Many biologically active compounds including neurotransmitters, metabolic precursors, and certain drugs are accumulated intracellularly by transporters that are coupled to the transmembrane Na+ gradient. Amino acid neurotransmitter transporters play a key role in the regulation of extracellular amino acid concentrations and termination of neurotransmission in the CNSAbbreviations: CNS, central nervous system; GABA, γ‐aminobutyric acid; cDNA, complementary deoxyribonucleic acid; mRNA, messenger ribonucleic acid; NMDA, N‐methyl‐D‐aspartate; PKC, protein kinase C; PMA, phorbol 12‐myristate 13‐acetate; DAG, diacyl glycerol; R59022, DAG kinase inhibitor; AA, arachidonic (...) acid; ACHC, cis‐3‐aminocyclohexanecarboxylic acid; GAT‐A, ACHC‐sensitive GABA transporter; GAT‐B, β‐alanine‐sensitive GABA transporter; GLY‐1 and GLYT‐1, glycine transporters; PROT‐1, proline transporter; BGT‐1, betaine transporter.. Transporters for the major amino acid neurotransmitters glutamate, GABA, and glycine are found in both neurons and glial cells. Recent work has resulted in the identification of cDNAs encoding several amino acid neurotransmitter transport proteins, all of which belong to the Na+‐and Cl−‐dependent transporter gene family. The diversity of this family suggests a degree of transporter heterogeneity that is greater than that indicated by biochemical and pharmacological studies. (shrink)

Recently a number of complex electrophysiological responses to neurotransmitters have been observed that cannot be described as simple excitation or inhibition. These responses are often characterized as modulatory, although there is no consensus on what defines modulation. Morphological studies reveal certain neurotransmitters stored in what might be release sites without synaptic contact. There is no direct evidence for nonsynaptic release from CNS sites, although such release does occur in the periphery and in invertebrates. Nonsynaptic release might provide a basis for (...) diffuse one-cell-to-many communication, but it might also simply be a means of sending the transmitter to a broader area of a single neuron than occurs in typical synapses. Several kinds of macromolecules have been found to be transported in a retrograde direction – and in some cases transsynaptically. There have been suggestions that some neurons may release more than one type of transmitter. Particularly intriguing is the possibility of release of substances that modulate actions of a primary transmitter. Taken together this range of evidence suggests that neurons may use a variety of forms of molecular communication in addition to traditionally described synaptic transmission.Several authors have suggested modes of communication distinct from classical synaptic transmission and have classified released substances using terms such as neurohumor, neurohormone, neuroregulator, and modulator. These suggestions have the heuristic value of drawing together diverse kinds of data, but it remains to be established that the pieces fit together in that fashion – for example, that complex electrophysiological effects are associated with substances released nonsynaptically. In order to reduce confusion, a flexible, generic approach to nomenclature for substances released from neurons and for hypothetical modes of communication is recommended. Some behavioral implications of nonconventional transmission are considered. (shrink)

The identification of neural substrates underlying the long lasting debilitating impact of drug cues is critical for developing novel therapeutic tools. Metabolic coupling has long been considered a key mechanism through which astrocytes and neurons actively interact in response of neuronal activity, but recent findings suggested that disrupting metabolic coupling may represent an innovative approach to prevent memory formation, in particular drug‐related memories. Here, we review converging evidence illustrating how memory and addiction share neural circuitry and molecular mechanisms implicating (...) lactate‐mediated metabolic coupling between astrocytes and neurons. With several aspects of addiction depending on mnemonic processes elicited by drug experience, disrupting lactate transport involved in the formation of a pathological learning, linking the incentive, and motivational effects of drugs with drug‐conditioned stimuli represent a promising approach to encourage abstinence. (shrink)

Thirty years after its initial characterization and more than 1000 publications listed in PubMed describing its properties, the small (ca15 kDa) protein profilin continues to surprise us with new, recently discovered functions. Originally described as an actin‐binding protein, profilin has now been shown to interact with more than a dozen proteins in mammalian cells. Some of the more recently described and intriguing interactions are within neurons involving a neuronal profilin family member. Profilin is now regarded as a regulator of (...) various cellular processes such as cytoskeletal dynamics, membrane trafficking and nuclear transport. Profilin is a necessary element in key steps of neuronal differentiation and synaptic plasticity, and embodies properties postulated for a synaptic tag. These findings identify profilin as an important factor linking cellular and behavioural plasticity in neural circuits. BioEssays 30:994–1002, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:A Still Life Is Really a Moving LifeThe Role of Mirror Neurons and Empathy in Animating Aesthetic ResponseCarol S. Jeffers (bio)IntroductionIn the Western aesthetic canon, the still life enjoys a certain prestige; its place in the museum and on the pages of the art history text is secure. Art aficionados who appreciate the character of Cezanne's apples help to ensure the lofty standing of the still life, as do (...) students who admire the dewdrops still glistening on flowers picked and painted in the nineteenth century. For some students, however, it is difficult to understand such veneration. Despite the coaxing of dedicated art or museum educators, these students find apples nestled among drapery folds or translucent petals in a spring bouquet to be "boring." No matter how compelling the apples, how exquisitely rendered the blossoms, the still life is much too static, offering little more than the lifelessness of inanimate objects.In my experience, even the most unappreciative of students can be persuaded to take a closer look at the inanimate—not by me or any strategies I may have devised but rather by classmates who have chosen still life paintings to serve as their personal metaphors. When shared during the courses I teach, these still lifes and their depicted objects acquire special meanings that are uniquely associated with the individual students who chose them. Reflecting on these class presentations, converted students offered these thoughts: "I related myself with the metaphors and the way my classmates felt"; and "What really stayed with me were the stories and the way my classmates connected with their paintings—how they connected to the art emotionally." Still another wrote: "I really liked the way their presentations went because I got to know [my classmates] a little bit more." Through these connections to still life and other genres, students explored [End Page 31] their concepts of self within a community of others and began to experience the power of empathy.Empathy, typically defined as "the intellectual or emotional identification with another,"1 is a human capacity that, according to the noted neuroscientist Vittorio Gallese, allows us to understand the world of objects as well as the world of others.2 With the recent discovery of the mirror neuron system in the human brain, Gallese and other investigators around the world have identified the neurological basis of empathy.3 Subsequent studies of the remarkable properties of mirror neurons have yielded potent new understandings of the connections between empathy, objects of art and material culture, and intrapersonal relationships among human beings. Interestingly, these twenty-first-century findings tend to confirm a nineteenth-century connection between aesthetics and empathy, or more precisely, Einfuhlung ("in-feeling," or "feeling into"), a term coined by the philosopher Robert Vischer in 1873 to describe the projection of human feeling onto art objects.4 As Vischer himself described this phenomenon, "I transport myself into the inner being of an object and explore its formal character from within, as it were."5These insights, whether gained through the use of state-of-the-art brain imaging technologies or dusty volumes in a German library, have led Gallese to consider some interesting implications, such as, for example, those involving the still life—its bottles, apples, even its brushstrokes—and to claim that "a still life is really a moving life" when understood from the perspective of neuroscience.6 To explore this claim and its relevance to classroom and museum practices, this article examines the relationship between mirror neurons, empathy, and aesthetic response as it developed among preservice teachers who presented metaphorical works of art in two teacher education courses. A brief synopsis of research results highlighting the workings of the mirroring mechanism is presented and then applied to two student presentations: one given by Molly about Cezanne's Still Life with Apples (1893-94) and the other by Deborah about Fantin-Latour's White and Pink Mallows in a Vase (1895). The stories told by Molly, Deborah, and their classmates allow additional insights with implications for art and museum education.Mirror Neurons: Some Research ResultsSome fifteen years ago, what Gallese characterizes as a "strange class" of neurons was discovered, first... (shrink)

