bluuebunny/crossref_metadata_2025 huggingface dataset:
The Neural Cell Adhesion Molecule Promotes FGFR-Dependent Phosphorylation and Membrane Targeting of the Exocyst Complex to Induce Exocytosis in Growth Cones
Authors: Chernyshova Yana , Leshchyns'ka Iryna , Hsu Shu-Chan , Schachner Melitta , Sytnyk Vladimir
Published: March 2011

The exocyst complex is an essential regulator of polarized exocytosis involved in morphogenesis of neurons. We show that this complex binds to the intracellular domain of the neural cell adhesion molecule (NCAM). NCAM promotes FGF receptor-mediated phosphorylation of two tyrosine residues in the sec8 subunit of the exocyst complex and is required for efficient recruitment of the exocyst complex to growth cones. NCAM at the surface of growth cones induces Ca2+-dependent vesicle exocytosis, which is blocked by an inhibitor of L-type voltage-dependent Ca2+channels and tetanus toxin. Preferential exocytosis in growth cones underlying neurite outgrowth is inhibited in NCAM-deficient neurons as well as in neurons transfected with phosphorylation-deficient sec8 and dominant-negative peptides derived from the intracellular domain of NCAM. Thus, we reveal a novel role for a cell adhesion molecule in that it regulates addition of the new membrane to the cell surface of growth cones in developing neurons.
The Survival of Motor Neuron (SMN) Protein Interacts with the mRNA-Binding Protein HuD and Regulates Localization of Poly(A) mRNA in Primary Motor Neuron Axons
Authors: Fallini Claudia , Zhang Honglai , Su Yuehang , Silani Vincenzo , Singer Robert H. , Rossoll Wilfried , Bassell Gary J.
Published: March 2011

Spinal muscular atrophy (SMA) results from reduced levels of the survival of motor neuron (SMN) protein, which has a well characterized function in spliceosomal small nuclear ribonucleoprotein assembly. Currently, it is not understood how deficiency of a housekeeping protein leads to the selective degeneration of spinal cord motor neurons. Numerous studies have shown that SMN is present in neuronal processes and has many interaction partners, including mRNA-binding proteins, suggesting a potential noncanonical role in axonal mRNA metabolism. In this study, we have established a novel technological approach using bimolecular fluorescence complementation (BiFC) and quantitative image analysis to characterize SMN-protein interactions in primary motor neurons. Consistent with biochemical studies on the SMN complex, BiFC analysis revealed that SMN dimerizes and interacts with Gemin2 in nuclear gems and axonal granules. In addition, using pull down assays, immunofluorescence, cell transfection, and BiFC, we characterized a novel interaction between SMN and the neuronal mRNA-binding protein HuD, which was dependent on the Tudor domain of SMN. A missense mutation in the SMN Tudor domain, which is known to cause SMA, impaired the interaction with HuD, but did not affect SMN axonal localization or self-association. Furthermore, time-lapse microscopy revealed SMN cotransport with HuD in live motor neurons. Importantly, SMN knockdown in primary motor neurons resulted in a specific reduction of both HuD protein and poly(A) mRNA levels in the axonal compartment. These findings reveal a noncanonical role for SMN whereby its interaction with mRNA-binding proteins may facilitate the localization of associated poly(A) mRNAs into axons.
Glutamate Transport Decreases Mitochondrial pH and Modulates Oxidative Metabolism in Astrocytes
Authors: Azarias Guillaume , Perreten Hélène , Lengacher Sylvain , Poburko Damon , Demaurex Nicolas , Magistretti Pierre J. , Chatton Jean-Yves
Published: March 2011

During synaptic activity, the clearance of neuronally released glutamate leads to an intracellular sodium concentration increase in astrocytes that is associated with significant metabolic cost. The proximity of mitochondria at glutamate uptake sites in astrocytes raises the question of the ability of mitochondria to respond to these energy demands. We used dynamic fluorescence imaging to investigate the impact of glutamatergic transmission on mitochondria in intact astrocytes. Neuronal release of glutamate induced an intracellular acidification in astrocytes, via glutamate transporters, that spread over the mitochondrial matrix. The glutamate-induced mitochondrial matrix acidification exceeded cytosolic acidification and abrogated cytosol-to-mitochondrial matrix pH gradient. By decoupling glutamate uptake from cellular acidification, we found that glutamate induced a pH-mediated decrease in mitochondrial metabolism that surpasses the Ca2+-mediated stimulatory effects. These findings suggest a model in which excitatory neurotransmission dynamically regulates astrocyte energy metabolism by limiting the contribution of mitochondria to the metabolic response, thereby increasing the local oxygen availability and preventing excessive mitochondrial reactive oxygen species production.
Modulation of Canonical Transient Receptor Potential Channel 1 in the Proliferation of Oligodendrocyte Precursor Cells by the Golli Products of the Myelin Basic Protein Gene
Authors: Paez Pablo M. , Fulton Daniel , Spreuer Vilma , Handley Vance , Campagnoni Anthony T.
Published: March 2011

