bluuebunny/crossref_metadata_2025 huggingface dataset:
Parameter estimation and inference for stochastic reaction-diffusion systems: application to morphogenesis in D. melanogaster
Authors: Dewar Michael A , Kadirkamanathan Visakan , Opper Manfred , Sanguinetti Guido
Published: March 2010

Background

Reaction-diffusion systems are frequently used in systems biology to model developmental and signalling processes. In many applications, count numbers of the diffusing molecular species are very low, leading to the need to explicitly model the inherent variability using stochastic methods. Despite their importance and frequent use, parameter estimation for both deterministic and stochastic reaction-diffusion systems is still a challenging problem.

Results

We present a Bayesian inference approach to solve both the parameter and state estimation problem for stochastic reaction-diffusion systems. This allows a determination of the full posterior distribution of the parameters (expected values and uncertainty). We benchmark the method by illustrating it on a simple synthetic experiment. We then test the method on real data about the diffusion of the morphogen Bicoid in Drosophila melanogaster. The results show how the precision with which parameters can be inferred varies dramatically, indicating that the ability to infer full posterior distributions on the parameters can have important experimental design consequences.

Conclusions

The results obtained demonstrate the feasibility and potential advantages of applying a Bayesian approach to parameter estimation in stochastic reaction-diffusion systems. In particular, the ability to estimate credibility intervals associated with parameter estimates can be precious for experimental design. Further work, however, will be needed to ensure the method can scale up to larger problems.
Glioma Pathogenesis-Related 1-Like 1 Is Testis Enriched, Dynamically Modified, and Redistributed during Male Germ Cell Maturation and Has a Potential Role in Sperm-Oocyte Binding
Authors: Gibbs Gerard M. , Lo Jennifer Chi Yi , Nixon Brett , Jamsai Duangporn , O'Connor Anne E. , Rijal Sewa , Sanchez-Partida L. Gabriel , Hearn Milton T. W. , Bianco Deborah M. , O'Bryan Moira K.
Published: March 2010

The glioma pathogenesis-related 1 (GLIPR1) family consists of three genes [GLIPR1, GLIPR1-like 1 (GLIPR1L1), and GLIPR1-like 2 (GLIPR1L2)] and forms a distinct subgroup within the cysteine-rich secretory protein (CRISP), antigen 5, and pathogenesis-related 1 (CAP) superfamily. CAP superfamily proteins are found in phyla ranging from plants to humans and, based largely on expression and limited functional studies, are hypothesized to have roles in carcinogenesis, immunity, cell adhesion, and male fertility. Specifically data from a number of systems suggests that sequences within the C-terminal CAP domain of CAP proteins have the ability to promote cell-cell adhesion. Herein we cloned mouse Glipr1l1 and have shown it has a testis-enriched expression profile. GLIPR1L1 is posttranslationally modified by N-linked glycosylation during spermatogenesis and ultimately becomes localized to the connecting piece of elongated spermatids and sperm. After sperm capacitation, however, GLIPR1L1 is also localized to the anterior regions of the sperm head. Zona pellucida binding assays indicate that GLIPR1L1 has a role in the binding of sperm to the zona pellucida surrounding the oocyte. These data suggest that, along with other members of the CAP superfamily and several other proteins, GLIPR1L1 is involved in the binding of sperm to the oocyte complex. Collectively these data further strengthen the role of CAP domain-containing proteins in cellular adhesion and propose a mechanism whereby CAP proteins show overlapping functional significance during fertilization.
Showing Off
Authors: Ivanovitch Roman
Published: March 2010

The article examines a group of closing gestures in Mozart's piano concertos, passages of soloistic virtuosity just before the last tuttis of the exposition and recapitulation. Serving as grand cadential clinchers and clothed in conventional figuration, these spots—sometimes called “display episodes”—appear to highlight performative prowess at the expense of compositional invention. As such, beyond an acknowledgment of the appropriateness of stock passagework at this point, analysis can have little to say: the episodes are either self-evidently simple or transparent to theoretical apparatus.

I suggest, however, that by using the vantage point of variation, conceived broadly, not just as a technique but as a manner of organizing musical thoughts, new insights can emerge about these passages. This wider conception of variation is sanctioned both by historical precedent (Daube, Koch) and by contemporary usage (Sisman, Agawu); the specific invocation of it in connection with the display episodes is suggested initially by their characteristic bipartite format. Seen through the variation lens, elements such as contrapuntal ingenuity, complex modular arrangements within and between phrases, and an affinity for textural exploration come to the fore. These elements constitute a display of compositional virtuosity that is a counterpart to the more evident performative fireworks.
Tiered Polyphony and Its Determinative Role in the Piano Music of Johannes Brahms
Authors: Auerbach Brent
Published: March 2010

Tiered polyphony describes segments of music that manifest rhythmic/metric layering (Lester 1986) in the presence of polyphony. This texture, though a hallmark of the baroque era, is capable of generating a variety of musical effects over many style periods. This article establishes three categories of the texture based on degrees of metrical dissonance: weakly, moderately, and strictly tiered polyphony. The last form is special not only for its rarity but also for the extreme independence of its lines, which create supermetrical dissonance through pitch cells and/or pitch-interval cycles.

