Skeletal muscle formation is studied in vitro with myogenic cell lines and primary muscle cell cultures, and in vivo with embryos of several species. We review several of the notable advances obtained from studies of cultured cells, including the recognition of myoblast diversity, isolation of the MyoD family of muscle regulatory factors, and identification of promoter elements required for muscle‐specific gene expression. These studies have led to the ideas that myoblast diversity underlies the formation of the multiple types of fast (...) and slow muscle fibers, and that myogenesis is controlled by a combination of ubiquitous and muscle‐specific transcriptional regulators that may be different for each gene. We further review some unexpected results that have been obtained when ideas from work in culture have been tested in developing animals. The studies in vivo point to additional molecular and cellular mechanisms that regulate muscle formation in the animal. (shrink)

This study examines the influence of stakeholder pressures and family ownership on strategic decarbonization choices of German Mittelstand firms. It distinguishes between _symbolic_ strategies focusing on compensating CO 2 -emissions and _substantive_ strategies directed toward reducing carbon emissions. The relative pressure exerted by _internal_ and _external_ stakeholders on these strategic choices is examined. Data from 443 manufacturing firms reveal that overall stakeholder pressures increase the pursuit of decarbonization strategies. Internal stakeholders pressures are associated with increased reliance on substantive decarbonization strategies (...) both in family-owned and non-family-owned firms. Pressure from external stakeholders are associated with increased reliance on both substantive and symbolic decarbonization strategies only in non-family-owned firms. No effect of external pressures was found in family-owned firms. Implications for theory, management practice, and policy makers are discussed. (shrink)

This study furthers scholarship on the religion-entrepreneurship link by proposing that aspects of a country’s religious profile impact individual entrepreneurial activity differently and that a country’s level of investments in knowledge serves as a contingency factor in this milieu. Our cross-level analyses of data from 9,266 individuals and 27 predominantly Christian countries support the second, but not the first suggestion. The study contributes to a more nuanced understanding of religion’s role for entrepreneurship and bridges the literatures on religion and knowledge-based (...) entrepreneurship. Furthermore, the study provides evidence of the effects of religion above and beyond the effects of national culture. (shrink)

Jordan agreed to extensive liberalization undertakings under the General Agreement on Trade in Services (“GATS”) that would open some sectors that were previously closed or restricted to foreign suppliers and investors. It undertook horizontal commitments in cross-border movement of individuals and commercial presence covering all types of services.

There are two concepts of consciousness that are easy to confuse with one another, access-consciousness and phenomenal consciousness. However, just as the concepts of water and H 2 O are different concepts of the same thing, so the two concepts of consciousness may come to the same thing in the brain. The focus of this paper is on the problems that arise when these two concepts of consciousness are conflated. I will argue that John Searle's reasoning about the function of (...) consciousness goes wrong because he conflates the two senses. And Francis Crick and Christof Koch fall afoul of the ambiguity in arguing that visual area V1 is not part of the neural correlate of consciousness. Crick and Koch's work raises issues that suggest that these two concepts of consciousness may have different neural correlates – despite Crick and Koch's implicit rejection of this idea. (shrink)

In this article the various descriptions and interpretations ofprofessional autonomy, as have been given in the articles from Belgium,Italy and the UK are subjected to a further analysis. The implicit claimthat professional autonomy of physicians is beneficial for the health ofpatients is scrutinized and is proven to be untrue and invalid. Theconclusion is that professional autonomy is more directed at theinterests of physicians than of those of patients and deserves nospecial place in health care.

According to Conceptual Role Semantics, the meaning of a representation is the role of that representation in the cognitive life of the agent, e.g. in perception, thought and decision-making. It is an extension of the well known "use" theory of meaning, according to which the meaning of a word is its use in communication and more generally, in social interaction. CRS supplements external use by including the role of a symbol inside a computer or a brain. The uses appealed to (...) are not just actual, but also counterfactual: not only what effects a thought does have, but what effects it would have had if stimuli or other states had differed. The view has arisen separately in philosophy and in cognitive science. The source of the view is Wittgenstein and Sellars, but the source in contemporary philosophy is a series of papers by Harman and Field. Other proponents in philosophy have included Block, Horwich, Loar, McGinn and Peacocke. In cognitive science, they include Woods and Miller and Johnson-Laird. (shrink)

