Meiotic defects cause abnormal chromosome segregation leading to aneuploidy in mammalian oocytes. Chromosome segregation is particularly error‐prone in human oocytes, but the mechanisms behind such errors remain unclear. To explain the frequent chromosome segregation errors, recent investigations have identified multiple meiotic defects and explained how these defects occur in female meiosis. In particular, we review the causes of cohesin exhaustion, leaky spindle assembly checkpoint (SAC), inherently unstable meiotic spindle, fragmented kinetochores or centromeres, abnormal aurora kinases (AURK), and clinical genetic variants (...) in human oocytes. We mainly focus on meiotic defects in human oocytes, but also refer to the potential defects of female meiosis in mouse models. (shrink)

In addition to monocentric eukaryotes, which have a single localized centromere on each chromosome, there are holocentric species, with extended repeat‐based or repeat‐less centromeres distributed over the entire chromosome length. At least two types of repeat‐based holocentromeres exist, one composed of many small repeat‐based centromere units (small unit‐type), and another one characterized by a few large centromere units (large unit‐type). We hypothesize that the transposable element‐mediated dispersal of hundreds of short satellite arrays formed the small centromere (...) unit‐type holocentromere in Rhynchospora pubera. The large centromere unit‐type of the plant Chionographis japonica is likely a product of simultaneous DNA double‐strand breaks (DSBs), which initiated the de novo formation of repeat‐based holocentromeres via insertion of satellite DNA, derived from extra‐chromosomal circular DNAs (eccDNAs). The number of initial DSBs along the chromosomes must be higher than the number of centromere units since only a portion of the breaks will have incorporated eccDNA at an appropriate position to serve as future centromere unit sites. Subsequently, preferential incorporation of the centromeric histone H3 variant at these positions is assumed. The identification of repeat‐based holocentromeres across lineages will unveil the centromere plasticity and elucidate the mechanisms underlying the diverse formation of holocentromeres. (shrink)

Stable maintenance of genetic information during meiosis and mitosis is dependent on accurate chromosome transmission. The centromere is a key component of the segregational machinery that couples chromosomes with the spindle apparatus. Most of what is known about the structure and function of the centromeres has been derived from studies on yeast cells. In Saccharomyces cerevisiae, the centromere DNA requirements for mitotic centromere function have been defined and some of the proteins required for an active complex have (...) been identified. Centromere DNA and the centromere proteins form a complex that has been studied extensively at the chromatin level. Finally, recent findings suggest that assembly and activation of the centromere are integrated in tethe cell cycle. (shrink)

The psychological and neurobiological processes underlying moral judgement have been the focus of many recent empirical studies1–11. Of central interest is whether emotions play a causal role in moral judgement, and, in parallel, how emotion-related areas of the brain contribute to moral judgement. Here we show that six patients with focal bilateral damage to the ventromedial prefrontal cortex (VMPC), a brain region necessary for the normal generation of emotions and, in particular, social emotions12–14, produce an abnor- mally ‘utilitarian’ pattern of (...) judgements on moral dilemmas that pit compelling considerations of aggregate welfare against highly emotionally aversive behaviours (for example, having to sacrifice one person’s life to save a number of other lives)7,8. In contrast, the VMPC patients’ judgements were normal in other classes of moral dilemmas. These findings indicate that, for a selective set of moral dilemmas, the VMPC is critical for normal judgements of right and wrong. The findings support a necessary role for emotion in the generation of those judgements. (shrink)

Hilde Lindemann Nelson focuses on the stories of groups of people--including Gypsies, mothers, nurses, and transsexuals--whose identities have been defined by those with the power to speak for them and to constrain the scope of their actions. By placing their stories side by side with narratives about the groups in question, Nelson arrives at some important insights regarding the nature of identity. She regards personal identity as consisting not only of how people view themselves but also of how others view (...) them. These perceptions combine to shape the person's field of action. If a dominant group constructs the identities of certain people through socially shared narratives that mark them as morally subnormal, those who bear the damaged identity cannot exercise their moral agency freely.Nelson identifies two kinds of damage inflicted on identities by abusive group relations: one kind deprives individuals of important social goods, and the other deprives them of self-respect. To intervene in the production of either kind of damage, Nelson develops the counterstory, a strategy of resistance that allows the identity to be narratively repaired and so restores the person to full membership in the social and moral community. By attending to the power dynamics that constrict agency, Damaged Identities, Narrative Repair augments the narrative approaches of ethicists such as Alasdair MacIntyre, Martha Nussbaum, Richard Rorty, and Charles Taylor. (shrink)

