bluuebunny/crossref_metadata_2025 huggingface dataset:
“First Pain” in Humans: Convergent and Specific Forebrain Responses
Authors: Matre Dagfinn A , Hernandez-Garcia Luis , Tran Tuan D , Casey Kenneth L
Published: November 2010

Background:

Brief heat stimuli that excite nociceptors innervated by finely myelinated (Aδ) fibers evoke an initial, sharp, well-localized pain (“first pain”) that is distinguishable from the delayed, less intense, more prolonged dull pain attributed to nociceptors innervated by unmyelinated (C) fibers (“second pain”). In the present study, we address the question of whether a brief, noxious heat stimulus that excites cutaneous Aδ fibers activates a distinct set of forebrain structures preferentially in addition to those with similar responses to converging input from C fibers. Heat stimuli at two temperatures were applied to the dorsum of the left hand of healthy volunteers in a functional brain imaging (fMRI) paradigm and responses analyzed in a set of volumes of interest (VOI).

Results:

Brief 41°C stimuli were painless and evoked only C fiber responses, but 51°C stimuli were at pain threshold and preferentially evoked Aδ fiber responses. Most VOI responded to both intensities of stimulation. However, within volumes of interest, a contrast analysis and comparison of BOLD response latencies showed that the bilateral anterior insulae, the contralateral hippocampus, and the ipsilateral posterior insula were preferentially activated by painful heat stimulation that excited Aδ fibers.

Conclusions:

These findings show that two sets of forebrain structures mediate the initial sharp pain evoked by brief cutaneous heat stimulation: those responding preferentially to the brief stimulation of Aδ heat nociceptors and those with similar responses to converging inputs from the painless stimulation of C fibers. Our results suggest a unique and specific physiological basis, at the forebrain level, for the “first pain” sensation that has long been attributed to Aδ fiber stimulation and support the concept that both specific and convergent mechanisms act concurrently to mediate pain.
The QUIT-PRIMO provider-patient Internet-delivered smoking cessation referral intervention: a cluster-randomized comparative effectiveness trial: study protocol
Authors: Houston Thomas K , Sadasivam Rajani S , Ford Daniel E , Richman Joshua , Ray Midge N , Allison Jeroan J
Published: November 2010

Background

Although screening for tobacco use is increasing with electronic health records and standard protocols, other tobacco-control activities, such as referral of patients to cessation resources, is quite low. In the QUIT-PRIMO study, an online referral portal will allow providers to enter smokers' email addresses into the system. Upon returning home, the smokers will receive automated emails providing education about tobacco cessation and encouragement to use the patient smoking cessation website (with interactive tools, educational resources, motivational email messages, secure messaging with a tobacco treatment specialist, and online support group).

Methods

The informatics system will be evaluated in a comparative effectiveness trial of 160 community-based primary care practices, cluster-randomized at the practice level. In the QUIT-PRIMO intervention, patients will be provided a paper information-prescription referral and then "e-referred" to the system. In the comparison group, patients will receive only the paper-based information-prescription referral with the website address. Once patients go to the website, they are subsequently randomized within practices to either a standard patient smoking cessation website or an augmented version with access to a tobacco treatment specialist online, motivational emails, and an online support group. We will compare intervention and control practice participation (referral rates) and patient participation (proportion referred who go to the website). We will then compare the effectiveness of the standard and augmented patient websites.

Discussion

Our goal is to evaluate an integrated informatics solution to increase access to web-delivered smoking cessation support. We will analyze the impact of this integrated system in terms of process (provider e-referral and patient login) and patient outcomes (six-month smoking cessation).

Trial Registration

Web-delivered Provider Intervention for Tobacco Control (QUIT-PRIMO) - a randomized controlled trial: NCT00797628.
Does left atrial volume affect exercise capacity of heart transplant recipients?
Authors: Abdul-Waheed Mohammad , Yousuf Mian , Kelly Stephanie J , Arena Ross , Ying Jun , Naz Tehmina , Dunlap Stephanie H , Shizukuda Yukitaka
Published: November 2010

Background

Heart transplant (HT) recipients demonstrate limited exercise capacity compared to normal patients, very likely for multiple reasons. In this study we hypothesized that left atrial volume (LAV), which is known to predict exercise capacity in patients with various cardiac pathologies including heart failure and hypertrophic cardiomyopathy is associated with limited exercise capacity of HT recipients.

Methods

We analyzed 50 patients [age 57 ±2 (SEM), 12 females] who had a post-HT echocardiography and cardiopulmonary exercise test (CPX) within 9 weeks time at clinic follow up. The change in LAV (ΔLAV) was also computed as the difference in LAV from the preceding one-year to the study echocardiogram. Correlations among the measured parameters were assessed with a Pearson's correlation analysis.

Results

LAV (n = 50) and ΔLAV (n = 40) indexed to body surface area were 40.6 ± 11.5 ml·m-2 and 1.9 ± 8.5 ml·m-2·year-1, data are mean ± SD, respectively. Indexed LAV and ΔLAV were both significantly correlated with the ventilatory efficiency, assessed by the VE/VCO2 slope (r = 0.300, p = 0.038; r = 0.484, p = 0.002, respectively). LAV showed a significant correlation with peak oxygen consumption (r = -0.328, p = 0.020).

