bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimation of Worm-Gear Drives’ Parameters Based on Computer Graphics 3D-Methods
Authors: Решетников М. , Reshetnikov M. , Рязанов С. , Ryazanov S.
Published: April 2018

The current state of the machine-building production market is such that various modifications of its products are produced by single specimens. This requires that production should, on the one hand, reduce the terms for preparation and production of new products along with increasing the same products’ nomenclature, and on the other hand, it is economically necessary to reduce these products’ factory labor hours and cost along with high quality of manufacturing thereof. Such production’s profitability depends largely on effectiveness of the use of computer equipment and software that will allow virtualization of design and technological processes, which in the final development will allow transfer all stages related to preparing for manufacturing of a new product to mathematical and geometric computer models of manufactured products. This permits to leave only one stage of preparing for manufacturing of a new product — geometric synthesis, taking into account the workspace configuration. Due to the complexity of processes for tooth-profiling and engagement, their exact calculation can be only performed by a computer. A mathematical model of engagement, for example, a worm pair, which takes into account not only geometric parameters, but also the enterprise’s machine capabilities, makes it possible, without manufacturing the worm pair in a metal, to obtain reliable information about all features of the worm pair operation. The modern computers’ processing speed allows in a short time to choose the option that gives the best approximation to consumer’s desired requirements. This paper shows an example for application of the method of geometric computer solid-state modeling for the technological process of worm gear shaping as an envelope of the tool model’s producing surface. The algorithm work consists in the mutual motion and rotation of a part blank and the tool. As a result of mutual intersection of the part blank and the tool surfaces, final shapes of tooth surfaces are formed as precise computer solid-state models. In this paper has been shown the final result for computer shaping of the worm’s working surface. One of the stages for determining the gaps between the working surfaces of the worm and the worm wheel has been described. One of variants for interactive analysis of the worm pair’s computer model is application of the cutting-plane method to obtain a set of sections. The mutual intersection of the worm and worm wheel’s planes and working surfaces makes it possible to determine points’ coordinates and thereon to define the gaps between the working surfaces of the product.
Manu Militari: The Institutional Contingencies of Stakeholder Relationships on Entrepreneurial Performance
Authors: Hiatt Shon R. , Carlos W. Chad , Sine Wesley D.
Published: April 2018

This study examines how ventures can leverage relationships with heterogeneous government stakeholders to enhance survival in different institutional environments. We consider how the distinct resources provided from venture ties to military and political actors represent complementary strategic assets that differentially influence performance in varying political and economic environments as well as under conditions of violence and political conflict. Empirically, we examine the effect of these respective stakeholder relationships on new venture survival across 10 countries over a 65-year period. By distinguishing between the resources obtained through relationships with different types of government stakeholders and showing how the value of these resources varies in different contexts, this study contributes to nonmarket strategy and stakeholder management research and highlights the need for studies to take a pluralistic view of government stakeholders. This paper also presents managerial insights to firms seeking to address the prevalent challenges associated with political, economic, and physical security issues in developing and underdeveloped economies.

The online appendix is available at https://doi.org/10.1287/orsc.2017.1178 .
Global transcriptome analysis to identify critical genes involved in the pathology of osteoarthritis
Authors: Zhang X. , Bu Y. , Zhu B. , Zhao Q. , Lv Z. , Li B. , Liu J.
Published: April 2018

Objectives

The aim of this study was to identify key pathological genes in osteoarthritis (OA).

Methods

We searched and downloaded mRNA expression data from the Gene Expression Omnibus database to identify differentially expressed genes (DEGs) of joint synovial tissues from OA and normal individuals. Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analyses were used to assess the function of identified DEGs. The protein-protein interaction (PPI) network and transcriptional factors (TFs) regulatory network were used to further explore the function of identified DEGs. The quantitative real-time polymerase chain reaction (qRT-PCR) was applied to validate the result of bioinformatics analysis. Electronic validation was performed to verify the expression of selected DEGs. The diagnosis value of identified DEGs was accessed by receiver operating characteristic (ROC) analysis.

Results

A total of 1085 DEGs were identified. KEGG pathway analysis displayed that Wnt was a significantly enriched signalling pathway. Some hub genes with high interactions such as USP46, CPVL, FKBP5, FOSL2, GADD45B, PTGS1, and ZNF423 were identified in the PPI and TFs network. The results of qRT-PCR showed that GADD45B, ADAMTS1, and TFAM were down-regulated in joint synovial tissues of OA, which was consistent with the bioinformatics analysis. The expression levels of USP46, CPVL, FOSL2, and PTGS1 in electronic validation were compatible with the bio-informatics result. CPVL and TFAM had a potential diagnostic value for OA based on the ROC analysis.

