Objective: The aim of the current study was to investigate associations, unique and interactive, between mothers’ and children’s histories of childhood sexual abuse (CSA) and children’s psychiatric outcomes using an intergenerational perspective. Further, we were particularly interested in examining whether maternal reflective functioning about their own trauma (T-RF) was associated with lower likelihood of children’s abuse exposure (among children of CSA-exposed mothers). Method: One hundred and eleven children (Mage= 9.53 years; 43 sexual abuse victims) and their mothers (Mage= 37.99; 63 (...) sexual abuse victims) participated in this study. Mothers completed the Parent Development Interview (PDI), which yielded assessments of RF regarding their own experiences of abuse, and also reported on their children’s internalizing and externalizing symptoms. Results: Children of CSA-exposed mothers were more likely to have experienced CSA. A key result was that among CSA-exposed mothers, higher maternal T-RF regarding their own abuse was associated with lower likelihood of child CSA-exposure. Mothers’ and children’s CSA histories predicted children’s internalizing and externalizing symptoms, such that CSA exposure for mother or child was associated with greater symptomatology in children. Conclusions: The findings show that the presence of either maternal or child CSA is associated with more child psychological difficulties. Importantly in terms of identifying potential protective factors, maternal T-RF is associated with lower likelihood of CSA exposure in children of CSA-exposed mothers. We discuss these findings in the context of the need for treatments focusing on increasing Trauma - RF in mothers and children in the context of abuse to facilitate adaptation and reduce the intergenerational risk. (shrink)

What does it mean to ‘drop out’ of therapy? Many definitions of ‘dropout’ have been proposed, but the most widely accepted is the client ending treatment without agreement of their therapist. However, this is in some ways an external criterion that does not take into account the client’s experience of therapy, or reasons for ending it prematurely. This study aimed to identify whether there were more meaningful categories of dropout than the existing dropout definition, and to test whether this refined (...) categorisation of dropout was associated with clinical outcomes. This mixed-methods study used a subset of data from the IMPACT trial, which investigated psychological therapies for adolescent depression. Adolescents were randomly allocated to a treatment arm (Brief Psychosocial Intervention; Cognitive-Behavioural Therapy; Short-Term Psychoanalytic Psychotherapy). The sample for this study comprised 99 adolescents, aged 11-17 years. 32 were classified as having dropped out of treatment and participated in post-therapy qualitative interviews about their experiences of therapy. For 26 dropout cases, the therapist was also interviewed. 67 cases classified as having completed treatment were included to compare their outcomes to dropout cases. Interview data for dropout cases were analysed using ideal type analysis. Three types of dropout were constructed: ‘dissatisfied’ dropout, ‘got-what-they-needed’ dropout, and ‘troubled’ dropout. ‘Dissatisfied’ dropouts reported stopping therapy because they did not find it helpful. ‘Got-what-they-needed’ dropouts reported stopping therapy because they felt they had benefitted from therapy. ‘Troubled’ dropouts reported stopping therapy because of a lack of stability in their lives. The findings indicate the importance of including the perspective of clients in definitions of drop out, as otherwise there is a risk that the heterogeneity of 'dropout' cases may mask more meaningful distinctions. Clinicians should be aware of the range of issues experienced by adolescents in treatment that lead to disengagement. Our typology of dropout may provide a framework for clinical decision-making in managing different types of disengagement from treatment. (shrink)

The moral justification for targeted killing turns on it being justified as an act of self-defense. That justification can be assessed by addressing five questions: Is the targeted person a threat who lacks the right to threaten? Has the targeted person forfeited some of her claim not to be killed? Even if the answer to the first two questions is positive, is targeted killing a necessary and proportionate response? Is the evidence in favor of targeted killing high enough to meet (...) the relevant standard of proof? And insofar as a person is selected for targeting from a larger group of possible targets, is the selection justifiable? The legal justifiability of targeted killing should aim to track, as much as problems of administrability and limiting unwanted effects allow, the answers to those moral questions. (shrink)

"This is an important new Cummins work.

In the literature on linguistic context-sensitivity, a recurrent move has been made with the intention of attacking Charles Travis's occasion-sensitivity. The move is to provide a semantic analysis of the meaning of an expression which makes the content of that expression context sensitive but without providing any reason to think that the meaning of the expression is a character. I argue that this move is off-target. Such proposals are entirely consistent with occasion-sensitivity and so don't constitute an attack on it.