Conclusions

Although our study is limited by a retrospective study design and relatively small number of patients, our findings suggest that enlarged LAV and increasing change in LAV is associated with the diminished exercise capacity in HT recipients and warrants further investigation to better elucidate this relationship.
Sleeping Beauty, Countable Additivity, and Rational Dilemmas
Authors: Ross Jacob
Published: November 2010

This essay argues that there is a conflict between the principle of Countable Additivity and standard views of how we should update centered or de se beliefs. The latter views, this essay argues, entail a general principle, which the essay calls the Generalized Thirder Principle, that conflicts with the principle of Countable Additivity. The essay then argues that the most plausible response to the conflict between these principles is to maintain that they are both valid and that, when an agent cannot satisfy them both, he or she is faced with a rational dilemma.

The essay is divided into five sections. In section 1, it generalizes the one-half and one-third solutions to the Sleeping Beauty problem. In section 2, it argues that while the Generalized Halfer Principle is compatible with Countable Additivity (CA), the Generalized Thirder Principle (GTP) is not. In section 3, it argues that thirders are committed to the GTP since it follows from the premises that underlie each of the main arguments for the one-third solution. In section 4, it discusses the relevance of Dutch book arguments to the conflict between CA and the GTP. And the essay argues that both synchronic and diachronic Dutch book arguments give greater support to CA than to the GTP. In the final section, the essay considers the possible responses to the conflict between CA and the GTP and argues that the most plausible response is to acknowledge the possibility of rational dilemmas.
Kant's First Paralogism
Authors: Proops Ian
Published: November 2010

In the chapter of the Critique of Pure Reason entitled “The Paralogisms of Pure Reason” Kant seeks to explain how rationalist philosophers, including thinkers of the caliber of Descartes and Leibniz, could have arrived at what he considers to be certain erroneous, “dogmatic” conclusions about the nature of the self or soul. His diagnosis has two main components: first, the positing of “Transcendental Illusion”—a pervasive intellectual illusion, modeled on perceptual illusion, which predisposes us to accept as sound certain invalid arguments for substantive theses about the nature of the soul; second, the identification of the relevant fallacies. This essay examines Kant's account in the First Paralogism of how these two elements combine to produce the doctrine that the soul is a substance. It is argued that Kant has a novel, ingenious—and even somewhat plausible—account of how the rational psychologist might arrive at such a view. It is further argued that the source of the fallacy in the first paralogism is a confusion about the very nature of conceivability and that, in identifying this confusion, Kant makes a philosophical contribution of lasting value.
Kant's Theory of Causation and Its Eighteenth-Century German Background: Eric Watkins (ed. and Trans.), Kant's ''Critique of Pure Reason'': Background Source Materials and Eric Watkins, Kant and the Metaphysics of Causality
Authors: Chignell Andrew , Pereboom Derk
Published: November 2010

This essay highlights the important contributions Watkins's books have made to our understanding of theories about causation developed in eighteenth-century German philosophy and by Kant in particular. Watkins provides a convincing argument that central to Kant's theory of causation is the notion of a real ground or causal power that is non-Humean (since it doesn't reduce to regularities or counterfactual dependencies among events or states) and non-Leibnizean because it doesn't reduce to logical or conceptual relations. However, we raise questions about Watkins's more specific claims that Kant completely rejects a model on which the first relatum of a phenomenal causal relation is an event and that he maintains that real grounds are metaphysically and not just epistemically indeterminate.
Adaptor protein XB130 is a Rac-controlled component of lamellipodia that regulates cell motility and invasion
Authors: Lodyga Monika , Bai Xiao-hui , Kapus András , Liu Mingyao
Published: November 2010

XB130 is a newly described cytosolic adaptor protein and tyrosine kinase substrate, involved in Src- and RET/PTC-dependent signaling. Although XB130 has been cloned as a homologue of actin-filament-associated protein (AFAP-110), its potential regulation by the actin skeleton and its putative roles in cytoskeleton regulation have not been addressed. Here, we show that XB130 (in contrast to AFAP-110) exhibited robust translocation to the cell periphery in response to various stimuli (including epidermal growth factor, wounding and expression of constitutively active Rac) that elicit lamellipodium formation. In stimulated cells, XB130 localized to the lamellipodial F-actin meshwork. Genetic and pharmacological data suggest that the key trigger for XB130 recruitment is the formation of the branched F-actin itself. Structure-function analysis revealed that both the XB130 N-terminus (167 amino acids) and C-terminus (63 amino acids) harbor crucial regions for its translocation to lamellipodia, whereas the PH domains and Src-targeted tyrosines are dispensable. Importantly, in TPC1 thyroid papillary carcinoma cells, silencing endogenous XB130 decreased the rate of wound closure, inhibited matrigel invasion, reduced lamellipodial persistence and slowed down spreading. Thus, XB130 is a novel Rac- and cytoskeleton-regulated and cytoskeleton-regulating adaptor protein that exhibits high affinity to lamellipodial (branched) F-actin and impacts motility and invasiveness of tumor cells.
IKKα controls canonical TGFβ–SMAD signaling to regulate genes expressing SNAIL and SLUG during EMT in Panc1 cells
Authors: Brandl Martina , Seidler Barbara , Haller Ferdinand , Adamski Jerzy , Schmid Roland M. , Saur Dieter , Schneider Günter
Published: November 2010