Conclusion

The deregulated genes including USP46, CPVL, FKBP5, FOSL2, GADD45B, PTGS1, ZNF423, ADAMTS1, and TFAM might be involved in the pathology of OA. Cite this article: X. Zhang, Y. Bu, B. Zhu, Q. Zhao, Z. Lv, B. Li, J. Liu. Global transcriptome analysis to identify critical genes involved in the pathology of osteoarthritis. Bone Joint Res 2018;7:298–307. DOI: 10.1302/2046-3758.74.BJR-2017-0245.R1.
„No pasaran“ – Lyrik, Kulturpolitik und Sprachdifferenz bei T. S. Eliot, Paul Celan und Rolf Dieter Brinkmann
Authors: Dembeck Till
Published: April 2018

The poems of T. S. Eliot, Paul Celan, and Rolf Dieter Brinkmann treated in this article engage language difference in order to highlight poetry’s distinctive modernity. This involves them, and modern poetry in general, in a politics of culture which we can analyze on two levels: in terms of formal qualities, especially meter, and in terms of the programs and strategies the poems develop for themselves and for culture. The need to regard lyrical form as an enactment of cultural-political strategies becomes obvious in poetry’s use of language difference, not only between distinct langues in the sense of Saussure but more generally between any different standardizations of language. Lyric poetry builds on language difference, and since all language differences are culturally significant, lyric poetry is a genre of genuine cultural politics.
Eine enzyklopädische Literatur der Dinge – Emile Zolas Warenhausroman Au Bonheur des Dames
Authors: Vedder Ulrike
Published: April 2018

Emile Zola’s novel „Au Bonheur des Dames“ abounds with excessive enumeration and description of clothes. The overwhelming arrangement of these clothes in the department store does not only irresistibly attract female customers but also draws the reader’s attention to a poetics of encyclopaedic writing. Thus, the novel opens up spaces that are filled with goods, systematically organising them in various stores and exhibitions. In view of the novel’s detailed depiction of architecture, economics and customer traffic, the paper argues that Zola asks for a conjunction between the novel and encyclopaedic discourse.
Écrire ‹ l’oral › dans Texaco de Patrick Chamoiseau
Authors: Kakish Shereen
Published: April 2018

In this analysis, I investigate the coexistence of the oral and writing in Texaco of Patrick Chamoiseau. I try first to explain how Chamoiseau arrived to a certain synthesis between the two registers. Then I examine the objective of the author to develop such a synthesis between oral and writing in the universe of a text. In the case of Texaco, it is not only a matter of two ways of expression but also of two languages and two states of civilization. This expressive and linguistic lining does not depend only on the exile of many intellectuals and some other historical factors, but on a certain cultural alienation. Indeed, the Martinican identity oscillates between two spaces and hesitates between two languages. By this coexistence of the creole oral mode and the French writing, Chamoiseau tried to create a new style in the world of literary texts. On the other hand, this meeting of the different languages and registers creates a certain composition of elements that do not stand in a relation of opposition to each other, but of a tangle in order to communicate a world vision and to assert the original identity.
Hausen außer Haus: Transitorische Räume in Marilynne Robinsons Housekeeping (1980) und Ernst Augustins Robinsons blaues Haus (2012)
Authors: Klappert Annina
Published: April 2018

The German figura etymologica ‘Hausen außer Haus,’ as ‘dwelling’ or ‘housing outside the house,’ is developed in this paper as a specific figure of thought in two contemporary literary texts in which the respective protagonists’ outside ‘housing’ contrasts with the space of the houses they pass through, thus transforming them into transitory spaces through the reflection of the outside. This dialectical movement challenges the concept of the house as a definable space. In terms of literary-spatial theory, the protagonists are examined as transitory figures; their transgressions of inside/outside and up/down are identified in a topological analysis, and finally the argument is presented that the imagination of the protagonists functions as a transitory modus as they move within the narrative. Both texts show the ability of literature to reflect on space and enable a link to the spatial turn of 1980 s cultural studies. The innovative contribution of my argument occurs in rethinking the concept of the house as a definable space with reliable boundaries and in proposing a conception of the outside as a potential change to the inside. By providing new insights into the concept of the house, literature itself can be seen as a space of thinking ‘outside the house.’
Translation policy and indigenous languages in Hispanic Latin America
Authors: Howard Rosaleen , Ricoy Raquel De Pedro , Ciudad Luis Andrade
Published: April 2018

This article examines the status of translation policy as it relates to public service interfaces between the dominant Spanish-speaking sectors of society and speakers of some of the many indigenous languages of Latin America. The article focuses on Mexico, Colombia, Ecuador, Bolivia and Paraguay, and Peru is used as a case study based on recent first-hand research. Translation policy is inherently bound up with language policy, where the latter exists. However, there is variation from state to state as to whether language rights legislation has been passed, whether it is implemented through policy, and the extent to which translation policy is part of the legislative framework. The case of Peru illustrates the need for translation and interpreting (T&I) services following conflicts and painful human rights infringements. Across the board, T&I have hitherto been ad hoc practices, giving rise to translation policy de facto. Formalized T&I training initiatives and legislative processes are now underway in Peru, and may give rise to explicit translation policies evolving there and elsewhere in the region in the future.
“Never Better”: Affliction, Consolation and the Culture of Protestantism in Early Modern England
Authors: van Dijkhuizen Jan Frans
Published: April 2018

