bluuebunny/crossref_metadata_2025 huggingface dataset:
G-Protein βγ-Complex Is Crucial for Efficient Signal Amplification in Vision
Authors: Kolesnikov Alexander V. , Rikimaru Loryn , Hennig Anne K. , Lukasiewicz Peter D. , Fliesler Steven J. , Govardovskii Victor I. , Kefalov Vladimir J. , Kisselev Oleg G.
Published: June 2011

A fundamental question of cell signaling biology is how faint external signals produce robust physiological responses. One universal mechanism relies on signal amplification via intracellular cascades mediated by heterotrimeric G-proteins. This high amplification system allows retinal rod photoreceptors to detect single photons of light. Although much is now known about the role of the α-subunit of the rod-specific G-protein transducin in phototransduction, the physiological function of the auxiliary βγ-complex in this process remains a mystery. Here, we show that elimination of the transducin γ-subunit drastically reduces signal amplification in intact mouse rods. The consequence is a striking decline in rod visual sensitivity and severe impairment of nocturnal vision. Our findings demonstrate that transducin βγ-complex controls signal amplification of the rod phototransduction cascade and is critical for the ability of rod photoreceptors to function in low light conditions.
Deletion of Astroglial Dicer Causes Non-Cell-Autonomous Neuronal Dysfunction and Degeneration
Authors: Tao Jifang , Wu Hao , Lin Quan , Wei Weizheng , Lu Xiao-Hong , Cantle Jeffrey P. , Ao Yan , Olsen Richard W. , Yang X. William , Mody Istvan , Sofroniew Michael V. , Sun Yi E.
Published: June 2011

The endoribonuclease, Dicer, is indispensable for generating the majority of mature microRNAs (miRNAs), which are posttranscriptional regulators of gene expression involved in a wide range of developmental and pathological processes in the mammalian CNS. Although functions of Dicer-dependent miRNA pathways in neurons and oligodendrocytes have been extensively investigated, little is known about the role of Dicer in astrocytes. Here, we report the effect of Cre-loxP-mediated conditional deletion ofDicerselectively from postnatal astroglia on brain development. Dicer-deficient mice exhibited normal motor development and neurological morphology before postnatal week 5. Thereafter, mutant mice invariably developed a rapidly fulminant neurological decline characterized by ataxia, severe progressive cerebellar degeneration, seizures, uncontrollable movements, and premature death by postnatal week 9–10. Integrated transcription profiling, histological, and functional analyses of cerebella showed that deletion ofDicerin cerebellar astrocytes altered the transcriptome of astrocytes to be more similar to an immature or reactive-like state before the onset of neurological symptoms or morphological changes. As a result, critical and mature astrocytic functions including glutamate uptake and antioxidant pathways were substantially impaired, leading to massive apoptosis of cerebellar granule cells and degeneration of Purkinje cells. Collectively, our study demonstrates the critical involvement of Dicer in normal astrocyte maturation and maintenance. Our findings also reveal non-cell-autonomous roles of astrocytic Dicer-dependent pathways in regulating proper neuronal functions and implicate that loss of or dysregulation of astrocytic Dicer-dependent pathways may be involved in neurodegeneration and other neurological disorders.
Social Bonding Decreases the Rewarding Properties of Amphetamine through a Dopamine D1 Receptor-Mediated Mechanism
Authors: Liu Yan , Young Kimberly A. , Curtis J. Thomas , Aragona Brandon J. , Wang Zuoxin
Published: June 2011