The epithelial to mesenchymal transition (EMT) is a crucial step in tumor progression, and the TGFβ–SMAD signaling pathway is an inductor of EMT in many tumor types. One hallmark of EMT is downregulation of the adherens junction protein E-cadherin, a process mediated by transcription factors such as the zinc fingers SNAIL and SLUG. Here, we report that the catalytic IκB kinase (IKK) subunit IKKα is necessary for the silencing of E-cadherin in a Panc1 cell model of TGFβ–SMAD-mediated EMT, independently of NFκB. IKKα regulates canonical TGFβ–SMAD signaling by interacting with SMAD3 and controlling SMAD complex formation on DNA. Furthermore, we demonstrate that the TGFβ–IKKα–SMAD signaling pathway induces transcription of the genes encoding SNAIL and SLUG. In addition, we demonstrate that IKKα also modulates canonical TGFβ–SMAD signaling in human MDA-MB231 breast cancer cells, arguing for a more general impact of IKKα on the control of TGFβ–SMAD signaling. Taken together, these findings indicate that IKKα contributes to the tumor-promoting function of the TGFβ–SMAD signaling pathway in particular cancers.
PI3KC2α, a class II PI3K, is required for dynamin-independent internalization pathways
Authors: Krag Claudia , Malmberg Emily Kim , Salcini Anna Elisabetta
Published: November 2010

Increasing evidence indicates that cellular uptake of several molecules can occur independently of functional dynamin, but the molecular players that regulate dynamin-independent endocytosis and the subsequent trafficking steps are still largely unknown. A survival-based short-hairpin (sh) RNA screen using a cell line expressing a diphtheria toxin receptor (DTR, officially known as HBEGF) anchored to GPI (DTR–GPI), which internalizes diphtheria toxin (DT, officially known as DTX) in a dynamin-independent manner, identified PI3KC2α, a class II phosphoinositide 3-kinase (PI3K), as a specific regulator of dynamin-independent DT internalization. We found that the internalization of several proteins that enter the cell through dynamin-independent pathways led to a relocalization of PI3KC2α to cargo-positive vesicles. Furthermore, downregulation of PI3KC2α impaired internalization of CD59 as well as fluid-phase endocytosis. Our data suggest a general role for PI3KC2α in regulating physiologically relevant dynamin-independent internalization pathways by recruiting early endosome antigen 1 (EEA1) to vesicular compartments, a step required for the intracellular trafficking of vesicles generated by dynamin-independent endocytic pathways.
SIRT2 regulates NF-κB-dependent gene expression through deacetylation of p65 Lys310
Authors: Rothgiesser Karin M. , Erener Süheda , Waibel Susanne , Lüscher Bernhard , Hottiger Michael O.
Published: November 2010

NF-κB regulates the expression of a large number of target genes involved in the immune and inflammatory response, apoptosis, cell proliferation, differentiation and survival. In this study, we identified SIRT2 as a deacetylase of the transcription factor p65. SIRT2 is a member of the family of sirtuins, which are NAD+-dependent deacetylases involved in several cellular processes. SIRT2 interacts with p65 in the cytoplasm and deacetylates p65 in vitro and in vivo at Lys310. Moreover, p65 is hyperacetylated at Lys310 in Sirt2−/− cells after TNFα stimulation, which results in the increase in expression of a subset of p65 acetylation-dependent target genes. Our work provides evidence that p65 is deacetylated by SIRT2 in the cytoplasm to regulate the expression of specific NF-κB-dependent genes.
Heterologous expression reveals distinct enzymatic activities of two DOT1 histone methyltransferases ofTrypanosoma brucei
Authors: Frederiks Floor , van Welsem Tibor , Oudgenoeg Gideon , Heck Albert J. R. , Janzen Christian J. , van Leeuwen Fred
Published: November 2010

Dot1 is a highly conserved methyltransferase that modifies histone H3 on the nucleosome core surface. In contrast to yeast, flies, and humans where a single Dot1 enzyme is responsible for all methylation of H3 lysine 79 (H3K79), African trypanosomes express two DOT1 proteins that methylate histone H3K76 (corresponding to H3K79 in other organisms) in a cell-cycle-regulated manner. Whereas DOT1A is essential for normal cell cycle progression, DOT1B is involved in differentiation and control of antigenic variation of this protozoan parasite. Analysis of DOT1A and DOT1B in trypanosomes or in vitro, to understand how H3K76 methylation is controlled during the cell cycle, is complicated by the lack of genetic tools and biochemical assays. To eliminate these problems, we developed a heterologous expression system in yeast. Whereas Trypanosoma brucei DOT1A predominantly dimethylated H3K79, DOT1B trimethylated H3K79 even in the absence of dimethylation by DOT1A. Furthermore, DOT1A activity was selectively reduced by eliminating ubiquitylation of H2B. The tail of histone H4 was not required for activity of DOT1A or DOT1B. These findings in yeast provide new insights into possible mechanisms of regulation of H3K76 methylation in Trypanosoma brucei.
The role of ubiquitylation and degradation in RhoGTPase signalling
Authors: Nethe Micha , Hordijk Peter L.
Published: November 2010