We discuss a case where clinical genomic investigation of muscle weakness unexpectedly found a genetic variant that might (or might not) predispose to kidney cancer. We argue that despite its off-target and uncertain nature, this variant should be discussed with the man who had the test, not because it is medical information, but because this discussion would allow the further clinical evaluation that might lead it to becoming so. We argue that while prominent ethical debates around genomics often take ‘results’ (...) as a starting point and ask questions as to whether to look for and how to react to them, the construction of genomic results is fraught with ethical complexity, although often couched as a primarily technical problem. We highlight the need for greater focus on, and appreciation of, the ethical work undertaken daily by scientists and clinicians working in genomic medicine and discuss how public conversations around genomics need to adapt to prepare future patients for potentially uncertain and unexpected outcomes from clinical genomic tests. (shrink)

Technological advances are bringing new light to privacy issues and changing the reasons for why privacy is important. These advances have changed not only the kind of personal data that is available to be collected, but also how that personal data can be used by those who have access to it. We are particularly concerned with how information about personal attributes inferred from collected data (such as online behaviour), can be used to tailor messages and services to specific individuals or (...) groups. This kind of ‘personalised targeting’ has the potential to influence individuals’ perceptions, attitudes, and choices in unprecedented ways. In this paper, we argue that because it is becoming easier for companies to use collected data for influence, threats to privacy are increasingly also threats to personal autonomy—an individual’s ability to reflect on and decide freely about their values, actions, and behaviour, and to act on those choices.4 While increasing attention is directed to the ethics of how personal data is collected, we make the case that a new ethics of privacy needs to also think more rigorously about how personal data may be used, and its potential impact on personal autonomy. (shrink)

Christine Swanton presents a new target centred virtue ethics, which is opposed to orthodox virtue ethics in two major ways. She rejects the 'natural goodness' metaphysics of neo-Aristotelian virtue ethics in favour of a 'hermeneutic ontology' of ethics, and she offers a new target centred framework for assessing rightness of acts.

This paper investigates the significance of T-duality in string theory: the indistinguisha- bility with respect to all observables, of models attributing radically different radii to space – larger than the observable universe, or far smaller than the Planck length, say. Two interpretational branch points are identified and discussed. First, whether duals are physically equivalent or not: by considering a duality of the familiar simple harmonic oscillator, I argue that they are. Unlike the oscillator, there are no measurements ‘outside’ string theory (...) that could distinguish the duals. Second, whether duals agree or disagree on the radius of ‘target space’, the space in which strings evolve according to string theory. I argue for the latter position, because the alternative leaves it unknown what the radius is. Since duals are physically equivalent yet disagree on the radius of target space, it follows that the radius is indeterminate between them. Using an analysis of Brandenberger and Vafa (1989), I explain why – even so – space is observed to have a determinate, large radius. The conclusion is that observed, ‘phenomenal’ space is not target space, since a space cannot have both a determinate and indeterminate radius: instead phenomenal space must be a higher-level phenomenon, not fundamental. (shrink)

We raise the following problem for so-called target-centred virtue ethics. An important motivation for adopting target-centred virtue ethics over other forms of virtue ethics is its supposedly distinctive account of right action: an action is right if and only if and because it is virtuous, and what makes an action virtuous is that it hits the target of the virtues. We argue that the account is not distinctive of target-centred virtue ethics, because it is an account that is widely endorsed (...) by Neo-Aristotelians. Hence, the argument of this paper undermines a central motivation for adopting target-centred virtue ethics. As a solution, we suggest that there is theoretical room for a target-centred account that is not Neo-Aristotelian, and we draw on the work of Confucian philosopher Wáng Yángmíng to provide one. We defend the resulting account by arguing that it has the advantage of being able to offer us a more plausible response to the self-centredness objection that has long been a problem for Neo-Aristotelians. (shrink)

