressor functions, but also in the gain of tumor promotion functions. These dual circumstances may be unique to p53 and, in part, could explain (...) the relatively powerful force behind this selection pressure. General mechanisms of gain of function by mutated p53 may include alteration in transcriptional modulation and newly acquired targets for transcriptional regulation and protein binding. Despite the direct significance of p53 mutations, loss of the remaining wild‐type allele is usually required for the formation of tumors in the natural setting. Novel applications of the basic scientific knowledge of p53 could lead to an improvement in cancer treatment, hopefully in the not so distant future. (shrink)

Dogs are known for their incredible ability to detect odours, extracting them from a “complex” environment and recognising them. This makes sniffer dogs precious assets in a broad variety of security applications. However, their use is subject to some intrinsic restrictions. Dogs can only be trained to a limited set of applications, get tired after a relatively short period, and thus require a high turnover. This has sparked a drive over the past decade to develop artificial sniffer devices—generally known as (...) “chemical sniffers” or “electronic noses”—able to complement and possibly replace dogs for some security applications. Such devices have been already deployed, or are intended to be deployed, at borders, airports and other critical installation security checkpoints. Similarly to dogs, they are adopted for detecting residual traces that indicate either the presence of, or recent contact with, substances like drugs and explosives. It goes without saying that, as with sniffer dogs, the use of artificial sniffer devices raises many sensitive issues. Adopting an ethical and legal perspective, the present paper discusses the privacy and data protection implications of the possible deployment of a hand-held body scanning sniffer for screening passengers at EU airport security checkpoints. (shrink)

Chromosome transmission in S. cerevisiae requires the activities of many structural and regulatory proteins required for the replication, repair, recombination and segregation of chromosomal DNA, and co‐ordination of the chromosome cycle with progression through the cell cycle. An important structural domain on each chromosome is the kinetochore (centromere DNA and associated proteins), which provides the site of attachment of chromosomes to the spindle microtubules. Stoler et al.(1) have recently reported the cloning of an essential gene CSE4, mutations in which cause (...) chromosome nondisjunction of a marked chromosome bearing a centromere DNA mutation. The cse4–1 mutation causes cells to arrest in the G2/M phase of the cell cycle with a 2N DNA content in a RAD9 checkpoint‐independent manner. The carboxyl terminus of Cse4p and the human centromere‐localized protein CENP‐A have a high degree of homology to the C‐terminal domain of histone H3. Since both CENP‐A and Cse4p also have biochemical properties similar to histones H3 and H4, it is tempting to speculate that these histone H3‐like proteins are components of specialized nucleosomes, a class of which may be unique to the centromeres. (shrink)

DNA double‐strand breaks (DSBs) are extremely hazardous lesions for all DNA‐bearing organisms and the mechanisms of DSB repair are highly conserved. In the eukaryotic mitotic cell cycle, DSBs are often present following DNA replication while, in meiosis, hundreds of DSBs are generated as a prelude to the reshuffling of the maternally and paternally derived genomes. In both cases, the DSBs are repaired by a process called homologous recombinational repair (HRR), which utilises an intact DNA molecule as the repair template. Mitotic (...) and meiotic HRR are managed by ‘checkpoints’ that inhibit cell division until DSB repair is complete. Here we attempt to summarise the substantial recent progress in understanding the checkpoint management of HRR in mitosis (focussing mainly on mammals) and then go on to use this information as a framework for understanding the presumed checkpoint management of HRR in mammalian meiosis. BioEssays 29:974–986, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Double strand break (DSB) repair is suppressed during mitosis because RNF8 and downstream DNA damage response (DDR) factors, including 53BP1, do not localize to mitotic chromatin. Discovery of the mitotic kinase‐dependent mechanism that inhibits DSB repair during cell division was recently reported. It was shown that restoring mitotic DSB repair was detrimental, resulting in repair dependent genome instability and covalent telomere fusions. The telomere DDR that occurs naturally during cellular aging and in cancer is known to be refractory to G2/M (...) checkpoint activation. Such DDR‐positive telomeres, and those that occur as part of the telomere‐dependent prolonged mitotic arrest checkpoint, normally pass through mitosis without covalent ligation, but result in cell growth arrest in G1 phase. The discovery that suppressing DSB repair during mitosis may function primarily to protect DDR‐positive telomeres from fusing during cell division reinforces the unique cooperation between telomeres and the DDR to mediate tumor suppression. (shrink)