Neurofilaments and microtubules are important components of the neuronal cytoskeleton. In axons or dendrites, these filaments are aligned in parallel arrays, and separated from one another by nonrandom distances. This distinctive organization has been attributed to cross bridges formed by NF side arms or microtubule‐associated proteins. We recently proposed a polymer‐brush‐based mechanism for regulating interactions between neurofilaments and between microtubules. In this model, the side arms of neurofilaments and the projection domains of microtubule‐associated proteins are highly unstructured and exert (...) long‐range repulsive forces that are largely entropic in origin; these forces then act to organize the cytoskeleton in axons and dendrites. Here, we review the biochemical, biophysical, genetic and cell biological data for the polymer‐brush and cross‐bridging models. We explore how the data traditionally used to support cross bridging may be reconciled with a polymer‐brush mechanism and compare the implications of recent experimental insights into axonal transport and physiology for each model. BioEssays 26:1017–1025, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Neurons have developed elaborate mechanisms for sorting of proteins to their destination in dendrites and axons as well as dynamic local trafficking. Recent evidence suggests that polarized axonal sorting of β‐site converting enzyme 1 (BACE1), a type I transmembrane aspartyl protease involved in Alzheimer's disease (AD) pathogenesis, entails an unusual journey. In hippocampal neurons, BACE1 internalized from dendrites is conveyed in recycling endosomes via unidirectional retrograde transport towards the soma and sorted to axons where BACE1 becomes enriched. In comparison (...) to other transmembrane proteins that undergo transcytosis or elimination in somatodendritic compartment, vectorial transport of internalized BACE1 in dendrites is unique and intriguing. Dysfunction of protein transport contributes to pathogenesis of AD and other neurodegenerative diseases. Therefore, characterization of BACE1 transcytosis is an important addition to the multiple lines of evidence that highlight the crucial role played by endosomal trafficking pathway as well as axonal sorting mechanisms in AD pathogenesis. (shrink)

Ras homolog enriched in the striatum (Rhes) is a striatal enriched protein that promotes the formation of thin membranous tubes resembling tunneling nanotubes (TNT)—“Rhes tunnels”—that connect neighboring cell and transport cargoes: vesicles and proteins between the neuronal cells. Here the literature on TNT‐like structures is reviewed, and the implications of Rhes‐mediated TNT, the mechanisms of its formation, and its potential in novel cell‐to‐cell communication in regulating striatal biology and disease are emphasized. Thought‐provoking ideas regarding how Rhes‐mediated TNT, if (...) it exists, in vivo, would radically change the way neurons communicate in the brain are discussed. (shrink)

A variety of studies show that parental absence early in life leads to deleterious effects on the developing CNS. This is thought to be largely because evolutionary-dependent stimuli are necessary for the appropriate postnatal development of the young brain, an effect sometimes termed the “experience-expectant brain,” with parents providing the necessary input for normative synaptic connections to develop and appropriate neuronal survival to occur. Principal among CNS systems affected by parental input are the monoamine systems. In the present study,N= (...) 434 rhesus monkeys (233 males, 201 females) were reared in one of two conditions: as mother-reared controls (MR;n= 269) or without adults with 24-h access to same-aged peers (PR;n= 165). When subjects were six-months-old, they underwent a separation paradigm involving 4, sequential, four-day social separations from their mothers or peers, with each separation followed by three-day reunions with their mothers or their peers. Prior to the separation paradigm, baseline cisternal CSF samples were obtained, as well as at the end of each the four social separations, and after final separation, during a recovery period. CSF was assayed for concentrations of monoamine metabolites and a blood sample was genotyped for the serotonin transporter (5-HTT) genotype. Replicating earlier landmark findings, PR subjects with thesallele exhibited lower baseline concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), when compared to PR subjects homozygous for theLallele. MR subjects were undifferentiated by genotype. PR subjects exhibited lower CSF 5-HIAA concentrations during baseline, but higher CSF 5-HIAA during social separations, when compared to MR subjects. There were rearing effects for the dopamine metabolite homovanillic acid (HVA) and for the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), with PR subjects showing higher HVA and lower MHPG when compared to MR subjects. These findings indicate that there are long-term deficits in the response of monoamines following early maternal absence. The results of this study confirm and extend earlier findings that early parental absence has deleterious consequences for the development of the monoamine systems, and that these consequences are modulated by the 5-HTT genotype. (shrink)

Aspects of peroxisome evolution, uncoupling, carnitine shuttles, supercomplex formation, and missing neuronal fatty acid oxidation (FAO) are linked to reactive oxygen species (ROS) formation in respiratory chains. Oxidation of substrates with high FADH2/NADH (F/N) ratios (e.g., FAs) initiate ROS formation in Complex I due to insufficient availability of its electron acceptor (Q) and reverse electron transport from QH2, e.g., during FAO or glycerol‐3‐phosphate shuttle use. Here it is proposed that the Q‐cycle of Complex III contributes to enhanced ROS (...) formation going from low F/N ratio substrates (glucose) to high F/N substrates. This contribution is twofold: 1) Complex III uses Q as substrate, thus also competing with Complex I; 2) Complex III itself will produce more ROS under these conditions. I link this scenario to the universally observed Complex III dimerization. The Q‐cycle of Complex III thus again illustrates the tension between efficient ATP generation and endogenous ROS formation. This model can explain recent findings concerning succinate and ROS‐induced uncoupling. (shrink)