This essay examines the central role of consolation in early modern Protestant culture. It first maps a number of the important tropes in early modern Protestant consolation literature, focusing on England. It then analyses the language of consolation in early modern printed and manuscript sources on the legal proceedings against the Puritan pamphleteers Bastwick, Burton and Prynne, showing how consolation was both widely shared and politically contentious, undermining the very idea of a unified Protestant cause which it served to foster. Finally, I examine the notebooks of the London wood-turner Nehemiah Wallington as a case study of the ways in which self-writers, in recording and reflecting on affliction, drew on consolation discourses. While consolation is a central strand in Wallington’s reflections on affliction, it is also elusive and provisional, especially where everyday, personal suffering is concerned. In Wallington, consolation seems available especially if the religious suffering it alleviates has a political dimension, and can be construed as a way of suffering for the true faith.
Amine Capped Gold Colloids at Oxidic Supports: Their Electronic Interactions
Authors: Siemer Michael , Mohrhusen Lars , Grebien Maximilian , Al-Shamery Katharina
Published: April 2018

Colloidal deposition of noble metal nanoparticles on oxidic supports is a recent approach for the fabrication of heterogeneous catalyst materials. We present studies on the interaction of different amine ligands with gold nanoparticles before and after deposition on several oxidic supports (titania, silica, alumina, magnesia or zinc oxide), using X-ray photoelectron and Auger spectroscopy, and high-resolution transmission electron microscopy. The adsorption of amines on thin gold films as well as on nanoparticles leads to a decrease in metal photoelectron binding energies. Usually, this is explained by donor-acceptor interactions via the amine group. By additional analysis of Auger signals, which are more sensitive to changes in the oxidation state than photoelectron spectra, we demonstrate that these shifts are due to a final state effect, namely, the increased photoelectron hole screening in presence of amine adsorbates. It will be shown, that this effect is not sensitive neither to the nanoparticle size nor the sterical properties of the capping amine. After deposition on oxide supports, the photoelectron binding energies are even further decreased. The presented findings exhibit that care has to be taken to interpret binding energy shifts simply with charging, which has impact on understanding the local electronic situation on the surface of metal-loaded oxides, crucial for heterogeneous catalysis.
Thermo-Mechanical Analysis of Activated Tungsten Inert Gas Welding (A-TIG) of Type 316LN Stainless Steel Thin Plates
Authors: Ganesh K. C. , Vasudevan M. , Balasubramanian K. R. , Vasantharaja P. , Chandrasekhar N.
Published: April 2018

In the present study, thermo-mechanical behavior of 316LN stainless steel thin plates during activated tungsten inert gas (A-TIG) welding was investigated using SYSWELD®. A-TIG welding was carried out with more reduced heat input for fabricating 3-mm-thick 316LN stainless steel plates than that of the conventional TIG welding process. Induced transient temperature during welding was measured using a K-type thermocouple. A pulse-echo ultrasonic test was carried out using a 2-MHz probe employing critically refracted longitudinal waves for measuring residual stresses across the weld joint. A digital height gauge was used to quantify the distortion caused during welding. There was a good agreement between the predicted and measured thermal cycles, residual stresses, and distortion. The concentrated heat intensity of A-TIG welding induced higher surface temperature in the weld center, produced a narrow weld bead, and exhibited a sharp temperature gradient at the weld/base metal interface. Peak residual stress and distortion of the A-TIG weld joint were found to be less than that of the TIG weld joint.
Muscarinic Receptor Activity Induces an Afterdepolarization in a Subpopulation of Hippocampal CA1 Interneurons
Authors: McQuiston A. Rory , Madison Daniel V.
Published: April 2018

Cholinergic input to the hippocampus may be involved in important behavioral functions and the pathophysiology of neurodegenerative diseases. Muscarinic receptor activity in interneurons of the hippocampus may play a role in these actions. In this study, we investigated the effects of muscarinic receptor activity on the excitability of different subtypes of interneurons in rat hippocampal CA1. Most interneurons displayed an afterhyperpolarizing potential (AHP) after depolarization by injected current or synaptic stimulation. In the presence of a muscarinic agonist, the AHP of a subset of these interneurons was replaced by an afterdepolarization (ADP), often of sufficient magnitude to evoke action potentials in the absence of further stimulation. The ADP was insensitive to cadmium and low extracellular calcium. It was blocked by low extracellular sodium but not by tetrodotoxin or low concentrations of amiloride. Muscarinic ADPs were sometimes observed in isolation but were often accompanied by depolarizing, hyperpolarizing, or biphasic changes in the membrane potential. Interneurons with muscarinic ADPs were found in all strata of CA1 and did not fall into a single morphological classification. The potential functions of the prolonged action potential output of interneurons produced by the ADP could include changes in hippocampal circuit properties and facilitation of the release of peptide cotransmitters in these interneurons.
Robust Regeneration of Adult Sensory Axons in Degenerating White Matter of the Adult Rat Spinal Cord
Authors: Davies Stephen J. A. , Goucher David R. , Doller Catherine , Silver Jerry
Published: April 2018