In this book, Leonard Talmy proposes that a single linguistic/cognitive system, targeting, underlies two domains of linguistic reference, those termed anaphora and deixis. Talmy argues that language engages the same cognitive system to single out referents whether they are speech-internal or speech-external. Talmy explains the targeting system in this way: as a speaker communicates with a hearer, her attention is on an object to which she wishes to refer; this is her target. To get the hearer's attention on (...) it as well, she uses a trigger -- a word such as this, that, here, there, or now. The trigger initiates a three-stage process in the hearer: he seeks cues of ten distinct categories; uses these cues to determine the target; and then maps the concept of the target gleaned from the cues back onto the trigger to integrate it into the speaker's sentence, achieving comprehension. The whole interaction, Talmy explains, rests on a coordination of the speaker's and hearer's cognitive processing. The process is the same whether the referent is anaphoric or deictic. Talmy presents and analyzes the ten categories of cues, and examines sequences in targeting, including the steps by which interaction leads to joint attention. A glossary defines the new terms in the argument. (shrink)

In international law and the ethics of war, there are a variety of actions which are seen as particularly problematic and presumed to be always or inherently wrong, or in need of some overwhelmingly strong justification to override the presumption against them. One of these actions is assassination, in particular, assassination of heads of state. In this essay I argue that the presumption against assassination is incorrect. In particular, I argue that if in a given scenario war is justified, then (...) assassination of the enemy state's leader is also justified, and in fact ought to be pursued as a means short of war. I defend this position on both consequential and deontic grounds, arguing that assassination is both more discriminate than war and serves to harm only those most responsible for the situation which justifies war in the first place. I conclude by arguing that a norm of assassination, far from being a destabilizing force, as some have argued, would in fact serve to reinforce international norms of rights and respect for persons by making clear that tyrants and would-be oppressors cannot hide behind military forces or notions of sovereignty to protect themselves from judgment and retribution. (shrink)

Apoptotic pathways have always been regarded as a key‐player in preserving tissue and organ homeostasis. Excessive activation or resistance to activation of cell death signaling may indeed be responsible for several mechanisms of disease, including malignancy and chronic degenerative diseases. Therefore, targeting apoptotic factors gained more and more attention in the scientific community and novel strategies emerged aimed at selectively blocking or stimulating cell death signaling. This is also the case for the TMEM219 death receptor, which is activated by (...) a circulating ligand, the Insulin‐like growth factor binding protein 3 (IGFBP3) and induces a caspase‐8‐dependent apoptosis of the target cells. Interestingly, stimulation of the IGFBP3/TMEM219 axis exerts an anti‐proliferative effect, while blockade of the TMEM219 deleterious signal protects TMEM219‐expressing cells of the endocrine pancreas, lung, and intestine from damage and death. Here, we summarize the most updated reports on the role of the IGFBP3/TMEM219 apoptotic axis in disease conditions, including intestinal disorders and diabetes, and we describe the advancements in designing and testing novel TMEM219‐based targeting approaches in emerging potential clinical applications. (shrink)

Bringing the views of Grayling, Moyal-Sharrock and Stroll together, I argue that in On Certainty, Wittgenstein explores the possibility of a new kind of foundationalism. Distinguishing propositional language-games from non-propositional, actional certainty, Wittgenstein investigates a foundationalism sui generis . Although he does not forthrightly state, defend, or endorse what I am characterizing as a "new kind of foundationalism," we must bear in mind that On Certainty was a collection of first draft notes written at the end of Wittgenstein's life. The (...) work was unprogrammatic, sometimes cryptic. Yet, his exploration into areas of knowledge, certitude and doubt suggest an identifiable direction to his thoughts. (shrink)

This study examines why and when negative workplace gossip promotes self-serving behaviors by the employees being targeted. Using conservation of resources theory, we find that targets tend to increase their political acts as a result of ego depletion triggered by negative gossip. We also show that sensitivity to interpersonal mistreatment and moral disengagement moderate this process. Specifically, we demonstrate that targets with high levels of sensitivity to interpersonal mistreatment are more likely to experience ego depletion, and that targets with high (...) levels of moral disengagement will find it easier to persuade themselves to engage in political acts. We conducted a three-wave time-lagged survey of 265 employees in Guangdong, China, to test our hypotheses. The results support our theoretical model and indicate that COR theory can be used to explain the impacts of negative workplace gossip. Alongside our important and timely theoretical contributions, we provide new perspectives on how managers can avoid or mitigate these political acts. (shrink)