A decade ago I postulated that ROS formation in mitochondria was influenced by different FADH2/NADH (F/N) ratios of catabolic substrates. Thus, fatty acid oxidation (FAO) would give higher ROS formation than glucose oxidation. Both the emergence of peroxisomes and neurons not using FAO, could be explained thus. ROS formation in NADH:ubiquinone oxidoreductase (Complex I) comes about by reverse electron transport (RET) due to high QH2 levels, and scarcity of its electron‐acceptor (Q) during FAO. The then new, unexpected, finding of (...) an FAO enzyme, ACAD9, being involved in complex I biogenesis, hinted at connections in line with the hypothesis. Recent findings about ACAD9's role in regulation of respiration fit with predictions the model makes: cementing connections between ROS production and F/N ratios. I describe how ACAD9 might be central to reversing the oxidative damage in complex I resulting from FAO. This seems to involve two distinct, but intimately connected, ACAD9 characteristics: (i) its upregulation of complex I biogenesis, and (ii) releasing FADH2, with possible conversion into FMN, the crucial prosthetic group of complex I. Also see the video abstract here: https://youtu.be/N7AT_HBNumg. (shrink)

continent. 2.2 (2012): 155–158 Michel Serres. Biogea . Trans. Randolph Burks. Minneapolis: Univocal Publishing. 2012. 200 pp. | ISBN 9781937561086 | $22.95 Conveying to potential readers the significance of a book puts me at risk of glad handing. It’s not in my interest to laud the undeserving, especially on the pages of this journal. This is not a sales pitch, but rather an affirmation of a necessary work on very troubled terms: human, earth, nature, and the problematic world we made. (...) It is this world that aspirates the silence (so to speak), and therefore the subject which, along with the development of the “made world” exports the excess augmentation of the cosmically missing, this silence of the natural, et cetera. Had we learned from Locke that lesson of “labor,” to consume what we need… but perhaps we need more than what matters? Serres’ Biogea has several functions on this manner, if it is indeed a book to be consumed. First, readers searching for novelistic entertainment have a place to dwell. Biogea deserves a place in your back pocket; biographical generosity and poetic fluidity should satisfy most textual fetishes. For lay philosophers who want to refresh their acumen, Biogea deserves a place on the book shelf, one already reads a sorely needed postmodern tune-up here. Serres’ style is clearly French; he leaves few cheese crumbs on his words, rather preciseness and breathing in the work give way to a sweeping manner that breaks the narrative line of sight. A circular narrative and anachronistic fragmentation of terms allows an abyssal atmosphere to swell, if only to pump into the book the externality of its broader text. Biogea aspires to a higher standard and the book, at times, is thinking this negentropic problem too. Univocal, the publisher, has crafted a book appropriate for the hands to hold and the translations are an achievement of an otherwise difficult writer to translate. Terms are the conditions of a broader text. It is important to note that Serres’ content is as much a thinking of terminal ports. There is a regard for the transportation technology of the written word. For me, this is the mark of genius, a craftiness that tells of a book device that I may trust. Serres is an accomplished thinker and a necessary voice to check the putative trendiness of anti-postmodernist and market-driven theory of endless cultural liquidation. Offering interventions on subjectivity as an open system we are given a chance to affirm the human, not merely to discard it, but to engage its poetic image emotion, the calibratory silent sense of the analogic world; the terms on which we base our efforts. 1 The human is the center of its own negation, constantly mediating it. Something deeper at stake appears in the work then, and it is quite obvious from the onset. Certainly, a book is an intensification of possible text and those who brought this actual book into existence have captured a rarity in regards to the subject matter and artistic accomplishment. I mentioned terms as conditions, so let us understand Biogea as bio-yea, a yes to bios . An affirmation of living and accepting presence for all of its defiance of images, words, and things temporal. Therefore Serres’ existence and its existants plays parts; out of linearity and still like a porous bone pumping blood it manufactures into the fleshy life it becomes. Starting from a man named silence chaos emerges, or the man “Old Taciturn” takes up a journey anticipating a great flood. In other words, a development akin to the one in Genesis. In dealing with this ancestral occupation, fusing Genesis with contemporary philosophical terms, Serres initiates this anachronistic fragmentation under the forming subjectivity of his own autobiography. This mutation in the open system is precisely one of Serres’ terms. There an abyss is at work, stated, but also measured by heels on the ground—the abyss dispatching earthen tensions, that which plays our tunes, that which we abide by and recognize in volcanoes, rivers, oceans, earthquakes and weaponry in the battles of the world. Set in later stages of the book, such tensions are harnessed through scientific principles in an attempt to unify the terms of natural force if only to terminate the world. Thus the elevation of the earth into the world is clearly set forth. Here already, and few pages in, a resonance is set forth under appellations such as the river Garonne, a subjectivity as much as it is inhuman, the river is the inhuman that makes us human. I get the sense that Serres is taking up a challenge issued by Wallace Stevens; namely, that the great poems of heaven and hell have been written, but that only the poem of the earth has resisted composition. 2 On this level we cannot avoid the killing factor of silence, given that our cognition blocks its pure, radical obliteration. Thus a silence of attunement to the earth is in a novel dialectic of the rithmic and rhythm. A technological world, a triumph of termination is set forth. If a text imposes its will given the reader who authorizes it, it is made to convey or convect a presupposition to a reader or its inhabitant(s). Text is therefore both, in-content, contenting, contentedness, and in reading it, a way to navigate self-destruction (dis-content). Here then would one note that the “inhuman” reveals itself, “an aperiodic rhythm of lovers and beloved…the sea as our friend…but as our enemy…maternal vivifying sea.” The sea is an open book, or vaginal birth canal, where the engagement of text comes forth: “…woman sea, open vulva.” One sees like the sea, but only after it, when the uninhabitable truth of inhabiting it switches the polarity of the sailors soul: “I was seeing like the sea” (9-11). In other words, we are invited to embrace the nonsense of the visible. At this point I am taken to Jean-François Lyotard’s work The Inhuman , specifically the first entry on negentropy that would be congruent with Serres’ thematic. 3 The human being exports, deports, or transplants its relation through text, through the system— and this is its sense or relation to silence, to music. Unaware of Serres’ proximity to this work, the concept of gender interrelation as regards a solar catastrophe runs clear. It would be, on this basis, that Serres references his peers, the other texts that, as mentioned above, are discarded in philosophy today. For students of philosophy what we have here is perhaps a gift, a needed project. If silence and death are at work, there is a political valence to deal with, and here, much like the domain of the text and the dominion of the reader, we confront the world of natural, fluid violence. The anti-postmodernist critique is in part based on a weak idea that the loss of ideology, of a world vision, motivates the “correlationist” project. 