Many morally important facts about the way we affect one another, in particular the psychological damage we can inflict, are hard to imagine .

Neuroimaging studies of brain-damaged patients diagnosed as in the vegetative state suggest that the patients might be conscious. This might seem to raise no new ethical questions given that in related disputes both sides agree that evidence for consciousness gives strong reason to preserve life. We question this assumption. We clarify the widely held but obscure principle that consciousness is morally significant. It is hard to apply this principle to difficult cases given that philosophers of mind distinguish between a range (...) of notions of consciousness and that is unclear which of these is assumed by the principle. We suggest that the morally relevant notion is that of phenomenal consciousness and then use our analysis to interpret cases of brain damage. We argue that enjoyment of consciousness might actually give stronger moral reasons not to preserve a patient's life and, indeed, that these might be stronger when patients retain significant cognitive function. (shrink)

Moral judgments, whether delivered in ordinary experience or in the courtroom, depend on our ability to infer intentions. We forgive unintentional or accidental harms and condemn failed attempts to harm. Prior work demonstrates that patients with damage to the ventromedial prefrontal cortex deliver abnormal judgments in response to moral dilemmas and that these patients are especially impaired in triggering emotional responses to inferred or abstract events, as opposed to real or actual outcomes. We therefore predicted that VMPC patients would deliver (...) abnormal moral judgments of harmful intentions in the absence of harmful outcomes, as in failed attempts to harm. This prediction was confirmed in the current study: VMPC patients judged attempted harms, including attempted murder, as more morally permissible relative to controls. These results highlight the critical role of the VMPC in processing harmful intent for moral judgment. (shrink)

I explore how considerations about psychological damage connect with moral theories.

This article focuses on the ethical implications of so-called ‘collateral damage’. It develops a moral typology of collateral harm to innocents, which occurs as a side effect of military or quasi-military action. Distinguishing between accidental and incidental collateral damage, it introduces four categories of such damage: negligent, oblivious, knowing and reckless collateral damage. Objecting mainstream versions of the doctrine of double effect, the article argues that in order for any collateral damage to be morally permissible, violent agents must comply with (...) high standards of care. In order for incidental harm to be permissible, an agent must take pains to avoid such harm even at higher cost to him- or herself. It is argued that accidentally but negligently caused collateral damage may be just as difficult to excuse as incidental harm. Only if high precautionary standards of care are met, can unintended harm to innocents – incidental or accidental – be permissible. In practice, such a strong commitment to avoiding harm to civilians may well lead us to question more generally and rethink more radically how violent conflicts ought to be fought, how military violence ought to be used and whether there are better ways of achieving those aims that we think are legitimate than those we are currently using. (shrink)

I show, building on Warren Quinn's puzzle of the self-torturer, that destructive conduct with respect to the environment can flourish even in the absence of interpersonal conflicts. As Quinn's puzzle makes apparent, in cases where individually negligible effects are involved, an agent, whether it be an individual or a unified collective, can be led down a course of destruction simply as a result of following its informed and perfectly understandable but intransitive preferences. This is relevant with respect to environmental ethics, (...) since environmental damage is often the result of the accumulation of individually negligible effects. (shrink)