Rho-like guanosine triphosphatases (RhoGTPases) control many aspects of cellular physiology through their effects on the actin cytoskeleton and on gene transcription. Signalling by RhoGTPases is tightly coordinated and requires a series of regulatory proteins, including guanine-nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs) and guanine-nucleotide dissociation inhibitors (GDIs). GEFs and GAPs regulate GTPase cycling between the active (GTP-bound) and inactive (GDP-bound) states, whereas GDI is a cytosolic chaperone that binds inactive RhoGTPases. Like many other proteins, RhoGTPases are subject to degradation following the covalent conjugation of ubiquitin. There have been increasing indications that ubiquitylation of small GTPases occurs in a regulated fashion, primarily upon activation, and is an important means to control signalling output. Recent work has identified cellular proteins that control RasGTPase and RhoGTPase ubiquitylation and degradation, allowing us to amend the canonical model for GTPase (in)activation. Moreover, accumulating evidence for indirect regulation of GTPase function through the ubiquitylation of GTPase regulators makes this post-translational modification a key feature of GTPase-dependent signalling pathways. Here, we will discuss these recent insights into the regulation of RhoGTPase ubiquitylation and their relevance for cell signalling.
What Makes Consumers Willing to Pay a Price Premium for National Brands over Private Labels?
Authors: Steenkamp Jan-Benedict E.M. , Van Heerde Harald J. , Geyskens Inge
Published: November 2010

The growing sales of private labels (PLs) pose significant challenges for national brands (NBs) around the world. A major question is whether consumers continue to be willing to pay a price premium for NBs over PLs. Using consumer survey data from 22,623 respondents from 23 countries in Asia, Europe, and the Americas across, on average, 63 consumer packaged goods categories per country, this article studies how marketing and manufacturing factors affect the price premium a consumer is willing to pay for an NB over a PL. These effects are mediated by consumer perceptions of the quality of NBs in relation to PLs. Although the results do not bode well for NBs in the sense that willingness to pay decreases as PLs mature, the authors offer several managerial recommendations to counter this trend. In countries in which PLs are more mature, the route to success is to go back to manufacturing basics. In PL development countries, there is a stronger role for marketing to enhance the willingness to pay for NBs.
Making Products Feel Special: When Metacognitive Difficulty Enhances Evaluation
Authors: Pocheptsova Anastasiya , Labroo Aparna A. , Dhar Ravi
Published: November 2010

More than 200 studies suggest that metacognitive difficulty reduces the liking of an object. In contrast to those findings, the authors demonstrate that the effects of metacognitive experiences on evaluation are sensitive to the consumption domain. In the domain of everyday goods, metacognitive difficulty reduces the attractiveness of a product by making it appear unfamiliar. However, in the context of special-occasion products, for which consumers value exclusivity, metacognitive difficulty increases the attractiveness of a product by making it appear unique or uncommon. The authors reconcile their findings with prior research by positing that the effect of metacognitive experiences on evaluation depends on the naive theory people associate with product consumption. Four studies demonstrate the proposed effect and test for the role of lay theories in the interpretation of metacognitive experiences. The authors conclude with a discussion of theoretical and marketing implications.
Category- versus Brand-Level Advertising Messages in a Highly Regulated Environment
Authors: Kolsarici Ceren , Vakratsas Demetrios
Published: November 2010

The authors examine the dynamic effects of category- and brand-level advertising for a new pharmaceutical in a market in which regulations require that the content of these two types of advertising be mutually exclusive. Specifically, category, or generic, messages should communicate information only about the disease without promoting any brand, whereas brand-level messages should be void of any therapeutic information. This brings up two questions of great managerial importance: Which type of message is generally more effective (category or brand level), and when is one type more effective than the other? The authors pursue these questions by analyzing the effects of advertising on new and refill prescriptions through the use of an augmented Kalman filter with continuous state and discrete observations. The findings suggest the presence of complex dynamics for both types of regulation-induced advertising messages. In general, brand advertising is more effective, especially after competitive entry. Extensive validation tests confirm the superiority of the modeling approach. The authors discuss implications for managers and regulators.
Dilution and Enhancement of Celebrity Brands through Sequential Movie Releases
Authors: Luo Lan , Chen Xinlei (Jack) , Han Jeanie , Park C. Whan
Published: November 2010

This article examines the effects of sequential movie releases on the dilution and enhancement of celebrity brands. The authors use favorability ratings collected over a 12-year period (1993–2005) to capture movement in the brand equity of a panel of actors. They use a dynamic panel data model to investigate how changes of brand equity are associated with the sequence of movies featuring these actors, after controlling for the possible influence from the stars’ off-camera activities. The authors also examine the underlying factors that influence the magnitude and longevity of such effects. In contrast with findings from existing research in product branding, the authors find evidence that supports the general existence of dilution and enhancement effects on the equity of a celebrity brand through his or her movie appearances. They also find that star favorability erodes substantially over time. Finally, this research offers insights for actors regarding how to make movie selections strategically to maximize their brand equity.
We are what we Consume: The Influence of Food Consumption on Impulsive Choice
Authors: Mishra Arul , Mishra Himanshu
Published: November 2010