4 Serres seems to offer another way to view this when he notes that whereas persons “sometimes kill,” it is clearly “the collective” that “always kills” (17). What is the collective today, if not an organizing function we never see yet acts in its favor in the name of truth? One feels a sense of enigma here, if only to link to what Stevens remarked of communism as a “grubby faith,” providing this applies for capitalism as well, namely any ideology of progress overly interested in absolutes. Here we get the sense that the inhuman, silence, this type of killing, always killing, could not be matched by human-made, political dynamos. Or that if it comes to an equilibrium, a catastrophe is never too far from us to read with our heels. We are left to note that the forces of nature presuppose and permeate political systems, the more these systems obtain force, the more the system takes upon itself the proper name of nature that motivates its dissemination, albeit falsely. This note, that in an age of ecocide and technological captivity (sustainability and transparency) political regimes won’t grow our soul-learning ears any larger than our tongues, stands clear to us. The promise of technological desubjectification is here pushed aside. Regarding politics, Serres illustrates this fact: Where did this corpse come from? Who was it? Who killed it? I don’t know. I won’t try to find out. I refuse to get vengeance for it. And I only see Garonne. For our victims, today, are the rivers, too. Their waters have irrigated my life, enchanted my thought, invigorated my body; I’ve known them to be threatening, untamable, as dangerous as the sea when it rages. Yes, murderous. They decided to control their courses; dams, sometimes senseless, destroying sites and valleys, reduced entire populations to servile displacements; programs for the irrigation of thirsty farmland, often beneficial of course, completed their drying up.(22) Serres enters into his idea concerning the captivity of language from the natural into a world system: For thousands of years, we have been licking things with our tongues, covering and daubing them so as to appropriate things for ourselves. If language boils down to a convention, this convention took place between the speakers without consulting the thing named, become as a result the property of those who covered it in this way with their drawn or voiced productions. Malfeasance analyzes these acts of appropriation. Thus every inert object, every living thing as well, sleeps under the covers of signs, a little in the way that, today, a thousand posters shouting messages and ugly riots of color drown, with their filthy flood, the landscapes, or better, exclude them from perception because the meaning, almost nil, of this false language and these base images forms an irresistible source of attraction to our neurons and eyes. This appropriation covers the world’s beauty with ugliness. (38-39) Technological concealment coming to bear, we begin to get a sense of another commentary on the condition of sensing, driving home the necessity of a text dealing with such subject matter to be what its terms insist. Thus toward new openings: The new opening. As low beneath our feet as you like, the Biogea opens us to another space, high enough for us to be able to acquire a wisdom there, that of redeveloping this same place differently from our fathers, this place that’s still politically cut up by old hatreds, beneath the flood of tears and blood that we call history. Without this soft place, spiritually very old, but newly conceived in this way, without the juridical construction of a common good, opposed to our filthy ownership, I don’t see how our planet, hard, will survive. Hardness that depends on a softness, material belonging that depends on this temporary rented location (51). Serres enters into a summit on the content and the structure of his work. Archimedes is brought in with the concept of three volcanoes. Meaning fire, but as well earth, water, air. For it was Archimedes’ war machines that sought to lift the earth, thus bringing in the question of principles of science: “can a principle be invented while controlling its consequences?” (66-7). May the earth be put in a sentence, terminated by terminology, appellations, gone wild? By means of these element-dominating laws, this old physicist began to tear nature away from the ancient myths; by a strange return, today we’re plunging our successes back into the anxieties and terrors from which that ancient physics was born. Yes, our new history of science and technology is plunging, today, as though in a loop, into the fundamental human myths from which Empedocles’ first laws came. A major progression and a regression on the nether side of the origins. Consequently, the contemporary time requires that we try to return to that unity in which the principles of hate and love are at the same time human, living, inert and global. We will never attain a deontology of our knowledge and actions without thinking the subjective, the objective, the collective, and the cognitive all together simultaneously. Here, hate and love are the result of these four components.(71) Working then on the concept of fire-starting mirrors to the atomic annihilation of the Second War, Serres works into the subjectivity in question on the matter of rhythm—say rithmic— precisely at that point: Knowledge is changing today. The all-political is dying; the monarchy of the sciences said to be hard is coming to a close. The science of the things of the world will have to communicate just as much as the things of the world do, which do it much better than humans do, who don’t always want to do it. Let’s celebrate two changes this morning. The first one strikes a new blow to our narcissism. No, knowledge and the world don’t resemble our analytical enjoyments of refined cutting up, of endless debates and of exclusions full of hate. They, on the contrary, form a bloc and a sum, alliance and alloys. Uniting the fields of knowledge among themselves the way the things are connected among themselves, the second newness puts into place sets united by interlacing, webs and simplexes that combine with the things of the world, themselves combined, the combined knowledge that understands them.(130-1) Biogea closes on its opening flood thematic, approaching the initial telos of Genesis. Here the trees are brought into a position with atmosphere, the opaque abyssal reservoir, the tomb of the sun, sea in the polarity of the earthen heaven and hell. The poem of the earth then is silent but deadly, indeed, as funny as that phrase is, mainly a tomb gas. The meaning of the living and the non-meaning of things converge in the muteness of the world; this meaning and non-meaning plunge there and come out, the ultimate eddy. Mundus patet: through a fissure, through an opening, a fault, a cleft come noises, calls as small as these apertures. I’m listening, attentive, I’m translating, I’m advancing in the scaled-down meaning and science. Mundus patet: should the world open greatly, it will launch me into its silence. The totality remains silent. Knowledge expanded in elation. White origin of meaning, fountain of joy. (198) Final Remarks One test of a review is the long term trajectory the referee thinks the book will have. I see Serres’ text lending greatly into the vision of Biogea . In fact, in the vision of the novel inquiries of Stephen Jay Gould’s work there is something to be thought on the level of the individual and the species; namely, that humanity and its uniqueness is in its deferral, its thinking and naming, a thinking surrounded by silence that filters into everything, that pulls us through the world, the kinetic pulse we recognize, and all of that we cleave away in the base philosophical maxim of difference itself. Unique individuals are spatial creatures: we dwell, and we ought to get good at it. Yet this is an imaginative space that, if you are crazy enough to believe it, de-term-ine the conditions of its own terms. That is why we are not merely creating spaces on the acceleration of time, or so this ignoramus thinks, to accidentally transcend. Imagination already has this insatiable silence that we drink up and fail to manifest. Space is timeless. The imagination itself, shared by humans for themselves, their objects, and the species as a whole, is a non-defined space of relation; a whole human trajectory as part of nature, and part of worlds that are the other side of thinking nature, the consequence of it, at least our attempt to do so. Our survival is based on our deliberation, our caution, our natural deconstructive sense toward this silence that is already part of the song, sung, singing of this century without end. Good books will let us inhabit this space and recognize a form of life. Serres’ text moves toward dwelling, as noted, in masterful and accessible ways. The pitched battles are the falling replays of anemic and dead politics. As soon as we realize there is humanity, we may be able to enjoy the end of it, our inhuman capability of listening to silence. NOTES 1. See Michel Serres. The Parasite . Minneapolis: University of Minnesota Press. 2007. 2. Wallace Stevens, “Imagination as Value” [ca. 1945], in Collected Poetry and Prose . New York: The Library of America. 1997. 724-39. 3. Jean-François Lyotard. The Inhuman: Reflections on Time . Trans. Geoffrey Bennington & Rachel Bowlby. Stanford, CA: Stanford University Press. 1992. 4. See the introduction: Quentin Melliassoux. After Finitude: An Essay on the Necessity of Contingency . Trans. Ray Brassier. New York: Continuum. 2008. EDITOR'S NOTE: This review was updated on August 8, 2012. Substantial edits include block quotes from the book under review as well as the inclusion of comments from the author. (shrink)