Neuroimaging studies of brain-damaged patients diagnosed as in the vegetative state suggest that the patients might be conscious. This might seem to raise no new ethical questions given that in related disputes both sides agree that evidence for consciousness gives strong reason to preserve life. We question this assumption. We clarify the widely held but obscure principle that consciousness is morally significant. It is hard to apply this principle to difficult cases given that philosophers of mind distinguish between a range (...) of notions of consciousness and that is unclear which of these is assumed by the principle. We suggest that the morally relevant notion is that of phenomenal consciousness and then use our analysis to interpret cases of brain damage. We argue that enjoyment of consciousness might actually give stronger moral reasons not to preserve a patient's life and, indeed, that these might be stronger when patients retain significant cognitive function. (shrink)

This article addresses a still unsolved puzzle in private law regarding the proper explanation of cases in which courts make substantial awards of damages to claimants whose rights have been infringed, but who appear to have suffered no factual loss in consequence of the infringement. The paradigm examples tend to involve awards of ‘user’, license fee or ‘hypothetical bargain’ damages in cases involving interference with property rights. It suggests that existing explanations of such cases are all unsatisfactory in one or (...) another respect and posits a new and potentially more powerful explanatory thesis, drawing on Hohfeld. Such awards, it argues, compensate right-holders for the loss of legal powers associated with their primary claim-rights—in particular, the loss of powers they are accorded by the law to ‘prevent’ the infringement of certain types of primary claim right ex ante. Legal powers are thus to be regarded as assets or amenities, the loss of which is amenable to monetary compensation. (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)

describes connections between a series of related papers.

Ribonucleotide reductase (RNR) catalyzes the rate limiting step in the production of deoxyribonucleotides needed for DNA synthesis. In addition to the well documented allosteric regulation, the synthesis of the enzyme is also tightly regulated at the level of transcription. mRNAs for both subunits are cell cycle regulated and inducible by DNA damage in all organisms examined, including E. coli, S. cerevisiae and H. sapiens. This DNA damage regulation is thought to provide a metabolic state that facilitates DNA replicational repair processes. (...) S. cerevisiae also encodes a second large subunit gene, RNR3, that is expressed only in the presence of DNA damage. Genetic analysis of the DNA damage response in S. cerevisiae has shown that RNR expression is under both positive and negative control. Among mutants constitutive for RNR expression are the general transcriptional repression genes, SSN6 and TUP1. Mutations in POL1 and POL3 also activate RNR expression, indicating that the DNA damage sensory network may respond directly to blocks in DNA synthesis. A protein kinase, Dun1, has been identified that controls inducibility of RNR1, RNR2 and RNR3 in response to DNA damage and replication blocks. This result suggests that the RNR genes in S. cerevisiae form a regulon that is coordinately regulated by protein phosphorylation in response to DNA damage. (shrink)

This article is a review of the 2010 book Collateral Damage by Dan Walter.

In Harris v Digital Pulse Pty Ltd (2003) 56 NSWLR 298, the New South Wales Court of Appeal held that exemplary (or punitive) damages are not available for breach of fiduciary duty or other equitable obligation. The decision runs counter to authorities in Canada, New Zealand and some U.S. states. Punitive (exemplary) damages is a hotly debated topic in the United States and it has attracted considerable interest among law and economics scholars, particularly in the tort litigation context. This article (...) analyzes the Digital Pulse case from a law and economics perspective. Polinsky and Shavell (among others) argue that the function of punitive damages is to achieve optimal deterrence in cases where the probability that the plaintiff will discover and successfully litigate the defendant’s wrongdoing is less than 1. Given the high costs of monitoring fiduciary behaviour, it might be tempting to conclude that exemplary damages should be routinely awarded for breach of fiduciary obligation. The article explains why this view is wrong. On the other hand, given the availability of gains-based remedies (the account of profits and the like) for breach of fiduciary obligation, it might be tempting to conclude that exemplary damages are never justified in fiduciary cases. The article explains why this view is wrong too. The main conclusions are that: (1) exemplary damages should be available for breach of fiduciary duty and the like, but not as a matter of course; and (2) exemplary damages were probably not warranted in Digital Pulse itself. (shrink)