Golli proteins, products of the myelin basic protein gene, function as a new type of modulator of intracellular Ca2+levels in oligodendrocyte progenitor cells (OPCs). Because of this, they affect a number of Ca2+-dependent functions, such as OPC migration and process extension. To examine further the Ca2+channels regulated by golli, we studied the store-operated Ca2+channels (SOCCs) in OPCs and acute brain slice preparations from golli knock-out and golli-overexpressing mice. Our results showed that pharmacologically induced Ca2+release from intracellular stores evoked a significant extracellular Ca2+entry after store depletion in OPCs. They also indicated that, under these pharmacological conditions, golli promoted activation of Ca2+influx by SOCCs in cultured OPCs as well as in tissue slices. The canonical transient receptor potential family of Ca2+channels (TRPCs) has been postulated to be SOCC subunits in oligodendrocytes. Using a small interfering RNA knockdown approach, we provided direct evidence that TRPC1 is involved in store-operated Ca2+influx in OPCs and that it is modulated by golli. Furthermore, our data indicated that golli is probably associated with TRPC1 at OPC processes. Additionally, we found that TRPC1 expression is essential for the effects of golli on OPC proliferation. In summary, our data indicate a key role for golli proteins in the regulation of TRPC-mediated Ca2+influx, a finding that has profound consequences for the regulation of multiple biological processes in OPCs. More important, we have shown that extracellular Ca2+uptake through TRPC1 is an essential component in the mechanism of OPC proliferation.
Functional Anatomy of Language and Music Perception: Temporal and Structural Factors Investigated Using Functional Magnetic Resonance Imaging
Authors: Rogalsky Corianne , Rong Feng , Saberi Kourosh , Hickok Gregory
Published: March 2011

Language and music exhibit similar acoustic and structural properties, and both appear to be uniquely human. Several recent studies suggest that speech and music perception recruit shared computational systems, and a common substrate in Broca's area for hierarchical processing has recently been proposed. However, this claim has not been tested by directly comparing the spatial distribution of activations to speech and music processing within subjects. In the present study, participants listened to sentences, scrambled sentences, and novel melodies. As expected, large swaths of activation for both sentences and melodies were found bilaterally in the superior temporal lobe, overlapping in portions of auditory cortex. However, substantial nonoverlap was also found: sentences elicited more ventrolateral activation, whereas the melodies elicited a more dorsomedial pattern, extending into the parietal lobe. Multivariate pattern classification analyses indicate that even within the regions of blood oxygenation level-dependent response overlap, speech and music elicit distinguishable patterns of activation. Regions involved in processing hierarchical aspects of sentence perception were identified by contrasting sentences with scrambled sentences, revealing a bilateral temporal lobe network. Music perception showed no overlap whatsoever with this network. Broca's area was not robustly activated by any stimulus type. Overall, these findings suggest that basic hierarchical processing for music and speech recruits distinct cortical networks, neither of which involves Broca's area. We suggest that previous claims are based on data from tasks that tap higher-order cognitive processes, such as working memory and/or cognitive control, which can operate in both speech and music domains.
Modulation of Visually Evoked Cortical fMRI Responses by Phase of Ongoing Occipital Alpha Oscillations
Authors: Scheeringa René , Mazaheri Ali , Bojak Ingo , Norris David G. , Kleinschmidt Andreas
Published: March 2011

Using simultaneous electroencephalography as a measure of ongoing activity and functional magnetic resonance imaging (fMRI) as a measure of the stimulus-driven neural response, we examined whether the amplitude and phase of occipital alpha oscillations at the onset of a brief visual stimulus affects the amplitude of the visually evoked fMRI response. When accounting for intrinsic coupling of alpha amplitude and occipital fMRI signal by modeling and subtracting pseudo-trials, no significant effect of prestimulus alpha amplitude on the evoked fMRI response could be demonstrated. Regarding the effect of alpha phase, we found that stimuli arriving at the peak of the alpha cycle yielded a lower blood oxygenation level-dependent (BOLD) fMRI response in early visual cortex (V1/V2) than stimuli presented at the trough of the cycle. Our results therefore show that phase of occipital alpha oscillations impacts the overall strength of a visually evoked response, as indexed by the BOLD signal. This observation complements existing evidence that alpha oscillations reflect periodic variations in cortical excitability and suggests that the phase of oscillations in postsynaptic potentials can serve as a mechanism of gain control for incoming neural activity. Finally, our findings provide a putative neural basis for observations of alpha phase dependence of visual perceptual performance.
Experimental Protocols Alter Phototransduction: The Implications for Retinal Processing at Visual Threshold
Authors: Azevedo Anthony W. , Rieke Fred
Published: March 2011

Vision in dim light, when photons are scarce, requires reliable signaling of the arrival of single photons. Rod photoreceptors accomplish this task through the use of a G-protein-coupled transduction cascade that amplifies the activity of single active rhodopsin molecules. This process is one of the best understood signaling cascades in biology, yet quantitative measurements of the amplitude and kinetics of the rod's response in mice vary by a factor of ∼2 across studies. What accounts for these discrepancies? We used several experimental approaches to reconcile differences in published properties of rod responses. First, we used suction electrode recordings from single rods to compare measurements across a range of recording conditions. Second, we compared measurements of single-cell photocurrents to estimates of rod function fromin vitroelectroretinograms. Third, we assayed the health of the post-receptor retinal tissue in these different conditions. Several salient points emerge from these experiments: (1) recorded responses can be altered dramatically by how the retina is stored; (2) the kinetics of the recovery of responses to bright but not dim flashes are strongly sensitive to the extracellular concentration of magnesium; (3) experimental conditions that produce very different single-photon responses measured in single rods produce near identical derived rod responses from the electroretinogram. The dependence of rod responses on experimental conditions will be a key consideration in efforts to extract general principles of G-protein signaling from studies of phototransduction and to relate these signals to downstream mechanisms that facilitate visual sensitivity.
Action Observation Circuits in the Macaque Monkey Cortex
Authors: Nelissen Koen , Borra Elena , Gerbella Marzio , Rozzi Stefano , Luppino Giuseppe , Vanduffel Wim , Rizzolatti Giacomo , Orban Guy A.
Published: March 2011