Consumers’ impulsive choices have traditionally been attributed either to contextual factors, such as product attributes and store environment, or to individual personality traits. In this article, the authors find that type of food consumed can also influence impulsive choice. Specifically, food that enhances the levels of the neurotransmitter serotonin can reduce impulsive choice. To test the hypotheses on the influence of serotonin on postconsumption impulsive choice, the authors collected data on the eve of Thanksgiving. The occasion of Thanksgiving dinner provides a naturalistic setting in which people consume a tryptophan-rich meal (tryptophan is a precursor to serotonin). The authors replicate these findings and obtain converging evidence in a lab setting in which they give some participants a tryptophan-rich beverage and observe their postconsumption impulsive choices.
Emotionality and Semantic Onsets: Exploring Orienting Attention Responses in Advertising
Authors: Nielsen Jesper H. , Shapiro Stewart A. , Mason Charlotte H.
Published: November 2010

Prior research on attention shifts to advertisements has focused primarily on demonstrating how perceptual features can shift attention to advertisements. In this article, the authors demonstrate that certain semantic characteristics of nonfocal advertising elements may similarly attract attention when consumers are focused on a primary task elsewhere in the visual field. In three experiments, the authors investigate how orienting attention responses to highly emotional advertising elements influence ad and brand awareness in cluttered environments. Specifically, they demonstrate that preattentive processing of the semantic information in nonfocal ad headlines can elicit orienting attention responses that result in predictable increases in ad and brand awareness.
When Good Cheer Goes Unrequited: How Emotional Receptivity Affects Evaluation of Expressed Emotion
Authors: Lee Yih Hwai , Lim Elison ai Ching
Published: November 2010

In three studies, the authors introduce and probe the role of emotional receptivity in consumer–marketer interactions. Emotional receptivity refers to a person's disposition toward experiencing a preferred level of emotional intensity. The results from the first two studies conducted in the laboratory and the field collectively demonstrate that consumers feel greater enjoyment and enhanced liking for the marketer when there is a close match between their emotional receptivity and the level of emotional intensity displayed by the marketer. In the third study, the authors show that consumers’ emotional receptivity can be temporarily increased or decreased using advertisements that depict more or less expressive social interactions, respectively. The findings are similar to those observed in the first two studies. In addition, a preliminary study establishes the discriminant validity of the proposed battery of emotional receptivity items from existing related constructs. The authors discuss the theoretical and managerial implications and offer suggestions for further research.
Subcellular Profiling Reveals Distinct and Developmentally Regulated Repertoire of Growth Cone mRNAs
Authors: Zivraj Krishna H. , Tung Yi Chun Loraine , Piper Michael , Gumy Laura , Fawcett James W. , Yeo Giles S. H. , Holt Christine E.
Published: November 2010

Cue-directed axon guidance depends partly on local translation in growth cones. Many mRNA transcripts are known to reside in developing axons, yet little is known about their subcellular distribution or, specifically, which transcripts are in growth cones. Here laser capture microdissection (LCM) was used to isolate the growth cones of retinal ganglion cell (RGC) axons of two vertebrate species, mouse andXenopus, coupled with unbiased genomewide microarray profiling. An unexpectedly large pool of mRNAs defined predominant pathways in protein synthesis, oxidative phosphorylation, cancer, neurological disease, and signaling. Comparative profiling of “young” (pathfinding) versus “old” (target-arriving)Xenopusgrowth cones revealed that the number and complexity of transcripts increases dramatically with age. Many presynaptic protein mRNAs are present exclusively in old growth cones, suggesting that functionally related sets of mRNAs are targeted to growth cones in a developmentally regulated way. Remarkably, a subset of mRNAs was significantly enriched in the growth cone compared with the axon compartment, indicating that mechanisms exist to localize mRNAs selectively to the growth cone. Furthermore, some receptor transcripts (e.g., EphB4), present exclusively in old growth cones, were equally abundant in young and old cell bodies, indicating that RNA trafficking from the soma is developmentally regulated. Our findings show that the mRNA repertoire in growth cones is regulated dynamically with age and suggest that mRNA localization is tailored to match the functional demands of the growing axon tip as it transforms into the presynaptic terminal.
ThreeDrosophilaLiprins Interact to Control Synapse Formation
Authors: Astigarraga Sergio , Hofmeyer Kerstin , Farajian Reza , Treisman Jessica E.
Published: November 2010

Liprin-α proteins are adaptors that interact with the receptor protein tyrosine phosphatase leukocyte common antigen-related (LAR) and other synaptic proteins to promote synaptic partner selection and active zone assembly. Liprin-β proteins bind to and share homology with Liprin-α proteins, but their functions at the synapse are unknown. TheDrosophilagenome encodes single Liprin-α and Liprin-β homologs, as well as a third related protein that we named Liprin-γ. We show that both Liprin-β and Liprin-γ physically interact with Liprin-α and that Liprin-γ also binds to LAR.Liprin-α mutations have been shown to disrupt synaptic target layer selection by R7 photoreceptors and to reduce the size of larval neuromuscular synapses. We have generated null mutations inLiprin-β andLiprin-γ to investigate their role in these processes. We find that, althoughLiprin-α mutant R7 axons terminate before reaching the correct target layer,Liprin-β mutant R7 axons grow beyond their target layer. Larval neuromuscular junction size is reduced in bothLiprin-α andLiprin-β mutants, and further reduced in double mutants, suggesting independent functions for these Liprins. Genetic interactions demonstrate that both Liprin proteins act through the exchange factor Trio to promote stable target selection by R7 photoreceptor axons and growth of neuromuscular synapses. Photoreceptor and neuromuscular synapses develop normally inLiprin-γ mutants; however, removingLiprin-γ improves R7 targeting inLiprin-α mutants, and restores normal neuromuscular junction size toLiprin-β mutants, suggesting that Liprin-γ counteracts the functions of the other two Liprins. We propose that context-dependent interactions between the three Liprins modulate their functions in synapse formation.
Orientation Selectivity in Rabbit Retinal Ganglion Cells Is Mediated by Presynaptic Inhibition
Authors: Venkataramani Sowmya , Taylor W. Rowland
Published: November 2010