Why are children better language learners than adults despite being worse at a range of other cognitive tasks? Here, we explore the role of multiword sequences in explaining L1–L2 differences in learning. In particular, we propose that children and adults differ in their reliance on such multiword units in learning, and that this difference affects learning strategies and outcomes, and leads to difficulty in learning certain grammatical relations. In the first part, we review recent findings that suggest that MWUs play (...) a facilitative role in learning. We then discuss the implications of these findings for L1–L2 differences: We hypothesize that adults are both less likely to extract MWUs and less capable of benefiting from them in the process of learning. In the next section, we draw on psycholinguistic, developmental, and computational findings to support these predictions. We end with a discussion of the relation between this proposal and other accounts of L1–L2 difficulty. (shrink)

The surviving portion of the tenth-century Egyptian Muḥammad b. Aḥmad al-Tamīmī’s recently edited Ṭīb al-ʿarūs has several formulas relating to the dying and perfuming of textiles. Some refer to the use of carved molds to impress designs upon textiles. Tamīmī’s formulas treat in particular the application of gold leaf and perfumed dye pastes with blocks, but presuppose the technology of using blocks to apply designs to textiles and include a vocabulary of technical terms for the process. This textual evidence provides (...) additional context for surviving early medieval Islamic block-printed gilded textiles. The attestation of the use of blocks to decorate textiles is contemporary with the use of blocks to print Arabic amulet texts, known by the tenth century from extant specimens and some literary evidence. (shrink)

According to Conceptual Role Semantics ("CRS"), the meaning of a representation is the role of that representation in the cognitive life of the agent, e.g. in perception, thought and decision-making. It is an extension of the well known "use" theory of meaning, according to which the meaning of a word is its use in communication and more generally, in social interaction. CRS supplements external use by including the role of a symbol inside a computer or a brain. The uses appealed (...) to are not just actual, but also counterfactual: not only what effects a thought does have, but what effects it would have had if stimuli or other states had differed. The view has arisen separately in philosophy (where it is sometimes called "inferential," or "functional" role semantics) and in cognitive science (where it is sometimes called "procedural semantics"). The source of the view is Wittgenstein (1953) and Sellars, but the source in contemporary philosophy is a series of papers by Harman (see his 1987) and Field (1977). Other proponents in philosophy have included Block, Horwich, Loar, McGinn and Peacocke (1992). In cognitive science, they include Woods (1981) and Miller and Johnson-Laird (1976). (See references in Block, 1987.). (shrink)

Perhaps you are wondering what I mean by ‘holism’. After all, everyone seems to use the term in a different sense. Even if we restrict ourselves to holism of meaning and content, we have many different holisms. Some take holism about meaning to be the doctrine that if you’ve got one meaning, you’ve got lots of them.2 On other views, to say meaning is holistic is to say that the meaning of each term depends on the meanings of all or (...) most other terms.3 Others take meaning holism to be the doctrine that there is no real distinction between language and theory or between the “dictionary” and the “encyclopedia”. (shrink)

In many theories in contemporary philosophy of mind, attention is constitutively linked to phenomenal consciousness. Ned Block has recently argued that ‘identity crowding’ provides an example of subjects consciously seeing something to which they are unable to attend. Here I examine the reasons that Block gives for thinking that this is a case of a consciously perceived item that we are unable to attend to, and I offer a different interpretation.

Human nature is enigmatic. Are we cruel, selfish creatures or good merciful Samaritans? This book takes you on a journey into the complexities of human mind and kind, from altruism, sharing, and large-scale cooperation, to cheating, distrust, and warfare. What are the building blocks of morality and sociality? Featuring contributions from leading researchers, such as Christophe Boesch, Leda Cosmides and John Tooby, Azar Gat, Dennis Krebs, Ara Norenzayan, and Frans B. M. de Waal, this fascinating interdisciplinary reader draws on evolutionary (...) and comparative perspectives, and is essential reading for any students interested in the unique characteristics that define humanity and society. (shrink)

