The conventional paradigm for developing new treatments for disease mainly involves either the discovery of new drug targets, or finding new, improved drugs for old targets. However, an ion channel found only in invertebrates offers the potential of a completely new paradigm in which an established drug target can be re‐engineered to serve as a new candidate therapeutic agent. The L‐glutamate‐gated chloride channels (GluCls) of invertebrates are absent from vertebrate genomes, offering the opportunity to introduce this (...) exogenous, inhibitory, L‐glutamate receptor into vertebrate neuronal circuits either as a tool with which to study neural networks, or a candidate therapy. Epileptic seizures can involve L‐glutamate‐induced hyper‐excitation and toxicity. Variant GluCls, with their inhibitory responses to L‐glutamate, when engineered into human neurons, might counter the excitotoxic effects of excess L‐glutamate. In reviewing recent studies on model organisms, it appears that this approach might offer a new paradigm for the development of candidate therapeutics for epilepsy. (shrink)

The identification of additional subunits of the cGMP-gated cation channel suggests exciting questions about their regulatory roles and about structure/functional relationships. How do the different subunits interact? How is the complex assembled into the plasma membrane? Divalent cations have been implicated in the regulation of adaptation. One often overlooked cation is magnesium. Could this ion play a role in phototransduction?

Chloride channels are probably found in every cell, from bacteria to mammals. Their physiological tasks range from cell volume regulation to stabilization of the membrane potential, signal transduction, transepithelial transport and acidification of intracellular organelles. These different functions require the presence of many distinct chloride channels, which are differentially expressed and regulated by various stimuli. These include various intracellular messengers (like calcium and cyclic AMP), pH, extracellular ligands and transmembrane voltage. Three major structural classes of chloride channels (...) are known to date, but there may be others not yet identified. After an overview of the general functions of chloride channels, this review will focus on these cloned chloride channels: the CLC chloride channel family, which includes voltage‐gated chloride channels, and the cystic fibrosis transmembrane regulator (CFTR), which performs other functions in addition to being a chloride channel. Finally, a short section deals with GABA and glycine receptors. Diseases resulting from chloride channel defects will be specially emphasized, together with the somewhat limited information about how these proteins work at the molecular level. (shrink)

This paper argues that nonphysical souls would violate fundamental physical laws if they were able to influence brain events. Though we have no idea how nonphysical souls might operate, we know quite a bit about how brains work, so we can consider each of the ways that an external force could interrupt brain processes enough to control one’s body. It concludes that there is no way that a nonphysical soul could interact with the brain—neither by introducing new energy into the (...) physical world, nor by borrowing existing energy from it—without apparently violating one or more basic laws of physics, such as the law of conservation of energy. And despite widespread appeals to quantum mechanics to give interactionism an air of scientific respectability, the essential randomness of quantum processes prohibits the distinctly nonrandom influence that a nonphysical soul must have on brain events in order to control the body, and quantum mechanical uncertainty is not great enough to allow neurons to fire action potentials. -/- 1. Introduction -- 2. How the Brain Works -- 3. Mind-Brain Interaction Mechanisms - 3.1 Opening Sodium Channels - 3.2 Altering Voltage Gradients - 3.3 Synaptic Transmission - 3.3.1 The Presynaptic Neuron - 3.3.2 The Post-Synaptic Neuron - 3.3.3 The Beck and Eccles Models - 3.4 Neuronal Modulation - 3.5 Self-Generation of Action Potentials by Neurons -- 4. Harnessing Energy -- 5. How Many Action Potentials for a Volitional Act? -- 6. Input: From Brain to Nonphysical Mind -- 7. Discussion -- Appendix A: Opening Gates on Membrane Channels - A.1 Directly Opening Gates - A.2 Changing Voltage Across the Membrane -- Appendix B: The Biochemical Approach. (shrink)