Though dividing one’s attention between two input streams typically impairs performance, detecting a behaviorally relevant stimulus can sometimes enhance the encoding of unrelated information presented at the same time. Previous research has shown that selection of this kind boosts visual cortical activity and memory for concurrent items. An important unanswered question is whether such effects are reflected in processing quality and functional connectivity in visual regions and in the hippocampus. In this fMRI study, participants were asked to memorize a stream (...) of naturalistic images and press a button only when they heard a predefined target tone. Images could be presented with a target tone, with a distractor tone, or without a tone. Auditory target detection increased activity throughout the ventral visual cortex but lowered it in the hippocampus. Enhancements in functional connectivity between the ventral visual cortex and the hippocampus were also observed following auditory targets. Multi-voxel pattern classification of image category was more accurate on target tone trials than on distractor and no tone trials in the fusiform gyrus and parahippocampal gyrus. This effect was stronger in visual cortical clusters whose activity was more correlated with the hippocampus on target tone than on distractor tone trials. In agreement with accounts suggesting that subcortical noradrenergic influences play a role in the attentional boost effect, auditory target detection also caused an increase in locus coeruleus activity and phasic pupil responses. These findings outline a network of cortical and subcortical regions that are involved in the selection and processing of information presented at behaviorally relevant moments. (shrink)

The title of this book echoes a phrase used by the Washington Post to describethe American attempt to kill Saddam Hussein at the start of the war againstIraq. Its theme is the notion of targeting (skopos) as the name of an intentionalstructure in which the subject tries to confirm its invulnerability by aiming todestroy a target. At the center of the first chapter is Odysseus’s killing of the suitors;the second concerns Carl Schmitt’s Roman Catholicism and Political Form; thethird and (...) fourth treat Freud’s “Thoughts for the Times on War and Death” and“The Man Moses and Monotheistic Religion.” Weber then traces the emergenceof an alternative to targeting, first within military and strategic thinking itself(“Network Centered Warfare”), and then in Walter Benjamin’s readings of“Capitalism as Religion” and “Two Poems of Friedrich Hölderlin.”. (shrink)

There are important ethical issues to be examined before launching any public health intervention, particularly when targeting vulnerable groups. The aim of this article is to identify and discuss ethical concerns that may arise when intervening for health behavior change among adolescents identified as overweight. These concerns originate from an intervention designed to capacitate adolescents to increase self-determined physical activity. Utilizing an ethical framework for prevention of overweight and obesity, we identified three ethical aspects as particularly significant: the attribution (...) of responsibility for health behavior, liberty to choose, and the effect on the participants’ psychosocial well-being. It is discussed whether and how measures can be taken to deal with these aspects. It seems evident that the ethical aspects are mainly concerned with the vulnerability of adolescents identified as overweight. However, we claim that when individual feedback and counseling is provided, tailored interventions have a unique potential to empower adolescents to make ethically anchored decisions about their own health behavior. (shrink)

There are important ethical issues to be examined before launching any public health intervention, particularly when targeting vulnerable groups. The aim of this article is to identify and discuss ethical concerns that may arise when intervening for health behavior change among adolescents identified as overweight. These concerns originate from an intervention designed to capacitate adolescents to increase self-determined physical activity. Utilizing an ethical framework for prevention of overweight and obesity, we identified three ethical aspects as particularly significant: the attribution (...) of responsibility for health behavior, liberty to choose, and the effect on the participants’ psychosocial well-being. It is discussed whether and how measures can be taken to deal with these aspects. It seems evident that the ethical aspects are mainly concerned with the vulnerability of adolescents identified as overweight. However, we claim that when individual feedback and counseling is provided, tailored interventions have a unique potential to empower adolescents to make ethically anchored decisions about their own health behavior. (shrink)

The controversy surrounding targeted killings represents a crisis of conscience for policymakers, lawyers, philosophers and leading military experts grappling with the moral and legal limits of the war on terror. The book examines the legal and philosophical issues raised by government efforts to target suspected terrorists without giving them the safeguards of a fair trial.