The hereditary neurodegenerative disease spinal muscular atrophy (SMA) with childhood onset is one of the most common genetic causes of infant mortality. The disease is characterized by selective loss of spinal cord motor neurons leading to muscle atrophy and is the result of mutations in the survival motor neuron (SMN) gene. The SMN protein has been implicated in diverse nuclear processes including splicing, ribosome formation and gene transcription. Even though the genetic basis of SMA is well understood, it is not (...) clear how defects in these ubiquitous processes result in motor neuron degeneration leaving other tissues unaffected. Recent evidence from animal and cell culture models of SMA points to roles for SMN in neurite outgrowth and axonal transport. Disruption of these functions might be particularly detrimental to motor neurons given their high metabolic demands and precise connectivity requirements, thus providing a possible explanation for the specificity of motor neuron susceptibility in SMA. Understanding the molecular mechanisms of SMN activity in neuronal processes may generate new targets for future therapeutic strategies. BioEssays 27:946–957, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

The transactivation response‐DNA binding protein of 43 kDa (TDP‐43) is an aggregation‐prone nucleic acid‐binding protein linked to the etiology of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). These conditions feature the accumulation of insoluble TDP‐43 aggregates in the neuronal cytoplasm that lead to cell death. The dynamics between cytoplasmic and nuclear TDP‐43 are altered in the disease state where TDP‐43 mislocalizes to the cytoplasm, disrupting Nuclear Pore Complexes (NPCs), and ultimately forming large fibrils stabilized by the C‐terminal (...) prion‐like domain. Here, we review three emerging and poorly understood aspects of TDP‐43 biology linked to its aggregation. First, how post‐translational modifications in the proximity of TDP‐43 N‐terminal domain (NTD) promote aggregation. Second, how TDP‐43 engages FG‐nucleoporins in the NPC, disrupting the pore permeability and function. Third, how the importin α/β heterodimer prevents TDP‐43 aggregation, serving both as a nuclear import transporter and a cytoplasmic chaperone. (shrink)

CB1 receptors are functionally present within brain mitochondria, although they are usually considered specifically targeted to plasma membrane. Acute activation of mtCB1 alters mitochondrial ATP generation, synaptic transmission, and memory performance. However, the detailed mechanism linking disrupted mitochondrial metabolism and synaptic transmission is still uncharacterized. CB1 receptors are among the most abundant G protein-coupled receptors in the brain and impact on several processes, including fear coping, anxiety, stress, learning, and memory. Mitochondria perform several key physiological processes for neuronal homeostasis, (...) including production of ATP and reactive oxygen species, calcium buffering, metabolism of neurotransmitters, and apoptosis. It is therefore possible that acute activation of mtCB1 impacts on these different mitochondrial functions to modulate synaptic transmission. In reviewing and integrating across the literature in this area, we describe the possible mechanisms involved in the regulation of brain physiology by mtCB1 receptors. Activation of mitochondrial CB1 but not of plasma membrane CB1 decreases brain mitochondrial activity, glutamatergic synaptic transmission, and memory performance. Several processes can be involved in this alteration of brain physiology, including mitochondrial ATP and ROS production, axonal mitochondrial transport, Ca2+ homeostasis, and/or metabolism of the neurotransmitter glutamate. (shrink)

Parvalbumins (PVs) are acidic, intracellular Ca2+‐binding proteins of low molecular weight. They are associated with several Ca2+‐mediated cellular activities and physiological processes. It has been suggested that PV might function as a “Ca2+ shuttle” transporting Ca2+ from troponin‐C (TnC) to the sarcoplasmic reticulum (SR) Ca2+ pump during muscle relaxation. Thus, PV may contribute to the performance of rapid, phasic movements by accelerating the contraction–relaxation cycle of fast‐twitch muscle fibers. Interestingly, PVs promote the generation of power stroke in fish by speeding (...) up the rate of relaxation and thus provide impetus to attain maximal sustainable speeds. However, immunological monitoring of diverse tissues demonstrated that PVs are also present in non‐muscle cells. The axoplasmic transport and various intracellular secretory mechanisms including the endocrine secretions seem to be controlled by the Ca2+ regulation machinery. Any defect in the Ca2+ handling apparatus may cause several clinical problems; for instance, PV deficiency alters the neuronal activity, a key mechanism leading to epileptic seizures. Moreover, atypical relaxation of the heart results in diastolic dysfunction, which is a major cause of heart failure predominantly among the aged people. PV may offer a unique potential to correct defective relaxation in energetically compromised failing hearts through PV gene transfer. Consequently, PV gene transfer may present a new therapeutic approach to correct cellular disturbances in Ca2+ signaling pathways of diseased organs. Hence, PVs appear to be amazingly useful candidate proteins regulating a variety of cellular functions through action on Ca2+ flux management. (shrink)

Light can kill the photoreceptors of the eye, not only very bright direct sunlight, but more moderate illumination if the light is present continuously. Recent experiments show that rod apoptosis can be triggered by strong and constant activation of transduction, and that death can be prevented if transduction is inhibited even though the eye is illuminated. Vitamin A deficiency and genetically inherited diseases, such as some forms of retinitis pigmentosa and Leber congenital amaurosis, appear to kill like this: transduction is (...) activated at a high rate and continuously, and this causes the rods to die. Why does transduction kill? Our best guess is that continuous activation produces a prolonged lowering of the Ca2+ concentration, which is also thought to kill neurons in tissue culture and during the development of the nervous system. To prevent death in constant light, rods have evolved protective mechanisms including modulation of channels and ion transport to keep the Ca2+ from going too low. Prolonged light exposure also causes migration of transduction proteins from one part of the cell to another and a reversible shortening of the rod outer segments, the part of the cell that contains the pigment rhodopsin. All of these mechanisms are at work in the normal eye to reduce transduction and prevent the Ca2+ concentration from dropping too low for too long a time. That most of us retain our vision our entire lives is a testament to their effectiveness. BioEssays 28: 344–354, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Both genetic and environmental factors have key roles in determining aggressive tendencies. In particular, reaction to stress appears to be an important factor in precipitating aggressive episodes and individuals may vary in their ability to cope with stressful environments depending on their genetic make up. Evidence from humans and primates indicates that adverse rearing conditions may interact with variants in stress and neurotransmitter pathway genes leading to antisocial and/or violent behaviour. Common alleles of some serotonin pathway genes, including those involved (...) in its degradation (monoamine oxidase A, MAOA), or its re‐uptake into pre‐synaptic neurones (serotonin transporter, SERT) have been shown to confer functional variation. Examination of the interaction between the alleles of such polymorphisms (in particular those affecting MAOA) and environmental stressors suggest that they may provide protection against, or increase sensitivity to, abusive upbringing; an observation that may explain part of the variability in developmental outcomes associated with maltreatment. BioEssays 29: 227–236, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

