The idea that there is such a thing as a human right to health has become pervasive. It has not only been acknowledged by a variety of international law documents and thus entered the political realm but is also defended in academic circles. Yet, despite its prominence the human right to health remains something of a mystery - especially with respect to its philosophical underpinnings. Addressing this unfortunate and intellectually dangerous insufficiency, this book critically assesses the stipulation that health is (...) a human right which - as international law holds - derives from the inherent dignity of the human person. Scrutinising the concepts underlying this stipulation, it shall conclude that such right cannot be upheld from a philosophical perspective. (shrink)

This work explores a controversial strategy for dealing with the chronic financial deficits in our health care system namely, rationing based on the criterion of personal responsibility. It argues that while rationing by personal responsibility is basically morally permissible, it is only possible in a very limited number of instances. For this reason, the use of this rationing criterion should be rejected.".

Der vorliegende Artikel plädiert dafür, die meist auf die Aspekte Todesdefinition, -kriterium und -feststellung fokussierte Diskussion über die moralische (Un-)Zulässigkeit der Spende und Transplantation vitaler Organe aufzubrechen und beim Nachdenken darüber das zum Ausgangspunkt der Überlegungen zu machen, was mit dem Tod eigentlich verloren geht, nämlich das Leben. Nach einer Antwort auf die Frage „Was ist Leben?“ suchend wird hierbei aufgezeigt, dass Leben nicht auf das Vorhandensein gewisser beobachtbarer physiologischer Größen reduzierbar ist, sondern in seinem wesentlichen Kern nur mit den (...) Mitteln der Philosophie als der actus primus alles Lebendigen und das, was wir gemeinhin Seele nennen, erklärt werden kann. Auf Basis der so gewonnenen Erkenntnisse wird geschlussfolgert, dass die Entnahme vitalen organischen Materials aus einer Person, deren Gehirnaktivitäten ausgefallen sind, immer prämortal erfolgt und damit einen Verstoß gegen die Tote-Spender-Regel bedeutet. (shrink)

Özlem, Doğan; philosophy; biography; Turkey.

Recent discoveries have suggested the concept that intracellular signals are the sum of multiple, site‐specified subsignals, rather than single, homogeneous entities. In the context of cancer, searching for compounds that selectively block subsignals essential for tumor progression, but not those regulating “house‐keeping” functions, could help in producing drugs with reduced side effects compared to compounds that block signaling completely. The Ras‐ERK pathway has become a paradigm of how space can differentially shape signaling. Today, we know that Ras proteins are found (...) in different plasma membrane microdomains and endomembranes. At these localizations, Ras is subject to site‐specific regulatory mechanisms, distinctively engaging effector pathways and switching‐on diverse genetic programs to generate different biological responses. The Ras effector pathway leading to ERKs activation is also under strict, space‐related regulatory processes. These findings may open a gate for aiming at the Ras‐ERK pathway in a spatially restricted fashion, in our quest for new anti‐tumor therapies. (shrink)

Activating the ERK pathway (extracellular signal‐regulated kinase pathway) has proven beneficial in several models of Huntington's disease (HD), and drugs that are protective in HD models have recently been found to activate ERK. Thus, the ERK cascade may be a potential target for therapeutic intervention in this currently untreatable disorder. HD is caused by an expanded polyglutamine repeat in the huntingtin (Htt) protein that actuates a diverse set of pathogenic mechanisms. In response to mutant Htt, ERK is activated and directs (...) a protective transcriptional response and inhibits caspase activation. Paradoxically, Htt also interferes with several signaling events of the ERK pathway. Mutant Htt compromises the ERK‐dependent transcriptional response to corticostriatal BDNF signaling. Mutant Htt also hinders glutamate uptake from the synaptic cleft by down‐regulating ERK‐dependent expression of glutamate transporters, leaving cells vulnerable to excitotoxicity. Some of this cellular complexity can be capitalized on to achieve selective activation of ERK, which can be protective. (shrink)