The purpose of this paper is the analysis of both legal and ethical ways of justifying targeted killings. I compare two legal models: the law enforcement model vs the rules of armed conflicts; and two ethical ones: retribution vs the right of self-defence. I argue that, if the targeted killing is to be either legally or ethically justified, it would be so due to fulfilling of some criteria common for all acceptable forms of killing, and not because terrorist activity is (...) somehow distinguished and gives special privileges to a state that fights it. The practical implication of my analysis is that one of the most spectacular targeted killings, which was the targeting and killing of Osama bin Laden in May 2011, was not justified, because it was only supposed to be a retribution for the September 11th terrorist attacks. (shrink)

As Nelson Goodman highlighted, there are two main senses of “abstract” that can be found in discussions about abstract art. On the one hand, a representation is abstract if it leaves out certain features of its target. On the other hand, something can be abstract to the extent that it does not represent a concrete subject. The first sense of “abstract” is well-known in philosophy of science. For example, philosophers discuss mathematical models of physical, biological, and economic systems as being (...) abstract in this sense. However, it is the second sense that dominates discussions of abstract art in aesthetics. For example, abstract art was (and is) considered revolutionary precisely for being non-figurative. Through an analysis of artists including Kandinsky, Malevich, and Mondrian, we develop a reading of this second sense, which we call “generative abstraction,” as opposed to “subtractive” abstraction. Generative abstraction is a process in which a new artifact is created which does not represent the initial concrete target system that inspired it (if there was one), where the artifact’s features are explored for their own sake, and where the “language” of the new artifact is in some way more “universal.” Focusing on this sense of abstraction is helpful in revealing the complexity of the process of crafting an abstract artifact, in problematizing the notion that abstraction can always be un-done (or concretized), as well as revealing new ways for abstractions to be epistemically (un)successful. (shrink)

In the atavistic model of cancer progression, tumor cell dedifferentiation is interpreted as a reversion to phylogenetically earlier capabilities. The more recently evolved capabilities are compromised first during cancer progression. This suggests a therapeutic strategy for targeting cancer: design challenges to cancer that can only be met by the recently evolved capabilities no longer functional in cancer cells. We describe several examples of this target‐the‐weakness strategy. Our most detailed example involves the immune system. The absence of adaptive immunity in (...) immunosuppressed tumor environments is an irreversible weakness of cancer that can be exploited by creating a challenge that only the presence of adaptive immunity can meet. This leaves tumor cells more vulnerable than healthy tissue to pathogenic attack. Such a target‐the‐weakness therapeutic strategy has broad applications, and contrasts with current therapies that target the main strength of cancer: cell proliferation. (shrink)

This article responds to Anh Le’s critique of my Journal of Military Ethics article entitled “The Morality of Retributive Targeted Killing.” Le argues that while retribution can in theory function...

Many phenomena in the natural world are complex, so scientists study them through simplified and idealised models. Philosophers of science have sought to explain how these models relate to the world. On most accounts, models do not represent the world directly, but through target systems. However, our knowledge of target systems is incomplete. First, what is the process by which target systems come about? Second, what types of entity are they? I argue that the basic conception of target systems, on (...) which other conceptions depend, is as parts of the world. I outline the process of target system specification and show that it is a crucial step in modelling. I also develop an account of target system evaluation, based on aptness. Paying close attention to target system specification and evaluation can help scientists minimise the frequency and extent of mistakes, when they are using models to investigate phenomena in complex real-world systems. (shrink)

Geron recently announced that it had begun enrolling patients in the world's first-in-human clinical trial involving cells derived from human embryonic stem cells (hESCs). This trial raises important questions regarding the future of hESC-based therapies, especially in spinal cord injury (SCI) patients. We address some safety and efficacy concerns with this research, as well as the ethics of fair subject selection. We consider other populations that might be better for this research: chronic complete SCI patients for a safety trial, subacute (...) incomplete SCI patients for an efficacy trial, and perhaps primary progressive multiple sclerosis (MS) patients for a combined safety and efficacy trial. (shrink)

Many have rejected contextualism about ?knows? because the view runs into trouble with intra- and inter-contextual disagreement reports. My aim in this paper is to show that this is a mistake. First, I outline four desiderata for a contextualist solution to the problem. Second, I argue that two extant solutions to the problem fail to satisfy the desiderata. Third, I develop an alternative solution which satisfies the four desiderata. The basic idea, put roughly, is that ?knowledge? ascriptions serve the function (...) of recommending good informants, and disagreement over ?knowledge? ascriptions is a matter of conflicting recommendations. The upshot is that intra- and inter-contextual disagreement reports provide little?if any?reason to reject contextualism. (shrink)