Edmund Pellegrino claims that medical ethics must be derived from a perception of the patient's damaged humanity, rather than from the self-imposed duties of professionals. This essay explores the meaning and examines the challenges to this patient-centered ethic. Social scientific and bioethical interpretations of medicine constitute one kind of challenge. A more pervasive challenge is the ascendancy of managed care, and especially investor-owned, for-profit managed care. A list of questions addressed to patients, physicians and organizations is offered as one means (...) of assessing this threat and moving toward morally trustworthy relationships. (shrink)

From schools advertising McDonald's, Nike, and Shell oil to military generals appointed as superintendents; from corporate CEOs hailed as education experts to students suspended for wearing Pepsi tee shirts on Coke day; Collateral Damage sifts through a wide range of incidents to reveal how the rising corporatization of public schools needs to be understood as a part of a broader attack on the public sector. Uniquely, Collateral Damage considers the privatization of public education in relation to both globalization and local (...) struggles over curriculum, schools, and culture. (shrink)

We argue that Graziano and Kastner are mistaken to claim that neglect favors their self-directed social perception account of consciousness. For the latter should not predict that neglect would result from damage to mechanisms of social perception. Neglect is better explained in terms of damage to attentional mechanisms.

For corrective justice, liability is the consequence of the parties' being correlatively situated as the doer and sufferer of an injustice, and the remedy is seen as undoing that injustice to the extent possible. Combining consideration of legal doctrine and private law theory, this article applies the framework of corrective justice to gain-based damages for torts. Within this framework, restitutionary damages ought to be available only insofar as they correspond to a constituent element in the injustice that the defendant has (...) done to the plaintiff. The radical proposal that allows restitutionary damages for any wrongful gain is unsatisfactory because it fails to link the damages that the plaintiff receives to the normative quality of the defendant's wrong. In contrast, dealings in another's property give rise to such damages because the idea of property includes within the owner's entitlement the potential gainsfrom the property's use or alienation. Restitutionary damages should not be seen as serving a deterrent or punitive function; such a function cannot account for why the plaintiff, of all people, is entitled to the defendant's gain. Properly understood, even situations where the plaintiff's wilfulness or calculation increases the damage award fit within the framework of corrective justice. The corrective justice approach thus repudiates the notion that restitutionary damages are occasions for the promotion of social purposes extrinsic to the juridical relationship between the parties. (shrink)

In 2006, Shinya Yamanaka and colleagues discovered how to reprogram terminally differentiated somatic cells to a pluripotent stem cell state. The resulting induced pluripotent stem cells (iPSCs) made a paradigm shift in the field, further nailing down the disproval of the long‐held dogma that differentiation is unidirectional. The prospect of using iPSCs for patient‐specific cell‐based therapies has been enticing. This promise, however, has been questioned in the last two years as several studies demonstrated intrinsic epigenetic and genomic anomalies in these (...) cells. Here, we not only review the recent critical studies addressing the genome integrity during the reprogramming process, but speculate about the underlying mechanisms that could create de novo genome damage in iPSCs. Finally, we discuss how much an elevated mutation load really matters considering the safety of future therapies with cells heavily cultured in vitro. (shrink)

For a little more than a decade, professional organizations and healthcare institutions have attempted to develop guidelines and policies to deal with seemingly intractable conflicts that arise between clinicians and patients (or their proxies) over appropriate use of aggressive life-sustaining therapies in the face of low expectations of medical benefit. This article suggests that, although such efforts at conflict resolution are commendable on many levels, inadequate attention has been given to their potential negative effects upon particular groups of patients/proxies. Based (...) on the well-documented tendency among many African Americans to prefer more aggressive end-of-life medical interventions, it is proposed that the use of institutional policy to break decision making impasse in cases for which aggressive treatment is deemed "medically inappropriate" will fall disproportionately on that group. Finally, it is suggested that the development and application of institutional conflict-resolution policies should be evaluated in the context of historical and current experiences of marginalization and disempowerment, lest such policies exacerbate that experience. (shrink)