In both monkeys and humans, the observation of actions performed by others activates cortical motor areas. An unresolved question concerns the pathways through which motor areas receive visual information describing motor acts. Using functional magnetic resonance imaging (fMRI), we mapped the macaque brain regions activated during the observation of grasping actions, focusing on the superior temporal sulcus region (STS) and the posterior parietal lobe. Monkeys viewed either videos with only the grasping hand visible or videos with the whole actor visible. Observation of both types of grasping videos activated elongated regions in the depths of both lower and upper banks of STS, as well as parietal areas PFG and anterior intraparietal (AIP). The correlation of fMRI data with connectional data showed that visual action information, encoded in the STS, is forwarded to ventral premotor cortex (F5) along two distinct functional routes. One route connects the upper bank of the STS with area PFG, which projects, in turn, to the premotor area F5c. The other connects the anterior part of the lower bank of the STS with premotor areas F5a/p via AIP. Whereas the first functional route emphasizes the agent and may relay visual information to the parieto-frontal mirror circuit involved in understanding the agent's intentions, the second route emphasizes the object of the action and may aid in understanding motor acts with respect to their immediate goal.
Inhibition of CNS Remyelination by the Presence of Semaphorin 3A
Authors: Syed Yasir A. , Hand Elisabeth , Möbius Wiebke , Zhao Chao , Hofer Matthias , Nave Klaus A. , Kotter Mark R.
Published: March 2011

Failure of oligodendrocyte precursor cell (OPC) differentiation has been recognized as the leading cause for the failure of myelin regeneration in diseases such as multiple sclerosis (MS). One explanation for the failure of OPC differentiation in MS is the presence of inhibitory molecules in demyelinated lesions. So far only a few inhibitory substrates have been identified in MS lesions. Semaphorin 3A (Sema3A), a secreted member of the semaphorin family, can act as repulsive guidance cue for neuronal and glial cells in the CNS. Recent studies suggest that Sema3A is also expressed in active MS lesions. However, the implication of Sema3A expression in MS lesions remains unclear as OPCs are commonly present in chronic demyelinated lesions. In the present study we identify Sema3A as a potent, selective, and reversible inhibitor of OPC differentiationin vitro. Furthermore, we show that administration of Sema3A into demyelinating lesions in the rat CNS results in a failure of remyelination. Our results imply an important role for Sema3A in the differentiation block occurring in MS lesions.
Membrane Voltage Fluctuations Reduce Spike Frequency Adaptation and Preserve Output Gain in CA1 Pyramidal Neurons in a High-Conductance State
Authors: Fernandez Fernando R. , Broicher Tilman , Truong Alan , White John A.
Published: March 2011

Modulating the gain of the input–output function of neurons is critical for processing of stimuli and network dynamics. Previous gain control mechanisms have suggested that voltage fluctuations play a key role in determining neuronal gainin vivo. Here we show that, under increased membrane conductance, voltage fluctuations restore Na+current and reduce spike frequency adaptation in rat hippocampal CA1 pyramidal neuronsin vitro. As a consequence, membrane voltage fluctuations produce a leftward shift in the frequency–current relationship without a change in gain, relative to an increase in conductance alone. Furthermore, we show that these changes have important implications for the integration of inhibitory inputs. Due to the ability to restore Na+current, hyperpolarizing membrane voltage fluctuations mediated by GABAA-like inputs can increase firing rate in a high-conductance state. Finally, our data show that the effects on gain and synaptic integration are mediated by voltage fluctuations within a physiologically relevant range of frequencies (10–40 Hz).
Contributions of Indirect Pathways to Visual Response Properties in Macaque Middle Temporal Area MT
Authors: Ponce Carlos R. , Hunter J. Nicholas , Pack Christopher C. , Lomber Stephen G. , Born Richard T.
Published: March 2011

The primate visual cortex exhibits a remarkable degree of interconnectivity. Each visual area receives an average of 10 to 15 inputs, many of them from cortical areas with overlapping, but not identical, functional properties. In this study, we assessed the functional significance of this anatomical parallelism to the middle temporal area (MT) of the macaque visual cortex. MT receives major feedforward inputs from areas V1, V2, and V3, but little is known about the properties of each of these pathways. We previously demonstrated that reversible inactivation of V2 and V3 causes a disproportionate degradation of tuning for binocular disparity of MT neurons, relative to direction tuning (Ponce et al., 2008). Here we show that MT neurons continued to encode speed and size information during V2/3 inactivation; however, many became significantly less responsive to fast speeds and others showed a modest decrease in surround suppression. These changes resemble previously reported effects of reducing stimulus contrast (Pack et al., 2005; Krekelberg et al., 2006), but we show here that they differ in their temporal dynamics. We find no evidence that the indirect pathways selectively target different functional regions within MT. Overall, our findings suggest that the indirect pathways to MT primarily convey modality-specific information on binocular disparity, but that they also contribute to the processing of stimuli moving at fast speeds.
Distinct Neural Substrates of Duration-Based and Beat-Based Auditory Timing
Authors: Teki Sundeep , Grube Manon , Kumar Sukhbinder , Griffiths Timothy D.
Published: March 2011