We consider the problem of choosing the location of a public facility either (a) on a tree network or (b) in a Euclidean space. (a) (1996) characterize the class of target rules on a tree network by Pareto efficiency and population-monotonicity. Using Vohra's (1999) characterization of rules that satisfy Pareto efficiency and replacement-domination, we give a short proof of the previous characterization and show that it also holds on the domain of symmetric preferences. (b) The result obtained for model (a) (...) proves to be crucial for the analysis of the problem of choosing the location of a public facility in a Euclidean space. Our main result is the characterization of the class of coordinatewise target rules by unanimity, strategy-proofness, and either replacement-domination or population-monotonicity. (shrink)

While mass spectrometry (MS)‐based quantification of small molecules has been successfully used for decades, targeted MS has only recently been used by the proteomics community to investigate clinical questions such as biomarker verification and validation. Targeted MS holds the promise of a paradigm shift in the quantitative determination of proteins. Nevertheless, targeted quantitative proteomics requires improvisation in making sample processing, instruments, and data analysis more accessible. In the backdrop of the genomic era reaching its zenith, certain questions arise: is the (...) proteomic era about to come? If we are at the beginning of a new future for protein quantification, are we prepared to incorporate targeted proteomics at the benchside for basic research and at the bedside for the good of patients? Here, an overview of the knowledge required to perform targeted proteomics as well as its applications is provided. A special emphasis is placed on upcoming areas such as peptidomics, proteoform research, and mass spectrometry imaging, where the utilization of targeted proteomics is expected to bring forth new avenues. The limitations associated with the acceptance of this technique for mainstream usage are also highlighted. (shrink)

The purpose of this paper is to provide a philosophical defense for targeted killings in the wars against terror. The paper argues that if one accepts the moral legitimacy of the large-scale killing of combatants in conventional wars, one cannot object - on moral grounds - to the targeted killing of terrorists in wars against terror. If one rejects this legitimacy, one must object to all killing in war, targeted and non-targeted alike, and thus not support the view, which is (...) criticized here, that targeted killings are particularly disturbing from a moral point of view. (shrink)

The EU General Data Protection Regulation recognizes the data subject’s consent as one of the legal grounds for data processing. Targeted advertising, based on personal data processing, is a central source of revenue for data controllers such as Google and Facebook. At present, the implementation of consent mechanisms for such advertisements are often not well developed in practice and their compliance with the GDPR requirements can be questioned. The absence of consent may mean an unlawful data processing and a lack (...) of control of the user on his personal data. However, consent mechanisms that do not fully satisfy GDPR requirements can give users a false sense of control, encouraging them to allow the processing of more personal data than they would have otherwise. In this paper, we identify the features, originating from GDPR requirements, of consent mechanisms. For example, the GDPR specifies that a consent must be informed and freely given, among other requirements. We then examine the Ad Consent Mechanism of Facebook that is based on processing of user activity data off Facebook Company Products provided by third parties with respect to these features. We discuss to what extent this consent mechanism respects these features. To the best of our knowledge, our evaluation of Facebook’s Ad Consent Mechanism is the first of its kind. (shrink)

Based on a comparative case study of six cross-sector partnerships (CSPs) in global health, we illustrate how a CSP’s aim to address a social issue on the basis of products influences the governance of collective action within the partnership and beyond, at the field level. We show how such product focus, through specialization, influences a CSP’s structures and interaction culture and, as a reflection of the partners’ underlying logics, generates different CSP-field effects. Specifically, if conceived as self-contained and without considering (...) the implications for other field players and programs, a product focus may expedite collective action within the CSP, but spur fragmentation and disruption at the field level. Conversely, if designed to strengthen field capacity and integration at the product-field interlinkages, a product focus may take longer to form but helps avoid the above field effects. On this basis, we advance theory on CSPs’ product focus as a multilevel coordination mechanism and elaborate on the implications for designing product-based CSPs. (shrink)

The role of membrane receptors is regarded as being to transduce the signal represented by ligand binding from the external cell surface across the membrane into the cell. Signals are subsequently conveyed from the cytoplasm to the nucleus through a combination of second-messenger molecules, kinase/phosphorylation cascades, and transcription factor (TF) translocation to effect changes in gene expression. Mounting evidence suggests that through direct targeting to the nucleus, polypeptide ligands and their receptors may have an important additional signaling role. Ligands (...) such as those of the platelet-derived and fibroblast growth factor classes, as well as cytokines such as interferon-γ and interleukins-1 and -5, have been found to localize in the nucleus through the action of nuclear localization sequences (NLSs). Where tested, these NLSs appear to be essential for full signaling activity and may be responsible for cotranslocating receptors to the nucleus in complexes with their ligands. The implication is that, subsequent to endocytosis at the membrane, particular polypeptide ligands or their receptors, or both, may translocate to the nucleus to participate directly in gene regulation. BioEssays 20:400–411, 1998.© 1998 John Wiley & Sons Inc. (shrink)

