Flap EndoNuclease‐1 (FEN‐1) is a multifunctional and structure‐specific nuclease involved in nucleic acid processing pathways. It plays a critical role in maintaining human genome stability through RNA primer removal, long‐patch base excision repair and resolution of dinucleotide and trinucleotide repeat secondary structures. In addition to its flap endonuclease (FEN) and nick exonuclease (EXO) activities, a new gap endonuclease (GEN) activity has been characterized. This activity may be important in apoptotic DNA fragmentation and in resolving stalled DNA replication forks. The multiple (...) functions of FEN‐1 are regulated via several means, including formation of complexes with different protein partners, nuclear localization in response to cell cycle or DNA damage and post‐translational modifications. Its functional deficiency is predicted to cause genetic diseases, including Huntington's disease, myotonic dystrophy and cancers. This review summarizes the knowledge gained through efforts in the past decade to define its structural elements for specific activities and possible pathological consequences of altered functions of this multirole player. BioEssays 27:717–729, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Tremor of the upper extremity is a significant cause of disability in some patients with multiple sclerosis. The MS tremor is complex because it contains an ataxic intentional tremor component due to the involvement of the cerebellum and cerebellar outflow pathways by MS plaques, which makes the MS tremor, in general, less responsive to medications or deep brain stimulation than those associated with essential tremor or Parkinson's disease. The cerebellar component has been thought to be the main reason for making (...) DBS less effective, although it is not clear whether it is due to the lack of suppression of the ataxic tremor by DBS or else. The goal of this study was to clarify the effect of DBS on cerebellar tremor compared to non-cerebellar tremor in a patient with MS. By wearing an accelerometer on the index finger of each hand, we were able to quantitatively characterize kinetic tremor by frequency and amplitude, with cerebellar ataxia component on one hand and that without cerebellar component on the other hand, at the beginning and end of the hand movement approaching a target at DBS Off and On status. We found that cerebellar tremor surprisingly had as good a response to DBS as the tremor without a cerebellar component, but the function control on cerebellar tremor was not as good due to its distal oscillation, which made the amplitude of tremor increasingly greater as it approached the target. This explains why cerebellar tremor or MS tremor with cerebellar component has a poor functional transformation even with a good percentage of tremor control. This case study provides a better understanding of the effect of DBS on cerebellar tremor and MS tremor by using a wearable device, which could help future studies improve patient selection and outcome prediction for DBS treatment of this disabling tremor. (shrink)

Proximity and interpersonal contact are prominent components of social connection. Giving affective touch to others is fundamental for human bonding. This brief report presents preliminary results from a pilot study. It explores if exposure to bonding scenes impacts the activity of specific muscles related to physical interaction. Fingers flexion is a very important component when performing most actions of affectionate contact. We explored the visuo-motor affective interplay by priming participants with bonding scenes and assessing the electromyographic activity of the fingers (...) flexor muscle, in the absence of any overt movements. Photographs of dyads in social interaction and of the same dyads not interacting were employed. We examined the effects upon the electromyographical activity: during the passive exposure to pictures, and during picture offset and when expecting the signal to perform a fingers flexion task. Interacting dyads compared to matched non-interacting dyads increased electromyographic activity of the fingers flexor muscle in both contexts. Specific capture of visual bonding cues at the level of visual cortex had been described in the literature. Here we showed that the neural processing of visual bonding cues reaches the fingers flexor muscle. Besides, previous visualization of bonding cues enhanced background electromyographic activity during motor preparation to perform the fingers flexion task, which might reflect a sustained leakage of central motor activity downstream leading to increase in firing of the respective motor neurons. These data suggest, at the effector level, an implicit visuo-motor connection in which social interaction cues evoke intrinsic dispositions toward affectionate social behavior. (shrink)

Let me offer an early disclaimer. I know exactly who the Founders were. I know exactly the crimes against humanity that they were responsible for and those they inherited and were not responsible for. I do not spend time extolling the virtues of Mr. Jefferson, Mr. Adams, Mr. Franklin, and Mr. Madison. Nothing in this work or in my experiment (my life's work) can change the fact or alter the history of the debasement of humanity that preceded the Declaration of (...) Independence (1776), the Constitution (1787), and the Bill of Rights (1791) they were a part of and the obvious fact that the major accomplishment of the Founders' theories about self-government did not apply to African Americans and Native Americans, women, and specifically Black women in their thinking. Still, there exists in their theological imagination infinite hope for their experiment. This work seeks to identify the evidence that shows and suggests that some of them were aware of a grand architectural experiment and design for the nation and its future. Every cracked, broken, and imperfect vessel can be used to bring forward hope. I am a personal witness to this fact of human existence. (shrink)