The extracellular‐signal regulated kinases 1/2 (ERK or ERKs) are involved in the regulation of important neuronal functions, including neuronal plasticity in normal and pathological conditions. We present findings that support the notion that the kinetics and localization of ERK are intrinsically linked, in that the duration of ERK activation dictates its subcellular compartmentalization and/or trafficking. The latter, in turn, dictates whether ERK‐expressing cells would enter a program of cell death, survival or differentiation. We summarize experimental data showing that chronic activation (...) of ERK plays a role in the mechanisms that trigger neurodegeneration. We also discuss how MKPs, members of the subclass of dual specificity phosphatases, might be the link between ERK kinetics and its subcellular localization. BioEssays 25:1085–1095, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Lysine methylation has been traditionally associated with histones and epigenetics. Recently, lysine methyltransferases and demethylases – which are involved in methylation of non‐histone substrates – have been frequently found deregulated in human tumours. In this realm, a new discovery has unveiled the methyltransferase SMYD3 as an enhancer of Ras‐driven cancer. SMYD3 is up‐regulated in different types of tumours. SMYD3‐mediated methylation of MAP3K2 increases mutant K‐Ras‐induced activation of ERK1/2. Methylation of MAP3K2 prevents it from binding to the phosphatase PP2A, thereby impeding (...) the impact of this negative regulator on Ras‐ERK1/2 signals, leading to the formation of lung and pancreatic adenocarcinomas. Furthermore, depletion of SMYD3 synergises with a MEK inhibitor, currently in clinical trials, to block Ras‐driven pancreatic neoplasia. These results underscore the importance of lysine methylation in the regulation of signalling pathways relevant for tumourigenesis and endorse the development of drugs targeting unregulated lysine methylation as therapeutic agents in the struggle against cancer. (shrink)

BREYSIG: SEIN U. ERK. GESCHICHTL. DINGE BD. 3.

Signal transduction pathways constructed around a core module of three consecutive protein kinases, the most distal being a member of the extracellular signal‐regulated kinase (ERK) family, are ubiquitous among eukaryotes. Recent work has defined two cascades activated preferentially by the inflammatory cytokines TNF‐α and IL‐1‐β, as well as by a wide variety of cellular stresses such as UV and ionizing radiation, hyperosmolarity, heat stress, oxidative stress, etc. One pathway converges on the ERK subfamily known as the ‘stress activated’ protein kinases (...) (SAPKs, also termed Jun N‐terminal kinases, JNKs), whereas the second pathway recruits the p38 kinases. Upstream inputs are diverse, and include small GTPases (primarily Rac and Cdc42; secondarily Ras) acting through mammalian homologs of the yeast Ste20 kinase, other kinase subfamilies (e.g. GC kinase) and ceramide, a putative second messenger for certain TNF‐α actions. These two cascades signal cell cycle delay, cellular repair or apoptosis in most cells, as well as activation of immune and reticuloendothelial cells. (shrink)

Spreds form a new protein family with an N‐terminal Enabled/VASP homology 1 domain (EVH1), a central c‐Kit binding domain (KBD) and a C‐terminal Sprouty‐related domain (SPR). They are able to inhibit the Ras–ERK signalling pathway after various mitogenic stimulations. In mice, Spred proteins are identified as regulators of bone morphogenesis, hematopoietic processes, allergen‐induced airway eosinophilia and hyperresponsiveness. They inhibit cell motility and metastasis and have a high potential as tumor markers and suppressors of carcinogenesis. Moreover, in vertebrates, XtSpreds help together (...) with XtSprouty proteins to coordinate gastrulation and mesoderm specification. Here, we give an overview of this new field and summarize the domain functions, binding partners, expression patterns and the cellular localizations, regulations and functions of Spred proteins and try to give perspectives for future scientific directions. BioEssays 29:897–907, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

