bluuebunny/crossref_metadata_2025 huggingface dataset:
Bioactive pyrrole alkaloids isolated from the Red Sea: marine sponge Stylissa carteri
Authors: Hamed Ashraf N.E. , Schmitz Roland , Bergermann Anja , Totzke Frank , Kubbutat Michael , Müller Werner E.G. , Youssef Diaa T.A. , Bishr Mokhtar M. , Kamel Mohamed S. , Edrada-Ebel RuAngelie , Wätjen Wim , Proksch Peter
Published: April 2018

Fifteen pyrrole alkaloids were isolated from the Red Sea marine sponge Stylissa carteri and investigated for their biological activities. Four of them were dibrominated [(+) dibromophakelline, Z-3-bromohymenialdisine, (±) ageliferin and 3,4-dibromo-1H-pyrrole-2-carbamide], nine compounds were monobrominated [(−) clathramide C, agelongine, (+) manzacidin A, (−) 3-bromomanzacidin D, Z-spongiacidin D, Z-hymenialdisine, 2-debromostevensine, 2-bromoaldisine and 4-bromo-1H-pyrrole-2-carbamide)] and finally, two compounds were non-brominated derivatives viz., E-debromohymenialdisine and aldisine. The structure elucidations of isolated compounds were based on 1D & 2D NMR spectroscopic and MS studies, as well as by comparison with literature. In-vitro, Z-spongiacidin D exhibited a moderate activity on (ARK5, CDK2-CycA, CDK4/CycD1, VEGF-R2, SAK and PDGFR-beta) protein kinases. Moreover, Z-3-bromohymenialdisine showed nearly similar pattern. Furthermore, Z-hymenialdisine displayed a moderate effect on (ARK5 & VEGF-R2) and (−) clathramide C showed a moderate activity on AURORA-A protein kinases. While, agelongine, (+) manzacidin A, E-debromohymenialdisine and 3,4-dibromo-1H-pyrrole-2-carbamide demonstrated only marginal inhibitory activities. The cytotoxicity study was evaluated in two different cell lines. The most effective secondary metabolites were (+) dibromophakelline and Z-3-bromohymenialdisine on L5178Y. Finally, Z-hymenialdisine, Z-3-bromohymenialdisine and (±) ageliferin exhibited the highest cytotoxic activity on HCT116. No report about inhibition of AURORA-A and B by hymenialdisine/hymenialdisine analogs existed and no reported toxicity of ageliferin existed in literature.
Naphthalenetetracarboxylic Diimide Derivatives: Molecular Structure, Thin Film Properties and Solar Cell Applications
Authors: Falkenberg Christiane , Hummert Markus , Meerheim Rico , Schünemann Christoph , Olthof Selina , Körner Christian , Riede Moritz K. , Leo Karl
Published: April 2018

The effciency of organic solar cells is not only determined by their absorber system, but also strongly dependent on the performance of numerous interlayers and charge transport layers. In order to establish new custom-made materials, the study of structure-properties relationships is of great importance. This publication examines a series of naphthalenetetracarboxylic diimide molecules (NTCDI) with varying side-chain length intended for the use as n-dopable electron transport materials in organic solar cells. While all compounds basically share very similar absorption spectra and energy level positions in the desired range, the introduction of alkyl chains has a large impact on thin film growth and charge transport properties: both crystallization and the increase of conductivity by molecular doping are suppressed. This has a direct influence on the series resistance of corresponding solar cells comprising an NTCDI derivative as electron transport material (ETM) as it lowers the power conversion efficiency to ≪1%. In contrast, using the side-chain free compound it is possible to achive an efficiency of 6.5%, which is higher than the efficiency of a comparable device comprising n-doped C60 as standard ETM.
Catalysis by Metallic Nanoparticles in Solution: Thermosensitive Microgels as Nanoreactors
Authors: Roa Rafael , Angioletti-Uberti Stefano , Lu Yan , Dzubiella Joachim , Piazza Francesco , Ballauff Matthias
Published: April 2018

Metallic nanoparticles have been used as catalysts for various reactions, and the huge literature on the subject is hard to overlook. In many applications, the nanoparticles must be affixed to a colloidal carrier for easy handling during catalysis. These “passive carriers” (e.g. dendrimers) serve for a controlled synthesis of the nanoparticles and prevent coagulation during catalysis. Recently, hybrids from nanoparticles and polymers have been developed that allow us to change the catalytic activity of the nanoparticles by external triggers. In particular, single nanoparticles embedded in a thermosensitive network made from poly(N-isopropylacrylamide) (PNIPAM) have become the most-studied examples of such hybrids: immersed in cold water, the PNIPAM network is hydrophilic and fully swollen. In this state, hydrophilic substrates can diffuse easily through the network, and react at the surface of the nanoparticles. Above the volume transition located at 32°C, the network becomes hydrophobic and shrinks. Now hydrophobic substrates will preferably diffuse through the network and react with other substrates in the reaction catalyzed by the enclosed nanoparticle. Such “active carriers”, may thus be viewed as true nanoreactors that open new ways for the use of nanoparticles in catalysis. In this review, we give a survey on recent work done on these hybrids and their application in catalysis. The aim of this review is threefold: we first review hybrid systems composed of nanoparticles and thermosensitive networks and compare these “active carriers” to other colloidal and polymeric carriers (e.g. dendrimers). In a second step we discuss the model reactions used to obtain precise kinetic data on the catalytic activity of nanoparticles in various carriers and environments. These kinetic data allow us to present a fully quantitative comparison of different nanoreactors. In a final section we shall present the salient points of recent efforts in the theoretical modeling of these nanoreactors. By accounting for the presence of a free-energy landscape for the reactants’ diffusive approach towards the catalytic nanoparticle, arising from solvent-reactant and polymeric shell-reactant interactions, these models are capable of explaining the emergence of all the important features observed so far in studies of nanoreactors. The present survey also suggests that such models may be used for the design of future carrier systems adapted to a given reaction and solvent.
Properties of Hydrogen-Bonded Liquids at Interfaces
Authors: Buntkowsky Gerd , Vogel Michael , Winter Roland
Published: April 2018