To localize wheat ESTs on chromosomes, 882 homoeologous group 6-specific ESTs were identified by physically mapping 7965 singletons from 37 cDNA libraries on 146 chromosome, arm, and sub-arm aneuploid and deletion stocks. The 882 ESTs were physically mapped to 25 regions flanked by 23 deletion breakpoints. Of the 5154 restriction fragments detected by 882 ESTs, 2043 were localized to group 6 chromosomes and 806 were mapped on other chromosome groups. The number of loci mapped was greatest on chromosome 6B and (...) least on 6D. The 264 ESTs that detected orthologous loci on all three homoeologs using one restriction enzyme were used to construct a consensus physical map. The physical distribution of ESTs was uneven on chromosomes with a tendency toward higher densities in the distal halves of chromosome arms. About 43% of the wheat group 6 ESTs identified rice homologs upon comparisons of genome sequences. Fifty-eight percent of these ESTs were present on rice chromosome 2 and the remaining were on other rice chromosomes. Even within the group 6 bins, rice chromosomal blocks identified by 1-6 wheat ESTs were homologous to up to 11 rice chromosomes. These rice-block contigs were used to resolve the order of wheat ESTs within each bin. (shrink)

A shift from a metaphysical framework of substance to one of process enables an integrated account of the emergence of normative phenomena. I show how substance assumptions block genuine ontological emergence, especially the emergence of normativity, and how a process framework permits a thermodynamic-based account of normative emergence. The focus is on two foundational forms of normativity, that of normative function and of representation as emergent in a particular kind of function. This process model of representation, called interactivism, compels (...) changes in many related domains. The discussion ends with brief attention to three domains in which changes are induced by the representational model: perception, learning, and language. (shrink)

In a large proportion of health care research based on the retrospective review of records, minimal breach of patient confidentiality appears to be inevitable. This occurs at initial identification of and access to the chart, selected on the basis of the condition under investigation, and while individual identifiability can be blocked at subsequent stages, at this point it does occur. Prospective individual consent is impractical because often neither the desirability nor the specific subject of the research is known at the (...) time of making the record, and retrospective patient tracing to obtain it is often impossible. I argue that the benefit of the research outweighs the minimal breach of confidentiality, and that in my own jurisdiction, this appears to be envisaged and accepted in Canadian law. (shrink)

There has recently been a revival of interest in ‘naturalizing’ ethics. A naturalization seeks to vindicate ethical realism — the idea that ethical judgments can be true reflections of a moral reality — without violating the naturalist constraint that science sets the limits of ontology. The recent revival has been prompted by examples of successful scientific reduction (e.g. temperature, water), and by the emergence of new, nonreductive naturalist strategies (e.g. for biological and mental properties). In this paper, I argue against (...) such naturalist approaches to ethics. My argument builds on the traditional one offered by G.E. Moore, namely that a naturalization would fail to respect an existing difference between the meanings of moral and naturalistic terms. I defend this line of argument against the common claim that it cannot block ‘synthetic’ property identities, ones grounded not in meaning equivalences but in empirical discoveries (as in the cases of temperature and water). I then go on to show that the Moorean argument can make trouble even for recent revisionist and nonreductive naturalist approaches. (shrink)

What makes something an embryo—as opposed to what is actually, and not just in biotech parlance, a collection of cells? This question has come to the fore in recent years with proposals for producing embryonic stem cells for research. While some of those opposed to use of standard embryonic stem cells emphasise that adult cells have a clinical track record, others argue that there may be further benefits obtainable from cells very like those of embryos, provided such cells can be (...) derived in new ways. Rather than deriving them in ways that kill or otherwise endanger a living human embryo, they could be obtained from an entity that merely resembles a human embryo sufficiently closely for its cells to be of use. Such an entity might be created after introducing genetic changes to an ovum before it is activated by, for example, a cloning-type procedure, such that a gene essential to embryogenesis will be either absent, blocked in its expression, or overexpressed.1,2 The claim is that the ovum could be made to give rise to embryonic stem cells—mere living parts—without ever giving rise to a whole embryo, who is killed to obtain them. Whereas cloning “proper” winds back the specialisation of the cell nucleus to a point where a whole embryo is formed who has not yet specialised its cells, oocyte-assisted reprogramming , it is claimed, would wind back the specialisation merely to an intermediate point at which no embryo is created. Other methods proposed for deriving pseudoembryonic cells include parthenogenesis, in which an ovum is activated without a sperm, or even the insertion of an adult cell nucleus.1MORAL STATUS OF THE EMBRYOIn this paper, I assume that a genuine …. (shrink)

