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)

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)

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)

Eukaryotic genomes are packaged into nucleosomal chromatin, and genomic activity requires the precise localization of transcription factors, histone modifications and nucleosomes. Classic work described the progressive reassembly and maturation of bulk chromatin behind replication forks. More recent proteomics has detailed the molecular machines that accompany the replicative polymerase to promote rapid histone deposition onto the newly replicated DNA. However, localized chromatin features are transiently obliterated by DNA replication every S phase of the cell cycle. Genomic strategies now observe the (...) rebuilding of locus‐specific chromatin features, and reveal surprising delays in transcription factor binding behind replication forks. This implies that transient chromatin disorganization during replication is a central juncture for targeted transcription factor binding within genomes. We propose that transient occlusion of regulatory elements by disorganized nucleosomes during chromatin maturation enforces specificity of factor binding. (shrink)

Sex steroids, through their receptors, have potent effects on the signal pathways involved in osteogenic or myogenic differentiation. However, a considerable segment of those signal pathways has a prominent role in epithelial neoplastic transformation. The capability to intervene locally has focused on specific ligands for the receptors. Nevertheless, many signals are mapped to interactions of steroid receptor motifs with heterologous regulatory proteins. Some of those proteins interact with the glucocorticoid receptor and other factors essential to cell fate. Interactions of steroid (...) receptor domain motifs with heterologous proteins affect specific target pathways; consequently, manipulation of specified protein modules complexed with steroid receptors may be a next major step for enhancing molecular targeted therapeutics. In the future, intervention at specific sections of receptor primary sequence may prove therapeutically more efficient in targeting pathways of choice than ligand selectivity can be. (shrink)

This chapter contains section titled: Introduction Classical Molecular Biology Genomics and Post‐Genomics Proteomics Towards a Systems Biology? Philosophical Implications Conclusions: An Invitation References.

Reproductive proteins maintain species‐specific barriers to fertilization, affect the outcome of sperm competition, mediate reproductive conflicts between the sexes, and potentially contribute to the formation of new species. However, the specific proteins and molecular mechanisms that underlie these processes are understood in only a handful of cases. Advances in genomic and proteomic technologies enable the identification of large suites of reproductive proteins, making it possible to dissect reproductive phenotypes at the molecular level. We first review these technological advances and describe (...) how reproductive proteins are identified in diverse animal taxa. We then discuss the dynamic evolution of reproductive proteins and the potential selective forces that act on them. Finally, we describe molecular and genomic tools for functional analysis and detail how evolutionary data may be used to make predictions about interactions among reproductive proteins. (shrink)

Traditional frameworks for evaluating scientific models have tended to downplay their exploratory function; instead they emphasize how models are inherently intended for specific phenomena and are to be judged by their ability to predict, reproduce, or explain empirical observations. By contrast, this paper argues that exploration should stand alongside explanation, prediction, and representation as a core function of scientific models. Thus, models often serve as starting points for future inquiry, as proofs of principle, as sources of potential explanations, and as (...) a tool for reassessing the suitability of the target system. This is illustrated by a case study of the varied career of reaction-diffusion models in the study of biological pattern formation, which was initiated by Alan Turing in a classic 1952 paper. Initially regarded as mathematically elegant, but biologically irrelevant, demonstrations of how, in principle, spontaneous pattern formation could occur in an organism, such Turing models have only recently rebounded, thanks to advances in experimental techniques and computational methods. The long-delayed vindication of Turing’s initial model, it is argued, is best explained by recognizing it as an exploratory tool. (shrink)

that can serve as a foundation for more refined ontologies in the field of proteomics. Standard data sources classify proteins in terms of just one or two specific aspects. Thus SCOP (Structural Classification of Proteins) is described as classifying proteins on the basis of structural features; SWISSPROT annotates proteins on the basis of their structure and of parameters like post-translational modifications. Such data sources are connected to each other by pairwise term-to-term mappings. However, there are obstacles which stand in (...) the way of combining them together to form a robust meta-classification of the needed sort. We discuss some formal ontological principles which should be taken into account within the existing datasources in order to make such a metaclassification possible, taking into account also the Gene Ontology (GO) and its application to the annotation of proteins. (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)

The theme of the third annual Spring workshop of the HUPO-PSI was proteomics and beyond and its underlying goal was to reach beyond the boundaries of the proteomics community to interact with groups working on the similar issues of developing interchange standards and minimal reporting requirements. Significant developments in many of the HUPO-PSI XML interchange formats, minimal reporting requirements and accompanying controlled vocabularies were reported, with many of these now feeding into the broader efforts of the Functional Genomics (...) Experiment data model and Functional Genomics Ontology ontologies. (shrink)

The human genome contains about 30,000 genes, each creating several transcripts per gene. Transcript structures and expression are studied by high‐throughput transcriptomic techniques using microarrays. Generally, transcripts are not directly operating molecules, but are translated into functional proteins, post‐translationally modified by proteolysis, glycosylation, phosphorylation, etc., sometimes with great functional impact. Proteins need to be analyzed by proteomic techniques, less suited for high‐throughput. Two‐dimensional polyacrylamide gel electrophoresis (2D‐PAGE), separating thousands of proteins has developed slowly over the past quarter of a century. (...) This technique is now quite reproducible and suitable for differential proteomics, comparing normal and diseased cells/tissues revealing differentially regulated proteins. 2D‐PAGE is combined with protein‐identification methods, currently mass spectrometry (MS), which has been significantly improved over the last decade. Other proteomic techniques studying protein–protein interactions are now either established or still being developed, such as peptide or protein arrays, phage display, and the yeast two‐hybrid system. The strengths and weaknesses of these techniques are discussed. BioEssays 26:901–915, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Our research examined understandings of individual student target setting processes through semi?structured interviews with staff and students from two schools in England: a special school for students with severe learning difficulties and a linked mainstream secondary school. This article details some of the tensions and issues arising from perceived ownership of targets and the communication and sharing of these between and within schools, specifically focusing on dimensions of power and agency.