Cells sensitive to the orientation of edges are ubiquitous in visual systems, and have been described in the vertebrate retina, yet the synaptic mechanisms that generate orientation selectivity in the retina are largely unknown. Here, we analyze the synaptic mechanisms that generate selective responses to vertically and horizontally oriented stimuli in rabbit retinal ganglion cells. The data indicate that the excitatory and inhibitory inputs to orientation-selective ganglion cells are rendered orientation selective within the presynaptic circuitry. In accordance with previous extracellular recordings, presynaptic GABAergic inhibition is critical to generate orientation selectivity, and we show that it includes lateral inhibition of glutamatergic bipolar cells and serial inhibitory connections between GABAergic and glycinergic amacrine cells. Despite very similar spiking properties, vertically and horizontally selective ganglion cells (VS-GCs and HS-GCs, respectively) show marked differences in their underlying synaptic mechanisms. Both cell types receive glutamatergic inputs via non-NMDA (AMPA/kainate) and NMDA receptors, while VS-GCs receive additional excitation mediated by glycinergic disinhibition. A striking difference between these cells is that during nonpreferred simulation, excitation is suppressed and direct glycinergic inhibition is increased in HS-GCs, whereas for VS-GCs, both excitatory and inhibitory inputs are suppressed. Thus, orientation selectivity is generated presynaptically both by modulation of bipolar cell output and by serial inhibitory connections between amacrine cells. Minimal circuit models are proposed that account for these observations.
Processing Afferent Proprioceptive Information at the Main Cuneate Nucleus of Anesthetized Cats
Authors: Leiras Roberto , Velo Patricia , Martín-Cora Francisco , Canedo Antonio
Published: November 2010

Medial lemniscal activity decreases before and during movement, suggesting prethalamic modulation, but the underlying mechanisms are largely unknown. Here we studied the mechanisms underlying proprioceptive transmission at the midventral cuneate nucleus (mvCN) of anesthetized cats using standard extracellular recordings combined with electrical stimulation and microiontophoresis. Dual simultaneous recordings from mvCN and rostroventral cuneate (rvCN) proprioceptive neurons demonstrated that microstimulation through the rvCN recording electrode induced dual effects on mvCN projection cells: potentiation when both neurons had excitatory receptive fields in muscles acting at the same joint, and inhibition when rvCN and mvCN cells had receptive fields located in different joints. GABA and/or glycine consistently abolished mvCN spontaneous and sensory-evoked activity, an effect reversed by bicuculline and strychnine, respectively; and immunohistochemistry data revealed that cells possessing strychnine-sensitive glycine receptors were uniformly distributed throughout the cuneate nucleus. It was also found that proprioceptive mvCN projection cells sent ipsilateral collaterals to the nucleus reticularis gigantocellularis and the mesencephalic locomotor region, and had slower antidromic conduction speeds than cutaneous fibers from the more dorsally located cluster region.

The data suggest that (1) the rvCN–mvCM network is functionally related to joints rather than to single muscles producing an overall potentiation of proprioceptive feedback from a moving forelimb joint while inhibiting, through GABAergic and glycinergic interneurons, deep muscular feedback from other forelimb joints; and (2) mvCN projection cells collateralizing to or through the ipsilateral reticular formation allow for bilateral spreading of ascending proprioceptive feedback information.
Lower-Frequency Event-Related Desynchronization: A Signature of Late Mismatch Responses to Sounds, Which Is Reduced or Absent in Children with Specific Language Impairment
Authors: Bishop Dorothy V. M. , Hardiman Mervyn J. , Barry Johanna G.
Published: November 2010

Poor discrimination of nonlinguistic sounds has been implicated in language-learning problems in children, but research evidence has been inconsistent. This study included 32 participants with specific language impairment (SLI) and 32 typically developing controls aged 7–16 years. Frequency discrimination thresholds were estimated in a task where participants had to distinguish a higher-frequency tone from a 1000 Hz tone. Neurophysiological responses were assessed in an oddball paradigm. Stimuli were either 1030 or 1200 Hz pure tones (deviants) presented in a series of standard 1000 Hz tones, or syllables (deviant [da] or [bi] in a series of standard /ba/). On the behavioral task, children (7- to 11-year-olds) had high thresholds, regardless of language status, but teenagers (12–16 years) with SLI had higher thresholds than their controls. Conventional analysis of electrophysiological responses showed no difference between groups for the mismatch negativity (MMN), but the late discriminative negativity (LDN) was reduced in amplitude for smaller deviants in participants with SLI. Time–frequency analysis revealed that, whereas the MMN reflected enhanced intertrial coherence in the theta frequency band, the LDN corresponded to a period of event-related desynchronization extending across a wide low-frequency band including delta, theta, and alpha. This manifested as a drop in power in those frequencies, which was marked in the controls but reduced or absent in children with SLI across all stimulus types. This provides compelling evidence for a low-level auditory perceptual impairment in SLI that affects a processing stage after initial detection of a sound change.
Counter-Regulation of Opioid Analgesia by Glial-Derived Bioactive Sphingolipids
Authors: Muscoli Carolina , Doyle Tim , Dagostino Concetta , Bryant Leesa , Chen Zhoumou , Watkins Linda R. , Ryerse Jan , Bieberich Erhard , Neumman William , Salvemini Daniela
Published: November 2010

