bluuebunny/crossref_metadata_2025 huggingface dataset:
Splicing of HDAC7 modulates the SRF-myocardin complex during stem-cell differentiation towards smooth muscle cells
Authors: Margariti Andriana , Xiao Qingzhong , Zampetaki Anna , Zhang Zhongyi , Li Hongling , Martin Daniel , Hu Yanhua , Zeng Lingfang , Xu Qingbo
Published: January 2009

Histone deacetylases (HDACs) have a central role in the regulation of gene expression. Here we investigated whether HDAC7 has an impact on embryonic stem (ES) cell differentiation into smooth muscle cells (SMCs). ES cells were seeded on collagen-IV-coated flasks and cultured in the absence of leukemia inhibitory factor in differentiation medium to induce SMC differentiation. Western blots and double-immunofluorescence staining demonstrated that HDAC7 has a parallel expression pattern with SMC marker genes. In ex vivo culture of embryonic cells from SM22-LacZ transgenic mice, overexpression of HDAC7 significantly increased β-galactosidase-positive cell numbers and enzyme activity, indicating its crucial role in SMC differentiation during embryonic development. We found that HDAC7 undergoes alternative splicing during ES cell differentiation. Platelet-derived growth factor enhanced ES cell differentiation into SMCs through upregulation of HDAC7 splicing. Further experiments revealed that HDAC7 splicing induced SMC differentiation through modulation of the SRF-myocardin complex. These findings suggest that HDAC7 splicing is important for SMC differentiation and vessel formation in embryonic development.
Cx43 has distinct mobility within plasma-membrane domains, indicative of progressive formation of gap-junction plaques
Authors: Simek Jamie , Churko Jared , Shao Qing , Laird Dale W.
Published: January 2009

Connexin 43 (Cx43) is a dynamic molecule, having a short half-life of only a few hours. In this study, we use fluorescent-protein-tagged Cx43 variants to examine Cx43 delivery to the cell surface, its residency status in various cell-surface membrane domains and its mobility characteristics. Rapid time-lapse imaging led to the identification of Cx43 being delivered to cell-surface domains that lacked a contacting cell, and also to its localization within membrane protrusions. Fluorescence recovery after photobleaching (FRAP) was used to investigate the mobility state of cell-surface-localized Cx43. Cx43 mobility within clustered cell-surface profiles of Cx43 could be categorized into those with generally a high degree of lateral mobility and those with generally a low degree of lateral mobility. Cx43 mobility was independent of cluster size, yet the C-terminal domain of Cx43 regulated the proportion of gap-junction-like clusters that acquired a low Cx43 mobility state. Collectively, these studies show that Cx43 establishes residency at all cell-surface membrane domains, and progressively acquires assembly states that probably reflect differences in either channel packing and/or its interactions with Cx43-binding proteins.
DrosophilaPast1 is involved in endocytosis and is required for germline development and survival of the adult fly
Authors: Olswang-Kutz Yael , Gertel Yaron , Benjamin Sigi , Sela Orly , Pekar Olga , Arama Eli , Steller Hermann , Horowitz Mia , Segal Daniel
Published: January 2009

Endocytosis, which is a key process in eukaryotic cells, has a central role in maintaining cellular homeostasis, nutrient uptake, development and downregulation of signal transduction. This complex process depends on several protein-protein interactions mediated by specific modules. One such module is the EH domain. The EH-domain-containing proteins comprise a family that includes four vertebrate members (EHD1-EHD4) and one Drosophila ortholog, Past1. We used Drosophila as a model to understand the physiological role of this family of proteins. We observed that the two predicted Past1 transcripts are differentially expressed both temporally and spatially during the life cycle of the fly. Endogenous Past1 as well as Past1A and Past1B, expressed from plasmids, were localized mainly to the membrane of Drosophila-derived cells. We generated mutants in the Past1 gene by excising a P-element inserted in it. The Past1 mutants reached adulthood but died precociously. They were temperature sensitive and infertile because of lesions in the reproductive system. Garland cells that originated from Past1 mutants exhibited a marked decrease in their ability to endocytose fluorescently labeled avidin. Genetic interaction was found between Past1 and members of the Notch signaling pathway, suggesting a role for Past1 in this developmentally crucial signaling pathway.
Mars, aDrosophilaprotein related to vertebrate HURP, is required for the attachment of centrosomes to the mitotic spindle during syncytial nuclear divisions
Authors: Zhang Gang , Breuer Manuel , Förster Ankathrin , Egger-Adam Diane , Wodarz Andreas
Published: January 2009

The formation of the mitotic spindle is controlled by the microtubule organizing activity of the centrosomes and by the effects of chromatin-associated Ran-GTP on the activities of spindle assembly factors. In this study we show that Mars, a Drosophila protein with sequence similarity to vertebrate hepatoma upregulated protein (HURP), is required for the attachment of the centrosome to the mitotic spindle. More than 80% of embryos derived from mars mutant females do not develop properly due to severe mitotic defects during the rapid nuclear divisions in early embryogenesis. Centrosomes frequently detach from spindles and from the nuclear envelope and nucleate astral microtubules in ectopic positions. Consistent with its function in spindle organization, Mars localizes to nuclei in interphase and associates with the mitotic spindle, in particular with the spindle poles, during mitosis. We propose that Mars is an important linker between the spindle and the centrosomes that is required for proper spindle organization during the rapid mitotic cycles in early embryogenesis.
Strategic Manipulation of Empirical Tests
Authors: Olszewski Wojciech , Sandroni Alvaro
Published: January 2009

Theories can be produced by experts seeking a reputation for having knowledge. Hence, a tester could anticipate that theories may have been strategically produced by uninformed experts who want to pass an empirical test.