Early embryogenesis is marked by a frail Spindle Assembly Checkpoint (SAC). The time of SAC acquisition varies depending on the species, cell size or a yet to be uncovered developmental timer. This means that for a specific number of divisions, biorientation of sister chromatids occurs unsupervised. When error‐prone segregation is an issue, an aneuploidy‐selective apoptosis system can come into play to eliminate chromosomally unbalanced cells resulting in healthy newborns. However, aneuploidy content can be too great to overcome, endangering viability.SAC (...) generates a diffusible signal to lengthen time spent in mitosis if needed, ensuring correct chromosome segregation, a fundamental factor in the generation of euploid cells. Thus, it remains puzzling what benefit could come from delaying SAC acquisition till later in the development. In this review, we describe what is known on SAC acquisition in distinct species and highlight pending research as well as potential applications for such knowledge. (shrink)

Quine's ethical views typify what might seem to be natural sympathies between empiricism and ethical noncognitivism. LikeAyer, he sees a case for noncognitivism rooted in an epistemic discontinuity between ethics and science. Quine argues that the absence of genuine moral observation sentences, and thus the absence of empirical checkpoints for the resolution of theoretical disputes, renders ethics, as he terms it, “methodologically infirm” However, recent papers in this journal make clear that Quine appears to be voicing mutually incompatible commitments to (...) both noncognitivism and cognitivism. Here I argue that Davidson's theory of interpretation offers promising ways to resolve these tensions. His constructive program fleshes out the implications of Quine's largely destructive critique of intensional semantics and contains a fairly well‐articulated account of evaluative semantics, one which seems to combine cognitivist and noncognitivist elements harmoniously. Moreover, it is argued that Davidson's long‐standing differences with Quine over the epistemological status Quine accords observation sentences with do not undermine Quine's metaethical critique. (shrink)

Human individuals often exhibit important differences in their sensitivity to ionising radiation. Extensive literature links radiation sensitivity with impaired DNA repair which is due to a lack of correct functioning in many proteins involved in DNA‐repair pathways and/or in DNA‐damage checkpoint responses. Given that ionising radiation is an important and widespread diagnostic and therapeutic tool, it is important to investigate further those factors and mechanisms that underlie individual radiosensitivity. Recently, evidence is accumulating that telomere function may well be involved (...) in cellular and organism responses to ionising radiation, broadening still further the currently complex and challenging scenario. BioEssays. BioEssays 28: 1172–1180, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

To ensure accurate chromosome segregation during mitosis, the spindle checkpoint monitors chromosome alignment on the mitotic spindle. Indjeian and colleagues have investigated the precise role of the shugoshin 1 protein (Sgo1p) in this process in budding yeast.1 The Sgo proteins were originally identified as highly conserved proteins that protect cohesion at centromeres during the first meiotic division. Together with other recent findings,2 the study highlighted here has identified Sgo1 as a component that informs the mitotic spindle checkpoint when (...) spindle tension is perturbed. This discovery has provided a molecular link between sister chromatid cohesion and tension‐sensing at the kinetochore–microtubule interface. BioEssays 27:588–591, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

The activity of Wnt and Notch signalling is central to many cell fate decisions during development and to the maintenance and differentiation of stem cell populations in homeostasis. While classical views refer to these pathways as independent signal transduction devices that co‐operate in different systems, recent work has revealed intricate connections between their components. These observations suggest that rather than operating as two separate pathways, elements of Wnt and Notch signalling configure an integrated molecular device whose main function is to (...) regulate transitions between cell states in development and homeostasis. Here, we propose a general framework for the structure and function of the interactions between these signalling systems that is focused on the notion of ‘transition states’, i.e. intermediates that arise during cell fate decision processes. These intermediates act as checkpoints in cell fate decision processes and are characterised by the mixed molecular identities of the states involved in these processes.Editor's suggested further reading in BioEssays: Notch: Implications of endogenous inhibitors for therapy Abstract. (shrink)