In order to make an attempt at grouping the various aspects of brain functional imaging (fMRI, MRS, EEG-MEG, ...) within a coherent frame, we implemented a model consisting of a system of differential equations, that includes: (1) sodium membrane transport, (2) Na/K ATPase, (3) neuronal energy metabolism (i.e. glycolysis, buffering effect of phosphocreatine, and mitochondrial respiration), (4) blood-brain barrier exchanges and (5) brain hemodynamics, all the processes which are involved in the activation of brain areas. We assumed that (...) the correlation between brain activation and metabolism could be due to either changes in the concentrations of ATP and ADP following activation of Na/K ATPase that result from the changes in ion concentrations, or the involvement, in different phases of metabolism, of a second messenger such as calcium. In this article, we show how this type of model enables interpretation of MRS and fMRI published data that were obtained during prolonged stimulations. (shrink)

The noncoding RNA 7SK is a critical regulator of transcription by adjusting the activity of the kinase complex P‐TEFb. Release of P‐TEFb from 7SK stimulates transcription at many genes by promoting productive elongation. Conversely, P‐TEFb sequestration by 7SK inhibits transcription. Recent studies have shown that 7SK functions are particularly important for neuron development and maintenance and it can thus be hypothesized that 7SK is at the center of many signaling pathways contributing to neuron function. 7SK activates neuronal gene expression (...) programs that are key for terminal differentiation of neurons. Proteomics studies revealed a complex protein interactome of 7SK that includes several RNA‐binding proteins. Some of these novel 7SK subcomplexes exert non‐canonical cytosolic functions in neurons by regulating axonal mRNA transport and fine‐tuning spliceosome production in response to transcription alterations. Thus, a picture emerges according to which 7SK acts as a multi‐functional RNA scaffold that is integral for neuron homeostasis. (shrink)

Mirror neurons are widely regarded as an important key to social cognition. Despite such wide agreement, there is very little consensus on how or why they are important. The goal of this paper is to clearly explicate the exact role mirror neurons play in social cognition. I aim to answer two questions about the relationship between mirroring and social cognition: What kind of social understanding is involved with mirroring? How is mirroring related to that understanding? I argue that philosophical and (...) empirical considerations lead us to accord a fairly minimal role for mirror neurons in social cognition. (shrink)

A new class of visuomotor neuron has been recently discovered in the monkey’s premotor cortex: mirror neurons. These neurons respond both when a particular action is performed by the recorded monkey and when the same action, performed by another individual, is observed. Mirror neurons appear to form a cortical system matching observation and execution of goal-related motor actions. Experimental evidence suggests that a similar matching system also exists in humans. What might be the functional role of this matching system? One (...) possible function is to enable an organism to detect certain mental states of observed conspecifics. This function might be part of, or a precursor to, a more general mind-reading ability. Two different accounts of mind-reading have been suggested. According to “theory theory‘, mental states are represented as inferred posits of a naive theory. According to “simulation theory‘, other people’s mental states are represented by adopting their perspective: by tracking or matching their states with resonant states of one’s own. The activity of mirror neurons, and the fact that observers undergo motor facilitation in the same muscular groups as those utilized by target agents, are findings that accord well with simulation theory but would not be predicted by theory theory. (shrink)

Lizardo argues that The Social Theory of Practices is refuted by the discovery of mirror neurons. The book argues that the kind of sameness of tacit mental content assumed by practice theorists such as Bourdieu is fictional, because there is no actual process by which the same mental content can be transmitted. Mirror neurons, Lizardo claims, provide such a mechanism, as they imply that bodily automatisms, which can be understood as the basis of habitus and concepts, can be shared and (...) copied from one person to another. This response to Lizardo points out that the Gallese arguments on which Lizardo relies relate to phylogenetic and universal body movements, not to the learned movements characteristic of practices, and that there is no sameness producing mechanism parallel to the genetic one. (shrink)

In numerous peripheral sense organs, external stimuli are detected by primary sensory neurons compartmentalized within specialized structures composed of cuticular or epithelial tissue. Beyond reflecting developmental constraints, such compartmentalization also provides opportunities for grouped neurons to functionally interact. Here, the authors review and illustrate the prevalence of these structural units, describe characteristics of compartmentalized neurons, and consider possible interactions between these cells. This article discusses instances of neuronal crosstalk, examples of which are observed in the vertebrate tastebuds and multiple (...) types of arthropod chemosensory hairs. Particular attention is paid to insect olfaction, which presents especially well‐characterized mechanisms of functional, cross‐neuronal interactions. These examples highlight the potential impact of peripheral processing, which likely contributes more to signal integration than previously considered. In surveying a wide variety of structural units, it is hoped that this article will stimulate future research that determines whether grouped neurons in other sensory systems can also communicate to impact information processing. (shrink)

Actors, undercover investigators, and readers of fiction sometimes report “losing themselves” in the characters they imitate or read about. They speak of “taking on” or “assuming” the beliefs, thoughts, and feelings of someone else. I offer an account of this strange but familiar phenomenon—what I call imaginative transportation.

Questions concerning the nature of representation and what representations are about have been a staple of Western philosophy since Aristotle. Recently, these same questions have begun to concern neuroscientists, who have developed new techniques and theories for understanding how the locus of neurobiological representation, the brain, operates. My dissertation draws on philosophy and neuroscience to develop a novel theory of representational content.

Are there universals of reading? There are three ways of construing this question. Is the region of the brain where reading is implemented identical regardless of what writing system the reader uses? Is the mental information-processing system used for reading the same regardless of what writing system the reader uses. Do the word's writing systems share certain universal features? Dehaene offers affirmative answers to all three questions in his book. Here I suggest instead that the answers should be negative. And (...) I ask: if reading is not universal in any sense, what does this imply about Dehaene's Neuronal Recycling hypothesis for reading? (shrink)

We all know that problems of transportation and allocation appear frequently in practical life. We need to transfer materials from production centers to consumption centers to secure the areas’ need for the transported material or allocate machines or people to do a specific job at the lowest cost, or in the shortest time. We know that the cost factors Time is one of the most important factors that decision-makers care about because it plays an “important” role in many of the (...) practical and scientific issues that we face in our daily lives, and we need careful study to enable us to avoid losses. For this, the linear programming method was used, which is one of the research methods. Processes, where the problem data is converted into a linear mathematical model for which the optimal solution achieves the desired goal. Since these models are linear models, we can solve them using the direct simplex method and its modifications, but the specificity that these models enjoy has enabled scholars and researchers to find special methods that help us in obtaining the optimal solution. Whatever the method used, the goal is to determine the number of units transferred from any material from production centers to consumption centers, or to allocate a machine or person to do a job so that the cost or time is as short as possible. These issues were addressed according to classical logic, but the ideal solution was a specific value appropriate to the conditions in which the data was collected and does not take into account the changes that may occur in the work environment. In order to obtain results that are more accurate and enjoy a margin of freedom, we present in this book a study of transport issues and neutrosophic allocation issues and some methods for solving them. By neutrosophic issues we mean These are the problems in which the data are neutrosophic values, i.e. the required quantities and the available quantities. (shrink)

Foetal neurones transplanted within the adult mammalian central nervous system survive and differentiate. Study of such transplants has yielded insights into the function, development and plasticity of brain structures, and suggests promising new therapies for a number of neurological disorders.