We show that, with no restriction on the domain of permissible theories, strategic experts cannot be discredited for an arbitrary but given number of periods, no matter which test is used (provided that the test does not reject the actual data-generating process).

Natural ways around this impossibility result include (1) assuming that unbounded data sets are available and (2) restricting the domain of permissible theories (opening the possibility that the actual data-generating process is rejected out-of-hand). In both cases, it is possible to dismiss strategic experts but only to a limited extent. These results show significant limits on what data can accomplish when experts produce theories strategically.
Unconstrained Convex Minimization in Relative Scale
Authors: Nesterov Yurii
Published: January 2009

In this paper, we present a new approach to constructing schemes for unconstrained convex minimization, which computes approximate solutions with a certain relative accuracy. This approach is based on a special conic model of the unconstrained minimization problem. Using a structural model of the objective function, we can employ the efficient smoothing technique. The fastest of our algorithms solves a linear programming problem with relative accuracy δ in at most e · m1/2 (2 + ln m) · (1 + 1/δ) iterations of a gradient-type scheme, where m is the largest dimension of the problem and e is the Euler number.
Markov Chains and Optimality of the Hamiltonian Cycle
Authors: Litvak Nelly , Ejov Vladimir
Published: January 2009

We consider the Hamiltonian cycle problem (HCP) embedded in a controlled Markov decision process. In this setting, HCP reduces to an optimization problem on a set of Markov chains corresponding to a given graph. We prove that Hamiltonian cycles are minimizers for the trace of the fundamental matrix on a set of all stochastic transition matrices. In case of doubly stochastic matrices with symmetric linear perturbation, we show that Hamiltonian cycles minimize a diagonal element of a fundamental matrix for all admissible values of the perturbation parameter. In contrast to the previous work on this topic, our arguments are primarily based on probabilistic rather than algebraic methods.
Stationary Distribution Convergence for Generalized Jackson Networks in Heavy Traffic
Authors: Budhiraja Amarjit , Lee Chihoon
Published: January 2009

In a recent paper, Gamarnik and Zeevi [Gamarnik, D., A. Zeevi. 2006. Validity of heavy traffic steady-state approximations in open queueing networks. Ann. Appl. Probab. 16(1) 56–90], it was shown that under suitable conditions stationary distributions of the (scaled) queue-lengths process for a generalized Jackson network converge to the stationary distribution of the associated reflected Brownian motion in the heavy traffic limit. The proof relied on certain exponential integrability assumptions on the primitives of the network. In this note we show that the above result holds under much weaker integrability conditions. We provide an alternative proof of this result assuming (in addition to natural heavy traffic and stability assumptions) only standard independence and square integrability conditions on the network primitives that are commonly used in heavy traffic analysis. Furthermore, under additional integrability conditions we establish convergence of moments of stationary distributions.
Monotone Covering Problems with an Additional Covering Constraint
Authors: Correa José R. , Levin Asaf
Published: January 2009

We provide preliminary results regarding the existence of a polynomial time approximation scheme (PTAS) for minimizing a linear function over a 0/1 covering polytope which is integral, with one additional covering constraint. Our algorithm is based on extending the methods of Goemans and Ravi for the constrained minimum spanning tree problem and, in particular, implies the existence of a PTAS for several covering integer programming problems with a totally unimodular constraint matrix. These include the cases when the columns of the constraint matrix either: have at most two nonzero elements; are incidence vectors of a laminar family; or have consecutive ones and no column is contained in another.
Seasonal and Sex Variation of High-Sensitivity C-Reactive Protein in Healthy Adults: A Longitudinal Study
Authors: Chiriboga David E , Ma Yunsheng , Li Wenjun , Stanek Edward J , Hébert James R , Merriam Philip A , Rawson Eric S , Ockene Ira S
Published: January 2009

Background: Cross-sectional studies have reported seasonal variation in high-sensitivity C-reactive protein (hsCRP). However, longitudinal data are lacking.

Methods: We collected data on diet, physical activity, psychosocial factors, physiology, and anthropometric measurements from 534 healthy adults (mean age 48 years, 48.5% women, 87% white) at quarterly intervals over a 1-year period between 1994 and 1998. Using sinusoidal regression models, we estimated peak-to-trough amplitude and phase of the peaks.

Results: At baseline, average hsCRP was 1.72 mg/L (men, 1.75 mg/L; women, 1.68 mg/L). Overall seasonal variation amplitude was 0.16 mg/L (95% CI 0.02 to 0.30) and was lower in men (0.10 mg/L, 95% CI −0.11 to 0.31) than in women (0.23 mg/L, 95% CI 0.04 to 0.42). In both sexes, hsCRP peaked in November, with a corresponding trough in May. Relative plasma volume, waist and hip circumference, diastolic blood pressure, and depression scores were major factors associated with changes in amplitude of seasonal variation of hsCRP, and taken together explain most of the observed seasonal change. There was a 20% increase in the percentage of participants classified in the high-risk category for hsCRP (≥3 mg/L) during late fall and early winter compared with late spring and early summer.

