Aiming at the problem of low pedestrian target detection accuracy, we propose a detection algorithm based on optimized Mask R-CNN which uses the latest research results of deep learning to improve the accuracy and speed of detection results. Due to the influence of illumination, posture, background, and other factors on the human target in the natural scene image, the complexity of target information is high. SKNet is used to replace the part of the convolution module in the (...) depth residual network model in order to extract features better so that the model can adaptively select the best convolution kernel during training. In addition, according to the statistical law, the length-width ratio of the anchor box is modified to make it more accord with the natural characteristics of the pedestrian target. Finally, a pedestrian target dataset is established by selecting suitable pedestrian images in the COCO dataset and expanded by adding noise and median filtering. The optimized algorithm is compared with the original algorithm and several other mainstream target detection algorithms on the dataset; the experimental results show that the detection accuracy and detection speed of the optimized algorithm are improved, and its detection accuracy is better than other mainstream target detection algorithms. (shrink)

A theory is presented to explain how accurate, single-joint movements are controlled. The theory applies to movements across different distances, with different inertial loads, toward targets of different widths over a wide range of experimentally manipulated velocities. The theory is based on three propositions. (1) Movements are planned according to “strategies” of which there are at least two: a speed-insensitive (SI) and a speed-sensitive (SS) one. (2) These strategies can be equated with sets of rules for performing diverse movement tasks. (...) The choice between SI and SS depends on whether movement speed and/or movement time (and hence appropriate muscle forces) must be constrained to meet task requirements. (3) The electromyogram can be interpreted as a low-pass filtered version of the controlling signal to the motoneuron pools. This controlling signal can be modelled as a rectangular excitation pulse in which modulation occurs in either pulse amplitude or pulse width. Movements to different distances and with loads are controlled by the SI strategy, which modulates pulse width. Movements in which speed must be explicitly regulated are controlled by the SS strategy, which modulates pulse amplitude. The distinction between the two movement strategies reconciles many apparent conflicts in the motor control literature. (shrink)