When someone hosts a party, when governments choose an aid program, or when assistive robots decide what meal to serve to a family, decision‐makers must determine how to help even when their recipients have very different preferences. Which combination of people’s desires should a decision‐maker serve? To provide a potential answer, we turned to psychology: What do people think is best when multiple people have different utilities over options? We developed a quantitative model of what people consider desirable behavior, characterizing (...) participants’ preferences by inferring which combination of “metrics” (maximax, maxsum, maximin, or inequality aversion [IA]) best explained participants’ decisions in a drink‐choosing task. We found that participants’ behavior was best described by the maximin metric, describing the desire to maximize the happiness of the worst‐off person, though participant behavior was also consistent with maximizing group utility (the maxsum metric) and the IA metric to a lesser extent. Participant behavior was consistent across variation in the agents involved and tended to become more maxsum‐oriented when participants were told they were players in the task (Experiment 1). In later experiments, participants maintained maximin behavior across multi‐step tasks rather than shortsightedly focusing on the individual steps therein (Experiment 2, Experiment 3). By repeatedly asking participants what choices they would hope for in an optimal, just decision‐maker, and carefully disambiguating which quantitative metrics describe these nuanced choices, we help constrain the space of what behavior we desire in leaders, artificial intelligence systems helping decision‐makers, and the assistive robots and decision‐makers of the future. (shrink)

The aim of this paper is to investigate how alternative land ethics of agricultural stakeholders may help explain recent land use changes. The paper first explores the historical development of the land ethic concept in the United States and how those ethics have impacted land use policy and use of private lands. Secondly, primary data gathered from semi-structured interviews of farmers, ranchers, and influential stakeholders are then analyzed using stakeholder analysis methods to identify major factors considered in land use decisions, (...) priorities of factors of each group, and to define relevant mental models describing each group’s view of the land ethic concept. Results show that these stakeholder groups prioritize land use factors qualitatively differently and possess strikingly different land ethics. It is concluded that shifts in stakeholder land ethics have contributed to recent land use changes. Lastly, we discuss how current agricultural policy sends mixed signals about preferred land use and the potential ramifications based on the different land ethics we’ve described. (shrink)

What importance does “race” have as a meaningful category in the study of literature and the shaping of critical theory? If we attempt to answer this question by examining the history of Western literature and its criticism, our initial response would probably be “nothing” or, at the very least, “nothing explicitly.” Indeed, until the past decade or so, even the most subtle and sensitive literary critics would most likely have argued that, except for aberrant moments in the history of criticism, (...) race has not been brought to bear upon the study of literature in any apparent way. Since T. S. Eliot, after all, the canonical texts of the Western literary tradition have been defined as a more or less closed set of works that somehow speak to, or respond to, “the human condition” and to each other in formal patterns of repetition and revision. And while most critics acknowledge that judgment is not absolute and indeed reflects historically conditioned presuppositions, certain canonical works do seem to transcend value judgments of the moment, speaking irresistibly to the human condition. The question of the place of texts written by the Other in the proper study of “literature,” “Western literature,” or “comparative literature” has, until recently, remained an unasked question, suspended or silenced by a discourse in which the canonical and the noncanonical stand as the ultimate opposition. In much of the thinking about the proper study of literature in this century, race has been an invisible quantity, a persistent yet implicit presence.This was not always the case, we know. By mid-nineteenth century, “national spirit” and “historical period” had become widely accepted categories within theories of the nature and function of literature which argued that the principal value in a great work of literary art resided in the extent to which these categories were reflected in that work of art Montesquieu’s De l’esprit des lois considered a culture’s formal social institution as the repository of its “guiding spirit,” while Giambattista Vico’s principi di una scienza nuova read literature against a complex pattern of historical cycles. Friedrich and August von Schlegel managed rather deftly to bring “both national spirit and historical period” to bear upon the interpretation of literature, as W. Jackson Bate has shown. But it was Hippolyte-Adolphe Taine who made the implicit explicit by postulating “race, moment, and milieu” as positivistic criteria through which any work could be read and which, by definition, any work reflected. Taine’s History of English Literature was the great foundation upon which subsequent nineteenth-century notions of “national literatures” would be constructed. Henry Louis Gates, Jr. is professor of English, comparative literature, and African studies at Cornell University. He has edited several books and has written Figures in Blood and The Signifying Monkey. (shrink)

Le pédagogue Antoine de La Garanderie (1920-2010) laisse un héritage intellectuel particulièrement riche et stimulant. Le rayonnement de sa pensée au cours des trois dernières décennies, tant en France qu'à l'étranger, et son influence sur les pratiques pédagogiques, formatives, voire thérapeutiques, font de lui l'une des figures marquantes de notre culture contemporaine. Cet ouvrage explore trois grands champs de réflexion et de recherche : le premier concerne la validité et la pertinence, au plan épistémologique, des recherches qu'il a conduites, désignées (...) sous le terme générique de " Gestion mentale ", et en référence à d'autres courants de pensée ; le second aborde l'orientation générale des expérimentations pédagogiques ou didactiques auxquelles ces recherches ont donné lieu et dont il convient d'évaluer la portée et la valeur, tant heuristiques que praxéologiques ; le troisième relève des fondements proprement anthropologiques où s'enracinent ses concepts et ses propositions et qu'il importe autant de dévoiler que de situer : sa foi en l'éducabilité, sa conception de l'évolution et du progrès. (shrink)