Impossible Minds: My Neurons, My Consciousness has been written to satisfy the curiosity each and every one of us has about our own consciousness. It takes the view that the neurons in our heads are the source of consciousness and attempts to explain how this happens. Although it talks of neural networks, it explains what they are and what they do in such a way that anyone may understand. While the topic is partly philosophical, the text makes no assumptions of (...) prior knowledge of philosophy; and so contains easy excursions into the important ideas of philosophy that may be missing in the education of a computer scientist. The approach is pragmatic throughout; there are many references to material on experiments that were done in our laboratories. The first edition of the book was written to introduce curious readers to the way that the consciousness we all enjoy might depend on the networks of neurons that make up the brain. In this second edition, it is recognized that these arguments still stand, but that they have been taken much further by an increasing number of researchers. A post-script has now been written for each chapter to inform the reader of these developments and provide an up-to-date bibliography. A new epilogue has been written to summarize the state-of-the art of the search for consciousness in neural automata, for researchers in computation, students of philosophy, and anyone who is fascinated by what is one of the most engaging scientific endeavours of the day. This book also tells a story. A story of a land where people think that they are automata without much in the way of consciousness, a story of cormorants and cliffs by the sea, a story of what it might be like to be a conscious machine... (shrink)

Recently, there has been a resurgence of interest in theories of mindreading. New discoveries in neuroscience have revitalized the languishing debate. The discovery of so-called mirror neurons has revived interest particularly in the Simulation Theory (ST) of mindreading. Both ST proponents and theorists studying mirror neurons have argued that mirror neurons are strong evidence in favor of ST over Theory Theory (TT). In this paper I argue against the prevailing view that mirror neurons are evidence for the ST of mindreading. (...) My view is that on an appropriate construal of their function, mirror neurons do not operate like simulation theorists claim. In fact, mirror neurons are more appropriately understood as one element in an information-rich mindreading process. As such, mirror neurons fit in better with some sort of TT account of mindreading. I offer a positive account, the Model TT, which better explains the role of mirror neurons in social cognition. (shrink)

The energy transport in one-dimensional nonlinear systems is discussed. By numerically studying a model system, we verify the Fourier heat law on purely dynamical grounds and we compute the coefficient of thermal conductivity K. The same value ofK is independently obtained by use of the Green-Kubo formalism.

In this chapter, I aim to examine the two central properties that are said to underlie the theory of mirror neurons, namely action execution and action observation. I shall call these the functional properties of mirror neurons. I will argue that attributing the functional properties of mirror cognition, as many neuroscientists do, to the so-called ‘mirror neurons’ suffers from the problem of misidentification. This is the problem of incorrectly identifying an object or a property of one sort with some other (...) object or property. In light of this, I will propose that the most promising solution for the problem of misidentification is to ground the functional properties of mirror neurons squarely in consciousness and its bearer. (shrink)

The transport of molecules across the nuclear envelope plays a central role in the metabolism of the cell. Significant advances hi three major areas highlight the limits of our current knowledge and point to the prospect of exciting future developments. Firstly, findings that ions and small proteins do not diffuse freely into the nucleus call into question the current views of nuclear envelope permeability. Secondly, indications that nuclear protein import can be regulated in conjunction with the cell cycle and (...) development have been confirmed by the clear demonstration of regulated nuclear entry of specific transcription factors and morphogens. Thirdly, identification and characterisation of candidate receptor proteins indicates that the recognition of the nuclear targeting sequence occurs in the cytoplasm, suggesting that a different recognition event occurs at the nuclear pore. (shrink)

Musical improvisation is a sophisticated activity in which a performer realizes, real-time, melodic, and rhythmic sequences in harmony with those from other musicians. The study of musical improvisation helps one to understand not only the cognition of creativity, but also the complex neuronal basis of executive functions, the relation between conscious and unconscious action, and even more. So far, the prevailing models, founded on the brain imaging method, have focused on the connection between the cortical areas and their cognitive (...) processes. Little attention, on the other hand, has been given to the huge variety of subcortical activities, especially in the basal ganglia. This fundamental subcortical component, through its implicit procedures and the role it plays in memory, is responsible to produce new information all the time, allowing the prefrontal cortex to transform a huge and disordered amount of data in explicit creative acts. The basal ganglia are strongly related to the activation of chemical signals generated by dissonance or lack of symmetry between perception and expectation, participating even in the responses to environmental demands according to the circumstances. Thus, they interact with the frontal cortex and with the limbic system, playing a key role in planning and selecting appropriate actions and in decision making. In this text, we try to explain in which sense improvisation is connected to the processes of executive functions, to creativity and to the integrated activity of cortical–subcortical areas controlling the free flow of ideas and to expressive spontaneity. Eventually, we purpose a model according to which structure and process take part at the centrencephalic space of functional integration, which, through both competing and cooperating dynamics, gives way to spontaneous composition. (shrink)

The Gram-negative outer membrane is a potent permeability barrier against antibiotics, limiting clinical options amid mounting rates of resistance. The Lol transport pathway delivers lipoproteins to the OM. All the OM assembly machines require one or more OM lipoprotein to function, making the Lol pathway central for all aspects of OM biogenesis. The Lol pathways of many medically important species clearly deviate from the Escherichia coli paradigm, perhaps with implications for efforts to develop novel antibiotics. Moreover, recent work reveals (...) the existence of an undiscovered alternate route for bringing lipoproteins to the OM. Here, lipoprotein transport mechanisms, and the quality control systems that underpin them, is re-examined in context of their diversity. All essential outer membrane assembly machines require lipoproteins to function. Hence, the transport mechanisms supplying these lipoproteins are critical for maintaining the integrity of the outer membrane barrier against antibiotics. Lipoprotein transport strategies of diverse Gram-negative bacteria will be reviewed in the context of recent discoveries. (shrink)

The aim of the article is to show how mirror neurons, a recent discovery in neurology, might play a vital role in the creation of unity in our lives. This unity is a formal one. But since we all share the illusion that there is more to personal identity than only a formal unity, and that deep in ourselves the inner essence of our true self lies hidden, this same mechanism should also be able to shed some light on the (...) inescapability of this illusion. I begin by elaborating on the parallel Wittgenstein saw between the problem of the Self and the problem of mental processes. I continue by focusing on the problem of mental processes, first by looking at the philosophy-of-mind-debate where the understanding of the other is studied, then by looking at developmental psychology studies of how a child understands itself. With the help of Sartre's being-for-the-other, the conclusion will lead us to the formal unity in our lives that Wittgenstein described with his limit-concept. (shrink)

In their analyses of the neural correlates of discrete emotionality, Lindquist et al. do not consider the numerous drawbacks to inferring psychological processes based on currently available cognitive neurometric technology. The authors also disproportionately emphasize the relevance of neuronal activation over deactivation, which, in our opinion, limits the scope and utility of their conclusions.