Targeted hypermutation has proven to be a useful survival strategy for bacteria under severe stress and is also used by multicellular organisms in specific instances such as the mammalian immune system. This might appear surprising, given the generally observed deleterious effects of poor replication fidelity/high mutation rate. A previous theoretical model designed to explore the role of replication fidelity in the origin of life was applied to a simulated hypermutation scenario. The results confirmed that the same model is useful for (...) analyzing hypermutation and can predict the effects of the same parameters (survival probability, replication fidelity, mutation effect, and others) on the survival of cellular populations undergoing hypermutation as a result of severe stress. (shrink)

Selective protein degradation maintains cellular homeostasis, but this process is disrupted in many diseases. Targeted protein degradation (TPD) approaches, built upon existing cellular mechanisms, are promising methods for therapeutically regulating protein levels. Here, we review the diverse palette of tools that are now available for doing so throughout the gene expression pathway and in specific cellular compartments. These include methods for directly removing targeted proteins via the ubiquitin proteasome system with proteolysis targeting chimeras (PROTACs) or dephosphorylation targeting chimeras (...) (DEPTACs). Similar effects can also be achieved through the lysosomal system with autophagy‐targeting chimeras (AUTACs), autophagosome tethering compounds (ATTECs), and lysosome targeting chimeras (LYTACs). Other methods act upstream to degrade RNAs (ribonuclease targeting chimeras; RIBOTACs) or transcription factors (transcription factor targeting chimeras; TRAFTACs), offering control throughout the gene expression process. We highlight the evolution and function of these methods and discuss their clinical implications in diverse disease contexts. (shrink)

Cancer drugs are broadly classified into two categories: cytotoxic chemotherapies and targeted therapies that specifically modulate the activity of one or more proteins involved in cancer. Major advances have been achieved in targeted cancer therapies in the past few decades, which is ascribed to the increasing understanding of molecular mechanisms for cancer initiation and progression. Consequently, monoclonal antibodies and small molecules have been developed to interfere with a specific molecular oncogenic target. Targeting gain‐of‐function mutations, in general, has been productive. (...) However, it has been a major challenge to use standard pharmacologic approaches to target loss‐of‐function mutations of tumor suppressor genes. Novel approaches, including synthetic lethality and collateral vulnerability screens, are now being developed to target gene defects in p53, PTEN, and BRCA1/2. Here, we review and summarize the recent findings in cancer genomics, drug development, and molecular cancer biology, which show promise in targeting tumor suppressors in cancer therapeutics. (shrink)

Targeted killing is a subspecies of assassination, deployed against irregular combatants such as terrorists. The justification for targeted killing bypasses the usual ‘war paradigm’ and ‘criminal enforcement paradigm’, and is thus unusual. There are various ways of securing such a justification, but also a number of dangers attending these arguments.

(2002). 'Target Approval Delays Cost Air Force Key Hits': Law, Policy, Ethics and the Warfighter's Dilemma. Journal of Military Ethics: Vol. 1, No. 2, pp. 113-124.

The nineteenth-century strategist Carl von Clausewitz describes “fog” and “friction” as fundamental features of war. Military leverage of sophisticated information technology in the twenty-first century has improved some tactical operations but has not lifted the fog of war, in part, because the means for reducing uncertainty create new forms of it. Drawing on active duty experience with an American special operations task force in Western Iraq from 2007 to 2008, this article traces the targeting processes used to “find, fix, (...) and finish” alleged insurgents. In this case they did not clarify the political reality of Anbar province but rather reinforced a parochial worldview informed by the Naval Special Warfare community. The unit focused on the performance of “direct action” raids during a period in which “indirect action” engagement with the local population was arguably more appropriate for the strategic circumstances. The concept of “data friction”, therefore, can be understood not simply as a form of resistance within a sociotechnical system but also as a form of traction that enables practitioners to construct representations of the world that amplify their own biases. (shrink)