Effects of interfaces on hydrogen-bonded liquids play major roles in nature and technology. Despite their importance, a fundamental understanding of these effects is still lacking. In large parts, this shortcoming is due to the high complexity of these systems, leading to an interference of various interactions and effects. Therefore, it is advisable to take gradual approaches, which start from well designed and defined model systems and systematically increase the level of intricacy towards more complex mimetics. Moreover, it is necessary to combine insights from a multitude of methods, in particular, to link novel preparation strategies and comprehensive experimental characterization with inventive computational and theoretical modeling. Such concerted approach was taken by a group of preparative, experimentally, and theoretically working scientists in the framework of Research Unit FOR 1583 funded by the Deutsche Forschungsgemeinschaft (German Research Foundation). This special issue summarizes the outcome of this collaborative research. In this introductory article, we give an overview of the covered topics and the main results of the whole consortium. The following contributions are review articles or original works of individual research projects.
Anisotropy of Structure and Optical Properties of Self-Assembled and Oriented Colloidal CdSe Nanoplatelets
Authors: Antanovich Artsiom , Prudnikau Anatol , Artemyev Mikhail
Published: April 2018

Atomically flat colloidal nanoplatelets with strong one-dimensional confinement represent the most recently discovered type of quantum-confined cadmium chalcogenide nanocrystals. In almost a decade a great progress has been achieved in the colloidal synthesis of nanoplatelets and understanding of their basic optical and electronic properties. However, up until recently methods of their controlled spatial orientation were quite scarce, what in turn hindered obtaining reliable information on their anisotropic structural and optical properties arising from their shape. In this paper we provide a mini-review of recent advances in this field of study.
Fluorescence Quenching of CdTe Quantum Dots with Co (III) Complexes via Electrostatic Assembly Formation
Authors: Pal Anuushka , Arora Bhawna , Rani Diksha , Srivastava Sumit , Gupta Rajeev , Sapra Sameer
Published: April 2018

The photoluminescence quenching of CdTe QDs in the presence of three different Co (III)-complexes is studied to elucidate the role of interactions between functional groups of positively charged cysteamine capped CdTe QDs and negatively charged Co (III) complexes bearing carboxylic groups. The steady state and time resolved spectroscopy has been used to investigate the mechanism of quenching. After detailed analysis, it is concluded that quenching is contributed by both static as well as dynamic processes. The static contribution has been assigned to the electrostatic assembly formation via ionic interactions between the amine functional groups of positively charged cysteamine capped CdTe QDs and carboxylic acid groups of negatively charged complexes. The electrostatic interactions were confirmed by zeta potential measurement as well as from effect of salt addition. These studies have implications in designing donor/acceptor pairs having complementary functional groups for efficient optoelectronic devices or photocatalytic systems.
Sergio Pitol, ensayista
Authors: Corral Elizabeth
Published: April 2018

RESEÑA
El arte de la vida. Wittgenstein en la encrucijada entre ética y estética
Authors: Nieto Blanco Carlos
Published: April 2018

Este artículo ofrece un aproximación al pensamiento de Witggenstein, examinando la relación que existe entre la ética y estética con el conjunto de su filosofía. El trabajo se divide en tres partes, argumentando: que la ética y la estética no se pueden expresar, pero se muestran; que la ética y la estética son trascendentales; y que la vida feliz abarca por igual a la ética y a la estética. El trabajo finaliza con un epílogo a modo de ensayo sobre la posible significación de “la casa de Wittgenstein”.
¿Qué son los modelos físicos?
Authors: Rolleri José Luis
Published: April 2018

En este artículo analizamos los principales conceptos propuestos de modelo con el propósito de resaltar el carácter idealizado y abstracto de los modelos físicos, que generalmente es pasado por alto en la literatura filosófica relevante desde diversas posiciones, como el instrumentalismo y el pragmatismo; el cual, sin embargo tiene importantes implicaciones en problemas filosóficos como el del realismo científico. Desde una posición conceptualista, sostenemos que los modelos desidealizados son los vehículos para conceptualizar los sistemas físicos desde la perspectiva de una teoría.
Literatura y azar
Authors: Oliva Carlos
Published: April 2018

Este texto aborda dos puntos centrales en la obra de Borges a través de la relación con Cervantes: a) la consideración de la lectura como el hecho más radical de la creación literaria; b) la tajante apuesta creativa que se fundamenta en la consideración de que toda obra es un borrador. En este contexto, Borges aparece como el autor primordial, junto con Kafka, de la literatura del siglo XX, y su relectura del Quijote es fundamental.
La distinción entre decir y mostrar y la superación de los problemas filosóficos
Authors: Wischin Kurt
Published: April 2018