Purpose: The article pursues three aims. First, it intends to differentiate between two different approaches for knowledge studies, namely an empirical and a normative mode. In a second move, two different epistemologies in the work of Ernst von Glasersfeld will be introduced under the labels of “Epistemology I” and “Epistemology II.” Epistemology I relates to empirical research, Epistemology II is normative in nature. Third, the article makes the point that while Ernst von Glasersfeld’s Epistemology II has already been presented in (...) a finite and mature form, his empirical analysis of cognitive processes still provides a rich pool of tools and designs that should be further developed and advanced in the years and decades ahead. Method: The article is analytical in nature, identifying the different building blocks and relational networks of von Glasersfeld’s two epistemologies. By this, the article intends to contribute to a further advancement of von Glasersfeld’s Epistemology I. Results: The main finding lies in recognizing the radical and innovative elements of von Glasersfeld’s Epistemology I and on the still-challenging research designs of Epistemology I. (shrink)

This is terribly hard, Thouless, I'm sorry. I have thought over all this for years. … It is now as if we had ploughed furrows in different parts of a field. There is a lot left to do. Judging from their writings, most contemporary analytic philosophers have not been persuaded that “the inverted spectrum problem” is – as Wittgenstein maintained – really a conceptual puzzle calling for dissolution, rather than a straight problem calling for a solution. In this paper, I (...) present Wittgenstein's view as clearly and persuasively as I can, contrasting it with the views of Sidney Shoemaker and Ned Block, two of his more prominent critics. I conclude with a look at Frank Jackson's well-known Knowledge Argument, which, if successful, would demonstrate the futility of looking for a physicalist solution to the inverted spectrum and related philosophical problems. My goal is to combat what I take to be the common and unfortunate failure – among both physicalistically inclined philosophers, including Shoemaker and Block, and anti-physicalists, such as Jackson – to appreciate the force of Wittgenstein's arguments. (shrink)

Context: The main problem is the rather marginal status of radical constructivism within its core domains of brain research, cognition and learning. Problem: The basic goal is to provide a short history of radical constructivism and its institutionalization processes. Additionally, the article specifies critical conditions that should be met in order for radical constructivism to become a mainstream endeavor. Method: The main methods used are those of comparative historical research. Results: The main results lie in the specification of missing elements (...) that have blocked radical constructivism becoming a mainstream endeavor. Implications: The paper might serve as a common reference for necessary steps to be taken over the following years in order to move radical constructivism out of its current weak position. (shrink)

Questions about the validity of eye fixations in the blocks task as a memory indicator are discussed. Examples from reading research illustrate the influence of extraneous factors.

We agree with Heintz & Scott-Phillips that pragmatics does not supplement, but is prior to and underpins, language. Indeed, human non-linguistic communication is astonishingly rich, flexible, and subtle, as we illustrate through the game of charades, where people improvise communicative signals when linguistic channels are blocked. The route from non-linguistic charade-like communication to combinatorial language involves (1) local processes of conventionalization and grammaticalization and (2) spontaneous order arising from mutual constraints between different communicative signals.

High yielding agriculture in less-industrialized countries, the green revolution, has been both honored and criticized over the past twenty years. Supporters point to the increased food supplies produced with the new practices, but detractors argue that the new technologies are environmentally destructive, unsustainable, and socially inequitable. This paper explores the origins of high yielding agriculture in order better to understand how the arguments over sustainability and equity originated. The Rockefeller Foundation was an important agency in promoting the development of the (...) new agricultural science. Its programs in Mexico and India, initiated in 1941 and 1956, were key building blocks in creating high yielding agricultural practices. The Foundation scientists saw rapid population growth as the main source of hunger and communist subversion. In order to alleviate hunger and instability, they created a strategy of agricultural development based on increased yields but paid no attention to the problem of distribution of harvested food. Sustainability was not recognized as a problem at the time Foundation scientists began their work. Indeed the technical successes of their programs prompted the development of concerns about sustainability. Equity of distribution was brought to the attention of the Foundation before it began its work, but the scientists paid no attention to the issue. (shrink)

Amongst philosophers, there is ongoing debate about what successful event remembering requires. Causal theorists argue that it requires a causal connection to the past event. Simulation theorists argue, in contrast, that successful remembering requires only production by a reliable memory system. Both views must contend with the fact that people can remember past events they have experienced with varying degrees of accuracy. The debate between them thus concerns not only the account of successful remembering, but how each account explains the (...) various forms of memory error as well. Advancing the debate therefore must include exploration of the cognitive architecture implicated by each view and whether that architecture is capable of producing the range of event representations seen in human remembering. Our paper begins by exploring these architectures, framing casual theories as best suited to the storage of event instances and simulation theories as best suited to store schemas. While each approach has its advantages, neither can account for the full range of our event remembering abilities. We then propose a novel hybrid theory that combines both instance and schematic elements in the event memory. In addition, we provide an implementation of our theory in the context of a cognitive architecture. We also discuss an agent we developed using this system and its ability to remember events in the blocks world domain. (shrink)