We have recently reported that minimally disturbed adult CNS white matter can support regeneration of adult axons by using a novel microtransplantation technique to inject minute volumes of dissociated adult rat dorsal root ganglion neurons directly into adult rat CNS pathways (Davies et al., 1997). This atraumatic injection procedure minimized scarring and allowed considerable numbers of regenerating adult axons immediate access to the adult CNS glial terrain where they rapidly extended for long distances. A critical question remained as to whether degenerating white matter at acute and chronic stages (up to 3 months) after injury could still support regeneration. To investigate this, we have microtransplanted adult sensory neurons into degenerating white matter of the adult rat spinal cord several millimeters rostral to a severe lesion of the dorsal columns. Regeneration of donor sensory axons in both directions away from the site of transplantation was robust even within white matter undergoing fulminant Wallerian degeneration despite intimate contact with myelin. Along their route, the regrowing axons extended large numbers of collaterals into the adjacent dorsal horn. However, after entering the lesion, the rapidly extending growth cones stopped and became dystrophic within high concentrations of reactive glial matrix. Our results offer compelling evidence that the major environmental impediment to regeneration in the adult CNS is the molecular barrier that forms directly at the lesion site, and that degenerating white matter beyond the glial scar has a far greater intrinsic ability to support axon regeneration than previously thought possible.
Modulation of Glioma Cell Migration and Invasion Using Cl−and K+Ion Channel Blockers
Authors: Soroceanu Liliana , Manning Timothy J. , Sontheimer Harald
Published: April 2018

Human malignant gliomas are highly invasive tumors. Mechanisms that allow glioma cells to disseminate, migrating through the narrow extracellular brain spaces are poorly understood. We recently demonstrated expression of large voltage-dependent chloride (Cl−) currents, selectively expressed by human glioma cellsin vitroandin situ(Ullrich et al., 1998). Currents are sensitive to several Cl−channel blockers, including chlorotoxin (Ctx), (Ullrich and Sontheimer, 1996; Ullrich et al., 1996), tetraethylammonium chloride (TEA), and tamoxifen (Ransom and Sontheimer, 1998). Using Transwell migration assays, we show that blockade of glioma Cl−channels specifically inhibits tumor cell migration in a dose-dependent manner. Ctx (5 μm), tamoxifen (10 μm), and TEA (1 mm) also prevented invasion of human glioma cells into fetal rat brain aggregates, used as anin vitromodel to assess tumor invasiveness. Anion replacement studies suggest that permeation of chloride ions through glioma chloride channel is obligatory for cell migration. Osmotically induced cell swelling and subsequent regulatory volume decrease (RVD) in cultured glioma cells were reversibly prevented by 1 mmTEA, 10 μmtamoxifen, and irreversibly blocked by 5 μmCtx added to the hypotonic media. Cl−fluxes associated with adaptive shape changes elicited by cell swelling and RVD in glioma cells were inhibited by 5 μmCtx, 10 μmtamoxifen, and 1 mmTEA, as determined using the Cl−-sensitive fluorescent dye 6-methoxy-N-ethylquinolinium iodide. Collectively, these data suggest that chloride channels in glioma cells may enable tumor invasiveness, presumably by facilitating cell shape and cell volume changes that are more conducive to migration and invasion.
Loss of Distal Axons and Sensory Merkel Cells and Features Indicative of Muscle Denervation in Hindlimbs of P0-Deficient Mice
Authors: Frei Regula , Mötzing Sandra , Kinkelin Ilka , Schachner Melitta , Koltzenburg Martin , Martini Rudolf
Published: April 2018

Mice lacking the major Schwann cell myelin component P0 show a severe dysmyelination with pathological features reminiscent of the Déjérine-Sottas syndrome in humans. Previous morphological and electrophysiological studies on these mice did not only demonstrate a compromised myelination and myelin maintenance, but were suggestive of an impairment of axons as well. Here, we studied the axonal pathology in P0-deficient mice by quantitative electron microscopy. In addition, we investigated epidermal receptor end organs by immunocytochemistry and muscle pathology by histochemistry.

In proximal sections of facial and femoral nerves, axon calibers were significantly reduced, whereas the number of myelin-competent axons was not diminished in 5- and 17-month-old P0-deficient mice. However, in distal branches of the femoral and sciatic nerve (digital nerves innervating the skin of the first toe) the numbers of myelin-competent axons were reduced by 70% in 6-month-old P0-deficient mice. Immunolabeling of foot pads revealed a corresponding loss of Merkel cells by 75%, suggesting that survival of these cells is dependent on the presence or maintenance of their innervating myelinated axons. In addition, quadriceps and gastrocnemius muscles showed pathological features indicative of denervation and axonal sprouting. These findings demonstrate that loss of an important myelin component can initiate degenerative mechanisms not only in the Schwann cell but also in the distal portions of myelinated axons, leading to the degeneration of specialized receptor end organs and impairment of muscle innervation.
Cognitive Deficits in a Genetic Mouse Model of the Most Common Biochemical Cause of Human Mental Retardation
Authors: Zagreda Leze , Goodman Jason , Druin Donald P. , McDonald David , Diamond Adele
Published: April 2018