Las dificultades que ofrece el Tractatus para la interpretación detallada de muchos de sus pasajes considerados clave, junto con la crítica que su autor ha formulado en su desarrollo filosófico posterior contra algunos aspectos de la visión del lenguaje de su primera obra, han tenido frecuentemente como consecuencia que los intérpretes pierdan de vista el objetivo general de la obra, y en qué grado la filosofía wittgensteiniana es movida por una misma preocupación filosófica durante toda la vida del pensador austrobritánico. Una discusión de las causas de la distinción clave del Tractatus entre lo que dicen y lo que muestran las oraciones sugiere que la visión que motiva esta distinción tractariana sigue vigente en la filosofía posterior de Wittgenstein.
El Killer. Representaciones inestables de un homicida
Authors: Fuentes Kraftcyck Felipe Oliver
Published: April 2018

El Killer, de Josué Montijo narra los asesinatos en serie de Juan Benito Aybar, un ciudadano “común” que súbitamente comienza a liquidar a los drogadictos de San Juan de Puerto Rico. Pero lejos de ofrecer una visión unilateral del asesino que permita descifrarlo como un psicópata tradicional, la novela entrega un conjunto de versiones contradictorias que imposibilitan cualquier intento de clasificación. En el proceso, lo siniestro irrumpe en la novela pues el lector descubre que el asesino es el último defensor del “orden convencional” en una sociedad en franca descomposición.
La traducción de los culturemas (Discusión al margen de la traducción de una novela de Guillermo Arriaga)
Authors: Petrescu Olivia
Published: April 2018

En este artículo nos proponemos revisar, sobre una base léxica y fraseológica, la traducción publicada al rumano de la novela de Guillermo Arriaga, Un dulce olor a muerte, a partir del análisis de las teorías de la traducción más relevantes en relación con el tratamiento de los elementos culturales (culturemas). En esencia, mediante el uso de las funciones del lenguaje definido por Nord (1994), respecto a las diferencias culturales en la traducción, nuestro objetivo es explorar las diversas prácticas culturales de transferencia, con el fin de centrarse en los aspectos lingüístico-culturales, dentro de la novela mexicana y su traducción, que ambos constituyen nuestro corpus. Por otra parte, tratamos de identificar los principales métodos de traducción que se han aplicado, con el propósito de establecer su porcentaje de uso y debatir sobre su funcionalidad.
Ejes y figuras. Estudios sobre problemas de teoría literaria Norma Angélica Cuevas, coord. Universidad Benemérita Autónoma de Puebla / Universidad Veracruzana, 2011
Authors: Noriega Hernández Lucía
Published: April 2018

Ejes y figuras. Estudios sobre problemas de teoría literaria Norma Angélica Cuevas, coord. Universidad Benemérita Autónoma de Puebla / Universidad Veracruzana, 2011
Catechol-O-Methyltransferase Genotype and Dopamine Regulation in the Human Brain
Authors: Akil Mayada , Kolachana Bhaskar S. , Rothmond Debora A. , Hyde Thomas M. , Weinberger Daniel R. , Kleinman Joel E.
Published: April 2018

A functional polymorphism in the gene for catechol-O-methyltransferase (COMT) has been shown to affect executive cognition and the physiology of the prefrontal cortex in humans, probably by affecting prefrontal dopamine signaling. TheCOMTvaline allele, associated with relatively poor prefrontal function, is also a gene that may increase risk for schizophrenia. Although poor performance on executive cognitive tasks and abnormal prefrontal function are characteristics of schizophrenia, so is psychosis, which has been related to excessive presynaptic dopamine activity in the striatum. Studies in animals have shown that diminished prefrontal dopamine neurotransmission leads to upregulation of striatal dopamine activity. We measured tyrosine hydroxylase (TH) mRNA in mesencephalic dopamine neurons in human brain and found that the COMT valine allele is also associated with increased TH gene expression, especially in neuronal populations that project to the striatum. This indicates that COMT genotype is a heritable aspect of dopamine regulation and it further explicates the mechanism by which the COMT valine allele increases susceptibility for psychosis.
The Binding of 2-(4′-Methylaminophenyl)Benzothiazole to Postmortem Brain Homogenates Is Dominated by the Amyloid Component
Authors: Klunk William E. , Wang Yanming , Huang Guo-feng , Debnath Manik L. , Holt Daniel P. , Shao Li , Hamilton Ronald L. , Ikonomovic Milos D. , DeKosky Steven T. , Mathis Chester A.
Published: April 2018

2-(4′-Methylaminophenyl)benzothiazole (BTA-1) is an uncharged derivative of thioflavin-T that has high affinity for Aβ fibrils and shows very good brain entry and clearance. In this study, we asked whether BTA-1, at concentrations typical of those achieved during positron emission tomography (PET) studies, could specifically bind to amyloid deposits in the complex milieu of human brain or whether amyloid binding was overshadowed by nonspecific binding, found even in brains that did not contain amyloid deposits. We quantitatively assessed [3H]BTA-1 binding to crude homogenates of postmortem brain obtained from nine Alzheimer's disease (AD) subjects, eight controls, and six subjects with non-AD dementia. BTA-1 binding was >10-fold higher in AD brain, and the majority (94%) of the binding was specific (displaceable). High-affinity [3H]BTA-1 was observed only in AD brain gray matter and was not present in control brain gray matter, AD brain white matter, or cerebellum. TheKdof [3H]BTA-1 for binding to AD brain (5.8 ± 0.90 nm) was very similar to theKdfor binding to synthetic Aβ fibrils. In addition, theKiof various BTA analogs for inhibition of [3H]BTA-1 binding to AD brain homogenates was very similar to theirKifor inhibition of [3H]BTA-1 binding to synthetic Aβ fibrils. Nanomolar concentrations of [3H]BTA-1 did not appear to bind to neurofibrillary tangles. Finally, BTA-1 did not appear to bind significantly to common neuroreceptors or transporter sites. These data suggest that the binding of BTA-1 to AD brain is dominated by a specific interaction with Aβ amyloid deposits.
Voltage-Gated Sodium Channels and AnkyrinG Occupy a Different Postsynaptic Domain from Acetylcholine Receptors from an Early Stage of Neuromuscular Junction Maturation in Rats
Authors: Bailey Sarah J. , Stocksley Mark A. , Buckel Alexandra , Young Carol , Slater Clarke R.
Published: April 2018