Research on interval timing strongly implicates the cerebellum and the basal ganglia as part of the timing network of the brain. Here we tested the hypothesis that the brain uses differential timing mechanisms and networks—specifically, that the cerebellum subserves the perception of the absolute duration of time intervals, whereas the basal ganglia mediate perception of time intervals relative to a regular beat. In a functional magnetic resonance imaging experiment, we asked human subjects to judge the difference in duration of two successive time intervals as a function of the preceding context of an irregular sequence of clicks (where the task relies on encoding the absolute duration of time intervals) or a regular sequence of clicks (where the regular beat provides an extra cue for relative timing). We found significant activations in an olivocerebellar network comprising the inferior olive, vermis, and deep cerebellar nuclei including the dentate nucleus during absolute, duration-based timing and a striato-thalamo-cortical network comprising the putamen, caudate nucleus, thalamus, supplementary motor area, premotor cortex, and dorsolateral prefrontal cortex during relative, beat-based timing. Our results support two distinct timing mechanisms and underlying subsystems: first, a network comprising the inferior olive and the cerebellum that acts as a precision clock to mediate absolute, duration-based timing, and second, a distinct network for relative, beat-based timing incorporating a striato-thalamo-cortical network.
Structural and Mechanistic Determinants of a Novel Site for Noncompetitive Inhibition of GluN2D-Containing NMDA Receptors
Authors: Hansen Kasper B. , Traynelis Stephen F.
Published: March 2011

NMDA receptors are ionotropic glutamate receptors that mediate excitatory synaptic transmission and have been implicated in several neurological diseases. We have evaluated the mechanism of action of a class of novel subunit-selective NMDA receptor antagonists, typified by (E)-4-(6-methoxy-2-(3-nitrostyryl)-4-oxoquinazolin-3(4H)-yl)-benzoic acid (QNZ46). We found that QNZ46 inhibits NMDA receptor function in a noncompetitive and voltage-independent manner by an unconventional mechanism that requires binding of glutamate to the GluN2 subunit, but not glycine binding to the GluN1 subunit. This dependency of antagonist association on glutamate binding to GluN2 renders these compounds nominally use-dependent, since inhibition will rely on synaptic release of glutamate. Evaluation of the structural determinants responsible for the subunit-selectivity of QNZ46 revealed that these compounds act at a new site that has not previously been described. Residues residing in the part of the agonist binding domain immediately adjacent to the transmembrane helices appear to control selectivity of QNZ46 for GluN2C- and GluN2D-containing receptors. These residues are well-positioned to sense glutamate binding to GluN2 and thus to mediate glutamate-dependent actions. This new class of noncompetitive antagonists could provide an opportunity for the development of pharmacological tools and therapeutic agents that target NMDA receptors at a new site and modulate function by a novel mechanism.
Reduced Spine Density in Specific Regions of CA1 Pyramidal Neurons in Two Transgenic Mouse Models of Alzheimer's Disease
Authors: Perez-Cruz Claudia , Nolte Marc W. , van Gaalen Marcel M. , Rustay Nathan R. , Termont Annelies , Tanghe An , Kirchhoff Frank , Ebert Ulrich
Published: March 2011

One major hallmark of Alzheimer's disease (AD) is the massive loss of synapses that occurs at an early clinical stage of the disease. In this study, we characterize alterations in spine density and the expression of synapse-associated immediate early gene Arc (activity-regulated cytoskeleton-associated protein) in the hippocampal CA1 regions of two different amyloid precursor protein (APP) transgenic mouse lines before plaque development and their connection to performance in hippocampus-dependent memory tests. The density of mushroom-type spines was reduced by 34% in the basal dendrites proximal to the soma of CA1 pyramidal neurons in 5.5-month-old Tg2576 mice, carrying the Swedish mutation, compared with wild-type littermates. A similar reduction of 42% was confirmed in the same region of 8-month-old APP/Lo mice, carrying the London mutation. In this strain, the reduction extended to the distal dendritic spines (28%), although no differences were found in apical dendrites in either transgenic mouse line. Both transgenic mice lines presented a significant increase in Arc protein expression in CA1 compared with controls, suggesting rather an overactivity and increased spine turnover that was supported by a significant decrease in number of somatostatin-immunopositive inhibitory interneurons in the stratum oriens of CA1. Behaviorally, the transgenic mice showed decrease freezing in the fear contextual conditioning test and impairment in spatial memory assessed by Morris water maze test. These data indicate that cognitive impairment in APP transgenic mice is correlated with impairment of synaptic connectivity in hippocampal CA1, probably attributable to loss of inhibitory interneurons and subsequent hyperactivity.
Cross-Modal Phase Reset Predicts Auditory Task Performance in Humans
Authors: Thorne Jeremy D. , De Vos Maarten , Viola Filipa Campos , Debener Stefan
Published: March 2011

In the multisensory environment, inputs to each sensory modality are rarely independent. Sounds often follow a visible action or event. Here we present behaviorally relevant evidence from the human EEG that visual input prepares the auditory system for subsequent auditory processing by resetting the phase of neuronal oscillatory activity in auditory cortex. Subjects performed a simple auditory frequency discrimination task using paired but asynchronous auditory and visual stimuli. Auditory cortex activity was modeled from the scalp-recorded EEG using spatiotemporal dipole source analysis. Phase resetting activity was assessed using time–frequency analysis of the source waveforms. Significant cross-modal phase resetting was observed in auditory cortex at low alpha frequencies (8–10 Hz) peaking 80 ms after auditory onset, at high alpha frequencies (10–12 Hz) peaking at 88 ms, and at high theta frequencies (∼7 Hz) peaking at 156 ms. Importantly, significant effects were only evident when visual input preceded auditory by between 30 and 75 ms. Behaviorally, cross-modal phase resetting accounted for 18% of the variability in response speed in the auditory task, with stronger resetting overall leading to significantly faster responses. A direct link was thus shown between visual-induced modulations of auditory cortex activity and performance in an auditory task. The results are consistent with a model in which the efficiency of auditory processing is improved when natural associations between visual and auditory inputs allow one input to reliably predict the next.
Depolarization-Induced Suppression of Spontaneous Release in the Avian Midbrain
Authors: Penzo Mario Alexander , Peña José Luis
Published: March 2011