Recent studies from several different laboratories have provided further insight into structure-function relationships of cyclic nucleotide-gated channel and in particular the cCMPgated channel of rod photoreceptors. Site-directed mutagenesis and rod-olfactory chimeria constructs have defined important amino acids and peptide segments of the channel that are important in ion blockage, ligand specificity, and gating properties. Molecular cloning studies have indicated that cyclic nucleotide-gated channels consist of two subunits that are required to reproduce the properties of the (...) native channels. Biochemical analysis of the cGMP-gated channel of rodcells have indicated that the 240 kDa protein that co-purifies with the 63 kDa channel subunit contains both the previously cloned second subunit of the channel and a glutamic acid-rich protein. The regulatory properties of the cGMP-gated channel from rod cells has also been studied in more detail. Studies indicate that the beta subunit of the cGMP-gated channel of rod cells contains the binding site for calmodulin. Interaction of calmodulin with the channel alters the apparent affinity of the channel for cGMP in all in vitro systems that have been studied. The significance of these recent studies are discussed in relation to the commentaries on the target article. (shrink)

b>. Recent findings in cognitive science suggest that the epistemic subject is more complex and epistemically porous than is generally pictured. Human knowers are open to the world via multiple channels, each operating for particular purposes and according to its own logic. These findings need to be understood and addressed by the philosophical community. The current essay argues that one consequence of the new findings is to invalidate certain arguments for epistemic anti-realism.

Whistleblowing refers to the disclosure by organization members of illegal, immoral, or illegitimate practices to persons or organizations that may be able to effect action. Most studies on the topic have been conducted in North American or European private sector organizations, and less attention has been paid to regions such as Turkey. In this study, we study the whistleblowing intentions and channel choices of Turkish employees in private and public sector organizations. Using data from 327 private sector and 405 (...) public sector employees, we find that public sector employees are more idealistic and less inclined to whistleblow externally and anonymously. Higher idealism among public sector employees does not moderate these effects. We find that private sector employees are more relativistic, and that they are more inclined to whistleblow through external and anonymous channels. More relativistic private sector employees are more likely to prefer external whistleblowing; however sector does not moderate the propensity to whistleblow anonymously. (shrink)

We present a population density and moment-based description of the stochastic dynamics of domain $${\text{Ca}}^{2+}$$ -mediated inactivation of L-type $${\text{Ca}}^{2+}$$ channels. Our approach accounts for the effect of heterogeneity of local $${\text{Ca}}^{2+}$$ signals on whole cell $${\text{Ca}}^{2+}$$ currents; however, in contrast with prior work, e.g., Sherman et al. :985–995, 1990), we do not assume that $${\text{Ca}}^{2+}$$ domain formation and collapse are fast compared to channel gating. We demonstrate the population density and moment-based modeling approaches using a 12-state Markov chain (...) model of an L-type $${\text{Ca}}^{2+}$$ channel introduced by Greenstein and Winslow :2918–2945, 2002). Simulated whole cell voltage clamp responses yield an inactivation function for the whole cell $${\text{Ca}}^{2+}$$ current that agrees with the traditional approach when domain dynamics are fast. We analyze the voltage-dependence of $${\text{Ca}}^{2+}$$ inactivation that may occur via slow heterogeneous domain [ $${\text{Ca}}^{2+}$$ ]. Next, we find that when channel permeability is held constant, $${\text{Ca}}^{2+}$$ -mediated inactivation of L-type channels increases as the domain time constant increases, because a slow domain collapse rate leads to increased mean domain [ $${\text{Ca}}^{2+}$$ ] near open channels; conversely, when the maximum domain [ $${\text{Ca}}^{2+}$$ ] is held constant, inactivation decreases as the domain time constant increases. Comparison of simulation results using population densities and moment equations confirms the computational efficiency of the moment-based approach, and enables the validation of two distinct methods of truncating and closing the open system of moment equations. In general, a slow domain time constant requires higher order moment truncation for agreement between moment-based and population density simulations. (shrink)