Spatial segregation of membrane proteins is a feature of many excitable cells. In skeletal muscle, clusters of acetylcholine receptors (AChRs) and voltage-gated sodium channels (NaV1s) occupy distinct domains at the neuromuscular junction (NMJ). We used quantitative immunolabeling of developing rat soleus muscles to study the mechanism of ion channel segregation and NaV1 clustering at NMJs. When NaV1s can first be detected, at birth, they already occupy a postsynaptic domain that is distinct from that occupied by AChRs. At this time, NaV1s are expressed only in a diffuse area that extends 50–100 μm from the immature NMJ. However, in the region of the high-density AChR cluster at NMJ itself, NaV1s are actually present in lower density than in the immediately surrounding membrane. These distinctive features of the NaV1 distribution at birth are closely correlated with the distribution of ankyrinG immunolabeling. This suggests that an interaction with ankyrinG plays a role in the initial segregation of NaV1s from AChRs. Both NaV1 and ankyrinG become clustered at the NMJ itself 1–2 weeks after birth, coincident with the formation of postsynaptic folds. Syntrophin immunolabeling codistributes with AChRs and never resembles that for NaV1 or ankyrinG. Therefore, syntrophin is unlikely to play an important part in the initial accumulation of NaV1 at the NMJ. These findings suggest that the segregation of NaV1 from AChRs begins early in NMJ formation and occurs as a result of the physical exclusion of NaV1 and ankyrinG from the region of nerve–muscle contact rather than by a process of active clustering.
Synchronized Formation and Remodeling of Postsynaptic Densities: Long-Term Visualization of Hippocampal Neurons Expressing Postsynaptic Density Proteins Tagged with Green Fluorescent Protein
Authors: Ebihara Tatsuhiko , Kawabata Izumi , Usui Shinichi , Sobue Kenji , Okabe Shigeo
Published: April 2018

To explore mechanisms governing the formation and remodeling of postsynaptic density (PSD), we used dissociated cultures of hippocampal neurons isolated from transgenic embryos expressing green fluorescent protein (GFP)-tagged PSD proteins PSD-Zip45 (Homer 1c) and PSD-95. Expression of GFP-tagged PSD molecules was stable, and the remodeling process of PSDs could be followed for >1 week. A higher expression level of GFP-PSD-Zip45 enabled us to quantitatively analyze the amount of PSD-Zip45 clusters during development. Repetitive imaging of the same cell populations between 11 and 17 d in culture revealed an increase of the average PSD-Zip45 cluster density from 0.32 to 0.73/μm. Newly generated dendrites rapidly acquired GFP-PSD-Zip45 clusters, and their density reached the level of parental dendrites within a few days. Temporal profiles of GFP-PSD-Zip45 cluster density showed a variety of patterns. Some dendrites showed a monotonous increase of clusters, whereas others showed complex patterns, including short decremental stages. Analysis of long-term remodeling of PSD-95-GFP clusters confirmed that the decremental stages were not specific to the PSD-Zip45 clusters. Comparison of the temporal profiles of the cluster density among neurons indicated synchronization of both GFP-PSD-Zip45 and PSD-95 clustering within individual cells. Furthermore, activation of cAMP-dependent protein kinase suppressed the decremental stages of cluster remodeling. These observations suggest the presence of signaling mechanisms that can induce synchronized addition or elimination of PSD proteins throughout dendritic arborization of a single neuron.
Ultrastructural Contributions to Desensitization at Cerebellar Mossy Fiber to Granule Cell Synapses
Authors: Xu-Friedman Matthew A. , Regehr Wade G.
Published: April 2018

Postsynaptic AMPA receptor desensitization leads to depression at some synapses. Here we examine whether desensitization occurs at mossy fiber to granule cell synapses and how synaptic architecture could contribute. We made whole-cell voltage-clamp recordings from granule cells in rat cerebellar slices at 34°C, and stimulated mossy fibers with paired pulses. The amplitude of the second EPSC was depressed by 60% at 10 msec and recovered with τ ∼30 msec. This fast component of recovery from depression was reduced by cyclothiazide and enhanced when release probability was increased, suggesting that it reflects postsynaptic receptor desensitization. We evaluated the importance of synaptic ultrastructure to spillover and desensitization by using serial electron microscopy to reconstruct mossy fiber glomeruli. We found that mossy fiber boutons had hundreds of release sites, that the average center-to-center distance between nearest release sites was 0.46 μm, and that these sites had an average of 7.1 neighbors within 1 μm. In addition, glia did not isolate release sites from each other. By contrast, desensitization plays no role in paired-pulse depression at the cerebellar climbing fiber, where glial ensheathment of synapses is nearly complete. This suggests that the architecture of the mossy fiber glomerulus can lead to desensitization and short-term depression. Modeling indicates that, as a consequence of the close spacing of release sites, glutamate released from a single site can desensitize AMPA receptors at neighboring sites, even when the probability of release (pr) is low. Whenpris high, desensitization would be accentuated by such factors as glutamate pooling.
Overlapping Microarray Profiles of Dentate Gyrus Gene Expression during Development- and Epilepsy-Associated Neurogenesis and Axon Outgrowth
Authors: Elliott Robert C. , Miles Michael F. , Lowenstein Daniel H.
Published: April 2018