Level measurements, thickness measurement or remote surface detection using ultrasonic pulse transit method require that the target surface be at 90 O to the incident beam so that reflected beam comes back at 180-degree angle to effectively use this method. This is perfectly true in case of flat, solid surface at right angle to the incident beam. But surface irregularities of a porous, non-smooth, uneven material such as snow cause penetration of incident wave into the surface, absorption of the (...) incident energy, scatter of energy in many directions and further attenuation of reflected signal making it difficult to detect the reflected echo. Such a received reflected echo is very low in amplitude and is heavily noise-ridden. The successful surface detection with excellent repeatability and accuracy without any false measurement in this case requires combination of physical acoustic, mechanical, hardware and software techniques together. In this paper we discuss the suitable physical, mechanical, electronics design to physically implement the theory of Arrayed Ultrasonic transducers to shape up the directional response, beam width and avoid interference to improve the chances of proper and sufficient reflection from the non-smooth, highly porous, uneven, non-planar irregular surface. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Diacritics 31.4 (2001) 54-82 [Access article in PDF] Seeing With The Body The Digital Image In Postphotography Mark B. N. Hansen In a well-known scene from the 1982 Ridley Scott film Bladerunner, Rick Deckard scans a photograph into a 3-D rendering machine and directs the machine to explore the space condensed in the two-dimensional photograph as if it were three-dimensional [see fig. 1]. Following Deckard's commands to zoom in (...) and to pan right and left within the image space, the machine unpacks the "real" three-dimensional world represented by the two-dimensional photograph [see figs. 2-3]. After catching a glimpse of his target—a fugitive replicant—reflected from a mirror within the space, Deckard instructs the machine to move around behind the object obstructing the two-dimensional photographic view of the replicant and to frame what it sees [see figs. 4-5]. Responding to the print command issued by Deckard, the machine dispenses a photograph of the replicant which is, quite literally, a close-up of an invisible—indeed nonexistent—part of the two-dimensional original [see fig. 6]. And yet, following the fantasy of this scene, this impossible photograph is—or would be—simply the image of one particular data point within the data set comprising this three-dimensional data space. As fascinating as it is puzzling, this scene of an impossible rendering—a rendering of two-dimensional data as a three-dimensional space—can be related to the crisis brought to photography by digitization in two ways. On the one hand, in line with the film's thematic questioning of photography as a reliable index of memory, this scene foregrounds the technical capacity of digital processing to manipulate photographs. In this way, it thematizes the threat posed by digital technologies to traditional indexical notions of photographic realism. On the other hand, in what has turned out to be a far more prophetic vein, the scene presents a radically new understanding of the photographic image as a three-dimensional "virtual" space. Such an understanding presupposes a vastly different material existence of the photographic image: instead of a physical inscription of light on sensitive paper, the photograph has become a data set that can be rendered in various ways and thus viewed from various perspectives.The first position corresponds to the arguments made by William Mitchell in his now classic book, The Reconfigured Eye. In a comprehensive analysis of the techniques and possibilities of digital imaging, Mitchell concentrates on demarcating the traditional photographic image from its digital doppelgänger. While the specter of manipulation has always haunted the photographic image, it remains the exception rather than the rule: "There is no doubt that extensive reworking of photographic images to produce seamless transformations and combinations is technically difficult, time-consuming, and outside the mainstream of photographic practice. When we look at photographs we presume, unless we have some clear indications to the contrary, that they have not been reworked" [Mitchell 7]. To buttress this claim, Mitchell sketches three criteria for evaluating traditional photographic images: (1) does the image follow the conventions of photography and seem internally coherent? (2) does the visual evidence it presents [End Page 54]Stills from Blade Runner (Ridley Scott, 1982), courtesy of Warner Brothers Home Video. Rick Deckard navigates a two-dimensional image as a three-dimensional space." width="72" height="33" />Click for larger viewFigure 1Still from Blade Runner (Ridley Scott, 1982), courtesy of Warner Brothers Home Video. Rick Deckard navigates a two-dimensional image as a three-dimensional space.Stills from Blade Runner (Ridley Scott, 1982), courtesy of Warner Brothers Home Video. Rick Deckard navigates a two-dimensional image as a three-dimensional space." width="72" height="32" />Click for larger viewFigure 2Still from Blade Runner (Ridley Scott, 1982), courtesy of Warner Brothers Home Video. Rick Deckard navigates a two-dimensional image as a three-dimensional space.Stills from Blade Runner (Ridley Scott, 1982), courtesy of Warner Brothers Home Video. Rick Deckard navigates a two-dimensional image as a three-dimensional space." width="72" height="33" />Click... (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 a lower likelihood of children’s abuse exposure (among children of CSA-exposed mothers). _Methods:_ One hundred and eleven children ( M age = 9.53 years; 43 sexual abuse victims) and their (...) mothers ( M age = 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. _Conclusion:_ 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 T-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 temporal widths of a light pulse as measured in different inertial frames are shown to have a relation more complicated than that of a simple time dilatation. The result is compared with the dilatation in the twin paradoxGedanken experiment. The light pulse measurement requires two observers in two different frames. The measurements of the observers are compared. For the twin experiment a comparison is made between two clocks which have undergone different histories between the two points at which their (...) world lines intersect. (shrink)

In electrical resistance tomography technology for human lung, under the same experimental conditions, the width of the sensitive field boundary electrode has a significant impact on the calculation accuracy of the inverse problem besides the finite element model topology. Aiming to improve the quality of reconstructed images, the FEM for human lung was set up based on prior knowledge. On this basis, the electrode width of the FEM was optimised by comparing the morbidity degrees of the sensitivity matrix (...) and Hessian matrix, the uniformity of sensitivity distribution, and the quality of reconstructed images, which can improve the accuracy of solving the inverse problem significantly. (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.

We study tree-like decompositions of models of a theory and a related complexity measure called partition width. We prove a dichotomy concerning partition width and definable pairing functions: either the partition width of models is bounded, or the theory admits definable pairing functions. Our proof rests on structure results concerning indiscernible sequences and finitely satisfiable types for theories without definable pairing functions. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Smart MR contrast agents exhibit modulation of their relaxivity by specific physiological or biochemical trigger-events, while targeted MR contrast agents are envisioned to deliver the large gadolinium chelates into the target tissue. In an effort to develop novel smart and targeted MR contrast agents, the series of the DO3A based multifunctional chelating agents with the variable length of the side chain has been synthesized. They serve as valuable multipurpose precursors for contrast agents based on gadolinium chelates in the design (...) of relaxometric MR probes. The presence of the amino group in the side chain of the macrocycle allows for conversion into various functional groups (aminophosponates, aminocarboxylates, etc.) or for conjugation with different biomolecules, dyes, and polymers. Choice of the functional groups depends on the.. (shrink)