Strictly tiered polyphony figures prominently in Brahms's piano music, where it lends passages an aura of extreme drive and inexorability. Importantly, awareness of this texture can provide insights into Brahms's works unavailable through conventional approaches. The analytical portion of this article examines the Two Rhapsodies, op. 79. The unusual harmonic structure of the G-minor rhapsody is read in light of 1-cycles present within the opening tiered polyphony. In the B-minor rhapsody, the content of three concurrent cycles at the opening—a 4-cycle, 1-cycle, and 5/7-cycle—is respectively reflected in the hexatonic organization of mm. 1–67, in the A section's stormy chromatic transitions, and in the cadential gestures that permeate the B section and coda.
Leibniz and the Puzzle of Incompossibility: The Packing Strategy
Authors: McDonough Jeffrey K.
Published: March 2010

Confronting the threat of a Spinozistic necessitarianism, Leibniz insists that not all possible substances are compossible—that they can't all be instantiated together—and thus that not all possible worlds are compossible—that they can't all be instantiated together. While it is easy to appreciate Leibniz's reasons for embracing this view, it has proven difficult to see how his doctrine of incompossibility might be reconciled with the broader commitments of his larger philosophical system. This essay develops, in four sections, a novel solution to the “puzzle of incompossibility.” The first section frames the difficulty more carefully and briefly argues that the two dominant strategies developed by Leibniz's commentators fail to solve it fully insofar as they require simply abandoning one or another of its motivating commitments. The second and third sections show how Leibniz's guiding analogy of a geometrical packing or tiling problem may be applied to solve the puzzle of incompossibility in the context of finite and infinite worlds composed of extended corporeal substances. Finally, the fourth section shows how the strategy of Leibniz's packing analogy might be applied even in the context of a thoroughly idealist metaphysics in which the only true substances are nonextended, mindlike “monads.” The essay concludes by drawing some connections between Leibniz's thinking about the puzzle of incompossibility and the development of his views concerning the status of corporeal substances and extended bodies.
Sustained synaptic-vesicle recycling by bulk endocytosis contributes to the maintenance of high-rate neurotransmitter release stimulated by glycerotoxin
Authors: Meunier Frederic A. , Nguyen Tam H. , Colasante Cesare , Luo Fujun , Sullivan Robert K. P. , Lavidis Nickolas A. , Molgó Jordi , Meriney Stephen D. , Schiavo Giampietro
Published: March 2010

Glycerotoxin (GLTx), a large neurotoxin isolated from the venom of the sea worm Glycera convoluta, promotes a long-lasting increase in spontaneous neurotransmitter release at the peripheral and central synapses by selective activation of Cav2.2 channels. We found that GLTx stimulates the very high frequency, long-lasting (more than 10 hours) spontaneous release of acetylcholine by promoting nerve terminal Ca2+ oscillations sensitive to the inhibitor ω-conotoxin GVIA at the amphibian neuromuscular junction. Although an estimate of the number of synaptic vesicles undergoing exocytosis largely exceeds the number of vesicles present in the motor nerve terminal, ultrastructural examination of GLTx-treated synapses revealed no significant change in the number of synaptic vesicles. However, we did detect the appearance of large pre-synaptic cisternae suggestive of bulk endocytosis. Using a combination of styryl dyes, photoconversion and horseradish peroxidase (HRP)-labeling electron microscopy, we demonstrate that GLTx upregulates presynaptic-vesicle recycling, which is likely to emanate from the limiting membrane of these large cisternae. Similar synaptic-vesicle recycling through bulk endocytosis also occurs from nerve terminals stimulated by high potassium. Our results suggest that this process might therefore contribute significantly to synaptic recycling under sustained levels of synaptic stimulation.
Ciz1 cooperates with cyclin-A–CDK2 to activate mammalian DNA replication in vitro
Authors: Copeland Nikki A. , Sercombe Heather E. , Ainscough Justin F. X. , Coverley Dawn
Published: March 2010

Initiation of mammalian DNA replication can be reconstituted from isolated G1-phase nuclei and cell extracts, supplemented with cyclin-dependent protein kinases (CDKs). Under these conditions, cyclin E supports pre-replication complex assembly, whereas cyclin-A-associated kinase acts later to terminate assembly and activate DNA replication. The mechanism by which these events are coordinated is unknown. Here, we show that the replication factor Ciz1 interacts with cyclins E and A sequentially through distinct cyclin-binding motifs. Cyclin A displaces cyclin E from Ciz1 in a manner that is dependent on functional domains that are essential for its role in DNA replication. Furthermore, in cell-free assays, recombinant cyclin-A–CDK2 complexes and recombinant Ciz1 cooperate to promote initiation of DNA replication in late G1-phase nuclei. In addition, Ciz1 supports immobilization of cyclin A in isolated nuclei and depletion of Ciz1 by RNAi impairs immobilization, suggesting that Ciz1 promotes initiation by helping to target the kinase to a specific subnuclear compartment. We propose that Ciz1 acts to coordinate the functions of cyclins E and A in the nucleus, by delivering cyclin-A-associated kinase to sites that are specified by cyclin E, helping to ensure that they execute their functions in the same place and in the correct order.
The Nine-Year Sustained Cost-Containment Impact of Swiss Pilot Physicians-Pharmacists Quality Circles
Authors: Niquille Anne , Ruggli Martine , Buchmann Michel , Jordan Dominique , Bugnon Olivier
Published: March 2010

Background

Six pioneer physicians-pharmacists quality circles (PPQCs) located in the Swiss canton of Fribourg (administratively corresponding to a state in the US) were under the responsibility of 6 trained community pharmacists moderating the prescribing process of 24 general practitioners (GPs). PPQCs are based on a multifaceted collaborative process mediated by community pharmacists for improving compliance with clinical guidelines within GPs’ prescribing practices.