In this essay we discuss a class of apparently metaphorical idioms, exemplified by “fine as frog's hair,” that do not afford any obvious interpretation, and appear to have originated, at least in part, in language play. We review recent trends in both play theory and metaphor theory, and show that a playful approach to language is often an important element in the use and understanding of metaphors (and idioms generally), even when metaphors can be readily interpreted by means of a (...) vehicle-to-topic mapping. Based on this evidence we call for a more deliberate inclusion of language play in metaphor theory and analysis. (shrink)

Conceptual integration theory (Fauconnier & Turner, 1998, 2002) is re-examined in the light of recent criticisms (e.g., Gibbs, 2000, 2001). It is argued that the assumption of four independent "cognitive spaces" enters the model primarily as an entailment of the "space," "blending," and "construction" metaphors, leads to unnecessary ambiguity, and works against statement of the theory in a form that supports derivation of testable hypotheses. Several examples from Fauconnier and Turner (2002) are analyzed to show that they can be interpreted (...) more simply, without need of four separate "spaces." Suggestions are made for reformulating conceptual integration theory without the problematic metaphors. (shrink)

Recent work has shown that many problematic aspects of metaphor use and comprehension can be resolved through an account that includes both relevance and perceptual simulation. It has also been shown that metaphors often imply stories, and that stories are often metaphorical. Previous research on narratives has focused primarily on stories that appear either in formal literature or in structured interviews; this essay focuses on stories that occur as an integral part of conversation. It extends recent work on metaphor comprehension (...) to show how use and comprehension of stories in natural, informal conversations can be usefully analyzed in terms of perceptual simulations. Conversely, it extends previous work on storytelling to reveal the metaphorical element in many stories, and to emphasize the social (bonding through shared enjoyment) as well as informative and persuasive functions of storytelling. (shrink)

Halliday’s theory of grammatical metaphor has been quite influential among scholars who study structural approaches to language but has received little attention among researchers in cognitive linguistics. In this paper we summarize the aspects of Halliday’s approach that are most relevant to cognitive linguists, and show how key aspects of grammatical metaphor are related to the analysis of lexical and conceptual metaphors. Using an example of scientific writing analyzed by Halliday as well as examples from discourse previously subjected to conceptual (...) metaphor analysis, we show how the two approaches might usefully be combined to yield new insights in the analysis of naturally occurring discourse. (shrink)

The way the brain, body, and mind interact with social structure to shape communication has so far not received the attention it deserves. This book addresses this gap by providing a novel account of communication as a social, biological and neurological force. Combining theories from communication studies and psycholinguistics, and drawing on biological and evolutionary perspectives, it shows how communication is inherently both biological and social, and that language and the neural systems that support it have evolved in response to (...) a complex social environment. It introduces a clear set of terms based on current research, and illustrates key concepts using real-life examples from everyday conversation - speaking to a number of current debates around the evolutionary and biological basis of language, and the relationship between language, cognition, and environment. Thought provoking and engaging, it will change the way we think about the relationship between communication and cognition. (shrink)

In this article, we examine how cognitive metaphor theories might contribute to the theory and practice of poetry translation. We focus on translations from Chinese to English by Xu Yuanchong, both...

IntroductionE.J. LOWE: Event Causation and Agent CausationRalf STOECKER: Agents in ActionGeert KEIL: How Do We Ever Get Up? On the Proximate Causation of Actions and EventsMaria ALVAREZ: Letting Happen, Omissions, and CausationFrederick STOUTLAND: Responsive Action and the Belief-Desire ModelMarco IORIO: How Are Agents Related to Their Actions? The Existentialist ResponseJens KULENKAMPFF: What Oedipus Did When He Married Jocasta or What Ancient Tragedy Tells Us About Agents, Their Actions, and the WorldRüdiger BITTNER: Agents as RulersMonika BETZLER: How Can an Agent Rationally (...) Guide His Actions?Martina HERRMANN: Competence, Options, and RelationsWeitere Abhandlungen/Further ArticlesEduardo FERMANDOIS: Kommunikation ohne Sprache? Zu Davidsons später SprachphilosophieGuido IMAGUIRE: Die Form der Externalität in Russells An Essay on the Foundations of Geometry und die Ursprünge seiner RelationstheorieBuch-Symposium/Book-SymposiumJohn BICKLE: Precis of Psychoneural Reduction: The New WaveAnsgar BECKERMANN: Physicalism and New Wave ReductionismJ. Christopher MALONEY: Reservations about New Wave ReductionAchim STEPHAN: How to Lose the Mind-Body ProblemJohn BICKLE: New Wave Metascience. Replies to Beckermann, Maloney, and StephanBuchnotizen/Critical NotesEingesandte Bücher/Books Received. (shrink)

