Coexistence of peptides with classical neurotransmitters

Summary In the present article the fact is emphasized that neuropeptides often are located in the same neurons as classical transmitters such as acetylcholine, 5-hydroxy-tryptamine, catecholamines, -aminobutyric acid (GABA) etc. This raises the possibility that neurons produce, store and release more than the one messenger molecule. The exact functional role of such coesisting peptides is often difficult to evaluate, especially in the central nervous system. In the periphery some studies indicate apparently meaningful interactions of different types with the classical transmitter, but other types of actions including trophic effects have been observed. More recently it has been shown that some neurons contain more than one classical transmitter, e.g. 5-HT plus GABA, further underlining the view that transfer of information across synapses may be more compex than perhaps hitherto assumed.     

Nervous control of smooth muscle by transmitters,cotransmitters and modulators

Conclusion The part played by peripheral neuroeffector control mechanisms has been underestimated. These are additional to central and ganglionic control mechanisms and are much more elaborate than originally thought. While the classical view is that the autonomic nervous system consists largely of antagonistic cholinergic and adrenergic nerves, about sixteen putative neurotransmitters have been proposed in autonomic nerves in the past few years, including various monoamines, polypeptides, purines and amino acids. Modulatory transmitter mechanisms have also been recognized, including prejunctional inhibition or enhancement of transmitter release, postjunctional modulation of transmitter action, and the secondary involvement of locally synthesized hormones and prostaglandins. The existence of more than one transmitter substance in some nerves is now widely recognized, and suggestions have been made about the ways that this can lead to differential peripheral control mechanisms at nerve terminals themselves. The cotransmitters always have synergistic actions on postjunctional effector cells, but two different operating mechanisms are postulated. 1) If both substances are stored in the same vesicles (for example, ACh or NA with ATP), release is closely parallel at all impulse frequencies. Upon release, the cotransmitter, in addition to having a direct action on postjunctional cells, may facilitate the action of the other transmitter and/or act as an inhibitor of its release. Differential actions at different impulse frequencies are achieved post-junctionally by ATP and NA acting via EJP-spike and spike-independent mechanisms, respectively. 2) If the two substances are stored in separate vesicle types (for example ACh or NA with some peptides), then differential release is possible at different impulse frequencies; the peptides released at higher frequencies modulate the role of the classical transmitter, by both prejunctional enhancement of its release and post-junctional facilitation of its action.     

GABAergic inhibition of neurons in the ventral tegmental area.

Stimulation of the nucleus accumbens evokes a potent inhibition in neurons of the ventral tegmental area. GABA is likely to act as a transmitter in this descending inhibitory system.     

GABAergic inhibition of neurons in the ventral tegmental area

Summary Stimulation of the nucleus accumbens evokes a potent inhibition in neurons of the ventral tegmental area. GABA is likely to act as a transmitter in this descending inhibitory system.     

Emergence and topological order in classical and quantum systems

There has been growing interest in systems in condensed matter physics as a potential source of examples of both epistemic and ontological emergence. One of these case studies is the fractional quantum Hall state (FQHS). In the FQHS a system of electrons displays a type of holism due to a pattern of long-range quantum entanglement that some argue is emergent. Indeed, in general, quantum entanglement is sometimes cited as the best candidate for one form of ontological emergence. In this paper we argue that there are significant formal and physical parallels between the quantum FQHS and classical polymer systems. Both types of system cannot be explained simply by considering an aggregation of local microphysical properties alone, since important features of each are globally determined by topological features. As such, we argue that if the FQHS is a case of ontological emergence then it is not due to the quantum nature of the system and classical polymer systems are ontologically emergent as well.     

GABA in the caudate nucleus: A possible synaptic transmitter of interneurons

Summary Microiontophoretic application of GABA and its antagonist, picrotoxin, altered focal potentials evoked in the caudate nucleus by stimulation near the recording site to a much greater extent than potentials elicited by stimulation of afferent pathways, suggesting that GABA is a transmitter of interneurons in this nucleus.This study was supported by funds from the Veterans Administration and by NIH research grant No. 06820.We thank Kathleen Downes and Clifford Smathers for their assistance.     