The "textbook explosion" in recent years in the field of logic has frequently been deplored on the grounds that it has resulted in a proliferation of repetitious and sometimes antiquated material. A sober evaluation of this volume, unfortunately, supports this thesis. Despite the subtitle, the bulk of the material in this book wasn't "modern" two centuries ago. Why should 196 pages of a 355 page text be devoted to such topics as "Logic and Psychology," "Types of Statements in Logical English," (...) "The Syllogism," "Translation into Logical English," and "Informal Fallacies"? Philosophic issues are often obscured by the unmanageable clutter of syllogistic form, squares of opposition, sorites, and other baggage. Moreover, why should an entire appendix be devoted to a "block diagram" of a machine which computes the logical relationship between any two sentences? Especially when it is known that no such machine is possible. There is material of genuine philosophical interest in this book and there is a rather desultory treatment of elementary symbolic logic by means of a confused set of natural deduction rules.—H. P. K. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:A Chance to CutBruce H. CampbellMy gloved hand reaches for progressively sharper surgical instruments. The prior radiation therapy and recurrent cancer [End Page E3] have made his neck tissues as stiff and hard as an old block of wood; everything appears too dull and feels too dry under the bright operating room lights. I push, dissect, urge, divide, prod, and spread with little effect.The nursing staff keeps to (...) its routine—completing computer entries, retrieving supplies, counting sponges—only intermittently aware that things are not going well at the point of attack. Nondescript music plays softly and the anesthesia machine continues to emit its gentle sounds. The junior resident—assisting me with the first of many neck dissections she will see during her five years of training—grips the retractor as she has been told and dabs the wound periodically to clear any blood or fluid.I glance up to recheck the CT scan. It confirms that this man’s recurrent cancer is just below the next layer of neck muscles. There are also some large blood vessels and major nerves nearby. I am confident, though, that I will be able to expose the mass, protect all of the critical structures, and safely remove the cancer.Curing cancer with surgery is no small feat, mind you. Cancer is, after all, a molecular disease not easily confined to an obvious lump, even though we sometimes refer to a malignant mass being “like a walnut” or “as hard and round as a marble.” The actual disease rests deep inside each cancer cell where the genetic code—the DNA—makes mistake–after–mistake. If cancer is to be cured with a surgical procedure, the surgeon must remove every last cell that is capable of making the same nonsensical, life–threatening error. Given Science’s rudimentary knowledge of cancer cell dynamics and signaling, it’s a miracle that surgery ever works. Yet, we continue to try. And we succeed just often enough to keep on trying.I rearrange the retractors and alter my approach. My mentors would have known what to do next, I imagine. My training included time well–spent with brilliant and technically–gifted surgeons. How would they have approached this case? Their experience and instincts might have told them to open the wound more widely, work the lateral and deep margins first, or position the instruments differently.Perhaps, one of my mentors would have attacked this man’s tumor using the same approach I am attempting but would have known exactly where to exploit some area of weakness that I cannot locate. A few swift, confident moves and he would have held the mass in his hands. “That’s it. We’re done,” he would have said.I met this patient several months ago when his cancer was first discovered and have seen him throughout his course of treatment. Recently, his daughter had accompanied him to the office to review his options. “Treatment has been rugged, Doc,” he reminded me. “The cancer’s still there and they said I can’t get any more radiation. Chemo would only prolong things. I don’t really want surgery, but what choice do I have if I want to be cured?”“Supportive care is an option, but the only curative approach is surgery.”“Well, I’m not ready to quit yet, Doc. I got grand-kids, y’know. I want to watch them grow up.” He nodded to his daughter. “I’m in charge of spoiling her little boys.”The daughter smiled. We crowded around the computer screen to look at the scans. I showed them how the tumor was invading and destroying surrounding structures. I described the surgery and the risks.“There are many things I will not know about your tumor until we are actually in the operating room,” I explained. Surgery in the setting of recurrent disease involves a series of on–the–spot decisions and course corrections. The odds of success are unknowable. “Sometimes, the only way to find out if we can remove the cancer is simply to try.”He took a deep breath and looked at his daughter. “Well then, Doc, if surgery is the only... (shrink)