Conclusions: Concentrations of hsCRP were modestly increased in fall and winter compared to summer, with greater seasonal amplitude of variation observed in women. Conventional classification methods fail to consider seasonality in hsCRP and may result in substantial misclassifications in the spring and fall. Future clinical practice and research should take these variations into account.
Different Apparent Prognostic Value of hsCRP in Type 2 Diabetic and Nondiabetic Patients with Acute Coronary Syndromes
Authors: Biasucci Luigi M , Liuzzo Giovanna , Della Bona Roberta , Leo Milena , Biasillo Gina , Angiolillo Dominick J , Abbate Antonio , Rizzello Vittoria , Niccoli Giampaolo , Giubilato Simona , Crea Filippo
Published: January 2009

Background: C-reactive protein (CRP) is an established prognostic marker in acute coronary syndromes (ACS); however, no study has specifically addressed its prognostic role in type 2 diabetes with ACS. We evaluated the prognostic role of CRP separately in diabetic and nondiabetic patients with ACS.

Methods: We enrolled 251 patients with unstable angina and measured serum concentrations of high sensitivity (hs)CRP. Ninety-seven patients underwent coronary angiography with evaluation of atherosclerotic disease severity and extent by Bogaty score. Assessed endpoint was the combined occurrence of myocardial infarction (MI) and death at 1 year.

Results: No significant differences were found in hs-CRP between patients with and without diabetes. By Cox regression, hsCRP was not associated with 1-year follow-up events in diabetic patients but was strongly associated with events in nondiabetic patients (P = 0.0012). Coronary angiography exhibited a higher extent index in patients with diabetes than in those without (P = 0.04). hsCRP concentrations were not associated with angiographic atherosclerotic burden. By Cox analysis, hsCRP and extent score were associated with events in patients who underwent coronary angiography (P < 0.001 and P = 0.034, respectively). In nondiabetic patients, hsCRP was the only predictor of events at 1-year follow-up (P < 0.001), whereas in diabetic patients, hsCRP was not associated with events and a weak association was observed for extent score (P = 0.06).

Conclusions: Our study suggests that different pathophysiological mechanisms may be responsible for MI and death in unstable angina patients with or without diabetes and that severity of coronary artery disease plays a major role in diabetes (and inflammation in the absence of diabetes).
TheDrosophilaBEACH Family Protein, Blue Cheese, Links Lysosomal Axon Transport with Motor Neuron Degeneration
Authors: Lim Angeline , Kraut Rachel
Published: January 2009

Impaired axon transport is one of the earliest pathological manifestations of several neurodegenerative diseases, and mutations in motor proteins can exacerbate or cause degeneration (Williamson and Cleveland, 1999; Gunawardena and Goldstein, 2004; Stokin and Goldstein, 2006). Compromised function in lysosomes and other degradative organelles that intersect with the lysosomal pathway are also strongly implicated in neurodegenerative disease pathology (Nixon and Cataldo, 2006; Rubinsztein, 2006). However, any functional link between these two phenomena has not as yet been recognized.Drosophilamutants inblue cheese(bchs) undergo progressive brain degeneration as adults and have shortened life span (Finley et al., 2003), but the cellular function of Bchs and the cause of degeneration have not been identified. A role in lysosomal trafficking is suggested by the homology of Bchs with the vesicle trafficking-associated BEACH (Beige and Chediak–Higashi) domain protein family (Wang et al., 2002; De Lozanne, 2003) and by its genetic interaction with a lysosomal transport pathway (Simonsen et al., 2007). Here, we describe the degeneration of a population of identified larval motor neurons inbchsmutants. We present evidence that Bchs is primarily lysosomal in those motor neurons in wild type and, using live fluorescence imaging of individual motor neurons in intact larvae, show that lysosomal vesicles fail to be transported toward motor neuron termini inbchsmutant and Bchs-overexpressing larvae. We suggest therefore that anterograde transport of lysosomes toward synaptic termini is a key factor in preventing motor neuron degeneration and that Bchs reveals a functional link between the lysosomal degradative pathway and transport.
The Contribution of Synaptic Inputs to Sustained Depolarizations in Reticulospinal Neurons
Authors: Antri Myriam , Fénelon Karine , Dubuc Réjean
Published: January 2009

Sensory stimulation elicits sustained depolarizations in lamprey reticulospinal (RS) cells for which intrinsic properties were shown to play a crucial role. The depolarizations last up to minutes, and we tested whether the intrinsic properties required the cooperation of synaptic inputs to maintain RS cells depolarized for such long periods of time. Ascending spinal inputs to RS cells were reversibly blocked by applying xylocaine over the rostral spinal cord segments. The duration of the sustained depolarizations was markedly reduced. The membrane potential oscillations in tune with locomotor activity that were present under control condition were also abolished. The contribution of excitatory glutamatergic inputs was then assessed by applying CNQX and AP-5 over one of two simultaneously recorded homologous RS cells on each side of the brainstem. The level of sensory-evoked depolarization decreased significantly in the cell exposed to the antagonists compared with the other RS cell monitored as a control. In contrast, local application of glycine only produced a transient membrane potential hyperpolarization with a marked reduction in the amplitude of membrane potential oscillations. Locally applied strychnine did not change the duration of the sustained depolarizations, suggesting that mechanisms other than glycinergic inhibition are involved in ending the sustained depolarizations in RS cells. It is concluded that excitatory glutamatergic inputs, including ascending spinal feedback, cooperate with intrinsic properties of RS cells to maintain the cells depolarized for prolonged periods, sustaining long bouts of escape swimming.
Subthreshold Receptive Field Properties Distinguish Different Classes of Corticothalamic Neurons in the Somatosensory System
Authors: Kwegyir-Afful Ernest E. , Simons Daniel J.
Published: January 2009