Presynaptic excitability decrease in the extensor group II afferent terminations

Summary The excitability of the extensor secondary afferent terminals is decreased by volleys applied to the flexor group II afferents. This presynaptic excitability decrease was completely abolished after bicuculline, indicating GABA may act as transmitter in this circuit.     

Ethanol and the benzodiazepine-GABA receptor-ionophore complex

Ethanol has a pharmacological profile similar to that of classes of drugs like benzodiazepines and barbiturates, which enhance GABAergic transmission in the mammalian CNS. Several lines of behavioral, electrophysiological and biochemical studies suggest that ethanol may bring about most of its effects by enhancing GABAergic transmission. Recently, ethanol at relevant pharmacological concentrations has been shown to enhance GABA-induced 36Cl-fluxes in cultured spinal cord neurons, synaptoneurosomes and microsacs. These enhancing effects of ethanol were blocked by GABA antagonists. Ro15-4513, an azido analogue of classical BZ antagonist Ro15-1788, reversed most of the behavioral effects of ethanol and other effects involving 36Cl-flux studies. The studies summarized below indicate that most of the pharmacological effects of ethanol can be related to its effects on GABAergic transmission.     

Cell lineage and cell migration in the developing cerebral cortex

Summary Modern techniques which trace lineages of individual progenitor cells have provided some clues about the processes that determine cell fate in the brain, and have also given us some information about migratory patterns of clonally related cells. In many parts of the central nervous system, progenitors are multipotent; single clones can contain multiple neuronal types or even mixtures of neurons and glia. In addition, one can observe a wide distribution in clone size, even when marking is done in a narrow time window. This suggests that progenitor cells may be fairly plastic and responsive to environmental signals. In the developing cortex, clonally related cells are initially grouped near each other, as in the retina and tectum. However, the subsequent migration of these cells from the ventricular zone to the cortex along glial fibers is accompanied by a progressive dispersion of clonally related neurons.     

The active role of astrocytes in synaptic transmission

In the central nervous system, astrocytes form an intimately connected network with neurons, and their processes closely enwrap synapses. The critical role of these cells in metabolic and trophic support to neurons, ion buffering and clearance of neurotransmitters is well established. However, recent accumulating evidence suggests that astrocytes are active partners of neurons in additional and more complex functions. In particular, astrocytes express a repertoire of neurotransmitter receptors mirroring that of neighbouring synapses. Such receptors are stimulated during synaptic activity and start calcium signalling into the astrocyte network. Intracellular oscillations and intercellular calcium waves represent the astrocyte's own form of excitability, as they trigger release of transmitter (i.e. glutamate) via a novel process sensitive to blockers of exocytosis and involving cyclooxygenase eicosanoids. Astrocyte-released glutamate activates receptors on the surrounding neurons and modifies their electrical and intracellular calcium ([Ca2+]i) state. These exciting new findings reveal an active participation of astrocytes in synaptic transmission and the involvement of neuronastrocyte circuits in the processing of information in the brain.     

Late inhibitory postsynaptic potentials in rat prefrontal cortex may be mediated by GABAB receptors

The GABAB antagonist phaclofen blocked the postsynaptic hyperpolarization induced by the GABAB agonist baclofen during intracellular recordings in rat cortical cells. This effect appears to be selective since responses to GABAA agonists (muscimol, THIP), GABA, 5-HT and L-glutamate were unaffected. Phaclofen also blocked synaptically evoked late inhibitory postsynaptic potentials (late IPSP). These results suggest that the late IPSPs in cortical neurons are mediated by GABA acting on GABAB receptors.     