In lieu of an abstract, here is a brief excerpt of the content:BOOK REVIEWS 127 seems to imply. Of course, this critique can easily be dismissed as asking for a book that Krieger did not wish to write. His method has produced important results, for Krieger has discerned developmental trends overlooked by others. Otherwise, the only area that I think needs further discussion is Ranke's conception of the nature and function of science. Krieger seems to imply that science automatically means (...) a nomological approach modeled upon the mechanical physical sciences. But Ranke was nourished in an atmosphere where science was often equated with Naturphilosophie. Certainly, Ranke's language is filled with images and terms popularized by Naturphilosophen. Ranke's quest for a science of history may fit very nicely with the ideal dimension of his thought if the science that he is talking about is analogous to Naturphilosophie. It may turn out that the basic polarity in Ranke's idea of history is an analytic construct that has little meaning for Ranke's own intentions. Krieger ends his study with a chapter devoted to the meaning of Ranke's work for modem historiography. It is the dialectical synthesis of the whole study. After recapitulating Ranke's achievements, Krieger then emphasizes the breach that separates Ranke from our conceptual world. We no longer share Ranke's beliefs or values. In fact, for most of us "he must seem simply archaic, and the more he is himself historically restored the more archaic he must seem" (p. 355). For the reader who had to struggle through this difficult book and to contend with Professor Krieger's passion for complex dependent clauses, this announcement appears as a grand denouement. But the shock is only temporary. Krieger's assertion of the differences that separate Ranke from us serves as a warning to those who still take Ranke's approach as an objective model for historical reconstruction. The deeper meaning of Ranke's view of history is the affirmation of history as an autonomous and independent form of knowledge. "History is an inimitable way of rendering comprehensible modes of humanity which must otherwise be incomprehensible" (p. 356). This form of knowledge, which is devoted "to the actual but equipped with a language of common sense organized around the categorical," proceedes by arranging things along a time line (p. 357). Here Krieger launches a spirited counterattack against those modem theorists who have questioned the viability of history as an independent form of knowledge or who have minimized the importance of developmental analysis, preferring instead to concentrate upon relatively static deep structures. Krieger's study affirms Ranke's project in its most general sense; that history is a cumulative logic of the actual, "the meeting ground of philosophy, science, and cataclysmic experience" (p. 356). And it serves, at the same time, as a positive demonstration that a developmental analysis does impart knowledge that other approaches cannot achieve. In this sense, Krieger's masterful study of Ranke reaffirms Ranke's central position as a founding father of modem historical thought. PETER HANNS REILL University of California, Los Angeles Arthur Quinn. The Confidence of British Philosophers:An Essay in Historical Narrative. Leiden: E. J. Brill, 1977. Pp. xii + 289. Gld. 80. This is a remarkable book. Almost all of it is a study, very well researched and presented, of four major English philosophical movements: Newtonians, the Utilitarians, the Oxford Hegelians, and the Russell, G. E. Moore, and Whitehead group. The study shows the initial enthusiasm, optimism, and confidence of each of the groups. Each believed that it had found a way to solve the intellectual and perhaps moral and social problems of mankind. As each movement developed, the confidence slowly eroded when philosophical problems and difficulties failed to disappear. The picture Quinn presents of these movements is very interesting. He has grouped together 128 HISTORY OF PHILOSOPHY much detail that makes us see the original intentions of the leaders of each of these movements. He also deftly shows how as stumbling blocks arose each movement lowered its goals and began to fade. Employing a very wide range of printed sources, Quinn presents a series of convincing vignettes, and in so doing be often reveals features of these movements that have been... (shrink)

Polyglutamine (polyQ) diseases are genetically inherited neurodegenerative disorders. They are caused by mutations that result in polyQ expansions of particular proteins. Mutant proteins form intranuclear aggregates, induce cytotoxicity and cause neuronal cell death. Protein interaction data suggest that polyQ regions modulate interactions between coiled‐coil (CC) domains. In the case of the polyQ disease spinocerebellar ataxia type‐1 (SCA1), interacting proteins with CC domains further enhance aggregation and toxicity of mutant ataxin‐1 (ATXN1). Here, we suggest that CC partners interacting with the polyQ (...) region of a mutant protein, increase its aggregation while partners that interact with a different region reduce the formation of aggregates. Computational analysis of genetic screens revealed that CC‐rich proteins are highly enriched among genes that enhance pathogenicity of polyQ proteins, supporting our hypothesis. We therefore suggest that blocking interactions between mutant polyQ proteins and their CC partners might constitute a promising preventive strategy against neurodegeneration. (shrink)