Most corticothalamic (CT) neurons in somatosensory cortex are silent in lightly anesthetized and even awake animals, making it difficult to investigate CT function and the underlying circuitry. Here we use juxtasomal recording and stimulation techniques to probe subthreshold response properties of antidromically identified CT neurons in the rat whisker/barrel system. When neuronal firing is facilitated by depolarizing juxtasomal currents, silent neurons become responsive to whisker stimuli, permitting identification of three functional classes of CT cells: those having a short-latency excitatory response to whisker deflection, those having a long-latency response, and neurons whose firing is suppressed by whisker deflection. During sensorimotor behaviors when the CT system may be active, cells having excitatory vs inhibitory receptive fields may participate in push–pull corticothalamic circuits that, acting together, selectively enhance sensory signaling in the thalamocortical system.
A Novel Nicotinic Acetylcholine Receptor Subtype in Basal Forebrain Cholinergic Neurons with High Sensitivity to Amyloid Peptides
Authors: Liu Qiang , Huang Yao , Xue Fenqin , Simard Alain , DeChon Jamie , Li Guohui , Zhang Jianliang , Lucero Linda , Wang Min , Sierks Michael , Hu Gang , Chang Yongchang , Lukas Ronald J. , Wu Jie
Published: January 2009

Nicotinic acetylcholine receptors (nAChRs) containing α7 subunits are thought to assemble as homomers. α7-nAChR function has been implicated in learning and memory, and alterations of α7-nAChR have been found in patients with Alzheimer's disease (AD). Here we report findings consistent with a novel, naturally occurring nAChR subtype in rodent, basal forebrain cholinergic neurons. In these cells, α7 subunits are coexpressed, colocalize, and coassemble with β2 subunit(s). Compared with homomeric α7-nAChRs from ventral tegmental area neurons, functional, presumably heteromeric α7β2-nAChRs on cholinergic neurons freshly dissociated from medial septum/diagonal band (MS/DB) exhibit relatively slow kinetics of whole-cell current responses to nicotinic agonists and are more sensitive to the β2 subunit-containing nAChR-selective antagonist, dihydro-β-erythroidine (DHβE). Interestingly, presumed, heteromeric α7β2-nAChRs are highly sensitive to functional inhibition by pathologically relevant concentrations of oligomeric, but not monomeric or fibrillar, forms of amyloid β1–42(Aβ1–42). Slow whole-cell current kinetics, sensitivity to DHβE, and specific antagonism by oligomeric Aβ1–42also are characteristics of heteromeric α7β2-nAChRs, but not of homomeric α7-nAChRs, heterologously expressed inXenopusoocytes. Moreover, choline-induced currents have faster kinetics and less sensitivity to Aβ when elicited from MS/DB neurons derived from nAChR β2 subunit knock-out mice rather than from wild-type mice. The presence of novel, functional, heteromeric α7β2-nAChRs on basal forebrain cholinergic neurons and their high sensitivity to blockade by low concentrations of oligomeric Aβ1–42suggests possible mechanisms for deficits in cholinergic signaling that could occur early in the etiopathogenesis of AD and might be targeted by disease therapies.
Modulation of the Dimer Interface at Ionotropic Glutamate-Like Receptor δ2 by d-Serine and Extracellular Calcium
Authors: Hansen Kasper B. , Naur Peter , Kurtkaya Natalie L. , Kristensen Anders S. , Gajhede Michael , Kastrup Jette S. , Traynelis Stephen F.
Published: January 2009

GluRδ2 is a member of the iGluR family, but despite a prominent role in cerebellar synaptic plasticity, this receptor does not appear to function as an ion channel. Endogenous ligands that modulate the activity of native GluRδ2 in the cerebellum have not been identified, but two candidate modulators ared-serine and extracellular calcium. Taking advantage of known crystal structures and spontaneously active GluRδ2 receptors containing thelurchermutation (GluRδ2Lc), we investigated the mechanism by which calcium andd-serine regulate the activity of GluRδ2Lc. Our data suggest that calcium binding stabilizes the dimer interface formed between two agonist-binding domains and increases GluRδ2Lccurrents. The data further suggest thatd-serine binding induces rearrangements at the dimer interface to diminish GluRδ2Lccurrents by a mechanism that resembles desensitization at AMPA and kainate receptors. Thus, we propose that calcium andd-serine binding have opposing effects on the stability of the dimer interface. Furthermore, the effects of calcium are observed at concentrations that are within the physiological range, suggesting that the ability of native GluRδ2 to respond to ligand binding may be modulated by extracellular calcium. These findings place GluRδ2 among AMPA and kainate receptors, where the dimer interface is not only a biologically important site for functional regulation, but also an important target for exogenous and endogenous ligands that modulate receptor function.
An Auditory Region in the Primate Insular Cortex Responding Preferentially to Vocal Communication Sounds
Authors: Remedios Ryan , Logothetis Nikos K. , Kayser Christoph
Published: January 2009