The clinical efficacy of opiates for pain control is severely limited by analgesic tolerance and hyperalgesia. Herein we show that chronic morphine upregulates both the sphingolipid ceramide in spinal astrocytes and microglia, but not neurons, and spinal sphingosine-1-phosphate (S1P), the end-product of ceramide metabolism. Coadministering morphine with intrathecal administration of pharmacological inhibitors of ceramide and S1P blocked formation of spinal S1P and development of hyperalgesia and tolerance in rats. Our results show that spinally formed S1P signals at least in part by (1) modulating glial function because inhibiting S1P formation blocked increased formation of glial-related proinflammatory cytokines, in particular tumor necrosis factor-α, interleukin-1βα, and interleukin-6, which are known modulators of neuronal excitability, and (2) peroxynitrite-mediated posttranslational nitration and inactivation of glial-related enzymes (glutamine synthetase and the glutamate transporter) known to play critical roles in glutamate neurotransmission. Inhibitors of the ceramide metabolic pathway may have therapeutic potential as adjuncts to opiates in relieving suffering from chronic pain.
Punishing an Error Improves Learning: The Influence of Punishment Magnitude on Error-Related Neural Activity and Subsequent Learning
Authors: Hester Robert , Murphy Kevin , Brown Felicity L. , Skilleter Ashley J.
Published: November 2010

Punishing an error to shape subsequent performance is a major tenet of individual and societal level behavioral interventions. Recent work examining error-related neural activity has identified that the magnitude of activity in the posterior medial frontal cortex (pMFC) is predictive of learning from an error, whereby greater activity in this region predicts adaptive changes in future cognitive performance. It remains unclear how punishment influences error-related neural mechanisms to effect behavior change, particularly in key regions such as pMFC, which previous work has demonstrated to be insensitive to punishment. Using an associative learning task that provided monetary reward and punishment for recall performance, we observed that when recall errors were categorized by subsequent performance—whether the failure to accurately recall a number–location association was corrected at the next presentation of the same trial—the magnitude of error-related pMFC activity predicted future correction. However, the pMFC region was insensitive to the magnitude of punishment an error received and it was the left insula cortex that predicted learning from the most aversive outcomes. These findings add further evidence to the hypothesis that error-related pMFC activity may reflect more than a prediction error in representing the value of an outcome. The novel role identified here for the insular cortex in learning from punishment appears particularly compelling for our understanding of psychiatric and neurologic conditions that feature both insular cortex dysfunction and a diminished capacity for learning from negative feedback or punishment.
ProNGF Induces PTEN via p75NTRto Suppress Trk-Mediated Survival Signaling in Brain Neurons
Authors: Song Wenyu , Volosin Marta , Cragnolini Andrea B. , Hempstead Barbara L. , Friedman Wilma J.
Published: November 2010

Proneurotrophins and mature neurotrophins activate different signaling pathways with distinct effects on their target cells: proneurotrophins can induce apoptotic signaling via p75NTR, whereas mature neurotrophins activate Trk receptors to influence survival and differentiation. Here, we demonstrate that the PTEN (phosphatase and tensin homolog deleted on chromosome 10) phosphatase represents a novel switch between the survival and apoptotic signaling pathways in rat CNS neurons. Simultaneous activation of p75NTRby proNGF and TrkB signaling by BDNF elicited apoptosis despite TrkB phosphorylation. Apoptosis induced by p75NTRrequired suppression of TrkB-induced phosphoinositide-3 kinase signaling, mediated by induction of PTEN, for apoptosis to proceed. Inhibition of PTEN restored the ability of BDNF to phosphorylate Akt and protect cultured basal forebrain neurons from proNGF-induced death.In vivo, inhibition or knockdown of PTEN after pilocarpine-induced seizures protected CNS neurons from p75NTR-mediated death, demonstrating that PTEN is a crucial factor mediating the balance between p75NTR-induced apoptotic signaling and Trk-mediated survival signaling in brain neurons.
Low-Threshold Ca2+Current Amplifies Distal Dendritic Signaling in Thalamic Reticular Neurons
Authors: Crandall Shane R. , Govindaiah G. , Cox Charles L.
Published: November 2010