There is a tension between the “growing block” account of time (closed past, open future) and the possibility of backwards time travel. If Tim the time traveler can someday travel backwards through time, then he has (in a certain sense) already been. He might discover this fact before (in another sense) he goes. Hence a dilemma: it seems that either Tim’s future is determined in an odd way or cases of (temporary) ontic indeterminate identity are possible. Either Tim cannot (...) avoid heading for the past or he is only indeterminately that guy who appeared in the past with many of Tim’s memories. Determinacy in the past implies a degree of determinism in the future; indeterminism about the future seeps back to the past. (shrink)

Angiogenesis is central to both the growth and metastasis of solid tumours. Anti‐angiogenic strategies result in blood vessel regression accompanied by tumour cell apoptosis. Radiotherapy and many chemotherapeutic agents kill tumours by inducing apoptotic cell death. We propose that, in addition to its role as an angiogenic factor, vascular endothelial growth factor (VEGF) can act as a survival factor for tumour cells protecting them from apoptosis. Thus anti‐angiogenics, in particular those directed against VEGF, have multiple anti‐tumour effects. We suggest that (...) anti‐VEGF strategies prevent vessel growth and block a tumour cell survival factor, VEGF, rendering tumour cells more sensitive to chemotherapy and radiotherapy. In addition, as chemotherapy and radiotherapy have been shown to increase VEGF expression, anti‐VEGF strategies may overcome therapy‐ induced tumour cell resistance. BioEssays 24:280–283, 2002. © 2002 Wiley Periodicals, Inc.; DOI 10.1002/bies.10043. (shrink)

The spinal mechanisms of action of opioids under normal conditions are reasonably well understood. The spinal effects of opioids can be enhanced or reduced depending on pathology and activity in other segmental and nonsegmental pathways. This plasticity will be considered in relation to the control of different pain states using opioids. The complex and contradictory findings on the supraspinal actions of opioids are explicable in terms of heterogeneous descending pathways to different spinal targets using multiple transmitters and receptors – therefore (...) opioids can both increase and decrease activity in descending pathways. These pathways could exhibit considerable plasticity. There is increasing evidence that delta opioid receptor agonists have the potential to replace morphine as major analgesics with reduced side-effect profiles. The concept of preemptive analgesia, based on preventing the induction of some of the negative plastic influences on opioid controls and the detrimental effects of pain, is sound, but experimental verification in the clinical setting is difficult. For example, a delayed compensatory upregulation of inhibitory systems, particularly in inflammation, may counter persistent painful inputs. Combination therapy with opioids may be beneficial in many pain states where either negative influences are blocked or inhibitory controls are enhanced. Finally, developmental aspects of these systems are discussed in connection with the treatment of pain in young children, where inhibitory systems in the spinal cord are immature. (shrink)

The explanatory gap refers to the lack of concepts for understanding “how it is that . . . a state of consciousness comes about as a result of irritating nervous tissue.” By assuming that there are colours in the outside world, Block needlessly widens this gap and Lycan and Kitcher simply fail to see the gap. When such assumptions are abandoned, an unnecessary and incomprehensible constraint disappears. It then becomes clear that the brain can use its own neural language (...) for representing aspects of the outside world. While this may not close the gap, it becomes clearer where we need new concepts. (shrink)

A numerical classification was performed on 69 elements with 54 chemicaland physicochemical properties. The elements fell into clusters in closeaccord with the electron shell s-, p- andd-blocks. The f-block elements were not included forlack of sufficiently complete data. The successive periods ofs- and p-block elements appeared in an ovalconfiguration, with d-block elements lying to one side. Morethan three axes were required to give good representation of thevariation, although the interpretation of the higher axes is difficult.Only 15 properties (...) were scorable for the noble gases, but despite thepaucity of properties reflecting chemical reactivity, analysis of the 69elements on these properties still showed the major features seen fromthe full set. (shrink)