Human imaging studies implicate the insular cortex in processing complex sounds and vocal communication signals such as speech. In addition, lesions of the insula often manifest as deficits in sound or speech recognition (auditory agnosia) and speech production. While models of acoustic perception assign an important role to the insula, little is known about the underlying neuronal substrate. Studying a vocal primate, we identified a predominantly auditory region in the caudal insula and therein discovered a neural representation of conspecific communication sounds. When probed with natural sounds, insula neurons exhibited higher response selectivity than neurons in auditory cortex, and in contrast to these, responded preferentially to conspecific vocalizations. Importantly, insula neurons not only preferred conspecific vocalizations over a wide range of environmental sounds and other animal vocalizations, but also over acoustically manipulated versions of these, demonstrating that this preference for vocalizations arises both from spectral and temporal features of the sounds. In addition, individual insula neurons responded highly selectively to only a few vocalizations and allowed the decoding of sound identity from single-trial responses. These findings characterize the caudal insula as a selectively responding auditory region, possibly part of a processing stream involved in the representation of communication sounds. Importantly, our results provide a neural counterpart for the human imaging and lesion findings and uncover a basis for a supposed role of the insula in processing vocal communication sounds such as speech.
Reduction of Spike Afterdepolarization by Increased Leak Conductance Alters Interspike Interval Variability
Authors: Fernandez Fernando R. , White John A.
Published: January 2009

Data from neuronsin vivohave shown that spike output can often sustain episodes of high variability. Theoretical studies have indicated that the high conductance state of neurons brought on by synaptic activity can contribute to an increase in the variability of spike output by decreasing the integration timescale of the neuron. In the present work, we were interested in understanding how background synaptic conductance activity alters the interspike interval (ISI) variability of layer III pyramidal cells of the medial entorhinal cortex. We compared ISI variability in pyramidal cells as a result of synaptic current- or conductance-mediated membrane fluctuations. We found that the effects of background synaptic conductance activity on ISI variability depend on the neuron type. In pyramidal cells lacking spike frequency adaptation, the variability increased in relation to a comparable synaptic current stimulus. In contrast, in pyramidal cells displaying spike frequency adaptation, the synaptic conductance stimulus produced lower ISI variability. To understand this result, we constructed a phenomenological model that reproduced the basic properties of these neurons under control and increased leak conductance. We found that leak can change the properties of the neuron by acting as a bifurcation parameter that reduces the afterdepolarization (ADP) and decreases the slope (gain) of the frequency–current relationship, particularly for transient stimuli. A lower gain with the added leak causes a reduction in ISI variability. We conclude that the ability of a high conductance state to increase ISI variability cannot be generalized and can depend on the spike ADP dynamics expressed by the neuron.
Network Architecture of Gap Junction-Coupled Neuronal Linkage in the Striatum
Authors: Fukuda Takaichi
Published: January 2009

Previous studies have revealed the existence of gap junctions between GABAergic interneurons of a particular type in the striatum. Because of the technical difficulties, however, there is no information about their positions within the striatal circuitry. We have developed a method to detect neuronal gap junctions reliably at the light microscopic level and thereby explored the network architecture of the gap junctional linkage. Gap junction-coupled networks among parvalbumin-containing GABAergic interneurons extended nonuniformly in the feline striatum. They were located predominantly in the methionine–enkephalin–poor matrix. Moreover, the density of gap junctional coupling showed a marked regional difference along the anterior–posterior axis of the striatum. The densest interconnectivity was found in the posterior part of both caudate nucleus and putamen that corresponds to the sensory-recipient area of the feline striatum. Electron microscopic observations provided clear evidence of internalization of neuronal gap junction, indicating the dynamic nature of gap junctional linkage between neuronsin vivo. The nonuniform organization of gap junction networks suggests differential modes of information processing in heterogeneous subregions of the striatum.
SV2 Renders Primed Synaptic Vesicles Competent for Ca2+-Induced Exocytosis
Authors: Chang Wen-Pin , Südhof Thomas C.
Published: January 2009

Synaptic vesicle protein 2 (SV2), one of the first synaptic vesicle proteins identified, is characterized by multiple transmembrane regions that exhibit homology to sugar transporters, and by a highly glycosylated intravesicular sequence. Deletion of SV2 causes postnatal lethality in mice, primarily because of fulminant epilepsy. At the cellular level, deletion of SV2 impairs neurotransmitter release, but its function is unknown, and even the exact point at which release is affected in SV2-deleted synapses remains unclear. Using electrophysiological approaches, we now examine at what step in exocytosis the deletion of SV2 impairs release. Our data demonstrate that deletion of SV2 produces a decrease in evoked synaptic responses without causing changes in mini frequency, mini amplitude, the readily releasable pool of vesicles, or the apparent Ca2+sensitivity of vesicle fusion. These findings indicate that a previously unidentified step may couple priming of synaptic vesicles to Ca2+triggering of fusion, and that SV2 acts in this step to render primed synaptic vesicles fully Ca2+responsive. To investigate the structural requirements for this function of SV2, we used rescue experiments. We demonstrate that conserved charged residues within the transmembrane regions and the intravesicular glycosylation of SV2 are required for its normal folding and trafficking. In contrast, the conserved putative synaptotagmin-binding sequence of SV2 is fully dispensable. Viewed together, these observations suggest that SV2 functions in a maturation step of primed vesicles that converts the vesicles into a Ca2+- and synaptotagmin-responsive state.
Medial Temporal Lobe Activity during Retrieval of Semantic Memory Is Related to the Age of the Memory
Authors: Smith Christine N. , Squire Larry R.
Published: January 2009