Objective

To assess, over a 9-year period (1999–2007), the cost-containment impact of the PPQCs.

Methods

The key elements of PPQCs are a structured continuous quality improvement and education process; local networking; feedback of comparative and detailed data regarding costs, drug choice, and frequency of prescribed drugs; and structured independent literature review for interdisciplinary continuing education. The data are issued from the community pharmacy invoices to the health insurance companies. The study analyzed the cost-containment impact of the PPQCs in comparison with GPs working in similar conditions of care without particular collaboration with pharmacists, the percentage of generic prescriptions for specific cardiovascular drug classes, and the percentage of drug costs or units prescribed for specific cardiovascular drugs.

Results

For the 9-year period, there was a 42% decrease in the drug costs in the PPQC group as compared to the control group, representing a $225,000 (USD) savings per GP only in 2007. These results are explained by better compliance with clinical and pharmacovigilance guidelines, larger distribution of generic drugs, a more balanced attitude toward marketing strategies, and interdisciplinary continuing education on the rational use of drugs.

Conclusions

The PPQC work process has yielded sustainable results, such as significant cost savings, higher penetration of generics and reflection on patient safety, and the place of “new” drugs in therapy. The PPQCs may also constitute a solid basis for implementing more comprehensive collaborative programs, such as medication reviews, adherence-enhancing interventions, or disease management approaches.
Diabetes Medications Related to an Increased Risk of Falls and Fall-Related Morbidity in the Elderly
Authors: Berlie Helen D , Garwood Candice L
Published: March 2010

Objective

To review literature regarding the effect of diabetes medications as a contributing risk for falls and fall-related morbidity in elderly patients with type 2 diabetes.

Data sources

Primary literature was identified through PubMed MEDLINE (1966–November 2009) using the search terms elderly, aged, older adults, diabetes type 2, diabetes mellitus, falls, fractures, medication, hypoglycemia, and vitamin B12 deficiency. Each drug class and the individual agents within the classes were also included in the search. Additional references were obtained through review of references from articles obtained.

Study selection and data extraction

Clinical studies evaluating diabetes medications and their association with falls, as well as studies evaluating their association with the complications of falls, were considered for inclusion. Selection emphasis was placed on randomized studies evaluating diabetes medications and falls.

Data synthesis

There is no direct link between metformin and falls; however, an indirect association caused by neuropathy secondary to vitamin B12 deficiency may be of concern. Although hypoglycemia is a risk factor, to date, there are no trials specifically linking insulin secretagogues to falls. Insulin use has been demonstrated to increase the risk of falls in the elderly. Thiazolidinediones increase fracture risk and thus may worsen fall-related outcomes. There are no studies to date linking other agents to an increased risk of falls.

Conclusions

Special considerations should be made when treating elderly patients with diabetes. At this time, a patient's functional level and risk factors for falls should weigh into decision-making regarding drug selection. The risk of falls and fall-related complications associated with diabetes medications should not be ignored.
Synthesis of arenes and heteroarenes by hydroarylation reactions catalyzed by electrophilic metal complexes
Authors: de Mendoza Paula , Echavarren Antonio M.
Published: March 2010

The hydroarylation of alkynes (also known as arylation of alkynes or alkenylation of arenes) catalyzed by gold or other electrophilic metal salts or complexes is reviewed from synthetic and mechanistic perspectives.
Positive (But Not Negative) Punishment Predicts Anxiety and Depression Among Prostate Cancer Patients: An Exploration of the Behaviour Analytic Model of Depression
Authors: Bitsika Vicki , Sharpley Christopher F. , Christie David R. H.
Published: March 2010

The relative power of Positive and Negative Punishment as predictors of anxiety and depression was investigated within the gender-specific population of Prostate Cancer patients. As well as being a more powerful predictor of total test scores, Positive Punishment was also a stronger predictor of the presence of clinical levels of anxiety and depression. Examination of the particular Positive Punishment events that were significantly associated with clinical anxiety and depression showed considerable overlap, supporting the concept of a combined anxiety-depression disorder. Suggestions for behavioural interventions with this patient group are made.
Online CBT I: Bridging the Gap Between Eliza and Modern Online CBT Treatment Packages
Authors: Helgadóttir Fjóla Dögg , Menzies Ross G. , Onslow Mark , Packman Ann , O'Brian Sue
Published: March 2010