This paper investigates Neoplatonist literary criticism by framing the special interest in the target of each dialogue within the context of cosmo-literary theory. The starting hypothesis is that the themes of Plato's dialogues do not fully meet the expectations of a new didactics based on isagogical schemes as an image of Neoplatonic metaphysics. Among these schemes is the target of each dialogue, whose relation to the theme can be explained, in a fruitful and innovative way, through a cosmic (...) analogy. Thus after examining the more or less explicit criticism of literary criteria of analysis by Plato's ancient exegetes, this article will focus on how Neoplatonists load the Greek termskopos(target) with metaphysical content and, accordingly, on how we should translate it in accordance with the commentators’ intentions. It will show that the target is the literary counterpart to the One, but that it should not be confused with the theme because the latter must be seen as the literary counterpart to the Intellect. (shrink)

Marr's theory of vision is often said to exemplify wide psychology. The claim rests primarily on Marr's appeal to a high level theory of computational functions. I agree that Marr's theory embodies an exemplary form of wide psychology; what is exemplary about it is the appeal to perceptual tasks. But I argue that the result of invoking task considerations is that we should not adhere to Marr's own conception of proper explanatory width. There is no one conception of (...) class='Hi'>width that has a priviledged place in explanation. (shrink)

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)

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)

Modern science is increasingly focused on research that solves specific technological problems. In the world literature there are different, but generally similar, names for such studies. For example, German and Russian researchers use the term «problem-oriented research», the names «mission-oriented research», research as a response to «great challenges» and «frontier research», «science mode 2» are also used. In Ukraine, particularly in the National Academy of Sciences of Ukraine, the name «targeted research programs» and «targeted scientific (scientific and technical) projects» are (...) used. The article analyzes features of targeted research and the status of the obtained knowledge. It emphasizes their direct involvement in the social sphere — economic, political, social relations in general, because they are the basis of modern technology and their development is interested in the general public — producers and consumers of material goods. The knowledge obtained in these studies is knowledge «to order», which requires a solution to the relationship between basic and applied research, the principles of professional activity of scientists, «academic freedoms», changes in epistemological, socio-humanitarian principles of science as a social institution. In the professional activity of a scientist, the praxeologization of science requires an orientation on the humanity of the produced knowledge, which, in fact, is a combination of knowledge about nature with knowledge about human. In this case, the scientist must be an expert in related disciplines. The organizers of targeted research solve this situation through the collective implementation of research, or, as expressed by R. Florida, the use of «social intelligence». At the same time, the latter requires from the scientist, as a specialist, not only purely professional competencies but also individual psychological skills of work (creativity) in an interdisciplinary team (mutual assistance, tolerance, empathy, etc.) and interaction with the transdisciplinary community. Otherwise, the profession of a scientist becomes socially engaged in terms of competencies and activities, and the leader in the research team performs moderative rather than directive functions. Although targeted research programs are becoming widespread, leading in solving urgent practical problems, but in the scientific field, a balance must be maintained between research «to order» and research that will be the basis for future development of science and society. (shrink)

This paper presents a generalization of Fine’s completeness theorem for transitive logics of finite width, and proves the Kripke completeness of transitive logics of finite “suc-eq-width”. The frame condition for each finite suc-eq-width axiom requires, in rooted transitive frames, a finite upper bound of cardinality for antichains of points with different proper successors. The paper also presents a generalization of Rybakov’s completeness theorem for transitive logics of prefinite width, and proves the Kripke completeness of transitive logics (...) of prefinite “suc-eq-width”. The frame condition for each prefinite suc-eq-width axiom requires, in rooted transitive frames, a finite upper bound of cardinality for antichains of points that have a finite lower bound of depth and have different proper successors. We will construct continuums of transitive logics of finite suc-eq-width but not of finite width, and continuums of those of prefinite suc-eq-width but not of prefinite width. This shows that our new completeness results cover uncountably many more logics than Fine’s theorem and Rybakov’s theorem respectively. (shrink)

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)