One of the central debates among British chemists during the 1830s concerned the use of symbols to represent elements and compounds. Chemists such as Edward Turner, who desired to use symbolic notation mainly for practical reasons, eventually succeeded in fending off metaphysical objections to their approach. These objections were voiced both by the philosopher William Whewell, who wished to subordinate the chemists' practical aims to the rigid standard of algebra, and by John Dalton, whose hidebound opposition to abbreviated notation symbolized (...) the suspicion with which older British chemists perceived continental innovations. It is argued that the success of chemists like Turner in this debate reflects their larger success in the 1830s in achieving disciplinary autonomy and in beginning to align themselves more closely with prevailing chemical practice across the Channel. (shrink)

At present, the concept of «social class» is in a pauperized cultural state, fully integrated within political channels that are unfavorable to its identification, understanding and acceptance. As it has been defined in two previous works by the present author, the concept can only be associated with territorially undelimited and specialized societies, originated in postindustrial western Europe, under a division of labor based on productive objectives rather than professional roles. The notion of «social class» is nowadays subsumed within the communicative (...) peculiarities channeled by the ruling class, so that it has been practically abolished from the mass communicative scene. Given this social conjuncture, which deeply affects both its academic and popular conception, the present research intends to offer a critical and final vision, after the two previous works, of its contemporary sense. First of all, the pauperization and collapse of the concept will be addressed, to later expose the reasons that make social classes perpetual and, finally, to delineate its role within the world-system as it was defined in the second half of the twentieth century. (shrink)

We recast parts of decision theory in terms of channel theory concentrating on qualitative issues. Channel theory allows one to move between model theoretic and language theoretic notions as is necessary for an adequate covering. Doing so clarifies decision theory and presents the opportunity to investigate alternative formulations. As an example, we take some of Savage’s notions of decision theory and recast them within channel theory. In place of probabilities, we use a particular logic of preference. We (...) introduce a logic for describing actions separate from the logic of preference over actions. The structures introduced by channel theory that represent the decision problems can be seen to be an abstract framework. This frame-work is very accommodating to changing the nature of the decision problems to handle different aspects or theories about decision making. (shrink)

Facial information is a powerful channel for human-to-human communication. Characteristically, faces can be defined as biological objects that are four-dimensional (4D) patterns, whereby they have concurrently a spatial structure as well as temporal dynamics. The spatial characteristics of facial objects possess three dimensions (3D), namely breadth, height and importantly, depth. The temporal properties of facial objects are defined by how a 3D facial structure evolves dynamically over time; where time is referred to as the fourth dimension (4D). Our entire (...) perspective of another’s face, whether it be social, affective or cognitive perceptions, is therefore built on a combination of 3D and 4D visual cues. Counterintuitively, over the past few decades of experimental research in psychology, facial stimuli have largely been presented to participants as a spatial pattern that has been flattened into two dimensions (2D), while remaining largely static. The following review aims to advance and update facial researchers, on the recent revolution in computer-generated, realistic 4D facial models produced from real-life human subjects. We delve in-depth to summarize recent studies which have utilized facial stimuli that possess 3D structural cues (geometry and depth) and 4D temporal cues (3D structure + dynamic viewpoint and movement). In sum, we have found that higher-order perceptions such as identity, gender, ethnicity, emotion and personality, are critically influenced by the 4D characteristics embedded within natural human faces. In future, it is recommended that facial stimuli incorporate the 4D space-time perspective with the proposed time-resolved methods. (shrink)

We discuss potential benefits of research in which attention is directed toward or away from a spoken channel and measures of the allocation of attention are used. This type of research is relevant to at least two basic, still-unresolved issues in cognitive psychology: the extent to which unattended information is processed and the extent to which unattended information that is processed can later be remembered. Four recent studies of this type that address these questions in various ways are reviewed (...) as illustrations. We conclude from these studies that unattended information appears to be partially processed automatically, though attention enhances the processing considerably, and the unattended information that is processed may not be retrievable in direct or many indirect memory tasks, though it remains possible that there is an automatically stored memory trace. (shrink)