Reviews have demonstrated large effect sizes when using computerised cognitive behaviour therapy (CBT) protocols for treating anxiety, depression and health related concerns. However, the amount of therapist contact per user seems to be the most significant prognostic indicator. Thus, in some ways current online interventions can be viewed primarily as an extension of one-on-one therapy. The present article provides guidelines for targeting this limitation of online psychological interventions. The goal is to mimic the therapeutic relationship using a computer, without having any therapist involved. Consequently, thousands of users would be able to receive treatment simultaneously, reaching a wider audience, which was the initial goal of the online model. The development of a treatment program using file audit data is suggested as an alternative to having an individual therapist for each user. This is done by allowing the ‘computer psychologist’ to tailor individualised treatments for each user based on their psychological profile. The user is provided with individualised corrective feedback based on a set of prewritten responses to common faulty thoughts. A new paradigm is proposed for online treatment delivery.
A Novel Intervention to Address Fears in Children with Asperger Syndrome: A Pilot Study of the Cognitive Behaviour Drama (CBD) Model
Authors: Karnezi Haris , Tierney Kevin
Published: March 2010

This article introduces a new intervention model designed to address phobic avoidances in children with Asperger syndrome, incorporating principles and techniques from cognitive and behaviour therapy into the art form of drama. This paper presents a single case study that outlines the application of the model in the treatment of a long-term fear of hand-driers in an 11-year-old boy, diagnosed with Asperger syndrome, for whom all other forms of therapy including variants of systematic desensitisation and traditional cognitive behaviour therapy had been found to be ineffective. The results of this study offer preliminary descriptive evidence of the efficacy of the model and durability of outcomes.
Generating mapping class groups of nonorientable surfaces with boundary
Authors: Stukow Michał
Published: March 2010

We obtain simple generating sets for various mapping class groups of a nonorientable surface with punctures and/or boundary. We also compute the abelianizations of these mapping class groups.
Translation as a Complementary Factor in Cultural Repertoire Formation
Authors: van Kalmthout Ton
Published: March 2010

Institutions have, from a systemic point of view, a complementary function in cultural repertoire formation. This function is illustrated by the role publishers and translators played in the literary socialisation of readers between 1880 and 1940, a role they took over, partly or entirely, from educators and teachers of literature. In this period, language teaching in the Netherlands assigned a key position to Dutch literature and marginalised literature in other languages. However, the activities of publishers and translators added an international frame of reference to the mainly national repertoire imparted to the pupils. Several circumstances stimulated this cosmopolitan transformation, such as internationalism and the advancing professionalization of translation at the beginning of the twentieth century.
Transnationale Literatur-Rezeption. Am Beispiel der Aufnahme Jean-Luc Benoziglios im deutschsprachigen Raum
Authors: Jurt Joseph
Published: March 2010

Scholars of German Reception Aesthetics have studied literary reception processes. However, their concept of the reader was rather abstract and text-based. Conversely, the sociology of reception has focused on social mechanisms and conditions outside the text. The theory of cultural transfer, as well as Bourdieu's propositions concerning the international circulation of ideas bring to the fore the decisive role of the fields of reception. The present case study of the Western Swiss author Jean-Luc Benoziglio shows various facets of international literary reception. It compares the reactions to the French work and its German translations in Switzerland, France and Germany. In spite of an early positive resonance, no work has been translated into German after 1993. Economic reasons, but also a stagnating interest in French avant-garde literature may explain this.
Her Dietrîch und sîn Hildebrant – die Unzertrennlichen? Aspekte von Herrschaft und Erziehung in einer langen literaturhistorischen Beziehung
Authors: Goller Detlef
Published: March 2010

Dietrich von Bern and his armourer Hildebrand seem inseparable. The article focuses on this phenomenon – which is evident in coeval texts – under two different aspects: In the first place, the relationship between Dietrich and Hildebrand is viewed as the tie between a monarch and his closest advisor according to the rules of medieval politics as they have been drawn up by Gerd Althoff. In this respect, the permanence of their relationship results from the lifelong bond that aligns Hildebrand with his lord Dietrich. Secondly, the teacher-student relationship which is evident throughout the text is focussed. Concerning this, Hildebrand does not manage to make his disciple Dietrich gain independence from his teacher.
Retinol potentiates the inhibitory effect of ascorbic acid on uric acid assay
Authors: Bouvier Damien , Sapin Vincent , Bonnard-Gougeon Michèle , Marceau Geoffroy
Published: March 2010

Background: The interference of ascorbic acid in the determination of plasma uric acid concentrations, by decreasing the formation of chromophore in Trinder's reaction, is well known. By contrast, the effects of other antioxidant vitamins, such as retinol and α-tocopherol have not been investigated. Knowledge of the analytical interaction of these antioxidants in the uric acid assay would be useful.

Methods: The effect of a mix of vitamins (Cernevit®) on uric acid analysis in a patient hospitalized in a neurological intensive care unit was observed. The effects of the different antioxidant components of the mixture (retinol, α-tocopherol and ascorbic acid) on the concentration of uric acid from a pool of plasma were also tested.

Results: Among the different combinations of vitamins tested, only retinol potentiated the antioxidant effect of ascorbic acid. The most marked effect was observed with 80 IU/mL of retinol and 5.7 mmol/L of ascorbic acid.

Conclusions: We demonstrate for the first time the synergistic interference of ascorbic acid and retinol on the measurement of uric acid in plasma. We established that ascorbic acid interference is potentiated by regeneration of reduced ascorbic acid by retinol. Such interference must be kept in mind to avoid misinterpreting low plasma uric acid concentrations in patients in whom this analyte is critical.