Ethanol and the benzodiazepine-GABA receptor-ionophore complex

Summary Ethanol has a pharmacological profile similar to that of classes of drugs like benzodiazepines and barbiturates, which enhance GABAergic transmission in the mammalian CNS. Several lines of behavioral, electrophysiological and biochemical studies suggest that ethanol may bring about most of its effects by enhancing GABAergic transmission. Recently, ethanol at relevant pharmacological concentrations has been shown to enhance GABA-induced³⁶Cl-fluxes in cultured spinal cord neurons, synaptoneurosomes and microsacs. These enhancing effects of ethanol were blocked by GABA antagonists. Ro15-4513, an azido analogue of classical BZ antagonist Ro15-1788, reversed most of the behavioral effects of ethanol and other effects involving³⁶Cl-flux studies. The studies summarized below indicate that most of the pharmacological effects of ethanol can be related to its effects on GABAergic transmission.     

Does time-symmetry imply retrocausality? How the quantum world says “Maybe”?

It has often been suggested that retrocausality offers a solution to some of the puzzles of quantum mechanics: e.g., that it allows a Lorentz-invariant explanation of Bell correlations, and other manifestations of quantum nonlocality, without action-at-a-distance. Some writers have argued that time-symmetry counts in favour of such a view, in the sense that retrocausality would be a natural consequence of a truly time-symmetric theory of the quantum world. Critics object that there is complete time-symmetry in classical physics, and yet no apparent retrocausality. Why should the quantum world be any different?This note throws some new light on these matters. I call attention to a respect in which quantum mechanics is different, under some assumptions about quantum ontology. Under these assumptions, the combination of time-symmetry without retrocausality is unavailable in quantum mechanics, for reasons intimately connected with the differences between classical and quantum physics (especially the role of discreteness in the latter). Not all interpretations of quantum mechanics share these assumptions, however, and in those that do not, time-symmetry does not entail retrocausality.     

On classical cloning and no-cloning

It is part of information theory folklore that, while quantum theory prohibits the generic (or universal) cloning of states, such cloning is allowed by classical information theory. Indeed, many take the phenomenon of no-cloning to be one of the features that distinguishes quantum mechanics from classical mechanics. In this paper, we argue that pace conventional wisdom, in the case where one does not include a machine system, there is an analog of the no-cloning theorem for classical systems. However, upon adjoining a non-trivial machine system (or ancilla) one finds that, pace the quantum case, the obstruction to cloning disappears for pure states. We begin by discussing some conceptual points and category-theoretic generalities having to do with cloning, and proceed to discuss no-cloning in both the case of (non-statistical) classical mechanics and classical statistical mechanics.     

The metabotropic GABA receptor: molecular insights and their functional consequences

Recent years have seen rapid and significant advances in our understanding of the G-protein-coupled gamma-amino butyric acid, B-type (GABA(B)) receptor, which could be a therapeutic target in conditions as diverse as epilepsy and hypertension. This progress originated with the ground-breaking work of Bernhard Bettler's team at Novartis who cloned the DNA encoding a GABA(B) receptor in 1997. Currently, the receptor is thought to be an unusual, possibly unique, example of a heterodimer composed of homologous, seven-transmembrane-domain (7TMD) subunits (named GABA(B) R1 and GABA(B) R2), neither of which is fully functional when expressed alone. The large N-terminal domain of the GABA(B) R1 subunit projects extracellularly and contains a ligand binding site. The similarity of the amino acid sequence of this region to some bacterial periplasmic amino acid-binding proteins of known structure has enabled structural and functional modelling of the N-terminal domain, and the identification of residues whose substitution modulates agonist/antagonist binding affinities. The intracellular C-terminal domains of the R1 and R2 subunits appear to constitute an important means of contact between the two subunits. Alternative splice variants, a common and functionally important feature of 7TMD proteins, have been demonstrated for the R1 subunit. Notably GABA(B) R1a differs from GABA(B) R1b by the possession of an N-terminal extension containing two complement protein modules (also called SCRs, or sushi domains) of unknown function. The levels at which each of the respective variants is expressed are not equal to one another, with variations occurring over the course of development and throughout the central nervous system. It is not yet clear, however, whether one variant is predominantly presynaptically located and the other postsynaptically located. The existence of as yet unidentified splice variants, additional receptor subtypes and alternative quaternary composition has not been ruled out as a source of receptor heterogeneity.     