Phenylalanine hydroxylase (Pah)-deficient “PKU mice” have a mutation in thePahgene that causes phenylketonuria (PKU) in humans. PKU produces cognitive deficits in humans if it is untreated. We report here the first evidence that the genetic mouse model of PKU (Pahenu2) also produces cognitive impairments. PKU mice were impaired on both odor discrimination reversal and latent learning compared with heterozygote littermates and with wild-type mice of the same BTBR strain. A small container of cinnamon-scented sand was presented on the right or left, and nutmeg-scented sand was presented on the other side; left–right location varied over trials. Digging in sand of the correct scent was rewarded by finding phenylalanine-free chocolate. To prevent scent cuing, new containers were used on every trial, and both containers always contained chocolate. Digging in the incorrect choice was stopped before the chocolate was uncovered. Once criterion was reached, the other scent was rewarded. PKU mice were impaired on reversals 2, 3, and 4. They were also impaired in latent learning. On day 1, half the mice were allowed to explore a maze and discover the location of water. On day 2, all mice were water-deprived and were placed in the maze. Whereas pre-exposed wild-type and heterozygous mice showed evidence that they remembered the location of the water and hence could find the water faster on day 2, pre-exposed PKU mice showed no significant benefit from their pre-exposure on day 1.
Interdependence of Multiple Theta Generators in the Hippocampus: a Partial Coherence Analysis
Authors: Kocsis Bernat , Bragin Anatol , Buzsáki György
Published: April 2018

The extracellularly recorded theta oscillation reflects a dynamic interaction of various synaptic and cellular mechanisms. Because the spatially overlapping dipoles responsible for the generation of theta field oscillation may represent different mechanisms, their separation might provide clues with regard to their origin and significance. We used a novel approach, partial coherence analysis, to reveal the various components of the theta rhythm and the relationship among its generators. Hippocampal field activity was recorded by a 16-site silicon probe in the CA1–dentate gyrus axis of the awake rat. Field patterns, recorded from various intrahippocampal or entorhinal cortex sites, were used to remove activity caused by a common source by the partialization procedure. The findings revealed highly coherent coupling between theta signals recorded (1) from the hippocampal fissure and stratum (str.) oriens of the CA1 region and (2) between CA1 stratum radiatum and the dentate molecular layer. The results of partial coherence analysis indicated that rhythmic input from the entorhinal cortex explained theta coherence between signals recorded from the hippocampal fissure and str. oriens but not the coherence between signals derived from str. radiatum and the dentate molecular layer. After bilateral lesions of the entorhinal cortex, all signals recorded from both below and above the CA1 hippocampal pyramidal cell layer became highly coherent. These observations indicate the presence of two, relatively independent, theta generators in the hippocampus, which are mediated by the entorhinal cortex and the CA3–mossy cell recurrent circuitry, respectively. The CA3–mossy cell theta generator is partially suppressed by the dentate gyrus interneuronal output in the intact brain. We suggest that timing of the action potentials of pyramidal cells during the theta cycle is determined by the cooperation between the active CA3 neurons and the entorhinal input.
Differences in the Ways Sympathetic Neurons and Endocrine Cells Process, Store, and Secrete Exogenous Neuropeptides and Peptide-Processing Enzymes
Authors: Marx Ruth , El Meskini Rajaâ , Johns David C. , Mains Richard E.
Published: April 2018

Most neurons store peptides in large dense core vesicles (LDCVs) and release the neuropeptides in a regulated manner. Although LDCVs have been studied in endocrine cells, less is known about these storage organelles in neurons. In this study we use the endogenous peptide NPY (neuropeptide Y) and the endogenous peptide-processing enzyme PAM (peptidylglycine α-amidating monooxygenase) as tools to study the peptidergic system in cultured neurons from the superior cervical ganglion (SCG). Once mature, SCG neurons devote as much of their biosynthetic capabilities to neurotransmitter production as endocrine cells devote to hormone production. Unlike pituitary and atrium, SCG neurons cleave almost all of the bifunctional PAM protein they produce into soluble monofunctional enzymes. Very little PAM or NPY is secreted under basal conditions, and the addition of secretagogue dramatically stimulates the secretion of PAM and NPY to a similar extent. Although endocrine cells typically package “foreign” secretory products together with endogenous products, pro-opiomelanocortin- and PAM-derived products encoded by adenovirus in large part were excluded from the LDCVs of SCG neurons. When expressed in corticotrope tumor cells and primary anterior pituitary cultures, the same virally encoded products were metabolized normally. The differences that were observed could reflect differences in the properties of neuronal and endocrine peptidergic systems or differences in the ability of neurons and endocrine cells to express viral transcripts.
δ Opioid Receptor Modulation of Several Voltage-Dependent Ca2+Currents in Rat Sensory Neurons
Authors: Acosta Cristian G. , López Héctor S.
Published: April 2018