Spontaneous neurotransmitter release has been considered synaptic noise for decades. Recent work, however, suggests that synaptic events arising from action potential (AP)-independent neurotransmitter release contribute to synaptic function in a manner qualitatively different from AP-dependent release. We investigated the effect of somatic depolarization on spontaneous neurotransmitter release in neurons of the external portion (EX) of the chicken inferior colliculus. We found this manipulation affects spontaneous but not AP-dependent release onto EX neurons in a retrograde manner. This depolarization-induced suppression of spontaneous release requires activation of NMDA receptors on the presynaptic cell and postsynaptic calcium-dependent vesicle fusion. These results show a novel form of plasticity that allows the postsynaptic cell to selectively modulate spontaneous neurotransmitter release of its afferent inputs.
Calcitonin Gene-Related Peptide-Mediated Enhancement of Purinergic Neuron/Glia Communication by the Algogenic Factor Bradykinin in Mouse Trigeminal Ganglia from Wild-Type and R192Q Cav2.1 Knock-In Mice: Implications for Basic Mechanisms of Migraine Pain
Authors: Ceruti Stefania , Villa Giovanni , Fumagalli Marta , Colombo Laura , Magni Giulia , Zanardelli Matteo , Fabbretti Elsa , Verderio Claudia , van den Maagdenberg Arn M. J. M. , Nistri Andrea , Abbracchio Maria P.
Published: March 2011

Within the trigeminal ganglion, crosstalk between neurons and satellite glial cells (SGCs) contributes to neuronal sensitization and transduction of painful stimuli, including migraine pain, at least partly through activation of purinergic receptor mechanisms. We previously showed that the algogenic mediator bradykinin (BK) potentiates purinergic P2Y receptors on SGCs in primary trigeminal cultures. Our present study investigated the molecular basis of this effect in wild-type (WT) mice and CaV2.1 α1 R192Q mutant knock-in (KI) mice expressing a human mutation causing familial hemiplegic migraine type 1. Single-cell calcium imaging of WT cultures revealed functional BK receptors in neurons only, suggesting a paracrine action by BK to release a soluble mediator responsible for its effects on SGCs. We identified this mediator as the neuropeptide calcitonin gene-related peptide (CGRP), whose levels were markedly increased by BK, while the CGRP antagonist CGRP8-37and the anti-migraine drug sumatriptan inhibited BK actions. Unlike CGRP, BK was ineffective in neuron-free SGC cultures, confirming the CGRP neuronal source. P2Y receptor potentiation induced by CGRP in SGCs was mediated via activation of the extracellular signal-regulated kinase 1/2 pathways, and after exposure to CGRP, a significant release of several cytokines was detected. Interestingly, both basal and BK-stimulated CGRP release was higher in KI mouse cultures, where BK significantly upregulated the number of SGCs showing functional UTP-sensitive P2Y receptors. Our findings suggest that P2Y receptors on glial cells might be considered as novel players in the cellular processes underlying migraine pathophysiology and might represent new targets for the development of innovative therapeutic agents against migraine pain.
Interleukin-1α and HMGB1 Mediate Hippocampal Dysfunction in SIGIRR-Deficient Mice
Authors: Costello Derek A. , Watson Melanie B. , Cowley Thelma R. , Murphy Niamh , Murphy Royal Ciarán , Garlanda Cecilia , Lynch Marina A.
Published: March 2011

Single-Ig-interleukin-1 related receptor (SIGIRR) is a member of the interleukin (IL)-1/Toll-like receptor (TLR) family. It negatively regulates inflammation, rendering SIGIRR−/−mice more susceptible to inflammatory challenge. This susceptibility extends to the brain, where increased responsiveness to lipopolysaccharide has been observed in SIGIRR-deficient mice. While this is likely due to enhanced TLR4-mediated signaling, the functional consequences of these changes have not yet been described. In the current study, we have investigated the impact of SIGIRR deficiency on hippocampal function, and show that novel object recognition, spatial reference memory, and long-term potentiation (LTP) were impaired in SIGIRR−/−mice. These changes were accompanied by increased expression of IL-1RI and TLR4, and upregulation of their downstream signaling events, namely IRAK1 (IL-1R-associated kinase 1), c-Jun N-terminal protein kinase (JNK), and nuclear factor κB (NF-κB). The deficit in LTP was attenuated by the endogenous IL-1 receptor antagonist (IL-1ra) and an anti-TLR4 antibody, and also by inhibition of JNK and NF-κB. We propose that IL-1RI is activated by IL-1α and TLR4 is activated by the endogenous agonist, high mobility group box 1 (HMGB1), as we identified enhanced expression of both cytokines in the hippocampus of SIGIRR−/−mice. Additionally, application of HMGB1 increased the activation of JNK and NF-κB and was found to be detrimental to LTP in a TLR4-dependent manner. These findings highlight the functional role of SIGIRR in regulating inflammatory-mediated synaptic and cognitive decline, and describe evidence of the key role of HMGB1 in this process.
Zur frühen Entwicklung der tschechischen Elegie
Authors: Ibler Reinhard
Published: March 2011