A dynamic view of peptides and proteins in membranes

Biological membranes are highly dynamic supramolecular arrangements of lipids and proteins, which fulfill key cellular functions. Relatively few high-resolution membrane protein structures are known to date, although during recent years the structural databases have expanded at an accelerated pace. In some instances the structures of reaction intermediates provide a stroboscopic view on the conformational changes involved in protein function. Other biophysical approaches add dynamic aspects and allow one to investigate the interactions with the lipid bilayers. Membrane-active peptides fulfill many important functions in nature as they act as antimicrobials, channels, transporters or hormones, and their studies have much increased our understanding of polypeptide-membrane interactions. Interestingly several proteins have been identified that interact with the membrane as loose arrays of domains. Such conformations easily escape classical high-resolution structural analysis and the lessons learned from peptides may therefore be instructive for our understanding of the functioning of such membrane proteins. Received 11 March 2008; received after revision 2 May 2008; accepted 5 May 2008     

Insights into NK cell biology from human genetics and disease associations

Rare human primary immunodeficiency disorders with extreme susceptibility to infections in infancy have provided important insights into immune function. Increasingly, however, primary immunodeficiencies are also recognized as a cause of other more common, often discrete, infectious susceptibilities. In a wider context, loss-of-function mutations in immune genes may also cause disorders of immune regulation and predispose to cancer. Here, we review the associations between human diseases and mutations in genetic elements affecting natural killer (NK) cell development and function. Although many such genetic aberrations significantly reduce NK cell numbers or severely impair NK cell responses, inferences regarding the role of NK cells in disease are confounded by the fact that most mutations also affect the development or function of other cell types. Still, data suggest an important role for NK cells in diseases ranging from classical immunodeficiency syndromes with susceptibility to viruses and other intracellular pathogens to cancer, autoimmunity, and hypersensitivity reactions.     

Towards in vitro molecular diagnostics using nanostructures

Nanostructures appear to be promising for a number of applications in molecular diagnostics, mainly due to the increased surface-to-volume ratio they can offer, the very low limit of detection achievable, and the possibility to fabricate point-of-care diagnostic devices. In this paper, we review examples of the use of nanostructures as diagnostic tools that bring in marked improvements over prevalent classical assays. The focus is laid on the various sensing paradigms that possess the potential or have demonstrated the capability to replace or augment current analytical strategies. We start with a brief introduction of the various types of nanostructures and their physical properties that determine the transduction principle. This is followed by a concise collection of various functionalization protocols used to immobilize biomolecules on the nanostructure surface. The sensing paradigms are discussed in two contexts: the nanostructure acting as a label for detection, or the nanostructure acting as a support upon which the molecular recognition events take place. In order to be successful in the field of molecular diagnostics, it is important that the nanoanalytical tools be evaluated in the appropriate biological environment. The final section of the review compiles such examples, where the nanostructure-based diagnostic tools have been tested on realistic samples such as serum, demonstrating their analytical power even in the presence of complex matrix effects. The ability of nanodiagnostic tools to detect ultralow concentrations of one or more analytes coupled with portability and the use of low sample volumes is expected to have a broad impact in the field of molecular diagnostics.     

Topology Change and the Unity of Space

Must space be a unity? This question, which exercised Aristotle, Descartes and Kant, is a specific instance of a more general one; namely, can the topology of physical space change with time? In this paper we show how the discussion of the unity of space has been altered but survives in contemporary research in theoretical physics. With a pedagogical review of the role played by the Euler characteristic in the mathematics of relativistic spacetimes, we explain how classical general relativity (modulo considerations about energy conditions) allows virtually unrestrained spatial topology change in four dimensions. We also survey the situation in many other dimensions of interest. However, topology change comes with a cost: a famous theorem by Robert Geroch shows that, for many interesting types of such change, transitions of spatial topology imply the existence of closed timelike curves or temporal non-orientability. Ways of living with this theorem and of evading it are discussed.