Neurogenesis and axon outgrowth are features shared by normal nervous system development and certain forms of epileptogenesis. This observation has led to the hypothesis that some aspects of normal development and epileptogenesis have common molecular mechanisms. To test this hypothesis, we have used DNA microarray analysis to characterize gene expression in the dentate gyrus and identify genes exhibiting similar patterns of regulation during development and epileptogenesis. Of more than 8000 sequences surveyed, over 600 were regulated during development or epileptogenesis, and 37 of these were either upregulated or downregulated during both processes.In situhybridization analysis of a subset of these “commonality genes” confirmed the patterns of regulation predicted by the microarray data in most cases and demonstrated various spatial and temporal patterns of commonality gene expression. Of the 25 named commonality genes in which some functional characteristics are known, 11 have been implicated in cell morphology and axon outgrowth or cellular proliferation and fate determination. This enrichment for candidate plasticity-related genes supports the concept that developmental mechanisms contribute to network alterations associated with epileptogenesis and offers a useful strategy for identifying molecules that may play a role in both of these processes.
Macrophage-Derived Factors Stimulate Optic Nerve Regeneration
Authors: Yin Yuqin , Cui Qi , Li Yiming , Irwin Nina , Fischer Dietmar , Harvey Alan R. , Benowitz Larry I.
Published: April 2018

After optic nerve injury in mature mammals, retinal ganglion cells (RGCs) are normally unable to regenerate their axons and undergo delayed apoptosis. However, if the lens is damaged at the time of nerve injury, many RGCs survive axotomy and regenerate their axons into the distal optic nerve. Lens injury induces macrophage activation, and we show here that factors secreted by macrophages stimulate RGCs to regenerate their axons. When macrophages were activated by intravitreal injections of Zymosan, a yeast cell wall preparation, the number of RGC axons regenerating into the distal optic nerve was even greater than after lens injury. These effects were further enhanced if Zymosan was injected 3 d after nerve crush. In a grafting paradigm, intravitreal Zymosan increased the number of RGCs that regenerated their axons through a 1.5 cm peripheral nerve graft twofold relative to uninjected controls and threefold if injections were delayed 3 d. In cell culture, media conditioned by activated macrophages stimulated adult rat RGCs to regenerate their axons; this effect was potentiated by a low molecular weight factor that is constitutively present in the vitreous humor. After gel-filtration chromatography, macrophage-derived proteins ≥30 kDa were found to be toxic to RGCs, whereas proteins <30 kDa reversed this toxicity and promoted axon regeneration. The protein(s) that stimulated axon growth is distinct from identified polypeptide trophic factors that were tested. Thus, macrophages produce proteins with both positive and negative effects on RGCs, and the effects of macrophages can be optimized by the timing of their activation.
N-Cadherin Regulates Ingrowth and Laminar Targeting of Thalamocortical Axons
Authors: Poskanzer Kira , Needleman Leigh A. , Bozdagi Ozlem , Huntley George W.
Published: April 2018

Thalamocortical axons are precisely targeted to cortical layer IV, but the identity of specific molecules that govern the establishment of laminar specificity in the thalamocortical projection has been elusive. In this study, we test the role of N-cadherin, a homophilic cell adhesion molecule, in laminar targeting of thalamocortical axons using cocultured thalamic and cortical slice explants exposed to N-cadherin function-blocking antibodies or inhibitory peptides. In untreated cocultures, labeled thalamocortical axons normally grow to and stop in layer IV, forming terminal-like arbors. In the N-cadherin-blocked cocultures, thalamic axons reach layer IV by growing through deep layers at the same rate as those in the untreated cocultures, but instead of terminating in layer IV, they continue growing uninterruptedly through layer IV and extend into supragranular layers to reach the outermost cortical edge, where some form terminal-like arbors in this aberrant laminar position. In cocultures in which the cortical slice is taken at an earlier maturational stage, one that corresponds to a time when thalamic axons are normally growing through deep layers before the emergence of layer IV from the cortical plate, thalamic axon ingrowth through deep layers is significantly attenuated by N-cadherin blocking reagents. These data indicate that N-cadherin has multifaceted roles in establishing the thalamocortical projection, governing aspects of both thalamic axon ingrowth and laminar targeting by acting as a layer IV stop signal, which progressively change in parallel with the maturational state of the cortex.
Functional Specialization of the Axon Initial Segment by Isoform-Specific Sodium Channel Targeting
Authors: Boiko Tatiana , Van Wart Audra , Caldwell John H. , Levinson S. Rock , Trimmer James S. , Matthews Gary
Published: April 2018