Endogenous enkephalins and δ opiates affect sensory function and pain sensation by inhibiting synaptic transmission in sensory circuits via delta opioid receptors (DORs). DORs have long been suspected of mediating these effects by modulating voltage-dependent Ca2+entry in primary sensory neurons. However, not only has this hypothesis never been validated in these cells, but in fact several previous studies have only turned up negative results. By using whole-cell current recordings, we show that the δ enkephalin analog [d-Ala2,d-Leu5]-enkephalin (DADLE) inhibits, via DORs, L-, N-, P-, and Q-high voltage-activated Ca2+channel currents in cultured rat dorsal root ganglion (DRG) neurons. The percentage of responding cells was remarkably high (75%) within a novel subpopulation of substance P-containing neurons compared with the other cells (18–35%). DADLE (1 μm) inhibited 32% of the total barium current through calcium channels (IBa). A δ (naltrindole, 1 μm), but not a μ (β-funaltrexamine, 5 μm), antagonist prevented the DADLE response, whereas a DOR-2 subtype (deltorphin-II, 100 nm), but not a DOR-1 (DPDPE, 1 μm), agonist mimicked the response. L-, N-, P-, and Q-type currents contributed, on average, 18, 48, 14, and 16% to the totalIBaand 19, 50, 26, and 20% to the DADLE-sensitive current, respectively. The drug-insensitive R-type current component was not affected by the agonist. This work represents the first demonstration that DORs modulate Ca2+entry in sensory neurons and suggests that δ opioids could affect diverse Ca2+-dependent processes linked to Ca2+influx through different high-voltage-activated channel types.
Cerebral Amyloid Induces Aberrant Axonal Sprouting and Ectopic Terminal Formation in Amyloid Precursor Protein Transgenic Mice
Authors: Phinney Amie L. , Deller Thomas , Stalder Martina , Calhoun Michael E. , Frotscher Michael , Sommer Bernd , Staufenbiel Matthias , Jucker Mathias
Published: April 2018

A characteristic feature of Alzheimer’s disease (AD) is the formation of amyloid plaques in the brain. Although this hallmark pathology has been well described, the biological effects of plaques are poorly understood. To study the effect of amyloid plaques on axons and neuronal connectivity, we have examined the axonal projections from the entorhinal cortex in aged amyloid precursor protein (APP) transgenic mice that exhibit cerebral amyloid deposition in plaques and vessels (APP23 mice). Here we report that entorhinal axons form dystrophic boutons around amyloid plaques in the entorhinal termination zone of the hippocampus. More importantly, entorhinal boutons were found associated with amyloid in ectopic locations within the hippocampus, the thalamus, white matter tracts, as well as surrounding vascular amyloid. Many of these ectopic entorhinal boutons were immunopositive for the growth-associated protein GAP-43 and showed light and electron microscopic characteristics of axonal terminals. Our findings suggest that (1) cerebral amyloid deposition has neurotropic effects and is the main cause of aberrant sprouting in AD brain; (2) the magnitude and significance of sprouting in AD have been underestimated; and (3) cerebral amyloid leads to the disruption of neuronal connectivity which, in turn, may significantly contribute to AD dementia.
Electromyographic Correlates of Learning an Internal Model of Reaching Movements
Authors: Thoroughman Kurt A. , Shadmehr Reza
Published: April 2018

Theoretical and psychophysical studies have suggested that humans learn to make reaching movements in novel dynamic environments by building specific internal models (IMs). Here we have found electromyographic correlates of internal model formation. We recorded EMG from four muscles as subjects learned to move a manipulandum that created systematic forces (a “force field”). We also simulated a biomechanical controller, which generated movements based on an adaptive IM of the inverse dynamics of the human arm and the manipulandum. The simulation defined two metrics of muscle activation. The first metric measured the component of the EMG of each muscle that counteracted the force field. We found that early in training, the field-appropriate EMG was driven by an error feedback signal. As subjects practiced, the peak of the field-appropriate EMG shifted temporally to earlier in the movement, becoming a feedforward command. The gradual temporal shift suggests that the CNS may use the delayed error–feedback response, which was likely to have been generated through spinal reflex circuits, as a template to learn a predictive feedforward response. The second metric quantified formation of the IM through changes in the directional bias of each muscle’s spatial EMG function, i.e., EMG as a function of movement direction. As subjects practiced, co-activation decreased, and the directional bias of each muscle’s EMG function gradually rotated by an amount that was specific to the field being learned. This demonstrates that formation of an IM can be represented through rotations in the spatial tuning of muscle EMG functions. Combined with other recent work linking spatial tunings of EMG and motor cortical cells, these results suggest that rotations in motor cortical tuning functions could underlie representation of internal models in the CNS.
Genetic Disorders of Vision Revealed by a Behavioral Screen of 400 Essential Loci in Zebrafish
Authors: Neuhauss Stephan C. F. , Biehlmaier Oliver , Seeliger Mathias W. , Das Tilak , Kohler Konrad , Harris William A. , Baier Herwig
Published: April 2018

We examined optokinetic and optomotor responses of 450 zebrafish mutants, which were isolated previously based on defects in organ formation, tissue patterning, pigmentation, axon guidance, or other visible phenotypes. These strains carry single point mutations in >400 essential loci. We asked which fraction of the mutants develop blindness or other types of impairments specific to the visual system. Twelve mutants failed to respond in either one or both of our assays. Subsequent histological and electroretinographic analysis revealed unique deficits at various stages of the visual pathway, including lens degeneration (bumper), melanin deficiency (sandy), lack of ganglion cells (lakritz), ipsilateral misrouting of axons (belladonna), optic-nerve disorganization (grumpyandsleepy), inner nuclear layer or outer plexiform layer malfunction (noir,dropje, and possiblysteifftier), and disruption of retinotectal impulse activity (machoandblumenkohl). Surprisingly, mutants with abnormally large or small eyes or severe wiring defects frequently exhibit no discernible behavioral deficits. In addition, we identified 13 blind mutants that display outer-retina dystrophy, making this syndrome the single-most common cause of inherited blindness in zebrafish. Our screen showed that a significant fraction (∼5%) of the essential loci also participate in visual functions but did not reveal any systematic genetic linkage to particular morphological traits. The mutations uncovered by our behavioral assays provide distinct entry points for the study of visual pathways and set the stage for a genetic dissection of vertebrate vision.
Extinction of Behavior in Infant Rats: Development of Functional Coupling Between Septal, Hippocampal, and Ventral Tegmental Regions
Authors: Nair H. P. , Gonzalez-Lima F.
Published: April 2018