The poetry of Karel Hynek Mácha, the main representative of Czech romanticism, is written in a deeply elegiac mode, thus standing opposite to the literary production of Czech National Revival with its clear tendency to the idyllic model. Mácha’s elegism was, first of all, influenced by German, English, and Polish romanticism, but has its roots also in the poetry of early Czech National Revival. The paper follows the beginnings and early development of Czech elegy from Thám’s and Puchmajer’s almanacs up to František Turinský’s sentimental elegies and Jan Kollár’s endeavours for a national elegy.
Manifestation der Poetik: Osip Mandel’štams „Razgovor o Dante“ als literarisches Kunstwerk und poetologischer Essay
Authors: Burghardt Anja
Published: March 2011

This paper investigates Mandel’shtam’s „Разговор о Данте“ both as a piece of literature and as a poetological work. It is argued that the structure of the text allows for an insight in some of the rather abstract notions, first and foremost the notion of “poetical matter” (“poeticheskaia materiia”). Mandel’shtam’s idiosyncratic discussion of Dante’s “Divine comedy”, it is argued, highlights the way in which reality leaves its traits or rather is integrated in a literary text in such a way that it can be brought to life again, at least by an active reader. Apart from the interplay between reality and poetry, the text’s imagery opens a deeper understanding of Mandel’shtam’s poetics in his later poems, i. e. the poems of the 1930s.
Juliusz Słowackis Drama „Mazepa“ im ukrainischen und russischen Kontext
Authors: Woldan Alois
Published: March 2011

Juliusz Słowacki’s play “Mazepa” (1840) does not have much in common with the famous Mazepa-texts of World literature, such as G. Byron’s “Mazeppa” (1819), V. Hugo’s poem of the same title (1829) and A. Pushkin’s “Poltava” (1829); and it does not show any greater affinities to the author’s earlier plays, like “Balladyna” and “Lilla Weneda”, or to his later plays like “Ksiądz Marek” and “Sen srebrny Salomei”. Ne­vertheless, for a better understanding of his “Mazepa”, this play should to be read in a larger context, including as well Słowacki’s own works, as well the texts of World literature on Mazepa.

A crucial question for that kind of contextualization is a new understanding of the central problem of that play. If we read “Mazepa” as a tragedy of delusion, defraud and betrayal, we can very well compare this play with Słowacki’s later works “Ksiądz Marek” and “Sen srebrny Salomei”, which are – still more than “Mazepa” – located in the historical context of the Polish-Ukrainian conflict.

But this kind of interpretation leads to a wider range of comparison: Pushkin’s “Poltava” does not only have a similar constellation of acting persons like Słowacki’s plays (a double love triangle), but is based on delusion and betrayal in various forms, too. There is, however one great difference when comparing it with Słowacki’s “Mazepa”: in this play the main hero is not at trickster at all, while in Pushkin’s poem he is the one who betrays in private as well as in political life an therefore has to fail. Słowacki’s Mazepa survives, because he is an honest man, Pushkin’s Mazepa perishes, because he is a traitor. It turns out that both of the authors, Słowacki and Pushkin, in connection with the historical person of Mazepa, seem to condemn betrayal as a means of political agitation. Setting Słowacki’s play in the larger context of Eastern Slavonic Mazepa-tradition, it is to be seen as a polemic with as well as an affirmation of Pushkin’s point of view, without any regard to the fact if Słowacki had known “Poltava” or not.
‚Giftige Früchte der Mutterschaft‘ in der kroatischen Frauenliteratur der ersten Hälfte des 20. Jahrhunderts
Authors: Grubišić Pulišelić Eldi , Kabić Slavija
Published: March 2011

The article analyses the strategies used by Croatian female authors for writing about the myth of motherhood in the first half of the 20th century. The focus is on the representative literary works and relations between traditional role expectations and attempts to offer alternative models for women’s lives. The paper also deals with the problem of female identity marked by the masculine domination and social repression in the patriar­chal culture. The female writers’ underlying issues are discussed on the basis of a combination of close tex­tual reading and topic-based analysis. In the conclusion, the paper emphasizes the brave criticism of the myth of motherhood as one of the main characteristics of the Croatian female authors’ writings in the first half of the 20th century.
The perfect-like construction in colloquial Polish
Authors: Sawicki Lea
Published: March 2011

The paper presents the periphrastic construction comprising the verb mieć ‘to have’ and a passive participle. The construction has been recently spreading in colloquial Polish, broadening its employment to include passive participles of imperfective and intransitive verbs. Although formally resembling the periphrastic perfect in European languages, the construction does not constitute an emerging new term of the tense opposition; rather it is a means to indicate the subject of mieć as affected by the action or process stated by the passive participle, irrespective of the identity of the agent of this action or process.
Der Größenfaktor im deutsch-slavischen Sprachkontakt (am Beispiel des Nieder- und Obersorbischen, Burgenlandkroatischen, Slovenischen, Čechischen und Polnischen)
Authors: Rabus Achim
Published: March 2011

The present study is concerned with contact-induced German–Slavic linguistic transfer occurring in several Slavic languages. It investigates the relevance of the so-called size factor which implies that the amount of transfer depends on the size of the speakers’ community. The central hypothesis the paper calls into question is, thus, as follows: the smaller the community, the greater the amount of linguistic transfer. After analyzing several linguistic variables (modals, definite article, habeo-factum constructions, dual), it is found that direct correlation between the size of the speakers’ community and the amount of linguistic transfer cannot be confirmed. A reason for varying amounts of transfer might, however, be the role of purism which, on its part, seems to be dependent on the size factor, at least to a certain degree.
Serbian-Type Features in the Curzon Gospel
Authors: Vakareliyska Cynthia M.
Published: March 2011