Voltage-dependent sodium channels cluster at high density at axon initial segments, where propagating action potentials are thought to arise, and at nodes of Ranvier. Here, we show that the sodium channel Nav1.6 is precisely localized at initial segments of retinal ganglion cells (RGCs), whereas a different isoform, Nav1.2, is found in the neighboring unmyelinated axon. During development, initial segments first expressed Nav1.2, and Nav1.6 appeared later, approximately in parallel with the onset of repetitive RGC firing. In Shiverer mice, Nav1.6 localization at the initial segment was unaffected, although Nav1.6 expression was severely disrupted in the aberrantly myelinated optic nerve. Targeting or retention of Nav1.6 requires molecular interactions that normally occur only at initial segments and nodes of Ranvier. Expression at nodes but not initial segments exhibits an additional requirement for intact myelination. Because of their high density at the initial segment, Nav1.6 channels may be crucial in determining neuronal firing properties.
Activation of Extracellular Signal-Regulated Kinase by Stretch-Induced Injury in Astrocytes Involves Extracellular ATP and P2 Purinergic Receptors
Authors: Neary Joseph T. , Kang Yuan , Willoughby Karen A. , Ellis Earl F.
Published: April 2018

Gliosis is characterized by hypertrophic and hyperplastic responses of astrocytes to brain injury. To determine whether injury of astrocytes produced by anin vitromodel of brain trauma activates extracellular signal-regulated protein kinase (ERK), a key regulator of cellular proliferation and differentiation, astrocytes cultured on deformable SILASTIC membranes were subjected to rapid, reversible strain (stretch)-induced injury. Activation of ERK was observed 1 min after injury, was maximal from 10 to 30 min, and remained elevated for 3 hr. Activation of ERK was dependent on the rate and magnitude of injury; maximum ERK activation was observed after a 20–60 msec, 7.5 mm membrane displacement. ERK activation was blocked by inhibiting MEK, the upstream activator of ERK. Activation of ERK was reduced when calcium influx was diminished. When extracellular ATP was hydrolyzed by apyrase or ATP/P2 receptors were blocked, injury-induced ERK activation was significantly reduced. P2 receptor antagonist studies indicated a role for P2X2 and P2Y1, but not P2X1, P2X3, or P2X7, receptors in injury-induced ERK activation. These findings demonstrate for the first time that ATP released by mechanical injury is one of the signals that triggers ERK activation and suggest a role for extracellular ATP, P2 purinergic receptors, and calcium-dependent ERK signaling in the astrocytic response to brain trauma.
Regulation of Extracellular Signal-Regulated Kinase by Cannabinoids in Hippocampus
Authors: Derkinderen Pascal , Valjent Emmanuel , Toutant Madeleine , Corvol Jean-Christophe , Enslen Hervé , Ledent Catherine , Trzaskos James , Caboche Jocelyne , Girault Jean-Antoine
Published: April 2018

Endocannabinoids form a novel class of intercellular messengers, the functions of which include retrograde signaling in the brain and mediation or modulation of several types of synaptic plasticity. Yet, the signaling mechanisms and long-term effects of the stimulation of CB1 cannabinoid receptors (CB1-R) are poorly understood. We show that anandamide, 2-arachidonoyl-glycerol, and Δ9-tetrahydrocannabinol (THC) activated extracellular signal-regulated kinase (ERK) in hippocampal slices. In living mice, THC activated ERK in hippocampal neurons and induced its accumulation in the nuclei of pyramidal cells in CA1 and CA3. Both effects were attributable to stimulation of CB1-R and activation of MAP kinase/ERK kinase (MEK). In hippocampal slices, the stimulation of ERK was independent of phosphatidyl-inositol-3-kinase but was regulated by cAMP. The endocannabinoid-induced stimulation of ERK was lost in Fyn knock-out mice, in slices andin vivo, although it was insensitive to inhibitors of Src-family tyrosine kinasesin vitro, suggesting a noncatalytic role of Fyn. Finally, the effects of cannabinoids on ERK activation were dependent on the activity of glutamate NMDA receptorsin vivo, but not in hippocampal slices, indicating the existence of several pathways linking CB1-R to the ERK cascade.In vivoTHC induced the expression of immediate-early genes products (c-Fos protein, Zif268, and BDNF mRNAs), and this induction was prevented by an inhibitor of MEK. The strong potential of cannabinoids for inducing long-term alterations in hippocampal neurons through the activation of the ERK pathway may be important for the physiological control of synaptic plasticity and for the general effects of THC in the context of drug abuse.
Coarticulation in Fluent Fingerspelling
Authors: Jerde Thomas E. , Soechting John F. , Flanders Martha
Published: April 2018

In speech, the phenomenon of coarticulation (differentiation of phoneme production depending on the preceding or following phonemes) suggests an organization of movement sequences that is not strictly serial. In the skeletal motor system, however, evidence for comparable fluency has been lacking. Thus the present study was designed to quantify coarticulation in the hand movement sequences of sign language interpreters engaged in fingerspelling. Records of 17 measured joint angles were subjected to discriminant and correlation analyses to determine to what extent and in what manner the hand shape for a particular letter was influenced by the hand shapes for the preceding or the following letters. Substantial evidence of coarticulation was found, revealing both forward and reverse influences across letters. These influences could be further categorized as assimilation (tending to reduce the differences between sequential hand shapes) or dissimilation (tending to emphasize the differences between sequential hand shapes). The proximal interphalangeal (PIP) joints of the index and middle fingers tended to show dissimilation, whereas at the same time (i.e., during the spelling of the same letters) the joints of the wrist and thumb tended to show assimilation. The index and middle finger PIP joints have been shown previously to be among the most important joints for computer recognition of the 26 letter shapes, and therefore the dissimilation may have served to enhance visual discrimination. The simultaneous occurrence of dissimilation in some joints and assimilation in others demonstrates an unprecedented level of parallel control of individual joint rotations in an essentially serial task.
Cooperation between Area 17 Neuron Pairs Enhances Fine Discrimination of Orientation
Authors: Samonds Jason M. , Allison John D. , Brown Heather A. , Bonds A. B.
Published: April 2018