Learning of a behavior at a particular age during the postnatal period presumably occurs when the functional brain circuit mediating the behavior matures. The inability to express a learned behavior, such as inhibition, may be accounted for by the functional dissociation of brain regions comprising the circuit. In this study we tested this hypothesis by measuring brain metabolic activity, as revealed by fluorodeoxyglucose (FDG) autoradiography, during behavioral extinction in 12- and 17-d-old rat pups. Subjects were first trained on a straight alley runway task known as patterned single alternation (PSA), wherein reward and nonreward trials alternate successively. They were then injected with FDG and given 50 trials of continuous nonreward (i.e., extinction). Pups at postnatal day 12 (P12) demonstrated significantly slower extinction rates compared to their P17 counterparts, despite the fact that both reliably demonstrated the PSA effect, i.e., both age groups distinguished between reward and nonreward trials during acquisition. Covariance analysis revealed that the dentate gyrus, hippocampal fields CA1–3, subiculum, and lateral septal area were significantly correlated in P17 but not P12 pups. Significant correlations were also found between the lateral septal area, ventral tegmental area, and the medial septal nucleus in P17 pups. Similar correlative patterns were not found in P12 and P17 handled control animals. Taken together, these results suggest that septal, hippocampal, and mesencephalic regions may be functionally dissociated at P12, and the subsequent maturation of functional connectivity between these regions allows for the more rapid expression of behavioral inhibition during extinction at P17.
Altered Entrainment and Feedback Loop Function Effected by a Mutant Period Protein
Authors: Schotland Peter , Hunter-Ensor Melissa , Lawrence Todd , Sehgal Amita
Published: April 2018

Theperiod (per) andtimeless (tim) genes encode interacting components of the circadian clock. Levels and phosphorylation states of both proteins cycle with a circadian rhythm, and the proteins drive cyclic expression of their RNAs through a feedback mechanism that is, at least in part, negative. We report here that a hypophosphorylated mutant PER protein, produced by creating a small internal deletion, displays increased stability and low-amplitude oscillations, consistent with previous reports that phosphorylation is required for protein turnover. In addition, this protein appears to be defective in feedback repression because it is associated with relatively high levels of RNA and high levels of TIM. Transgenic flies carrying the mutant PER protein display a temperature-dependent shortening of circadian period and are impaired in their response to light, particularly to pulses of light in the late night that normally advance the phase of the rhythm. Interestingly,perRNA is induced by light in these flies, most likely because of the removal of the light-sensitive TIM protein, thus implicating a more direct role for TIM in transcriptional inhibition. These data have relevance for mechanisms of feedback repression, and they also address existing models for the differential behavioral response to light at different times of the night.
ERKI/II Regulation by the Muscarinic Acetylcholine Receptors in Neurons
Authors: Rosenblum Kobi , Futter Marie , Jones Matthew , Hulme E. C. , Bliss T. V. P.
Published: April 2018

Muscarinic acetylcholine receptors (mAChRs) are known to be involved in learning and memory, but the molecular basis of their involvement is not well understood. The availability of new and specific biochemical tools has revealed a crucial role for the mitogen-activated protein kinase (MAPK) family in learning and memory. Here, we examine the link between mAChRs and MAPK in neurons. Using the MAPK kinase (MEK)-specific inhibitor PD98059, we first demonstrate a necessary role for active ERKI/II in long-term potentiationin vivo. Using phospho-specific antibodies that recognize the activated form of ERKI/II, we find that the level of ERKI/II activation in brain is regulated by mAChRs. Carbachol, a muscarinic agonist, induces prolonged activation of ERKI/II, without effect on the related kinase SAPK/JNK (stress-activated protein kinase/c-Jun N-terminal protein kinase) in primary cortical cultures. ERKI/II activation is Src-dependent and partially phosphoinositide-3 kinase- and Ca2+-dependent but is PKC-independent. M1–M4 mAChR subtypes expressed in COS-7 cells can all induce ERKI/II activation using a signal transduction pathway similar to that operating in neurons. The nature of the signal transduction suggests that ERKI/II can serve as a convergence site for mAChR activation and other neurotransmitter receptors.
Role of Circadian Activation of Mitogen-Activated Protein Kinase in Chick Pineal Clock Oscillation
Authors: Sanada Kamon , Hayashi Yuichiro , Harada Yuko , Okano Toshiyuki , Fukada Yoshitaka
Published: April 2018