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)

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.

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)

Is the “act itself” of separating a pregnant woman and her previable child neither good nor bad morally, considered in the abstract? Recently, Maureen Condic and Donna Harrison have argued that such separation is justified to protect the mother’s life and that it does not constitute an abortion as the aim is not to kill the child. In our article on maternal–fetal conflicts, we agree there need be no such aim to kill (supplementing aims such as to remove). However, we (...) argue that to understand “abortion” as performed only where the death of the child is intended is to define the term too narrowly. Respect for the mother, the fetus, and the bond between them goes well beyond avoiding any such aim. We distinguish between legitimate maternal treatments simply aimed at treating or removing a damaged part of the woman and illegitimate treatments that focus harmfully on the fetal body and its presence within the mother’s body. In obstetrics as elsewhere, not all side effects for one subject of intervention can be outweighed by intended benefits for another. Certain side effects of certain intended interventions are morally conclusive. (shrink)

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)

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)

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 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)

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)

"This is an important new Cummins work.

This study examines social issues shareholder resolutions filed at S&P 500 companies in 2007. These firms received 86% of all social issues resolutions filed. Findings indicate that green resolutions were the most common single type (30% of social issues resolutions), but nearly one third (32%) of resolutions contained non-traditional content. Firms were more likely to be targeted if they were large in size and demonstrated poor treatment of employees and customers. As might be expected, the primary sponsors of social (...) issues resolutions were socially responsible investment funds, religious groups, and pension funds. Surprisingly, over half (52%) of resolutions made it onto proxy ballots in 2007, while there was sufficient dialogue between the target companies and shareholder activists for filers to withdraw only 29% of the resolutions (although 41% of green resolutions were withdrawn). Resolution content and firm response differed by type of filer. (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)

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)

An assumption underpinning the literature on human shields is that it is possible to distinguish between a voluntary shield and an involuntary shield. This is a claim I challenge with the purpose of demonstrating that the conventional basis on which we currently determine which human shields are liable to targeting is morally unjustifiable. Given the difficulty in tracking intentions, any presumption on the part of the targeting agent to know ex ante whether a civilian is volunteering to be a shield (...) cannot be adequately substantiated. I argue that, in lieu of categorising human shields as ‘voluntary’ and ‘involuntary’, we accept our epistemic limitations and recognise that we cannot know whether a shield has volunteered in the relevant sense of the word. This leads me to the conclusion that shields ought not be considered direct participants in hostilities, but rather be presumed to be non-combatants. (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)

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)

Mitochondria have been fundamental to the eco‐physiological success of eukaryotes since the last eukaryotic common ancestor (LECA). They contribute essential functions to eukaryotic cells, above and beyond classical respiration. Mitochondria interact with, and complement, metabolic pathways occurring in other organelles, notably diversifying the chloroplast metabolism of photosynthetic organisms. Here, we integrate existing literature to investigate how mitochondrial metabolism varies across the landscape of eukaryotic evolution. We illustrate the mitochondrial remodelling and proteomic changes undergone in conjunction with major evolutionary transitions. We (...) explore how the mitochondrial complexity of the LECA has been remodelled in specific groups to support subsequent evolutionary transitions, such as the acquisition of chloroplasts in photosynthetic species and the emergence of multicellularity. We highlight the versatile and crucial roles played by mitochondria during eukaryotic evolution, extending from its huge contribution to the development of the LECA itself to the dynamic evolution of individual eukaryote groups, reflecting both their current ecologies and evolutionary histories. (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)

(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.

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)

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)

We examine whether and when socially oriented shareholder activists use firms’ corporate social performance (CSP) to identify them as attractive targets for their activism. We build on the research in social movements theory and stakeholder theory to theorize how firms’ engagement with primary and secondary stakeholders reflected in their technical and institutional CSP respectively allows socially oriented shareholder activists to identify targets. We develop a theoretical model by identifying corporate targets’ degree of (1) receptivity to and (2) need to comply (...) with activist demands as two key dimensions of their corporate opportunity structure that explains the variance in firms’ attractiveness as targets for activist demands. We show that a firm’s technical and institutional CSP independently affect the likelihood of activists targeting the firm. We also show that our model has greater explanatory power at firms with high resource slack and from activists not identifying as socially responsible investment funds. Analysis of CSP and shareholder proposals data of 992 U.S. public firms over an 8-year window of observation largely supports our theory. (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.

Rapid actions to persons holding weapons were simulated using desktop virtual reality. Subjects responded to simulated (a) criminals, by pointing the computerÕs mouse at them and left-clicking (simulated shooting), (b) fellow police officers, by pressing the spacebar (safety signal), and (c) citizens, by inaction. In one of two tasks Black males holding guns were police officers while White males holding guns were criminals. In the other, Whites with guns were police and Blacks with guns were criminals. In both tasks Blacks (...) or Whites holding harmless objects were citizens. Signal detection analyses revealed two race effects that led to Blacks being incorrectly shot at more than Whites: a perceptual sensitivity effect (when held by Blacks guns were less distinguishable from harmless objects) and a response bias effect (objects held by Blacks were more likely to be treated as guns). Ó 2003 Elsevier Science (USA). All rights reserved. (shrink)

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)

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)

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)