We examined 66 complex cells in area 17 of cats that were paralyzed and anesthetized with propofol and N2O. We studied changes in ensemble responses for small (<10°) and large (>10°) differences in orientation. Examination of temporal resolution and discharge history revealed advantages in discrimination from both dependent (e.g., synchronization) and independent (e.g., bursting) interspike interval properties. For 27 pairs of neurons, we found that the average cooperation (the advantage gained from the joint activity) was 57.6% for fine discrimination of orientation but <5% for gross discrimination. Dependency (probabilistic quantification of the interaction between the cells) was measured between 29 pairs of neurons while varying orientation. On average, the dependency tuning for orientation was 35.5% narrower than the average firing rate tuning. The changes in dependency around the peak orientation (at which the firing rate remains relatively constant) lead to substantial cooperation that can improve discrimination in this region. The narrow tuning of dependency and the cooperation provide evidence to support a population-encoding scheme that is based on biologically plausible mechanisms and that could account for hyperacuities.
Genetic Mapping of Variation in Spatial Learning in the Mouse
Authors: Steinberger Daniela , Reynolds David S. , Ferris Pushpindar , Lincoln Rachael , Datta Susmita , Stanley Joanna , Paterson Andrea , Dawson Gerard R. , Flint Jonathan
Published: April 2018

Inbred strains of mice are known to differ in their performance in the Morris water maze task, a test of spatial discrimination and place navigation in rodents, but the genetic basis of individual variation in spatial learning is unknown. We have mapped genetic effects that contribute to the difference between two strains, DBA/2 and C57BL6/J, using an F2 intercross and methods to detect quantitative trait loci (QTL). We found two QTL, one on chromosome 4 and one on chromosome 12, that influence behavior in the probe trial of the water maze (genome-wide significancep= 0.017 and 0.015, respectively). By including tests of avoidance conditioning and behavior in a novel environment, we show that the QTL on chromosomes 4 and 12 specifically influence variation in spatial learning. QTL that influence differences in fearful behavior (on chromosomes 1, 3, 7, 15, and 19) operate while mice are trained in the water maze apparatus.
Reduced Inhibition of Dentate Granule Cells in a Model of Temporal Lobe Epilepsy
Authors: Kobayashi Masayuki , Buckmaster Paul S.
Published: April 2018

Patients and models of temporal lobe epilepsy have fewer inhibitory interneurons in the dentate gyrus than controls, but it is unclear whether granule cell inhibition is reduced. We report the loss of GABAergic inhibition of granule cells in the temporal dentate gyrus of pilocarpine-induced epileptic rats.In situhybridization for GAD65 mRNA and immunocytochemistry for parvalbumin and somatostatin confirmed the loss of inhibitory interneurons. In epileptic rats, granule cells had prolonged EPSPs, and they discharged more action potentials than controls. Although the conductances of evoked IPSPs recorded in normal ACSF were not significantly reduced and paired-pulse responses showed enhanced inhibition of granule cells from epileptic rats, more direct measures of granule cell inhibition revealed significant deficiencies. In granule cells from epileptic rats, evoked monosynaptic IPSP conductances were <40% of controls, and the frequency of GABAAreceptor-mediated spontaneous and miniature IPSCs (mIPSCs) was <50% of controls. Within 3–7 d after pilocarpine-induced status epilepticus, miniature IPSC frequency had decreased, and it remained low, without functional evidence of compensatory synaptogenesis by GABAergic axons in chronically epileptic rats. Both parvalbumin- and somatostatin-immunoreactive interneuron numbers and the frequency of both fast- and slow-rising GABAAreceptor-mediated mIPSCs were reduced, suggesting that loss of inhibitory synaptic input to granule cells occurred at both proximal/somatic and distal/dendritic sites. Reduced granule cell inhibition in the temporal dentate gyrus preceded the onset of spontaneous recurrent seizures by days to weeks, so it may contribute, but is insufficient, to cause epilepsy.
A Critical Role for the Cannabinoid CB1Receptors in Alcohol Dependence and Stress-Stimulated Ethanol Drinking
Authors: Racz Ildiko , Bilkei-Gorzo Andras , Toth Zsuzsanna E. , Michel Kerstin , Palkovits Miklós , Zimmer Andreas
Published: April 2018