The integrated stress response (ISR) is a key determinant of tumorigenesis in response to oncogenic forms of stress like genotoxic, proteotoxic and metabolic stress. ISR relies on the phosphorylation of the translation initiation factor eIF2 to promote the translational and transcriptional reprogramming of gene expression in stressed cells. While ISR promotes tumor survival under stress, its hyperactivation above a level of tolerance can also cause tumor death. The tumorigenic function of ISR has been recently demonstrated for lung adenocarcinomas (LUAD) with (...) KRAS mutations. ISR mediates the translational repression of the dual‐specificity phosphatase DUSP6 to stimulate ERK activity and LUAD growth. The significance of this finding is highlighted by the strong anti‐tumor responses of ISR inhibitors in pre‐clinical LUAD models. Elucidation of the mechanisms of ISR action in LUAD progression via cell‐autonomous and immune regulatory mechanisms will provide a better understanding of its tumorigenic role to fully exploit its therapeutic potential in the treatment of a deadly form of cancer. (shrink)

There are remarkable behavioral, neural, and genetic similarities between the way songbirds learn to sing and human infants learn to speak. Furthermore, the brain regions involved in birdsong learning, perception, and production have been identified and characterized in detail. In particular, the caudal medial nidopallium (the avian analog of the mammalian auditory‐association cortex) has been found to contain the neural substrate of auditory memory, paving the way for analyses of the underlying molecular mechanisms. Recently, the zebra finch genome was sequenced, (...) and annotated cDNA databases representing over 15,000 unique brain‐expressed genes are available, enabling high‐throughput gene expression analyses. Here we review the involvement of immediate early genes (e.g. zenk and arc), their downstream targets (e.g. synapsins), and their regulatory signaling pathways (e.g. MAPK/ERK) in songbird memory. We propose that in‐depth investigations of zenk‐ and ERK‐dependent cascades will help to further unravel the molecular basis of auditory memory. (shrink)