The article identifies orthographic, lexical and textual Serbisms in the western Bulgarian Curzon Gospel (c. 1354) and proposes three plasts of Serbian influence on the manuscript: Serbian-type spellings of specific words traceable to the hypothetical common ancestor for the Curzon Gospel and its two close relatives, the western Bulgarian Dobrejšo and Banica gospels; sporadic Serbian orthographic and lexical features, and textual parallels with Serbian long lectionary gospels, in the Curzon Gospel’s independent first half of Matthew; and sporadic Serbian-type orthographic features, and hypercorrections of perceived Serbian spellings found in the Curzon Gospel alone that were transmitted from its immediate antigraph.
Buchbesprechungen
Authors: Bruns Thomas
Published: March 2011

Boeckh, Katrin, Serbien  Montenegro. Geschichte und Gegenwart. Regensburg: Verlag Friedrich Pustet; Südosteuropa-Gesellschaft München, 2009.
Association Genetics of Wood Physical Traits in the Conifer White Spruce and Relationships With Gene Expression
Authors: Beaulieu Jean , Doerksen Trevor , Boyle Brian , Clément Sébastien , Deslauriers Marie , Beauseigle Stéphanie , Blais Sylvie , Poulin Pier-Luc , Lenz Patrick , Caron Sébastien , Rigault Philippe , Bicho Paul , Bousquet Jean , MacKay John
Published: March 2011

Marker-assisted selection holds promise for highly influencing tree breeding, especially for wood traits, by considerably reducing breeding cycles and increasing selection accuracy. In this study, we used a candidate gene approach to test for associations between 944 single-nucleotide polymorphism markers from 549 candidate genes and 25 wood quality traits in white spruce. A mixed-linear model approach, including a weak but nonsignificant population structure, was implemented for each marker–trait combination. Relatedness among individuals was controlled using a kinship matrix estimated either from the known half-sib structure or from the markers. Both additive and dominance effect models were tested. Between 8 and 21 single-nucleotide polymorphisms (SNPs) were found to be significantly associated (P ≤ 0.01) with each of earlywood, latewood, or total wood traits. After controlling for multiple testing (Q ≤ 0.10), 13 SNPs were still significant across as many genes belonging to different families, each accounting for between 3 and 5% of the phenotypic variance in 10 wood characters. Transcript accumulation was determined for genes containing SNPs associated with these traits. Significantly different transcript levels (P ≤ 0.05) were found among the SNP genotypes of a 1-aminocyclopropane-1-carboxylate oxidase, a β-tonoplast intrinsic protein, and a long-chain acyl-CoA synthetase 9. These results should contribute toward the development of efficient marker-assisted selection in an economically important tree species.
Identification of the Pr1 Gene Product Completes the Anthocyanin Biosynthesis Pathway of Maize
Authors: Sharma Mandeep , Cortes-Cruz Moises , Ahern Kevin R , McMullen Michael , Brutnell Thomas P , Chopra Surinder
Published: March 2011

In maize, mutations in the pr1 locus lead to the accumulation of pelargonidin (red) rather than cyanidin (purple) pigments in aleurone cells where the anthocyanin biosynthetic pathway is active. We characterized pr1 mutation and isolated a putative F3′H encoding gene (Zmf3′h1) and showed by segregation analysis that the red kernel phenotype is linked to this gene. Genetic mapping using SNP markers confirms its position on chromosome 5L. Furthermore, genetic complementation experiments using a CaMV 35S::ZmF3′H1 promoter–gene construct established that the encoded protein product was sufficient to perform a 3′-hydroxylation reaction. The Zmf3′h1-specific transcripts were detected in floral and vegetative tissues of Pr1 plants and were absent in pr1. Four pr1 alleles were characterized: two carry a 24 TA dinucleotide repeat insertion in the 5′-upstream promoter region, a third has a 17-bp deletion near the TATA box, and a fourth contains a Ds insertion in exon1. Genetic and transcription assays demonstrated that the pr1 gene is under the regulatory control of anthocyanin transcription factors red1 and colorless1. The cloning and characterization of pr1 completes the molecular identification of all genes encoding structural enzymes of the anthocyanin pathway of maize.
Role of Omeprazole Dosage and Cytochrome P450 2C19 Genotype in Patients Receiving Omeprazole‐Amoxicillin Dual Therapy for Helicobacter pylori Eradication
Authors: Yang Jyh‐Chin , Wang Hong‐Long , Chern Herng‐Der , Shun Chia‐Tung , Lin Bor‐Ru , Lin Chun‐Jung , Wang Teh‐Hong
Published: March 2011

Study Objective. To determine the factors that may influence Helicobacter pylori eradication in patients receiving omeprazole‐amoxicillin dual therapy.

Design. Prospective, randomized study.

Setting. University‐affiliated hospital in Taiwan.

Patients. A total of 128 adults (age range 20–75 yrs) with H. pylori‐positive duodenal ulcer were enrolled; 121 completed the final evaluation.