Although many people drink alcohol regularly, only some become addicted. Several studies have shown that genetic and environmental factors contribute to individual differences in the vulnerability to the effects of alcohol (Nestler, 2000; Kreek, 2001; Crabbe, 2002). Among the environmental factors, stress is perhaps the most important trigger for relapse after a period of abstinence (Koob and Nestler, 1997; Piazza and Le Moal, 1998; Koob and Le Moal, 2001; Weiss et al., 2001). Here we show that ethanol withdrawal symptoms were completely absent in cannabinoid CB1receptor-deficient mice, although acute effects of ethanol and ethanol tolerance and preference were basically normal. Furthermore, foot-shock stress had no affect on alcohol preference in Cnr1−/−mice, although it induced a dramatic increase in Cnr1+/+animals. These results reveal a critical role for the CB1receptor in clinically important aspects of alcohol dependence and provide a rationale for the use of CB1receptor antagonists in the treatment of alcohol addiction.
A Fast-Conducting, Stochastic Integrative Mode for Neocortical NeuronsInVivo
Authors: Rudolph Michael , Destexhe Alain
Published: April 2018

During activated states, neocortical neurons receive intense synaptic background activity that induces large-amplitude membrane potential fluctuations and a strong conductance in the membrane. However, little is known about the integrative properties of neurons during such high-conductance states. Here we investigated the integrative properties of neocortical pyramidal neurons underin vivoconditions simulated by computational models. We show that the presence of high-conductance fluctuations induces a stochastic state in which active dendrites are fast conducting and have a different dynamics of initiation and forward-propagation of Na+-dependent spikes. Synaptic efficacy, quantified as the probability that a synaptic input specifically evokes a somatic spike, was approximately independent of the dendritic location of the synapse. Synaptic inputs evoked precisely timed responses (milliseconds), which also showed a reduced location dependence. This scheme was found to apply to a broad range of kinetics and density distributions of voltage-dependent conductances, as well as to different dendritic morphologies. Synaptic efficacies were, however, modulable by the balance of excitation and inhibition in background activity, for all synapses at once. Thus, models predict that the intense synaptic activityin vivocan confer advantageous computational properties to neocortical neurons: they can be set to an integrative mode that is stochastic, fast conducting, and optimized to process synaptic inputs at high temporal resolution independently of their position in the dendrites. Some of these predictions can be tested experimentally.
The Edinger-Westphal–Lateral Septum Urocortin Pathway and Its Relationship to Alcohol Consumption
Authors: Bachtell Ryan K. , Weitemier Adam Z. , Galvan-Rosas Agustin , Tsivkovskaia Natalia O. , Risinger Fred O. , Phillips Tamara J. , Grahame Nicholas J. , Ryabinin Andrey E.
Published: April 2018

Identifying and characterizing brain regions regulating alcohol consumption is beneficial for understanding the mechanisms of alcoholism. To this aim, we first identified brain regions changing in expression of the inducible transcription factor c-Fos in the alcohol-preferring C57BL/6J (B6) and alcohol-avoiding DBA/2J (D2) mice after ethanol consumption. Drinking a 5% ethanol/10% sucrose solution in a 30 min limited access procedure led to induction of c-Fos immunoreactivity in urocortin (Ucn)-positive cells of the Edinger-Westphal nucleus (EW), suppression of c-Fos immunoreactivity in the dorsal portion of the lateral septum (LS) of both strains of mice, and strain-specific suppression in the intermediate portion of the LS and the CA3 hippocampal region. Because the EW sends Ucn projections to the LS, and B6 and D2 mice differ dramatically in EW Ucn expression, we further analyzed the Ucn EW–LS pathway using several genetic approaches. We find that D2 mice have higher numbers of Ucn-immunoreactive processes than B6 mice in the LS and that consumption of ethanol/sucrose in the F2 offspring of a B6D2 intercross positively correlates with Ucn immunoreactivity in the EW and negatively correlates with Ucn immunoreactivity in the LS. In agreement with these findings, we find that alcohol-avoiding male B6.D2Alcp1line 2.2 congenic mice have lower Ucn immunoreactivity in the EW than male B6.B6 mice. Finally, we also find that HAP mice, selectively bred for high alcohol preference, have higher Ucn immunoreactivity in EW, than LAP mice, selectively bred for low alcohol preference. Taken together, these studies provide substantial evidence for involvement of the EW–LS Ucn pathway in alcohol consumption.
The Involvement of Glucose Metabolism in the Regulation of Inducible Nitric Oxide Synthase Gene Expression in Glial Cells: Possible Role of Glucose-6-Phosphate Dehydrogenase and CCAAT/Enhancing Binding Protein
Authors: Won Je-Seong , Im Yeong-Bin , Key Lyndon , Singh Inderjit , Singh Avtar K.
Published: April 2018

In rat glial cells the lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) gene expression was enhanced by extracellular glucose concentration in a dose-dependent manner. On the other hand, 2-deoxy-d-glucose decreased the LPS-induced iNOS gene expression even in the presence of glucose (6 gm/l), suggesting that glucose metabolism is linked to the regulation of iNOS gene expression. The intracellular NADPH/NADP+directly correlated with the extracellular glucose concentration, and the reduction of NADPH generation via a block of glucose-6-phosphate dehydrogenase (G6PD) by treatment with dehydroepiandrosterone or the antisense DNA oligomer of G6PD mRNA resulted in the inhibition of iNOS gene expression. Gel shift assays showed that CAAT/enhancing binding protein (C/EBP), rather than AP-1 or NF-κB, correlated better with a glucose-dependent increase in iNOS gene expression. The induction of C/EBP DNA binding activity by LPS and glucose was attributable mainly to the increase in C/EBP-δ protein. The cotransfection with wild-type C/EBP-δ increased the iNOS promoter activity to the level achieved with a higher glucose concentration in the presence of LPS. Therefore, our results suggest that C/EBP-δ may be a critical mediator in glucose-mediated regulation of iNOS gene expression.