We measured brain activity using event-related fMRI as participants recalled answers to 160 questions about news events that had occurred during the past 30 years. Guided by earlier findings from patients with damage limited to the hippocampus who were given the same test material, we looked for regions that exhibited gradually decreasing activity as participants recalled memories from 1–12 years ago and a constant level of activity during recall of more remote memories. Regions in the medial temporal lobe exhibited a decrease in brain activity in relation to the age of the memory (hippocampus, temporopolar cortex, and amygdala). Regions in the frontal lobe, temporal lobe, and parietal lobe exhibited the opposite pattern. The findings for all of these regions were unrelated to the richness of the memories, to how well test questions were remembered later (encoding for subsequent memory), nor to how frequently semantic memories were accompanied by personal, episodic recollections. Last, activity in a different group of regions (perirhinal cortex, parahippocampal cortex, and inferior temporal gyrus) was associated with how well the test questions were subsequently remembered. The results support the idea that medial temporal lobe structures play a time-limited role in semantic memory.
Intracellular Zn2+Accumulation Contributes to Synaptic Failure, Mitochondrial Depolarization, and Cell Death in an Acute Slice Oxygen–Glucose Deprivation Model of Ischemia
Authors: Medvedeva Yuliya V. , Lin Bin , Shuttleworth C. William , Weiss John H.
Published: January 2009

Despite considerable evidence for contributions of both Zn2+and Ca2+in ischemic brain damage, the relative importance of each cation to very early events in injury cascades is not well known. We examined Ca2+and Zn2+dynamics in hippocampal slices subjected to oxygen–glucose deprivation (OGD). When single CA1 pyramidal neurons were loaded via a patch pipette with a Ca2+-sensitive indicator (fura-6F) and an ion-insensitive indicator (AlexaFluor-488), small dendritic fura-6F signals were noted after several (∼6–8) minutes of OGD, followed shortly by sharp somatic signals, which were attributed to Ca2+(“Ca2+deregulation”). At close to the time of Ca2+deregulation, neurons underwent a terminal increase in plasma membrane permeability, indicated by loss of AlexaFluor-488 fluorescence. In neurons coloaded with fura-6F and a Zn2+-selective indicator (FluoZin-3), progressive rises in cytosolic Zn2+levels were detected before Ca2+deregulation. Addition of the Zn2+chelatorN,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) significantly delayed both Ca2+deregulation and the plasma membrane permeability increases, indicating that Zn2+contributes to the degenerative signaling. Present observations further indicate that Zn2+is rapidly taken up into mitochondria, contributing to their early depolarization. Also, TPEN facilitated recovery of the mitochondrial membrane potential and of field EPSPs after transient OGD, and combined removal of Ca2+and Zn2+markedly extended the duration of OGD tolerated. These data provide new clues that Zn2+accumulates rapidly in neurons during slice OGD, is taken up by mitochondria, and contributes to consequent mitochondrial dysfunction, cessation of synaptic transmission, Ca2+deregulation, and cell death.
Genetically Determined Interaction between the Dopamine Transporter and the D2Receptor on Prefronto-Striatal Activity and Volume in Humans
Authors: Bertolino Alessandro , Fazio Leonardo , Di Giorgio Annabella , Blasi Giuseppe , Romano Raffaella , Taurisano Paolo , Caforio Grazia , Sinibaldi Lorenzo , Ursini Gianluca , Popolizio Teresa , Tirotta Emanuele , Papp Audrey , Dallapiccola Bruno , Borrelli Emiliana , Sadee Wolfgang
Published: January 2009

Dopamine modulation of neuronal activity during memory tasks identifies a nonlinear inverted-U shaped function. Both the dopamine transporter (DAT) and dopamine D2receptors (encoded byDRD2) critically regulate dopamine signaling in the striatum and in prefrontal cortex during memory. Moreover,in vitrostudies have demonstrated that DAT and D2proteins reciprocally regulate each other presynaptically. Therefore, we have evaluated the genetic interaction between aDRD2polymorphism (rs1076560) causing reduced presynaptic D2receptor expression and theDAT3′-VNTR variant (affecting DAT expression) in a large sample of healthy subjects undergoing blood oxygenation level-dependent (BOLD)-functional magnetic resonance imaging (MRI) during memory tasks and structural MRI. Results indicated a significantDRD2/DATinteraction in prefrontal cortex and striatum BOLD activity during both working memory and encoding of recognition memory. The differential effect on BOLD activity of theDATvariant was mostly manifest in the context of theDRD2allele associated with lower presynaptic expression. Similar results were also evident for gray matter volume in caudate. These interactions describe a nonlinear relationship between compound genotypes and brain activity or gray matter volume. Complementary data from striatal protein extracts from wild-type and D2knock-out animals (D2R−/−) indicate that DAT and D2proteins interactin vivo. Together, our results demonstrate that the interaction between genetic variants inDRD2andDATcritically modulates the nonlinear relationship between dopamine and neuronal activity during memory processing.
The Parkinson Disease Protein Leucine-Rich Repeat Kinase 2 Transduces Death Signals via Fas-Associated Protein with Death Domain and Caspase-8 in a Cellular Model of Neurodegeneration
Authors: Ho Cherry Cheng-Ying , Rideout Hardy J. , Ribe Elena , Troy Carol M. , Dauer William T.
Published: January 2009