It has long been known that brain damage has important negative effects on one’s mental life and even eliminates one’s ability to have certain conscious experiences. It thus stands to reason that when all of one’s brain activity ceases upon death, consciousness is no longer possible and so neither is an afterlife. It seems clear that human consciousness is dependent upon functioning brains. This essay reviews some of the overall neurological evidence from brain damage studies and concludes that our argument (...) from brain damage has been vindicated by such overwhelming evidence. It also puts forth a more mature philosophical rationale against an afterlife and counters several replies to the argument. -/- 1. Philosophical Background -- 2. The Dependence of Consciousness on the Brain: Some Preliminary Evidence -- 3. Brain Damage, Lesion Studies, and the Localization of Mental Function - 3.1 Perception - 3.2 Awareness, Comprehension, and Recognition - 3.3 Memory - 3.4 Personality - 3.5 Language - 3.6 Emotion - 3.7 Decision-Making - 3.8 Social Cognition and Theory of Mind - 3.9 Moral Judgment and Empathy - 3.10 Neurological Disorders and Disease - 3.11 The Unity of Consciousness -- 4. Objections and Replies - 4.1 Souls, Minds, and Energy Fields - 4.2 The Instrument Theory - 4.3 The Embodied Soul Alone is Affected -- 5. Conclusion. (shrink)

On December 20, 2002, the Ohio Supreme Court issued an opinion in Dardinger v. Anthem Blue Cross & Blue Shield granting a landmark punitive damages award against the defendant-insurer for breach of contract and bad faith in its coverage of a cancer patient. The court directed that the punitive damages award of $30 million, should it be accepted by the plaintiff, be apportioned between the plaintiff and a cancer research fund to be established in the name of the plaintiff's deceased (...) wife, Esther Dardinger. In so doing, the court broke new ground in the scope and social purpose of punitive damages in health care litigation, as well as the courts’ role in distributing those damages.After being diagnosed with metastatic brain tumors in October 1996, Esther began intra-arterial chemotherapy treatments at the recommendation of her physician, Dr. Newton. IAC is a targeted form of chemotherapy in which an arterial catheter is threaded through a cranial artery near the tumor and into the brain. (shrink)

On December 20, 2002, the Ohio Supreme Court issued an opinion in Dardinger v. Anthem Blue Cross & Blue Shield granting a landmark punitive damages award against the defendant-insurer for breach of contract and bad faith in its coverage of a cancer patient. The court directed that the punitive damages award of $30 million, should it be accepted by the plaintiff, be apportioned between the plaintiff and a cancer research fund to be established in the name of the plaintiff's deceased (...) wife, Esther Dardinger. In so doing, the court broke new ground in the scope and social purpose of punitive damages in health care litigation, as well as the courts’ role in distributing those damages.After being diagnosed with metastatic brain tumors in October 1996, Esther began intra-arterial chemotherapy treatments at the recommendation of her physician, Dr. Newton. IAC is a targeted form of chemotherapy in which an arterial catheter is threaded through a cranial artery near the tumor and into the brain. (shrink)

The centromere is a specialized chromosomal structure that dictates kinetochore assembly and, thus, is essential for accurate chromosome segregation. Centromere identity is determined epigenetically by the presence of a centromere‐specific histone H3 variant, CENP‐A, that replaces canonical H3 in centromeric chromatin. Here, we discuss recent work by Roulland et al. that identifies structural elements of the nucleosome as essential determinants of centromere function. In particular, CENP‐A nucleosomes have flexible DNA ends due to the short αN helix (...) of CENP‐A. The higher flexibility of the DNA ends of centromeric nucleosomes impairs binding of linker histones H1, while it facilitates binding of other essential centromeric proteins, such as CENP‐C, and is required for mitotic fidelity. This work extends previous observations indicating that the differential structural properties of CENP‐A nucleosomes are on the basis of its contribution to centromere identity and function. Here, we discuss the implications of this work and the questions arising from it. (shrink)