Inhaltsverzeichnis/Table of Contents Themenschwerpunkt/Special Topic: Bolzano & Kant Gastherausgeber/Guest Editor: Sandra Lapointe Sandra Lapointe: Introduction Sandra Lapointe: Is Logic Formal? Bolzano, Kant and the Kantian Logicians Nicholas F. Stang: A Kantian Reply to Bolzano¿s Critique of Kant¿s Analytic-Synthetic Distinction Clinton Tolley: Bolzano and Kant on the Place of Subjectivity in a Wissenschaftslehre Timothy Rosenkoetter: Kant and Bolzano on the Singularity of Intuitions Waldemar Rohloff: From Ordinary Language to Definition in Kant and Bolzano Weitere Artikel/Further Articles Christian Damböck: Wilhelm Diltheys empirische (...) Philosophie und der rezente Methodenstreit in der analytischen Philosophie Bernd Prien: Socially Constituted Actions and Objects Daniel Enrique Kalpokas: Two Dogmas of Coherentism Jon Cogburn & Jeff W. Roland: Strong, therefore Sensitive. Misgivings about DeRose¿s Contextualism Andre Abath: Brewer¿s Switching Argument Essay-Wettbewerb/Essay Competition Amadeus Magrabi: The Value of Feelings for Decision-Making Stefan Reining: Do Pain-Accompanying Emotions Mislead Us?¿Considerations in the Light of Reactive Dissociation Phenomena Peter Königs: Patriotism. A Case Study in the Philosophy of Emotions Besprechungsaufsatz/Review Essay Christopher Gauker: What Do Your Senses Say? On Burge¿s Theory of Perception Diskussion/Discussion Georg Brun: Adequate Formalization and De Morgan¿s Argument Buchnotizen/Critical Notes. (shrink)

Inhaltsverzeichnis/Table of Contents Abhandlungen/Articles Massimiliano Vignolo: Why Non-Factualists Should Love Conceptual Role Semantics Jeffrey Goodman: Fictionalia as Modal Artifacts Alberto Voltolini: Against Against Fictional Realism Roderick Batchelor: Grounds and Consequences Timm Lampert and Michael Baumgartner: The Problem of Validity Proofs Ish Haji: On the Direct Argument for the Incompatibility of Determinism and Moral Responsibility Matthias Neuber: Philosophie der modernen Physik ¿ Philipp Frank und Abel Rey Nicola Mössner: Testimoniale Akte neu definiert ¿ ein zentrales Problem des Zeugnisses Anderer Simon Dierig: (...) Goldmans Scheunen-Beispiel und das Problem der Vereinbarkeit von Externalismus und Selbstkenntnis Diskussionen/Discussions Essay-Wettbewerb/Essay Competition Besprechungen/Review Essays Buchnotizen/Critical Notes Eingelangte Bücher/Books Received. (shrink)

Toxoplasma gondii is a highly successful parasite capable of infecting virtually all warm-blooded animals by actively invading nucleated host cells and forming a modified compartment where it replicates within the cytosol. The parasite-containing vacuole provides a safe haven, even in professional phagocytes such as macrophages, which normally destroy foreign microbes. In an effort to eliminate the parasite, the host up-regulates a family of immunity-related p47 GTPases (IRGs), which are recruited to the parasite-containing vacuole, resulting in membrane rupture and digestion of (...) the parasite. To avoid this fate, highly virulent strains of Toxoplasma coat the external surface of their vacuole with a secretory serine/threonine kinase, known as ROP18. At this host-pathogen interface, ROP18 phosphorylates and inactivates IRGs, thereby protecting the parasite from killing. These findings reveal a novel molecular mechanism by which the parasite disarms host innate immunity. (shrink)

BackgroundDecisions about appropriate treatment at the end of life are common in modern healthcare. Non-treatment decisions (NTDs), comprising both withdrawal and withholding of (potentially) life-prolonging treatment are in principle accepted in Norway. However, in practice they may give rise to significant moral problems for health professionals, patients and next of kin. Here, patient values must be considered. It is relevant to study the moral views and intuitions of the general population on NTDs and special areas of contention such as the (...) role of next of kin in decision-making.MethodsElectronic survey to members of a nationally representative panel of Norwegian adults. Respondents were presented with vignettes describing patients with disorders of consciousness, dementia, and cancer where patient preferences varied. Respondents answered ten questions about the acceptability of non-treatment decision making and the role of next of kin.ResultsWe received 1035 complete responses (response rate 40.7%). A large majority, 88%, supported the right of competent patients to refuse treatment in general. When an NTD was in line with the patient’s previously expressed preferences, more respondents tended to find NTDs acceptable. More respondents would accept NTDs for themselves than for the vignette patients. In a scenario with an incompetent patient, clear majorities wanted the views of next of kin to be given some but not decisive weight, and more weight if concordant with the patient’s wishes. There were, however, large variations in the respondents’ views.ConclusionThis survey of a representative sample of the Norwegian adult population indicates that attitudes to NTDs are often in line with national laws and guidelines. However, the high variance among the respondents and relatively large weight given to next of kin’s views, indicate a need for appropriate dialogue among all stakeholders to prevent conflicts and extra burdens. Furthermore, the emphasis given to previously expressed opinions indicates that advance care planning may increase the legitimacy of NTDs and prevent challenging decision-making processes. (shrink)