Neurodegenerative illnesses such as Parkinson and Alzheimer disease are an increasingly prevalent problem in aging societies, yet no therapies exist that retard or prevent neurodegeneration. Dominant missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson disease (PD), but the mechanisms by which mutant forms of LRRK2 disrupt neuronal function and cause cell death remain poorly understood. We report that LRRK2 interacts with the death adaptor Fas-associated protein with death domain (FADD), and that in primary neuronal culture LRRK2-mediated neurodegeneration is prevented by the functional inhibition of FADD or depletion of caspase-8, two key elements of the extrinsic cell death pathway. This pathway is activated by disease-triggering mutations, which enhance the LRRK2-FADD association and the consequent recruitment and activation of caspase-8. These results establish a direct molecular link between a mutant PD gene and the activation of programmed cell death signaling, and suggest that FADD/caspase-8 signaling contributes to LRRK2-induced neuronal death.
Opposing Aminergic Modulation of Distinct Spinal Locomotor Circuits and Their Functional Coupling during Amphibian Metamorphosis
Authors: Rauscent Aude , Einum James , Le Ray Didier , Simmers John , Combes Denis
Published: January 2009

The biogenic amines serotonin (5-HT) and noradrenaline (NA) are well known modulators of central pattern-generating networks responsible for vertebrate locomotion. Here we have explored monoaminergic modulation of the spinal circuits that generate two distinct modes of locomotion in the metamorphosing frogXenopus laevis. At metamorphic climax when propulsion is achieved by undulatory larval tail movements and/or by kicking of the newly developed adult hindlimbs, the underlying motor networks remain spontaneously activein vitro, producing either separate fast axial and slow appendicular rhythms or a single combined rhythm that drives coordinated tail-based and limb-based swimmingin vivo. In isolated spinal cords already expressing distinct axial and limb rhythms, bath-applied 5-HT induced coupled network activity through an opposite slowing of axial rhythmicity (by increasing motoneuron burst and cycle durations) and an acceleration of limb rhythmicity (by decreasing burst and cycle durations). In contrast, in preparations spontaneously expressing coordinated fictive locomotion, exogenous NA caused a dissociation of spinal activity into separate faster axial and slower appendicular rhythms by decreasing and increasing burst and cycle durations, respectively. Moreover, in preparations from premetamorphic and postmetamorphic animals that express exclusively axial-based or limb-based locomotion, 5-HT and NA modified the developmentally independent rhythms in a similar manner to the amines' opposing effects on the coexisting circuits at metamorphic climax. Thus, by exerting differential modulatory actions on one network that are opposite to their influences on a second adjacent circuit, these two amines are able to precisely regulate the functional relationship between different rhythmogenic networks in a developing vertebrate's spinal cord.
SustainedIn VivoInhibition of Protein Domains Using Single-Chain Fv Recombinant Antibodies and Its Application to Dissect RGMa Activity on Axonal Outgrowth
Authors: Tassew Nardos G. , Charish Jason , Chestopalova Larisa , Monnier Philippe P.
Published: January 2009

Antibodies are powerful tools for delineating the specific function of protein domains, yet several limitations restrict theirin vivoapplicability. Here we present a new method to obtain sustainedin vivoinhibition of specific protein domains using recombinant antibodies. We show that long termin vivoexpression of single-chain Fv (scFv) fragments in the developing CNS can be achieved through retroviral transduction. Moreover, specific scFvs generated against the N- and C-terminal domains of the repulsive guidance molecule, RGMa, prevent proper axon targeting in the visual system. This work reveals a previously unappreciated role for the RGMa N-terminal domain in axon guidance, and provides a novel, broadly applicable and rapid procedure to functionally antagonize any protein domainin vivo.
Synaptopodin Regulates Plasticity of Dendritic Spines in Hippocampal Neurons
Authors: Vlachos Andreas , Korkotian Eduard , Schonfeld Eldi , Copanaki Ekaterini , Deller Thomas , Segal Menahem
Published: January 2009

The spine apparatus is an essential component of dendritic spines of cortical and hippocampal neurons, yet its functions are still enigmatic. Synaptopodin (SP), an actin-binding protein, is tightly associated with the spine apparatus and it may play a role in synaptic plasticity, but it has not yet been linked mechanistically to synaptic functions. We studied endogenous and transfected SP in dendritic spines of cultured hippocampal neurons and found that spines containing SP generate larger responses to flash photolysis of caged glutamate than SP-negative ones. An NMDA-receptor-mediated chemical long-term potentiation caused the accumulation of GFP-GluR1 in spine heads of control but not of shRNA-transfected, SP-deficient neurons. SP is linked to calcium stores, because their pharmacological blockade eliminated SP-related enhancement of glutamate responses, and release of calcium from stores produced an SP-dependent increase of GluR1 in spines. Thus, SP plays a crucial role in the calcium store-associated ability of neurons to undergo long-term plasticity.
Genesis and Architecture of the GTTM Project
Authors: Lerdahl Fred
Published: January 2009

I EXAMINE THE INTELLECTUAL AND MUSIC-THEORETIC origins of A Generative Theory of Tonal Music (Lerdahl & Jackendoff, 1983) and review the crucial steps in theory construction that led to its overall architecture. This leads to a discussion of how shortcomings in GTTM motivated developments in Tonal Pitch Space (Lerdahl, 2001). I conclude with a diagram that encompasses the major components of the expanded GTTM/TPS theory.
Tonal Priming Beyond Tonics
Authors: Marmel Frédéric , Tillmann Barbara
Published: January 2009