Adapter molecules in a variety of signal transduction systems link receptors to a limited number of commonly used downstream signaling pathways. During T‐cell development and mature T‐cell effector function, a multichain receptor (the pre‐T‐cell antigen receptor or the T‐cell antigen receptor) activates several protein tyrosine kinases. Receptor and kinase activation is linked to distal signaling pathways (PLC‐γ1 activation, Ca2+ influx, PKC activation and Ras/Erk activation) via the adapter protein LAT (Linker for Activation of T cells). Structure/function studies of LAT including (...) expression of selected LAT point mutations in vivo reveals that these multiple pathways are integrated at the level of the LAT adapter. These studies suggest that similar levels of control may be found in other systems where adapter molecules are known to have important functions. BioEssays 26:61–67, 2004. Published 2003 Wiley Periodicals, Inc. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:LIGHT AND METAPHOR IN PLOTINUS AND ST. THOMAS AQUINAS KEVIN CORRIGAN St. Thomas More College University of Saskatchewan Saskatoon, Saskatchewan I HAVE TWO CONCERNS in this paper. The first is a broad concern, related to the nature of metaphor, which stems from the destructionist or deconstructionist tendencies in some contemporary phenomenology or phenomenological existentialism. According to these views, the logocentric emphasis of the Western tradition must be shown for (...) what it really is : an attempt to erect a cover upon a fundamental absence. In Nietzsche's well known view, "truths are illusions of which one has forgotten that they are illusions; worn-out metaphors which have become powerless to affect the senses, coins which have their obverse effaced and now are no longer of account as coins but merely as metal." 1 For Jacques Derrida all metaphoricity is caught up in an endless circle, which precludes any privileged vantage-point from which one might determine order, hierarchy and center-point. In particular, the unique heliotropic metaphor which, in Derrida's polemic, determines the whole course of Western philosophy " from the Platonic eidos to the Hegelian idea" 2 rests only upon the infinite absence of circularity, for the movement of transference " which turns the sun into metaphor " also inevitably "turns philosophical metaphor towards the sun." 3 1 Nietzsche, "On Truth and Falsity in their Ultramoral Sense (1873)," Works 2 (New York: Russell and Russell, 1964), p. 180. 2 J. Derrida, "White Mythology", trans. F. C. T. Moore, New Literary History 6 (1974), 1: 5-74 ["La mythologie blanche" in Rhetorique et philosophie, Poetique 5 (Paris: Editions du Seliu, 1971)], p. 55. a Ibid., p. 51. 187 188 KEVIN CORRIGAN In this paper I shall examine the thought of Plotinus and Aquinas, broadly described as idealist and realist respectively, with a view to determining whether or not this transference from the physical to the metaphysical is only an illicit, covert erasure of the material sense and a forgetting that all metaphor is self-implicating, that there is no non-metaphorical standpoint from which to grasp the order and structure of the metaphorical. My second concern is much more specific. It is, first, to compare Plotinus and Aquinas on light and metaphor-two thinkers who might be considered to be poles apart on these questions: on the one hand, Plotinus, the father of Neoplatonic emanationism with its insistence upon the primacy of divine light and the father, surely too, of the tradition of light-metaphysics in the later, mediaeval period; on the other hand, St. Thomas, staunchly realist in the Aristotelian tradition. Second, I will seek to show that this first impression of the gulf between the two thinkers is not borne out by a close textual analysis, and that their respective theories, despite the admitted significant difference in viewpoint, are in some respects very close indeed. Let us look briefly at the light-metaphysics tradition first. For Robert Grosseteste light is the source of all activity and its diffusion is not a material change or a change in place, but rather an instantaneous and substantial multiplication of itself in three dimensions.4 Thus, for the author of the De Intelligentiis light is the fundamental principle of motion and life: " Est autem prima lucis operatio in sensibilibus quad motum et vitam operatur in viventibus." 5 Since light is the noblest of corporeal things, it therefore has an intermediate place between pure form and matter, and for Grosseteste and also Bonaventure it is consequently named the forma corporeitatis, the fundamental form of body as 4 De philosophischen W erke des Robert Grosseteste, ed. Ludwig Baur, in Clemens Baeumker, Beitriige zur Geschichte der Philosophic des Mittelalters, vol. IX (Munster, 1912), De Luce, p. 51. 5 Clemens Baeumker, Witelo: Ein Philosoph und Naturforscher des XIII Jahrhunderts, Band III, Heft 2 of Beitriige zur Geschichte der Philosophie des Mittelalters (Munster, 1908), Liber de intelligentiis IX, p. 11. PLOTINUS AND ST. THOMAS AQUINAS 189 such, since light introduces dimension into matter. Light then is the substantial form of the physical universe.6 But how is physical light related to spiritual light? For the light-metaphysics tradition, spiritual light (whether the Uncreated Light which is God himself or the... (shrink)

1. Ḳlorshṭeln dem emes̀'n Toyrehdign 'ṿeg tsu a gliḳlikh leb' durkh arbeṭn af di mides̀ on darfn nutsn profesyonale ṭerapi. Ṿen darfn yo nutsn ṭerapi un ṿos iz der rikhṭiger tsugang dertsu. A breyṭe erḳlerung iber di yesoydes̀ fun Idishḳeyṭ.

Growth factors and the extracellular matrix provide the environmental cues that control the proliferation of most cell types. The binding of growth factors and matrix proteins to receptor tyrosine kinases and integrins, respectively, regulates several cytoplasmic signal transduction cascades, among which activation of the mitogen-activated protein kinase cascade, ras → Raf → MEK → ERK, is perhaps the best characterized. Curiously, ERK activation has been associated with both stimulation and inhibition of cell proliferation. In this review, we summarize recent studies (...) that connect ERK signaling to G1 phase cell cycle control and suggest that the cellular response to an ERK signal depends on both ERK signal intensity and duration. We also discuss studies showing that receptor tyrosine kinases and integrins differentially regulate the ERK signal in G1 phase. BioEssays 22:818–826, 2000. © 2000 John Wiley & Sons, Inc. (shrink)