The tetratricopeptide repeat (TPR) motif is a protein-protein interaction module found in multiple copies in a number of functionally different proteins that facilitates specific interactions with a partner protein(s). Three-dimensional structural data have shown that a TPR motif contains two antiparallel α-helices such that tandem arrays of TPR motifs generate a right-handed helical structure with an amphipathic channel that might accommodate the complementary region of a target protein. Most TPR-containing proteins are associated with multiprotein complexes, and there is extensive (...) evidence indicating that TPR motifs are important to the functioning of chaperone, cell-cycle, transcription, and protein transport complexes. The TPR motif may represent an ancient protein-protein interaction module that has been recruited by different proteins and adapted for specific functions. BioEssays 1999;21:932–939. © 1999 John Wiley & Sons, Inc. (shrink)

The tetratricopeptide repeat (TPR) motif is a protein-protein interaction module found in multiple copies in a number of functionally different proteins that facilitates specific interactions with a partner protein(s). Three-dimensional structural data have shown that a TPR motif contains two antiparallel α-helices such that tandem arrays of TPR motifs generate a right-handed helical structure with an amphipathic channel that might accommodate the complementary region of a target protein. Most TPR-containing proteins are associated with multiprotein complexes, and there is extensive (...) evidence indicating that TPR motifs are important to the functioning of chaperone, cell-cycle, transcription, and protein transport complexes. The TPR motif may represent an ancient protein-protein interaction module that has been recruited by different proteins and adapted for specific functions. BioEssays 1999;21:932–939. © 1999 John Wiley & Sons, Inc. (shrink)

Traditional accounts of the role of learning in evolution have concentrated upon its capacity as a source of fitness to individuals. In this paper I use a case study from invasive species biology—the role of conditioned taste aversion in mitigating the impact of cane toads on the native species of Northern Australia—to highlight a role for learning beyond this—as a source of evolvability to populations. This has two benefits. First, it highlights an otherwise under-appreciated role for learning in evolution that (...) does not rely on social learning as an inheritance channel nor “special” evolutionary processes such as genetic accommodation (both of which many are skeptical about). Second, and more significantly, it makes clear important and interesting parallels between learning and exploratory behaviour in development. These parallels motivate the applicability of results from existing research into learning and learning evolution to our understanding of the evolution of evolvability more generally. (shrink)

The topic of Chief Executive Officer (CEO) compensation has been a focus of interest for many years. The purpose of this article is to explore the ethical dimensions of various generally accepted theories of CEO renumeration. We argue that a contractarian approach, based on the Kantian ethical framework, can be used to augment the existing contingent pay models.While the neoclassical economic model of the firm views the maximization of the shareholders'' wealth as the sole responsibility of top management, a contractarian (...) approach regards the balancing of various stakeholders'' interests as the primary task of top management. Ethical problems emerge when there are divergent, yet equally justifiable interests which compete in order to channel organizational resources to meet their own needs. In this situation, given the inherent ambiguities and ever present possibilities of multiple perspectives, it may not always be feasible to provide a categorical answer to the question of whether the CEO''s decisions are ethical. We suggest that a broad interpretation of the neoclassical theory of the firm, one that is grounded in Kantian and contractarian ethics, can serve as a basis for a reconciliation of different theories of executive compensation. (shrink)

Calcium storage is one of the functions commonly attributed to the endoplasmic reticulum (ER) in non‐muscle cells. Several recent studies have added support to this concept. Analysis of reticuloplasm, the luminal ER content, has shown that it contains several proteins (reticuloplasmins) which are prospective calcium storage proteins. One of these, calreticulin, is also present in the sarcoplasmic reticulum (SR). In sea urchin eggs, a calsequestrin‐like protein has been clearly localised to the ER. The recent demonstration that the IP3 receptor, which (...) has similarities with the calcium release channel in the SR is also localised in the ER membrane suggests that calcium stored in the ER is important for intracellular signalling. The alternative view, that the physiologically important calcium store is a specialised organelle, the calciosome, is not supported by these observations. Recent evidence also suggests that ER calcium might be important in ER structure and in the retention of the luminal ER proteins. (shrink)

The particle internal clock conjectured by de Broglie in 1924 was investigated in a channeling experiment using a beam of ∼80 MeV electrons aligned along the 〈110〉 direction of a 1 μm thick silicon crystal. Some of the electrons undergo a rosette motion, in which they interact with a single atomic row. When the electron energy is finely varied, the rate of electron transmission at 0° shows a 8% dip within 0.5% of the resonance energy, 80.874 MeV, for which the (...) frequency of atomic collisions matches the electron’s internal clock frequency. A model is presented to show the compatibility of our data with the de Broglie hypothesis. (shrink)