Naturalistic ethics is the reigning paradigm among contemporary ethicists; in God and Cosmos, Baggett and Walls argue that this approach is seriously flawed. This book canvasses a broad array of secular and naturalistic ethical theories in an effort to test their adequacy in accounting for moral duties, intrinsic human value, prospects for radical moral transformation, and the rationality of morality. In each case, the authors argue, although various secular accounts provide real insights and indeed share common ground with theistic ethics, (...) the resources of classical theism and orthodox Christianity provide the better explanation of the moral realities under consideration. Among such realities is the fundamental insight behind the problem of evil, namely, that the world is not as it should be. Baggett and Walls argue that God and the world, taken together, exhibit superior explanatory scope and power for morality classically construed, without the need to water down the categories of morality, the import of human value, the prescriptive strength of moral obligations, or the deliverances of the logic, language, and phenomenology of moral experience. This book thus provides a cogent moral argument for God's existence, one that is abductive, teleological, and cumulative. (shrink)

"Legend is overdue for replacement, and an adequate replacement must attend to the process of science as carefully as Hull has done. I share his vision of a serious account of the social and intellectual dynamics of science that will avoid both the rosy blur of Legend and the facile charms of relativism.... Because of [Hull's] deep concern with the ways in which research is actually done, Science as a Process begins an important project in the study of science. It (...) is one of a distinguished series of books, which Hull himself edits."—Philip Kitcher, Nature "In Science as a Process, [David Hull] argues that the tension between cooperation and competition is exactly what makes science so successful.... Hull takes an unusual approach to his subject. He applies the rules of evolution in nature to the evolution of science, arguing that the same kinds of forces responsible for shaping the rise and demise of species also act on the development of scientific ideas."—Natalie Angier, New York Times Book Review "By far the most professional and thorough case in favour of an evolutionary philosophy of science ever to have been made. It contains excellent short histories of evolutionary biology and of systematics (the science of classifying living things); an important and original account of modern systematic controversy; a counter-attack against the philosophical critics of evolutionary philosophy; social-psychological evidence, collected by Hull himself, to show that science does have the character demanded by his philosophy; and a philosophical analysis of evolution which is general enough to apply to both biological and historical change."—Mark Ridley, Times Literary Supplement "Hull is primarily interested in how social interactions within the scientific community can help or hinder the process by which new theories and techniques get accepted.... The claim that science is a process for selecting out the best new ideas is not a new one, but Hull tells us exactly how scientists go about it, and he is prepared to accept that at least to some extent, the social activities of the scientists promoting a new idea can affect its chances of being accepted."—Peter J. Bowler, Archives of Natural History "I have been doing philosophy of science now for twenty-five years, and whilst I would never have claimed that I knew everything, I felt that I had a really good handle on the nature of science, Again and again, Hull was able to show me just how incomplete my understanding was.... Moreover, [Science as a Process] is one of the most compulsively readable books that I have ever encountered."—Michael Ruse, Biology and Philosophy. (shrink)

Drawing on work of the past decade, this volume brings together articles from the philosophy, history, and sociology of science, and many other branches of the biological sciences. The volume delves into the latest theoretical controversies as well as burning questions of contemporary social importance. The issues considered include the nature of evolutionary theory, biology and ethics, the challenge from religion, and the social implications of biology today (in particular the Human Genome Project).

Compares classic and contemporary theories of genetics and evolution and explores the role of teleological thought in biology.

Biological species have been treated traditionally as spatiotemporally unrestricted classes. If they are to perform the function which they do in the evolutionary process, they must be spatiotemporally localized individuals, historical entities. Reinterpreting biological species as historical entities solves several important anomalies in biology, in philosophy of biology, and within philosophy itself. It also has important implications for any attempt to present an "evolutionary" analysis of science and for sciences such as anthropology which are devoted to the study of single (...) species. (shrink)