The low-threshold transient calcium current (IT) plays a critical role in modulating the firing behavior of thalamic neurons; however, the role ofITin the integration of afferent information within the thalamus is virtually unknown. We have used two-photon laser scanning microscopy coupled with whole-cell recordings to examine calcium dynamics in the neurons of the strategically located thalamic reticular nucleus (TRN). We now report that a single somatic burst discharge evokes large-magnitude calcium responses, viaIT, in distal TRN dendrites. The magnitude of the burst-evoked calcium response was larger than those observed in thalamocortical projection neurons under the same conditions. We also demonstrate that direct stimulation of distal TRN dendrites, via focal glutamate application and synaptic activation, can locally activate distalIT, producing a large distal calcium response independent of the soma/proximal dendrites. These findings strongly suggest that distally locatedITmay function to amplify afferent inputs. Boosting the magnitude ensures integration at the somatic level by compensating for attenuation that would normally occur attributable to passive cable properties. Considering the functional architecture of the TRN, elongated nature of their dendrites, and robust dendritic signaling, these distal dendrites could serve as sites of intense intra-modal/cross-modal integration and/or top-down modulation, leading to focused thalamocortical communication.
A Robust and Biologically Plausible Spike Pattern Recognition Network
Authors: Larson Eric , Perrone Ben P. , Sen Kamal , Billimoria Cyrus P.
Published: November 2010

The neural mechanisms that enable recognition of spiking patterns in the brain are currently unknown. This is especially relevant in sensory systems, in which the brain has to detect such patterns and recognize relevant stimuli by processing peripheral inputs; in particular, it is unclear how sensory systems can recognize time-varying stimuli by processing spiking activity. Because auditory stimuli are represented by time-varying fluctuations in frequency content, it is useful to consider how such stimuli can be recognized by neural processing. Previous models for sound recognition have used preprocessed or low-level auditory signals as input, but complex natural sounds such as speech are thought to be processed in auditory cortex, and brain regions involved in object recognition in general must deal with the natural variability present in spike trains. Thus, we used neural recordings to investigate how a spike pattern recognition system could deal with the intrinsic variability and diverse response properties of cortical spike trains. We propose a biologically plausible computational spike pattern recognition model that uses an excitatory chain of neurons to spatially preserve the temporal representation of the spike pattern. Using a single neural recording as input, the model can be trained using a spike-timing-dependent plasticity-based learning rule to recognize neural responses to 20 different bird songs with >98% accuracy and can be stimulated to evoke reverse spike pattern playback. Although we test spike train recognition performance in an auditory task, this model can be applied to recognize sufficiently reliable spike patterns from any neuronal system.
The Somatosensory Cortex ofreelerMutant Mice Shows Absent Layering But Intact Formation and Behavioral Activation of Columnar Somatotopic Maps
Authors: Wagener Robin J. , Dávid Csaba , Zhao Shanting , Haas Carola A. , Staiger Jochen F.
Published: November 2010

Sensory information acquired via the large facial whiskers is processed and relayed in the whisker-to-barrel pathway, which shows multiple somatotopic maps of the receptor periphery. These maps consist of individual structural modules, the development of which may require intact cortical lamination. In the present study we examined the whisker-to-barrel pathway in thereelermouse and thus used a model with disturbed cortical organization. A combination of histological (fluorescent Nissl and cytochrome oxidase staining) as well as molecular methods (c-Fos and laminar markersRgs8,RORB, andER81expression) revealed wild type-equivalent modules inreeler. At the neocortical level, however, we found extensive alterations in the layout of the individual modules of the map. Nevertheless, they showed a columnar organization that included compartments equivalent to those of their wild-type counterparts. Moreover, all examined modules showed distinct activation as a consequence of behavioral whisker stimulation. Analysis of the magnitude of the cortical lamination defect surprisingly revealed an extensive disorganization, rather than an inversion, as assumed previously. Striking developmental plasticity of thalamic innervation, as suggested by vGluT2 immunohistochemistry, seems to ensure the proper formation of columnar modules and topological maps even under highly disorganized conditions.
Ventrolateral Prefrontal Cortex Plays an Executive Regulation Role in Comprehension of Abstract Words: Convergent Neuropsychological and Repetitive TMS Evidence
Authors: Hoffman Paul , Jefferies Elizabeth , Lambon Ralph Matthew A.
Published: November 2010

Neuroimaging studies reliably reveal ventrolateral prefrontal cortex (VLPFC) activation for processing of abstract relative to concrete words, but the cause of this effect is unclear. Here, in a convergent neuropsychological and repetitive transcranial magnetic stimulation (rTMS) investigation, we tested the hypothesis that abstract words require VLPFC because they depend heavily on the semantic–executive control processes mediated by this region. Specifically, we hypothesized that accessing the meanings of abstract words require more executive regulation because they have variable, context-dependent meanings. In the neuropsychology component of the study, aphasic patients with multimodal semantic deficits following VLPFC lesions had impaired comprehension of abstract words, but this deficit was ameliorated by providing a sentence cue that placed the word in a specific context. Concrete words were better comprehended and showed more limited benefit from the cues. In the second part of the study, rTMS applied to left VLPFC in healthy subjects slowed reaction times to abstract but not concrete words, but only when words were presented out of context. TMS had no effect when words were preceded by a contextual cue. These converging results indicate that VLPFC plays an executive regulation role in the processing of abstract words. This role is less critical when words are presented with a context that guides the system toward a particular meaning or interpretation. Regulation is less important for concrete words because their meanings are constrained by their physical referents and do not tend to vary with context.