A circadian pacemaker generates a rhythm with a period of ∼24 hr even in the absence of environmental time cues. Several photosensitive neuronal tissues such as the retina and pineal gland contain the autonomous circadian pacemaker together with the photic-input pathway responsible for entrainment of the pacemaker to the daily light/dark cycle. We show here that, in constant darkness, chick pineal mitogen-activated protein kinase (MAPK) exhibited anin vivocircadian rhythm in tyrosine phosphorylation and in enzymatic activity with a peak during subjective night. Phosphorylated and hence activated MAPK was rapidly dephosphorylated after light illumination during the nighttime when light induces a phase-shift of the pacemaker. The circadian rhythmicity in MAPK phosphorylation was also observed in the cultured pineal gland, and importantly, MAPK kinase inhibitor treatment during subjective night not only shifted the time-of-peak of MAPK phosphorylation but also induced a remarkable phase-delay of the circadian pacemaker. These results indicate an important role of MAPK for time keeping in circadian clock systems.
short stopIs Allelic tokakapo, and Encodes Rod-Like Cytoskeletal-Associated Proteins Required for Axon Extension
Authors: Lee Seungbok , Harris Kerri-Lee , Whitington Paul M. , Kolodziej Peter A.
Published: April 2018

short stop (shot)is required for sensory and motor axons to reach their targets in theDrosophilaembryo. Growth cones inshotmutants initiate at the normal times, and they appear normal with respect to overall morphology and their abilities to orient and fasciculate. However, sensory axons are unable to extend beyond a short distance from the cell body, and motor axons are unable to reach target muscles. Theshotgene encodes novel actin binding proteins that are related to plakins and dystrophin and expressed in axons during development. The longer isoforms identified are predicted to contain an N-terminal actin binding domain, a long central triple helical coiled-coil domain, and a C-terminal domain that contains two EF-hand Ca2+binding motifs and a short stretch of homology to the growth arrest-specific 2 protein. Other isoforms lack all or part of the actin binding domains or are truncated and contain a different C-terminal domain. Only the isoforms containing full-length actin binding domains are detectably expressed in the nervous system.shotis allelic tokakapo, a gene that may function in integrin-mediated adhesion in the wing and embryo. We propose that Shot's interactions with the actin cytoskeleton allow sensory and motor axons to extend.
Cryptic Peripheral Ribosomal Domains Distributed Intermittently along Mammalian Myelinated Axons
Authors: Koenig Edward , Martin Rainer , Titmus Margaret , Sotelo-Silveira José R.
Published: April 2018

A growing body of metabolic and molecular evidence of an endogenous protein-synthesizing machinery in the mature axon is a challenge to the prevailing dogma that the latter is dependent exclusively on slow axoplasmic transport to maintain protein mass in a steady state. However, evidence for a systematic occurrence of ribosomes in mature vertebrate axons has been lacking until recently, when restricted ribosomal domains, called “periaxoplasmic plaques,” were described in goldfish CNS myelinated axons. Comparable restricted RNA/ribosomal “plaque” domains now have been identified in myelinated axons of lumbar spinal nerve roots in rabbit and rat on the basis of RNase sensitivity of YOYO-1-binding fluorescence, immunofluorescence of ribosome-specific antibodies, and ribosome phosphorus mapping by electron spectroscopic imaging (ESI). The findings were derived from examination of the axoplasm isolated from myelinated fibers as axoplasmic whole mounts and delipidated spinal nerve roots. Ribosomal periaxoplasmic plaque domains in rabbit axons were typically narrow (∼2 μm), elongated (∼10 μm) sites that frequently were marked by a protruding structure. The domain complexity included an apparent ribosome-binding matrix. The small size, random distribution, and variable intermittent axial spacing of plaques around the periphery of axoplasm near the axon–myelin border are likely reasons why their systematic occurrence has remained undetected in ensheathed axons. The periodic but regular incidence of ribosomal domains provides a structural basis for previous metabolic evidence of protein synthesis in myelinated axons.
Developmental Expression of Muscarinic Acetylcholine Receptors in Chick Retina: Selective Induction of M2Muscarinic Receptor ExpressionIn Ovoby a Factor Secreted by Müller Glial Cells
Authors: Belmonte Kristen E. , McKinnon Lise A. , Nathanson Neil M.
Published: April 2018

Muscarinic acetylcholine receptors (mAChRs) play an important role in signal processing in the retina. We have used subtype-specific antibodies to identify the changes in the localization of mAChR expression during embryonic development of the retinain vivoand their relationship to the changes in mAChRs in retinal cells in culture. We have demonstrated previously that treatment of fresh retinal cultures with conditioned media from mature retinal cultures specifically induces expression of the M2mAChR (McKinnon et al., 1998). We show that the M2-inducing activity, which we tentatively have called MARIA (muscarinic acetylcholine receptor-inducing activity) is produced by Müller glial cells in culture, because significant activity can be found in media conditioned by essentially neuron-free cultures of Müller glia, as well as by a Müller glial cell line but not several neuroblastoma cell lines. We also demonstrate that the appearance of the M2receptorin vivooccurs concomitantly with the appearance of significant numbers of Müller glial cells in the developing retina. Furthermore, the administration of crude or partially purified preparations of MARIA to developing chick embryosin ovoinduces precocious expression of M2mAChRs in the appropriate cell types in the retina. These results show that a factor secreted by cultured retinal Müller glia can regulate M2mAChR expressionin vivoandin vitroand suggest that the secretion of MARIA by Müller gliain vivomay be responsible for the normal induction of M2mAChR expression during embryonic development.