Several million people are treated with neuroleptic medications in North America each year. A large percentage of these patients develop a chronic neurologic disorder-tardive dyskinesia-characterized by abnormal movements of the voluntary muscles. Most cases are permanent and there is no known treatment. Evidence has been accumulating that the neuroleptics also cause damage to the highest centers of the brain, producing chronic mental dysfunction, tardive dementia and tardive psychosis. These drug effects may be considered a mental equivalent of tardive dyskinesia. Relevant (...) data are derived from human autopsies, brain imaging , neurophysical tests, and clinical research. That the neuroleptics can damage higher brain centers is confirmed by their known neurotoxicity and neurophysiological impact, animal autopsies, and a comparison to diseases that mimic neuroleptic effects, such as Huntington's chorea and lethargic encephalitis. Patients and the public should be informed of the danger of both tardive dyskinesia and tardive dementia. The mental health professions should severely limit the use of neuroleptics and develop safer and better alternatives to these dangerous substances. (shrink)

Drawing on their extensive research, Nichols and Berliner document and categorize the ways that high-stakes testing threatens the purposes and ideals of the American education system. For more than a decade, the debate over high-stakes testing has dominated the field of education. This passionate and provocative book provides a fresh perspective on the issue and powerful ammunition for opponents of high-stakes tests. Their analysis is grounded in the application of Campbell’s Law, which posits that the greater the social consequences associated (...) with a quantitative indicator, the more likely it is that the indicator itself will become corrupted—and the more likely it is that the use of the indicator will corrupt the social processes it was intended to monitor. Nichols and Berliner illustrate both aspects of this “corruption,” showing how the pressures of high-stakes testing erode the validity of test scores and distort the integrity of the education system. Their analysis provides a coherent and comprehensive intellectual framework for the wide-ranging arguments against high-stakes testing, while putting a compelling human face on the data marshalled in support of those arguments. (shrink)

Contemporary development goals of the Philippines, like those of many post-colonial states in the Third Word, strongly emphasize the need to catch up with the living standards of western industrialized countries. This article argues that following the western model of development through industrialization can only exacerbate existing socio-economic and ecological problems. The article contends that an historically appropriate and total development should aim for a reconstitution of natural, social, and moral ecologies. Drawing from historical sources, the first part of the (...) article examines the ecological consequences of Spanish colonization in order to provide the rationale for a definition of development as a reconstitution of damaged ecologies. The second part propose that the ethics of post-colonial development should be based on equality of access to life-sustaining resources and the transformation of values. The article conceptualizes ethics as a social discourse that defends human communities from further environmental and social degradation. (shrink)

Four models of forgiveness are identified; the health model, the philosophical model, the Christian model and the prosocial model. All define the term ‘forgiveness’ in a way which is consistent with their particular perspective. The authors offer a definition of forgiveness and propose an integrated model of forgiveness which seeks to incorporate contributions from all four areas, but is not biased towards any one model. Four levels of transgression are identified and categorized according to the degree of perceived damage. Apology-automatic (...) and apology-dependent responses are distinguished from a forgiveness response which is restricted to Levels 3 and 4. The advantages of adopting a forgiveness strategy for both the forgiver and forgiven as opposed to other responses, i.e., revenge, denial, and condoning are discussed. The authors provide a definition and model which integrates the important contributions from each of the areas discussed. (shrink)

What does it mean to look? How does looking relate to damage? These are the fundamental questions addressed in Overlooking Damage. From the Roman triumph to the iconoclasm of ISIS and the Taliban to the aerial views of looted landscapes and destroyed temples visible on Google, the relationship between beauty and violence is far more intimate than we sometimes acknowledge. Jonah Siegel makes the daring argument that a thoughtful reaction to images of damage need not stop at melancholy, but can (...) lead us to a new reckoning. Would the objects we admire be more beautiful if they were not injured or displaced, if they did not remind us of unbearable violence? Siegel takes up writers from the time of the French Revolution to today who have reacted to the depredations of revolutionary iconoclasm, colonial looting, and industrial capitalism, and proposes that in these authors we may find resources with which to navigate our contemporary situation. Deftly bringing the methods of literary studies to bear on important debates in the study of heritage, archaeology, and visual culture, Overlooking Damage reflects on the ways in which concepts of beauty intersect with periods of epochal violence in an attempt to resist the separation of broken things from the worlds in which they have come to be embedded. (shrink)