Clin Chem Lab Med 2010;48:693–5.
Reviewing imagery in resemblance and non-resemblance metaphors
Authors: Ureña José Manuel , Faber Pamela
Published: March 2010

This article analyses the nature of mental imagery in metaphoric thought as envisaged by the contemporary theory of metaphor in Cognitive Linguistics (Lakoff, Cambridge University Press, 1993). Our study of metaphor in the field of marine biology draws on two crucial aspects of mental imagery, namely dynamicity and pervasiveness. Image metaphors and behaviour-based metaphors have generally been regarded as two different types of resemblance metaphor. In our view, the dynamicity of certain mental images highlights inherent similarities between these two types of metaphor, and makes the differences between them more apparent than real. For this reason, we propose a more refined description of resemblance metaphors in terms of the static or dynamic nature of the mental images underlying them. Our study also underlines the fact that mental images permeate all classes of metaphor, and that the pervasiveness and dynamicity of mental images affords insights into both resemblance metaphors and non-resemblance metaphors.
The interplay of humor and conflict in conversation and scripted humorous performance
Authors: Norrick Neal R. , Spitz Alice
Published: March 2010

In this article we explore the interrelationship of humor and conflict. We focus first on contexts where humor provides a constructive means of attenuating conflict and ending disagreements in conversation. Then we turn to conflict talk as a source of humor. We identify three characteristic strategies for constructing humor around patterns of conflict talk, both in everyday conversation and in professionally scripted dialogue. The momentum and coherence of argument structure tends toward automatization even in everyday talk, and this property lends itself especially well to the creation of humorous dialogue. We show both how humor can mitigate conflict, and how conflict talk can be funny.
Development of Electrochemical Standards for Corrosion Testing
Authors: Dean Sheldon W.
Published: March 2010

Although the understanding that corrosion is an electrochemical process has been known for almost a century, the exploitation of electrochemical techniques for corrosion testing has largely occurred in the past four decades. The development of standard conventions in ASTM G 3 and calculation procedures in ASTM G 102 have stimulated the development of electrochemical test methods. The development of reference test methods G 5, G 59, G 61, G 100, and G 106 that allow the verification of both equipment and procedures has been an important contribution to the development and expansion of these test methods. The availability of reliable electrometers, potentiostatic power supplies and recording equipment has also made these methods simpler to use. This paper reviews the development of these standards and discusses three electrochemical test methods. It also outlines several areas for new standards development and provides ideas for improvements to existing standards.
Use of Coupled Multi-Electrode Arrays to Advance the Understanding of Selected Corrosion Phenomena
Authors: Cong H. , Bocher F. , Budiansky N. D. , Hurley M. F. , Scully J. R.
Published: March 2010

The use of coupled multi-electrode arrays in various corrosion applications is discussed with the main goal of advancing the understanding of various corrosion phenomena. Both close-packed and far-spaced electrode configurations are discussed. Far-spaced electrode arrays are optimized for high throughput experiments capable of elucidating the effects of various variables on corrosion properties. For instance, the effects of a statistical distribution of flaws on corrosion properties can be examined. Close-packed arrays enable unprecedented spatial and temporal information on the behavior of local anodes and cathodes. Interactions between corrosion sites can trigger or inhibit corrosion phenomena and affect corrosion damage evolution.
Dissociation within the Frontoparietal Network in Verbal Working Memory: A Parametric Functional Magnetic Resonance Imaging Study
Authors: Champod Anne Sophie , Petrides Michael
Published: March 2010

Concomitant increase in activity within the mid-dorsolateral prefrontal cortex (MDLFC) and the posterior parietal cortex (PPC) is observed in most functional neuroimaging studies of working memory (Collette et al., 1999; Gerton et al., 2004; Sun et al., 2005; Postle et al., 2006; Champod and Petrides, 2007; Emery et al., 2008). Despite broad consensus on the importance of these two brain regions in working memory, their unique contribution, especially that of the PPC, remains a matter of heated debate (Paulesu et al., 1993; Smith and Jonides, 1998; Postle et al., 1999; Berryhill and Olson, 2008). The main objective of the present parametric event-related functional magnetic resonance imaging study was to examine the hypothesis that the cortex in the intraparietal sulcus region in the PPC is involved in the manipulation (i.e., rearrangement) of verbal information in working memory and to dissociate the involvement of this brain region from that of the MDLFC in working memory processes. The results demonstrated a linear increase in activity within the MDLFC during the manipulation and monitoring of a linearly increasing number of words in working memory. In sharp contrast, there was a linear increase in activity within the PPC during the manipulation but not the monitoring of a linearly increasing number of words. This study provides the first parametric dissociation of activation in these two cortical regions indicating a crucial role of the PPC in the manipulation of information in working memory, with the MDLFC playing a major role in monitoring this information.
Anatomical Correlate of Impaired Covert Visual Attentional Processes in Patients with Cerebellar Lesions
Authors: Baier Bernhard , Dieterich Marianne , Stoeter Peter , Birklein Frank , Müller Notger G.
Published: March 2010

