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)

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)

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?

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)

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)

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)

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)

The decolonization of science and reconciliation with Indigenous Peoples are leading archaeologists to adopt a new praxis that is more collaborative and more respectful of Indigenous issues, considerations and perspectives. Despite the generally positive consequences emanating from this type of project, tensions can arise between the stakeholders when their needs and objectives do not concur. The fictive case study presented here illustrates the complexity of such situations and the ethical dilemmas that can arise from them.

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)

CALHM1 was recently demonstrated to be a voltage‐gated ATP‐permeable ion channel and to serve as a bona fide conduit for ATP release from sweet‐, umami‐, and bitter‐sensing type II taste cells. Calhm1 is expressed in taste buds exclusively in type II cells and its product has structural and functional similarities with connexins and pannexins, two families of channel protein candidates for ATP release by type II cells. Calhm1 knockout in mice leads to loss of perception of sweet, (...) umami, and bitter compounds and to impaired gustatory nerve responses to these tastants. These new studies validate the concept of ATP as the primary neurotransmitter from type II cells to gustatory neurons. Furthermore, they identify voltage‐gated ATP release through CALHM1 as an essential molecular mechanism of ATP release in taste buds. We discuss these new findings, as well as unresolved issues in peripheral taste signaling that we hope will stimulate future research. (shrink)

The primary sequence of two subunits of the rod and one subunit of the cone cGMP-gated channel have been described, but describing how structure determines function is only just beginning. The discovery that the affinity of the rod channel for its agonist can be modulated indicates that the relationship between intracellular cGMP and the channel's open probability (current) during the course of the photoresponse may be more complex than previously thought.

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)

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)

The cyclic GMP-gated channel responds to changes in free intracellular cGMP, and as a result, it plays a central role in the phototransduction process in rod and cone photoreceptor cells. Recent biochemical, immunochemical, and molecular biology studies indicate that this channel consists of a complex of two distinct subunits and one or more associated proteins. Primary structural analysis indicates that the a and (3 subunits contain a cGMP-binding domain, an even number of membrane-spanning segments, a voltage sensor (...) motif and a pore region. The latter two features are found in voltage-gated channels and suggest that these two classes of channels have evolved from the same ancestral channel protein. A working model for the membrane topography of the channel subunits is proposed based on immunogold labeling studies and sequence analysis. Recent studies also indicate that calmodulin binds to the 240 kDa protein of the channel complex and modulates the sensitivity of the channel for cGMP in a Ca2+-dependent manner. The molecular properties of the channel complex and the possible role of Ca2+-calmodulin modulation of the channel during photoactivation and photorecovery are discussed in relation to the current mechanism of phototransduction in photoreceptor cells. (shrink)

The subunit structure of the cGMP-gated cation channel of rod photoreceptors is rapidly being defined, and in the process the mode of regulation by Ca2+-calmodulin unraveled. Intriguingly, early results suggest that additional subunits of unknown function are associated with the channel and remain to be identified.

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)

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)

Calcium acting through calmodulin has been shown to regulate the affinity of cyclic nucleotide-gated channels expressed in cell lines. But is calmodulin the Ca-sensor that normally regulates these channels?