Acoustic emission technique is a common approach to identify the damage of the refractories; however, there is a complex problem since there are as many as fifteen involved parameters, which calls for effective data processing and classification algorithms to reduce the level of complexity. In this paper, experiments involving three-point bending tests of refractories were conducted and AE signals were collected. A new data processing method of merging the similar parameters in the description of the damage and reducing the dimension (...) was developed. By means of the principle component analysis for dimension reduction, the fifteen related parameters can be reduced to two parameters. The parameters were the linear combinations of the fifteen original parameters and taken as the indexes for damage classification. Based on the proposed approach, the Gaussian mixture model was integrated with the Bayesian information criterion to group the AE signals into two damage categories, which accounted for 99% of all damage. Electronic microscope scanning of the refractories verified the two types of damage. (shrink)

Health care professionals’ and trainees’ conceptions of their responsibilities to patients can change over time for a number of reasons: evolving career goals, desires to serve different patient populations, and changing family obligations, for example. Some changes in conceptions of responsibility are healthy, but others express moral damage. Clinicians’ changes in their conceptions of what they are responsible for express moral damage when their responses to others express a meager, rather than robust, sense of what they owe others. At least (...) two important expressions of moral damage in the context of health care are these: callousness and divestiture. Callousness describes the poor condition of a clinician's capacity for moral perception; when her capacity to accurately appreciate features of moral relevance that configure others’ needs, vulnerabilities, and desert of care diminishes, such that she fails to respond with care to those for whom she has duties to care, she is callous. Callousness has been explored in detail elsewhere,1 and so the focus of this paper is divestiture. A clinician divests when the value of responding with care to others becomes less centrally and importantly constitutive of his personal and professional identity. Divestiture has important consequences for patients and health professions education, which I will explore here. (shrink)

The access-to-justice movement broadly concerns the extent to which people have the ability to resolve legally actionable problems. To the extent that individuals seek resolution through civil litigation, they can be disadvantaged by their unmet need for legal services, particularly in high-stakes cases and complicated areas of law. In part, this is because legal services and litigation are cost-prohibitive, especially for indigent plaintiffs. As a result, these individuals are priced out of litigation and, by extension, unable to use law to (...) seek justice. I propose an innovative legal intervention to this problem called “compensatory preliminary damages,” which builds from the work of Gideon Parchomovsky and Alex Stein. I argue that preliminary damages should function as compensatory awards for harm to a plaintiff’s ability to access justice, rather than a contingency loan that might make indigent plaintiffs worse off than before if they lose. As compensatory awards, preliminary damages address a defendant’s liability for a plaintiff’s prospective litigation costs that inequitably affect the plaintiff’s ability to access justice. In short, given a suitable connection between the underlying harms of the case and the plaintiff’s resources to meet their legal needs, the litigation costs that plaintiffs must face to litigate should, in some cases, be compensable. To seek such compensation, I propose that plaintiffs would have to plead, among other things, that their alleged injuries have resulted in various barriers to accessing justice, but that the hardship to the plaintiff and the balance of equities favor shifting the cost to access justice onto the defendant. By awarding such damages, courts make plaintiffs whole for harm to their access to justice that is not conditional on a decision after the merits or their final recovery for the injuries alleged. As such, the award would not need to be repaid. -/- . (shrink)

Non‐coding centromeres, which dictate kinetochore formation for proper chromosome segregation, are extremely divergent in DNA sequences across species but are under active transcription carried out by RNA polymerase (RNAP) II. The RNAP II‐mediated centromeric transcription has been shown to facilitate the deposition of the centromere protein A (CENP‐A) to centromeres, establishing a conserved and critical role of centromeric transcription in centromere maintenance. Our recent work revealed another role of centromeric transcription in chromosome segregation: maintaining centromeric cohesion during mitosis. (...) Interestingly, this role appears to be fulfilled through ongoing centromeric transcription rather than centromeric transcripts. In addition, we found that centromeric transcription may not require some of the traditional transcription initiation factors, suggestive of “uniqueness” in its regulation. In this review, we discuss the novel role and regulation of centromeric transcription as well as the potential underlying mechanisms. (shrink)