From the daily life, how to get the access to philosophy, what is the approaches to philosophy? Regarding the big topics /big affair in the world, are they related to the philosophy? what and how shall the philosophy do? About some concept, word, have we already fully confirmed their meaning? What shall the philosophy do to make their meaning clear and confirmed? Refers to the philosophy itself, have we already confirmed its study object? What is Philosophy? what is the main (...) study object for the philosophy? It is the pity that till now, for the whole world philosophy field, the main study object for the philosophy have not been confirmed. There are various kinds of answer, this means philosophy, from the past one hundred years, till now, has not work out the state of downturn and confusion.Since the philosophy itself is not clear, then no wonder from the late of 19 century to now, philosophy seems did litting achievement for the human being, for the civilization, for the progress, its glory looks gray, compared with Science, which is in fact born by philosophy although. So, before the philosophy could work well for the civilization, firstly, we should make the philosophy clear, confirm the main object of philosophy, target the correct object for philosophy! Only after this first work, we could expect philosophy do well on its tasks and function. For my this paper, its essential point is to present an answer for the target object belongs to the philosophy. Through demonstrate as per scientific logic and philosophy’s whole history, this answer, namely, the only target object belongs to philosophyis the Ontology and Cognition. Let philosophy go back to its correct place, its correct way. Then, it could move ahead. only after we get new progress on the study of Ontology and Cognition, and with the help of this new achievement of Ontology and Cognition, we can get progress on the study of the fields related to the human being and progress of civilization. As far as what is the Ontology and Cognition, which kind new achievement of Ontology and Cognition we couldexpect, that is the next step. (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 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. (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)

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)

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)

We develop a method for showing that various modal logics that are valid in their countably generated canonical Kripke frames must also be valid in their uncountably generated ones. This is applied to many systems, including the logics of finite width, and a broader class of multimodal logics of ‘finite achronal width’ that are introduced here.

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)

Known terrorists are often targeted for death by the governments of Israel and the United States. Several thousand have been killed by drones or by operatives on the ground in the last twenty years. Is this form of killing justified? Is there anything about it that should disturb us? In this for-and-against book, political theorists Jeremy Waldron and Tamar Meisels engage in extended debate to illuminate these issues. They consider the actions of targeting and hunting down named individuals, and they (...) address concerns about the possibility of this practice getting out of hand and being extended beyond the realm of counter-terrorism. (shrink)

The federal government is funding a sea change in health care by investing in interventions targeting social determinants of health, which are significant contributors to illness and health inequity. This funding power has encouraged states, professional and accreditation organizations, health care entities, and providers to focus heavily on social determinants. We examine how this shift in focus affects clinical practice in the fields of oncology and emergency medicine, and highlight potential areas of reform.

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)

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)

(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.

Proteolysis-targeting chimeric molecules represent an emerging technique that is receiving much attention for therapeutic intervention. The mechanism is based on the inhibition of protein function by hijacking a ubiquitin E3 ligase for protein degradation. The hetero-bifunctional PROTACs contain a ligand for recruiting an E3 ligase, a linker, and another ligand to bind with the protein targeted for degradation. Thus, PROTACs have profound potential to eliminate “undruggable” protein targets, such as transcription factors and non-enzymatic proteins, which are not limited to physiological (...) substrates of the ubiquitin-proteasome system. These findings indicate great prospects for PROTACs in the development of therapeutics. However, there are several limitations related to poor stability, biodistribution, and penetrability in vivo. This review provides an overview of the main PROTAC-based approaches that have been developed and discusses the promising opportunities and considerations for the application of this technology in therapies and drug discovery. The hetero-bifunctional PROTAC molecules contain a ligand for recruiting an E3 ligase linked with a ligand to bind with the protein targeted for degradation. Thus, PROTACs have profound potential to eliminate “undruggable” disease-causing proteins, which are not limited to physiological substrates of the ubiquitin-protease system, suggesting great prospects for therapeutic development. (shrink)

This paper by Prof. Daniel Statman, moral philosopher at the University of Haifa in Israel and author of the books Moral Dilemmas and Religion and Morality , offers a philosophical defense for such targeted killings or assassinations as those by Israel of Palestinians. The paper argues that if one accepts the moral legitimacy of the large-scale killing of combatants in conventional (what may come to be called 'old-fashioned') wars, one cannot object -- on moral grounds -- to the targeted killing (...) of terrorists in what are called 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)