In the past years, claims of cognitive and attentional function of the cerebellum have first been raised but were later refuted. One reason for this controversy might be that attentional deficits only occur when specific cerebellar structures are affected. To further elucidate this matter and to determine which cerebellar regions might be involved in deficits of covert visual attention, we used new brain imaging tools of lesion mapping that allow a direct comparison with control patients. A total of 26 patients with unilateral right-sided cerebellar infarcts were tested on a covert visual attention task. Eight (31%) patients showed markedly slowed responses, especially in trials in which an invalid cue necessitated reorienting of the focus of attention for target detection. Compared with the 18 patients who performed within the range of healthy control subjects, only the impaired patients had lesions of cerebellar vermal structures such as the pyramid. We suggest that these midcerebellar regions are indirectly involved in covert visual attention via oculomotor control mechanisms. Thus, specific cerebellar structures do influence attentional orienting, whereas others do not.
Synaptic Clustering of PSD-95 Is Regulated by c-Abl through Tyrosine Phosphorylation
Authors: de Arce Karen Perez , Varela-Nallar Lorena , Farias Olivia , Cifuentes Alejandra , Bull Paulina , Couch Brian A. , Koleske Anthony J. , Inestrosa Nibaldo C. , Alvarez Alejandra R.
Published: March 2010

The c-Abl tyrosine kinase is present in mouse brain synapses, but its precise synaptic function is unknown. We found that c-Abl levels in the rat hippocampus increase postnatally, with expression peaking at the first postnatal week. In 14 din vitrohippocampal neuron cultures, c-Abl localizes primarily to the postsynaptic compartment, in which it colocalizes with the postsynaptic scaffold protein postsynaptic density protein-95 (PSD-95) in apposition to presynaptic markers. c-Abl associates with PSD-95, and chemical or genetic inhibition of c-Abl kinase activity reduces PSD-95 tyrosine phosphorylation, leading to reduced PSD-95 clustering and reduced synapses in treated neurons. c-Abl can phosphorylate PSD-95 on tyrosine 533, and mutation of this residue reduces the ability of PSD-95 to cluster at postsynaptic sites. Our results indicate that c-Abl regulates synapse formation by mediating tyrosine phosphorylation and clustering of PSD-95.
The Relationship of Lyrics and Tunes in the Processing of Unfamiliar Songs: A Functional Magnetic Resonance Adaptation Study
Authors: Sammler Daniela , Baird Amee , Valabrègue Romain , Clément Sylvain , Dupont Sophie , Belin Pascal , Samson Séverine
Published: March 2010

The cognitive relationship between lyrics and tunes in song is currently under debate, with some researchers arguing that lyrics and tunes are represented as separate components, while others suggest that they are processed in integration. The present study addressed this issue by means of a functional magnetic resonance adaptation paradigm during passive listening to unfamiliar songs. The repetition and variation of lyrics and/or tunes in blocks of six songs was crossed in a 2 × 2 factorial design to induce selective adaptation for each component. Reductions of the hemodynamic response were observed along the superior temporal sulcus and gyrus (STS/STG) bilaterally. Within these regions, the left mid-STS showed an interaction of the adaptation effects for lyrics and tunes, suggesting an integrated processing of the two components at prelexical, phonemic processing levels. The degree of integration decayed toward more anterior regions of the left STS, where the lack of such an interaction and the stronger adaptation for lyrics than for tunes was suggestive of an independent processing of lyrics, perhaps resulting from the processing of meaning. Finally, evidence for an integrated representation of lyrics and tunes was found in the left dorsal precentral gyrus (PrCG), possibly relating to the build-up of a vocal code for singing in which musical and linguistic features of song are fused. Overall, these results demonstrate that lyrics and tunes are processed at varying degrees of integration (and separation) through the consecutive processing levels allocated along the posterior–anterior axis of the left STS and the left PrCG.
Glycinergic Pacemaker Neurons in PreBötzinger Complex of Neonatal Mouse
Authors: Morgado-Valle Consuelo , Baca Serapio M. , Feldman Jack L.
Published: March 2010

The preBötzinger complex (preBötC) is essential for normal respiratory rhythm generation in rodents, for which the underlying mechanisms remain unknown. Excitatory preBötC pacemaker neurons are proposed to be necessary for rhythm generation. Here we report the presence of a population of preBötC glycinergic pacemaker neurons. We used rhythmicin vitrotransverse slice preparations from transgenic mice where neurons expressing the glycine transporter 2 (GlyT2) gene coexpress enhanced green fluorescent protein (EGFP). We combined epifluorescence and whole-cell patch-clamp recording to study preBötC EGFP-labeled, i.e., glycinergic, inspiratory-modulated neurons with pacemaker properties. We defined glycinergic pacemaker neurons as those preBötC EGFP neurons that exhibited the following: (1) ectopic bursting in rhythmic slices when depolarized during their normally silent period and (2) bursting when depolarized in nonrhythmic slices (following AMPA receptor blockade). Forty-two percent of EGFP-labeled neurons were inspiratory (n= 48 of 115), of which 23% (n= 11 of 48 inspiratory; 10% of the total recorded) were pacemakers. We conclude that there is a population of preBötC inspiratory-modulated glycinergic, presumably inhibitory, pacemaker neurons that constitute a substantial fraction of all preBötC pacemaker neurons. These findings challenge contemporary models for respiratory rhythmogenesis that assume the excitatory nature of preBötC pacemaker neurons. Testable and nontrivial predictions of the functional role of excitatory and inhibitory pacemaker neurons need to be proposed and the necessary experiments performed.
Histone Methylation Regulates Memory Formation
Authors: Gupta Swati , Kim Se Y. , Artis Sonja , Molfese David L. , Schumacher Armin , Sweatt J. David , Paylor Richard E. , Lubin Farah D.
Published: March 2010