Homologous centromeres compete for segregation to the secondary oocyte nucleus at female meiosis I. Centromeric repeats also compete with each other to populate centromeres in mitotic cells of the germline and have become adapted to use the recombinational machinery present at centromeres to promote their own propagation. Repeats are not needed at centromeres, rather centromeres appear to be hospitable habitats for the colonization and proliferation of repeats. This is probably an indirect consequence of two distinctive features of centromeric DNA. Centromeres (...) are subject to breakage by the mechanical forces exerted by microtubules and meiotic crossing‐over is suppressed. Centromeric proteins acting in trans are under selection to mitigate the costs of centromeric repeats acting in cis. Collateral costs of mitotic competition at centromeres may help to explain the high rates of aneuploidy observed in early human embryos. (shrink)

The mammalian centromere is a multifunctional chromosomal domain with a complexity that is reflected in its higher order structure, DNA sequence organization and protein composition. The centromere plays a major role during cell division where it functions as the site for the integration of the chromosome with the mitotic spindle, the site of the mechanochemical motor responsible for the movement of chromosomes and the major and last point of interaction between sister chromatids. Recent studies have focused on characterizing (...) the components of the centromere and establishing their relationship to its function. The following brief review summarizes some selected aspects of this recent work. (shrink)

The formation of DNA photoproducts by ultraviolet (UV) light is responsible for induction of mutations and development of skin cancer. To understand UV mutagenesis, it is important to know the mechanisms of formation and repair of these lesions. Cyclobutane pyrimidine dimers and (6–4)photoproducts are the two major classes of UV‐induced DNA lesions. Their distribution along DNA sequences in vivo is strongly influenced by nucleosomes and other DNA binding proteins. Repair of UV photoproducts is dependent on the transcriptional status of the (...) sequences to be repaired and on the chromatin environment. Sensitive techniques are now available to study repair of UV damage at the level of nucleotide resolution in mammalian cells. With the aid of in vitro systems, the entire nucleotide excision repair process has been reconstituted from purified protein components with naked DNA as a substrate. Future work will focus on the development of in vitro assays for transcription‐coupled repair and repair in chromatin. (shrink)

Two reports have shown that mammalian artificial chromosomes (MAC) can be constructed from cloned human centromere DNA and telomere repeats, proving the principle that chromosomes can form from naked DNA molecules transfected into human cells. The MACs were mitotically stable, low copy number and bound antibodies associated with active centromeres. As a step toward second-generation MACs, yeast and bacterial cloning systems will have to be adapted to achieve large MAC constructs having a centromere, two telomeres, and genomic copies (...) of mammalian genes. Available construction techniques are discussed along with a new P1 artificial chromosome (PAC)-derived telomere vector (pTAT) that can be joined to other PACs in vitro, avoiding a cloning step during which large repetitive arrays often rearrange. The PAC system can be used as a route to further define the optimal DNA elements required for efficient MAC formation, to investigate the expression of genes on MACs, and possibly to develop efficient MAC-delivery protocols. BioEssays 1999;21:76–83. © 1999 John Wiley & Sons, Inc. (shrink)

We should adopt the following principle with regard to compensatory justice. (1) If an unjust act benefits an innocent person and there is no reasonable way to assess the amount of damages to the victim, then compensatory justice does not require that the innocent beneficiary pay compensation for those damages. We cannot reasonably assess the amount of damages to current racial minorities that have resulted from past discriminatory acts. Problems arise in determining the identity of the injured parties, the identity (...) of the injuring agents and injuring acts (and omissions), and the degree of injury that directly resulted from these acts (or omissions). Since such compensable damages cannot be accurately estimated and since white male applicants are innocent beneficiaries of past discriminatory acts, the value of compensatory justice does not justify strong affirmative action programs. (shrink)