THE MUSICAL PRIMING PARADIGM ALLOWS FOR INVESTIGATION of listeners' expectations based on their implicit knowledge of tonal stability. To date, priming data are limited to reports of facilitated processing for tonic over nontonic events. The special status of the tonic as a cognitive reference point brings into question the subtlety of listeners' tonal knowledge: Is the facilitated processing observed in priming studies limited to tonic events, or is tone processing influenced by subtler tonal contrasts? The present study investigated tonal priming for mediants (the third scale degree) over leading tones (the seventh scale degree) presented in melodic contexts. Experiment 1 used a timbre discrimination task and Experiment 2 an intonation task. Facilitated processing was observed for the more tonally stable mediants over the less stable leading tones, thus showing that priming effects are not limited to pairs of tonal degrees including the tonic. This finding emphasizes the subtlety of nonexpert listeners' tonal knowledge.
On Listening to Atonal Variants of Two Piano Sonatas by Beethoven
Authors: Lalitte Philippe , Bigand Emmanuel , Kantor-Martynuska Joanna , Delbé Charles
Published: January 2009

WE INVESTIGATED THE CONTRIBUTION OF TONAL relationships to the perception of musical ideas and to the feelings of "arousal." Two excerpts of piano sonatas by Beethoven and two atonal variants were used as experimental stimuli. This manipulation destroyed the tonal relationships but preserved both the local and global temporal organization (rhythm and formal). Listeners were asked to indicate the onset of musical ideas, to estimate the arousing properties of the music in a continuous response task, and to rate the similarity of the pieces. A drastic change in the pitch structure strongly affected judgments of similarity. However, it had no effect on the segmentation of musical ideas, nor on the response of arousal. This finding emphasizes the importance of local and global levels of temporal structures on perceptual and emotional judgments, at the cost of the influence of tonal relationships.
Music Training Facilitates Lexical Stress Processing
Authors: Kolinsky Régine , Cuvelier Héléne , Goetry Vincent , Peretz Isabelle , Morais José
Published: January 2009

WE INVESTIGATED WHETHER MUSIC TRAINING facilitates the processing of lexical stress in natives of a language that does not use lexical stress contrasts. Musically trained (musicians) or untrained (nonmusicians) French natives were presented with two tasks: speeded classification that required them to focus on a segmental contrast and ignore irrelevant stress variations, and sequence repetition involving either segmental or stress contrasts. In the latter situation, French natives are usually "deaf" to lexical stress, but this was less the case for musicians, demonstrating that music expertise enhances sensitivity to stress contrasts. This increased sensitivity does not seem, however, to unavoidably bias musicians' attention to stress contrasts: in segmental-based speeded classification, musicians were not more affected than nonmusicians by irrelevant stress variations when overall performance was controlled for. Implications regarding both the notion of modularity of processing and the advantage that musicianship may afford for second language learning are discussed.
Temporal Semiotic Units as Minimal Meaningful Units in Music? An Electrophysiological Approach
Authors: Frey Aline , Marie Céline , Prod'Homme Lucie , Timsit-Berthier Martine , Schön Daniele , Besson Mireille
Published: January 2009

THE AIM OF THIS STUDY WAS TO DETERMINE WHETHER conceptual priming occurs between successively presented short musical pieces called Temporal Semantic Units (TSUs). Behavioral and ERP data were recorded while participants, experts and nonexperts in TSUs, were listening to pairs of TSUs and were asked to determine whether the target TSU evoked the same or a different concept than the prime TSU. Target TSUs were either congruous (i.e., they developed the same musical concept as the prime TSUs) or incongruous (i.e., they started as congruous TSUs but shifted midstream into a different concept). Results showed that, whereas P3a components were elicited in both groups by the shifting into incongruous TSUs, thereby reflecting an automatic shift of attention when the changes occurred, P3b components were elicited in experts and N400-like components were found in nonexperts. The functional significance of these results is discussed in regard of previous results with environmental sounds.
All the Pain and Joy of the World in a Single Melody: A Transylvanian Case Study on Musical Emotion
Authors: Baraldi Filippo Bonini
Published: January 2009

THE STUDY OF MUSICAL EMOTIONS IS A CHALLENGE for psychology and neuroscience, but the ethnomusicological account is often excluded from the debate. The present article focuses on types of performances that differ from the model of Western classical music: weddings and funerals in a Gypsy community of Transylvania. Analysis of musical activity and expression of emotions in these contexts showed that aesthetic meanings are transformed when music is embedded in social action: the same tunes are played while people dance at weddings and while they cry at funerals. The major anthropological hypothesis suggested by this study is that music acts in rituals as a means for establishing and reinforcing the emotional experiences of different kinds of relationships. The hypotheses and data are discussed in light of recent psychological research on musical emotion.
Sacrifice Before the Secular
Authors: Sheehan Jonathan
Published: January 2009

Early modern secularism—and early modern religion—are plagued by tales of demystification, where each is made into the other's mutual secret, token of bad faith and self-alienation. This essay hopes to chart an alternative story, by looking at an early modern moment when the practices of legal and theological reason worked in tandem on the problem of sacrifice. Before the secular, it argues, sacrifice did not mark sacrality as such, but was rather the material that helped rethink both the functions of authority and the transactions between contingent humanity and the universal demands of law and God.