It has been established that regulation of chromatin structure through post-translational modification of histone proteins, primarily histone H3 phosphorylation and acetylation, is an important early step in the induction of synaptic plasticity and formation of long-term memory. In this study, we investigated the contribution of another histone modification, histone methylation, to memory formation in the adult hippocampus. We found that trimethylation of histone H3 at lysine 4 (H3K4), an active mark for transcription, is upregulated in hippocampus 1 h following contextual fear conditioning. In addition, we found that dimethylation of histone H3 at lysine 9 (H3K9), a molecular mark associated with transcriptional silencing, is increased 1 h after fear conditioning and decreased 24 h after context exposure alone and contextual fear conditioning. Trimethylated H3K4 levels returned to baseline levels at 24 h. We also found that mice deficient in the H3K4-specific histone methyltransferase,Mll, displayed deficits in contextual fear conditioning relative to wild-type animals. This suggests that histone methylation is required for proper long-term consolidation of contextual fear memories. Interestingly, inhibition of histone deacetylases (HDACs) with sodium butyrate (NaB) resulted in increased H3K4 trimethylation and decreased H3K9 dimethylation in hippocampus following contextual fear conditioning. Correspondingly, we found that fear learning triggered increases in H3K4 trimethylation at specific gene promoter regions (Zif268andbdnf) with altered DNA methylation and MeCP2 DNA binding.Zif268DNA methylation levels returned to baseline at 24 h. Together, these data demonstrate that histone methylation is actively regulated in the hippocampus and facilitates long-term memory formation.
Changes in Simple Spike Activity of Some Purkinje Cells in the Oculomotor Vermis during Saccade Adaptation Are Appropriate to Participate in Motor Learning
Authors: Kojima Yoshiko , Soetedjo Robijanto , Fuchs Albert F.
Published: March 2010

Adaptation of saccadic eye movements provides an excellent motor learning model to study theories of neuronal plasticity. When primates make saccades to a jumping target, a backward step of the target during the saccade can make it appear to overshoot. If this deception continues for many trials, saccades gradually decrease in amplitude to go directly to the back-stepped target location. We used this adaptation paradigm to evaluate the Marr–Albus hypothesis that such motor learning occurs at the Purkinje (P)-cell of the cerebellum. We recorded the activity of identified P-cells in the oculomotor vermis, lobules VIc and VII. After documenting the on and off error directions of the complex spike activity of a P-cell, we determined whether its saccade-related simple spike (SS) activity changed during saccade adaptation in those two directions. Before adaptation, 57 of 61 P-cells exhibited a clear burst, pause, or a combination of both for saccades in one or both directions. Sixty-two percent of all cells, including two of the four initially unresponsive ones, behaved differently for saccades whose size changed because of adaptation than for saccades of similar sizes gathered before adaptation. In at least 42% of these, the changes were appropriate to decrease saccade amplitude based on our current knowledge of cerebellum and brainstem saccade circuitry. Changes in activity during adaptation were not compensating for the potential fatigue associated with performing many saccades. Therefore, many P-cells in the oculomotor vermis exhibit changes in SS activity specific to adapted saccades and therefore appropriate to induce adaptation.
GSK-3β Inhibits Presynaptic Vesicle Exocytosis by Phosphorylating P/Q-Type Calcium Channel and Interrupting SNARE Complex Formation
Authors: Zhu Ling-Qiang , Liu Dan , Hu Juan , Cheng Jin , Wang Shao-Hui , Wang Qun , Wang Fang , Chen Jian-Guo , Wang Jian-Zhi
Published: March 2010

Glycogen synthase kinase-3 (GSK-3), a Ser/Thr protein kinase abundantly expressed in neurons, plays diverse functions in physiological and neurodegenerative conditions. Our recent study shows that upregulation of GSK-3 suppresses long-term potentiation and presynaptic release of glutamate; however, the underlying mechanism is elusive. Here, we show that activation of GSK-3β retards the synaptic vesicle exocytosis in response to membrane depolarization. Using calcium imaging, whole-cell patch-clamp, as well as specific Ca2+channel inhibitors, we demonstrate that GSK-3β phosphorylates the intracellular loop-connecting domains II and III (LII-III) of P/Q-type Ca2+channels, which leads to a decrease of intracellular Ca2+rise through the P/Q-type voltage-dependent calcium channel. To further illustrate the mechanisms of GSK-3β's action, we show that activation of GSK-3β interferes with the formation of the solubleN-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor (SNARE) complex through: (1) weakening the association of synaptobrevin with SNAP25 and syntaxin; (2) reducing the interactions among the phosphorylated LII-IIIand synaptotagmin, SNAP25, and syntaxin; and (3) inhibiting dissociation of synaptobrevin from synaptophysin I. These results indicate that GSK-3β negatively regulates synaptic vesicle fusion events via interfering with Ca2+-dependent SNARE complex formation.
Chronic Consumption of a High-Fat Diet during Pregnancy Causes Perturbations in the Serotonergic System and Increased Anxiety-Like Behavior in Nonhuman Primate Offspring
Authors: Sullivan Elinor L. , Grayson Bernadette , Takahashi Diana , Robertson Nicola , Maier Adriane , Bethea Cynthia L. , Smith M. Susan , Coleman Kristine , Grove Kevin L.
Published: March 2010