Intervention. Patients were randomly assigned to one of four omeprazole‐amoxicillin treatment groups, with each treatment administered for 2 weeks: O2A2 group (33 patients)—omeprazole 20 mg twice/day plus amoxicillin 500 mg 4 times/day; O2A1 group (32 patients)—omeprazole 20 mg twice/day plus amoxicillin 250 mg 4 times/day; O1A2 group (32 patients)—omeprazole 20 mg once/day plus amoxicillin 500 mg 4 times/day; and O1A1 group (31 patients)—omeprazole 20 mg once/day plus amoxicillin 250 mg 4 times/day

Measurements and Main Results. Data were collected on H. pylori status, histologic parameters, antibiotic resistance, intragastric pH, cytochrome P450 (CYP) 2C19 genotype, and adverse reactions. The intent‐to‐treat cure rates (95% confidence interval [CI]) in groups O2A2, O2A1, O1A2, and O1A1 were 76% (95% CI 59–87%), 72% (95% CI 54–84%), 50% (95% CI 34–66%) and 52% (95% CI 35–68%), respectively. Eradication of H pylori infection was statistically significantly dependent on omeprazole dosage, CYP2C19 genotype, age, gastritis status, and H. pylori density. All CYP2C19 poor metabolizers were cured, whereas the H pylori cure rate in CYP2C19 extensive metabolizers varied from 44–76% in the different treatment groups. Eradication of H. pylori was favored in the omeprazole higher dose groups versus the lower dose groups (79% vs 53%, p=0.004). No secondary antibiotic resistance was found. Thirty‐seven (95%) of 39 patients who failed with the initial treatment were cured by subsequent antibiotic susceptibility‐driven proton pump inhibitor‐based triple therapy.

Conclusion. Provided a maintenance dose of amoxicillin is given every 6 hours, eradication of H pylori infection was significantly dependent on omeprazole dosage, CYP2C19 genotype, age, gastritis status, and H pylori density.
Clinical Implications of the Nelfinavir‐Proton Pump Inhibitor Drug Interaction in Patients with Human Immunodeficiency Virus
Authors: Saberi Parya , Ranatunga Dilrini K. , Quesenberry Charles P. , Silverberg Michael J.
Published: March 2011

Study Objective. To determine if the concomitant use of nelfinavir and proton pump inhibitors (PPIs) in patients with human immunodeficiency virus (HIV) infection results in the loss of virologic control.

Design. Retrospective cohort study.

Data Source. Pharmacy, laboratory, and administrative databases of a large integrated health care system in northern California.

Patients. A total of 1147 HIV‐positive adults who started nelfinavir therapy between November 1, 1998, and June 20, 2003; within this cohort, 141 patients (12.3%) were also prescribed PPIs.

Measurements and Main Results. The effects on two virologic outcomes—achievement of undetectable HIV viral load and subsequent virologic rebound—were compared between patients receiving nelfinavir alone and those receiving nelfinavir with PPIs. Cox proportional hazards models were used, with adjustments for age, sex, race, HIV risk factors, hepatitis B or C coinfection, and other concurrent drugs known to affect the metabolism of nelfinavir. The use of PPIs had little effect on the ability to achieve an undetectable HIV viral load (adjusted hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.58–1.19, p=0.29), but there was an approximate 50% increased risk of virologic rebound with the concurrent use of PPIs (adjusted HR 1.53, 95% CI 1.06–2.19, p=0.02). Short‐term use of PPIs (defined as within 30 days of initial PPI dispensation) was not associated with increased risk of virologic rebound (HR 1.07, 95% CI 0.26–4.41, p=0.93) compared with no use of PPIs.

Conclusion. Use of PPIs should be minimized or avoided in patients who have attained an undetectable HIV viral load while taking a nelfinavir‐based antiretroviral regimen. However, concomitant use of these drugs may be acceptable for indications where PPIs are required for fewer than 30 days.
Ultrasound Visualization of Ingested Tablets: A Pilot Study
Authors: Nordt Sean Patrick , Campbell Colleen , Medak Anthony , Tomaszweski Christian , Clark Richard F.
Published: March 2011

Study Objective. To evaluate the ability of ultrasonography as a radiographic technique to visualize ingested tablets in the human stomach.

Design. Prospective, ultrasonographer‐blinded, pilot study.

Setting. Tertiary care medical center.

Subjects. Fifteen healthy adults (12 male, 3 female; mean age 35.5 yrs).

Intervention. After fasting for at least 12 hours, subjects were randomized to either ingest a total of 10 tablets (four acetaminophen, four ibuprofen, and two multivitamin tablets) with 500 ml of water or to drink 500 ml of water alone (control group).

Measurements and Main Results. Nine subjects were randomized to the group taking the tablets and six to the control group. Within 30 minutes after ingesting the tablets with water or the water alone, each subject underwent ultrasonography 2 times by two respective blinded ultrasono‐graphers (emergency department physicians who were experienced with the ultrasound technique). Each performed the radiographic technique in isolation of the other ultrasonographer so as not to influence each other's interpretation. They recorded whether or not they thought tablets were visible. One ultrasonographer was correct for 14 (93%) of the 15 subjects, but the other ultrasonographer was correct for only 6 subjects (40%). Interobserver agreement was assessed, with no agreement found between the two ultrasonographers (Cohen κ coefficient ‐0.25 [95% confidence interval ‐0.7–0.2]). The ultrasonographers also found six false positives (no drugs present in the stomach but incorrectly identified as present by the ultrasonographer) and four false negatives (tablets present in the stomach but not identified by the ultrasonographer).

Conclusion. Our results do not support the application of ultrasonography to determine the presence or absence of tablets in an individual's stomach after an acute poisonings. We did show that, similar to other radiologic techniques (e. g., projection radiography), the absence of tablet visualization does not exclude their presence. However, the ultrasonographers also found several false positives. Thus, further studies are needed with larger numbers of both subjects and ultrasonographers to elucidate the potential benefit of ultrasonography in individuals who experience acute poisoning.