Selected contributions to the symposium on "Mirror neurons and the evolution of brain and language" held on July 5-8, 2000 in Delmenhorst, Germany.

The complex spectral representation of the Liouville operator introduced by Prigogine and others is applied to moderately dense gases interacting through hard-core potentials in arbitrary d-dimensional spaces. Kinetic equations near equilibrium are constructed in each subspace as introduced in the spectral decomposition for collective, renormalized reduced distribution functions. Our renormalization is a nonequilibrium effect, as the renormalization effect disappears at equilibrium. It is remarkable that our renormalized functions strictly obey well-defined Markovian kinetic equations for all d, even though the ordinary (...) distribution functions obey nonMarkovian equations with memory effects. One can now define transport coefficients associated to the collective modes for all dimensional systems including d = 2. Our formulation hence provides a microscopic meaning of the macroscopic transport theory. Moreover, this gives an answer to the long-standing question whether or not transport equations exist in two-dimensional systems. The non-Markovian effects for the ordinary distribution function, such as the long-time tails for arbitrary n-mode coupling, are estimated by superposition of the Markovian evolutions of the dressed distribution functions. (shrink)

A major problem in the treatment of cancer is the specific targeting of anti‐tumor drugs to these abnormal cells. Ideally, such a drug should act over short distances to minimize damage to healthy cells, and target subcellular compartments that have the highest sensitivity to the drug. Photosensitizers, alpha‐emitting radionuclides and many other medicines could be considered as such drugs if they possessed cellular and subcellular specificity. The author describes a novel approach of using modular recombinant transporters to target photosensitizers and (...) alpha‐emitting radionuclides to the nucleus, where their action is most pronounced, of cancer cells. Photosensitizer‐transporter conjugates have up to 3000 times greater efficacy than free photosensitizers and display cell specificity in contrast to free photosensitizers. Alpha‐emitting radionuclides, conjugated with the modular transporters, acquired similar properties. The different modules of the transporters are interchangeable, meaning that they can be tailored for particular applications. BioEssays 30:278–287, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Traditionally, the impairment of cognitive functions in Alzheimeŕs disease (AD) is thought to result from a reduction in neuronal and synaptic activities, and ultimately cell death. Here, we review recent in vivo evidence from mouse models and human patients indicating that, particularly in early stages of AD, neuronal circuits are hyperactive instead of hypoactive. Functional analyses at many levels, from single neurons to neuronal populations to large‐scale networks, with a variety of electrophysiological and imaging techniques have revealed (...) two forms of AD‐related hyperactivity and provided first insights into the synaptic mechanisms. The unexpected finding that hyperactivity is an early neuronal dysfunction represents a major conceptual shift in our understanding of AD that may have important implications for the development of therapeutic approaches. (shrink)

Adenosine transport in cultured human umbilical vein endothelial cells (HUVEC) was characterized and shown to be mediated by a single facilitated diffusion mechanism. Initial rates of adenosine influx at 22 degrees C were saturable [apparent Michaelis constant, 69 +/- 10 mu M; maximum velocity (V-max), 600 +/- 70 pmol.10(6) cells(-1).s(-1)] and inhibited by nitrobenzylthioinosine (NBMPR). Formycin B had an unusually high affinity [inhibitory constant K-i), 18 +/- 4.3 mu M], whereas inosine had a low affinity (K-i, 440 +/- 68 (...) mu M) and nucleobases were without effect on adenosine influx. The number of transporters (1.2 x 10(6) sites/cell) was estimated by NBMPR equilibrium binding (apparent dissociation constant, 0.11 +/- 0.01 nM; maximum binding, 2.0 +/- 0.15 pmol/10(6) cells). In addition, we compared these endothelial cells with those obtained from cords from pregnancies complicated by diabetes (HUVEC-D), since embriopathy may occur in these conditions. HUVEC-D exhibited a 2.3-fold reduction in both the V-max for adenosine influx and the maximum number of NBMPR binding sites (260 +/- 40 pmol.10(6) cells(-1).s(-1) and 0.86 +/- 0.08 pmol/10(6) cells, respectively). However, the turnover number for each nucleoside transporter in normal and diabetic HUVEC was similar (approximate to 300 adenosine molecules/s). Adenosine metabolism at 10 mu M in HUVEC-D was modified compared with normal cells. Intracellular phosphorylation (> 90%) was the predominant pathway in normal HUVEC, whereas in HUVEC-D, substantial levels of adenine and adenosine were detected. The present results demonstrate therefore the downregulation of the NBMPR-sensitive nucleoside transporter and changes in adenosine metabolism in HUVEC from diabetic pregnancies. (shrink)

In recent years, philosophical examinations of automated vehicles have progressed far beyond initial concerns over the ethical decisions that pertain to programming in the event of a crash. In turn, this paper moves in that direction, focusing on the motivations behind efforts to implement driverless vehicles into urban settings. The author argues that the many perceived benefits of these technologies yield a received view of automated vehicles. This position holds that driverless vehicles can solve most if not all urban mobility (...) issues. However, the problem with such an outlook is that it lends itself to transportation planning for automated vehicles, rather than using them as part of planning efforts that could serve urban mobility. Due to this condition, present efforts aimed at improving transportation systems should resist dogmatic thinking. Instead, they should focus on goals that keep topics such a human flourishing, sustainability, and transportation justice firmly in view. (shrink)

The neurological discovery of mirror neurons is of eminent importance for the phenomenological theory of intersubjectivity. G. Rizzolatti and V. Gallese found in experiments with primates that a set of neurons in the premotor cortex represents the visually registered movements of another animal. The activity of these mirror neurons presents exactly the same pattern of activity as appears in the movement of one's own body. These findings may be extended to other cognitive and emotive functions in humans. I show how (...) these neurological findings might be “translated” phenomenologically into our own experienced sensations, feelings and volitions. (shrink)