Childhood obesity is associated with increased risk of behavioral/psychological disorders including depression, anxiety, poor learning, and attention deficient disorder. As the majority of women of child-bearing age are overweight or obese and consume a diet high in dietary fat, it is critical to examine the consequences of maternal overnutrition on the development of brain circuitry that regulates offspring behavior. Using a nonhuman primate model of diet-induced obesity, we found that maternal high-fat diet (HFD) consumption caused perturbations in the central serotonergic system of fetal offspring. In addition, female infants from HFD-fed mothers exhibited increased anxiety in response to threatening novel objects. These findings have important clinical implications as they demonstrate that exposure to maternal HFD consumption during gestation, independent of obesity, increases the risk of developing behavioral disorders such as anxiety.
Noninvasive Detection of Presymptomatic and Progressive Neurodegeneration in a Mouse Model of Spinocerebellar Ataxia Type 1
Authors: Öz Gülin , Nelson Christopher D. , Koski Dee M. , Henry Pierre-Gilles , Marjańska Małgorzata , Deelchand Dinesh K. , Shanley Ryan , Eberly Lynn E. , Orr Harry T. , Clark H. Brent
Published: March 2010

Recent studies with a conditional mouse model of spinocerebellar ataxia type 1 (SCA1) suggest that neuronal dysfunction is reversible and neurodegeneration preventable with early interventions. Success of such interventions will depend on early detection of neuronal and glial abnormalities before cell loss and availability of objective methods to monitor progressive neurodegeneration. Cerebellar concentrations ofN-acetylaspartate (NAA),myo-inositol, and glutamate as measured by magnetic resonance spectroscopy (MRS) correlate with ataxia scores of patients with SCA1, indicating their potential as reliable biomarkers of neurodegeneration. Here we investigated whether neurochemical levels are altered by early, presymptomatic disease and whether they gauge disease progression in a mouse model of SCA1. Cerebellar neurochemical profiles of transgenic mice that overexpress the mutant human ataxin-1 (theSCA1[82Q] line) were measured longitudinally up to 1 year by MRS at 9.4 T and compared to those of transgenic mice that overexpress the normal human ataxin-1 (theSCA1[30Q] line) and wild-type controls. Multiple neurochemicals distinguished theSCA1[82Q] mice from controls with no overlap at all ages. Six neurochemicals were significantly different inSCA1[82Q] mice at 6 weeks, before major pathological and neurological changes. Alterations in NAA,myo-inositol, and glutamate progressively worsened and were significantly correlated (p< 0.0001) with disease progression as assessed by histology (molecular layer thickness and an overall severity score). Therefore, the neurochemicals that correlate with clinical status in patients reflected progressive pathology in the mouse model. These data demonstrate that presymptomatic and progressive neurodegeneration in SCA1 can be noninvasively monitored using MRS.
Acute Polyglutamine Expression in Inducible Mouse Model Unravels Ubiquitin/Proteasome System Impairment and Permanent Recovery Attributable to Aggregate Formation
Authors: Ortega Zaira , Díaz-Hernández Miguel , Maynard Christa J. , Hernández Félix , Dantuma Nico P. , Lucas José J.
Published: March 2010

The presence of intracellular ubiquitylated inclusions in neurodegenerative disorders and the role of the ubiquitin/proteasome system (UPS) in degrading abnormal hazardous proteins have given rise to the hypothesis that UPS-impairment underlies neurodegenerative processes. However, this remains controversial for polyglutamine disorders such as Huntington disease (HD). Whereas studies in cellular models have provided evidence in favor of UPS-impairment attributable to expression of the N-terminal fragment of mutant huntingtin (N-mutHtt), similar studies on mouse models failed to do so. Furthermore, we have recently shown that the increase in polyubiquitin conjugates reported in the brain of N-mutHtt mice occurs in the absence of a general UPS-impairment. In the present study we aim to clarify the potential of N-mutHtt to impair UPS functionin vivoas well as the mechanisms by which neurons may adapt after prolonged exposure to N-mutHtt in genetic models. By combining UPS reporter mice with an inducible mouse model of HD, we demonstrate for the first time polyglutamine-induced global UPS-impairmentin vivo. UPS-impairment occurred transiently after acute N-mutHtt expression and restoration correlated with appearance of inclusion bodies (IBs). Consistently, UPS recovery did not take place when IB formation was prevented through administration of N-mutHtt aggregation-inhibitors in both cellular and animal models. Finally, no UPS-impairment was detected in old mice constitutively expressing N-mutHtt despite the age-associated decrease in brain proteasome activity. Therefore, our data reconcile previous contradictory reports by showing that N-mutHtt can indeed impair UPS functionin vivoand that N-mutHtt aggregation leads to long lasting restoration of UPS function.