Although the protective effects of social bonds on drug use/abuse have been well documented, we know little about the underlying neural mechanisms. Using the prairie vole (Microtus ochrogaster)—a socially monogamous rodent that forms long-term pair bonds after mating—we demonstrate that amphetamine (AMPH) conditioning induced a conditioned place preference (CPP) in sexually naive (SN), but not pair-bonded (PB), males. Although AMPH treatment induced a similar magnitude of dopamine release in the nucleus accumbens (NAcc) of SN and PB males, it had differential effects on NAcc D1 receptor (D1R) binding. Specifically, AMPH treatment increased D1R binding in SN, but decreased D1R binding in PB males. NAcc D1R, but not D2 receptor, antagonism blocked AMPH-induced CPP in SN males and NAcc D1R activation before AMPH conditioning enabled AMPH-induced CPP in PB males. Together, our data demonstrate that pair-bonding experience decreases the rewarding properties of AMPH through a D1R-mediated mechanism.
The Cytoskeletal Adaptor Protein Band 4.1B Is Required for the Maintenance of Paranodal Axoglial Septate Junctions in Myelinated Axons
Authors: Buttermore Elizabeth D. , Dupree Jeffrey L. , Cheng JrGang , An Xiuli , Tessarollo Lino , Bhat Manzoor A.
Published: June 2011

Precise targeting and maintenance of axonal domains in myelinated axons is essential for saltatory conduction. Caspr and Caspr2, which localize at paranodal and juxtaparanodal domains, contain binding sites for the cytoskeletal adaptor protein 4.1B. The exact role of 4.1B in the organization and maintenance of axonal domains is still not clear. Here, we report the generation and characterization of4.1B-null mice. We show that loss of 4.1B in the PNS results in mislocalization of Caspr at paranodes and destabilization of paranodal axoglial septate junctions (AGSJs) as early as postnatal day 30. In the CNS, Caspr localization is progressively disrupted and ultrastructural analysis showed paranodal regions that were completely devoid of AGSJs, with axolemma separated from the myelin loops, and loops coming off the axolemma. Most importantly, our phenotypic analysis of previously generated4.1Bmutants, used in the study by Horresh et al. (2010), showed that Caspr localization was not affected in the PNS, even after 1 year; and 4.1R was neither expressed, nor enriched at the paranodes. Furthermore, ultrastructural analysis of these4.1Bmutants showed destabilization of CNS AGSJs at ∼1 year. We also discovered that the4.1Blocus is differentially expressed in the PNS and CNS, and generates multiple splice isoforms in the PNS, suggesting 4.1B may function differently in the PNS versus CNS. Together, our studies provide direct evidence that 4.1B plays a pivotal role in interactions between the paranodal AGSJs and axonal cytoskeleton, and that 4.1B is critically required for long-term maintenance of axonal domains in myelinated axons.
Phosphoinositide 3-Kinase Enhancer Regulates Neuronal Dendritogenesis and Survival in Neocortex
Authors: Bun Chan Chi , Liu Xia , Pradoldej Sompol , Hao Chunhai , An Jie , Yepes Manuel , Luo Hongbo R. , Ye Keqiang
Published: June 2011

Phosphoinositide 3-kinase enhancer (PIKE) binds and enhances phosphatidylinositol 3-kinase (PI3K)/Akt activities. However, its physiological functions in brain have never been explored. Here we show that PIKE is important in regulating the neuronal survival and development of neocortex. During development, enhanced apoptosis is observed in the ventricular zone ofPIKEknock-out (PIKE−/−) cortex. Moreover,PIKE−/−neurons show reduced dendritic complexity, dendritic branch length, and soma size. These defects are due to the reduced PI3K/Akt activities inPIKE−/−neurons, as the impaired dendritic arborization can be rescued when PI3K/Akt cascade is augmentedin vitroor inPIKE−/−PTEN−/−double-knock-out mice. Interestingly,PIKE−/−mice display behavioral abnormality in locomotion and spatial navigation. Because of the diminished PI3K/Akt activities,PIKE−/−neurons are more vulnerable to glutamate- or stroke-induced neuronal cell death. Together, our data established the critical role of PIKE in regulating neuronal survival and development by substantiating the PI3K/Akt pathway.
Girdin Is an Intrinsic Regulator of Neuroblast Chain Migration in the Rostral Migratory Stream of the Postnatal Brain
Authors: Wang Yun , Kaneko Naoko , Asai Naoya , Enomoto Atsushi , Isotani-Sakakibara Mayu , Kato Takuya , Asai Masato , Murakumo Yoshiki , Ota Haruko , Hikita Takao , Namba Takashi , Kuroda Keisuke , Kaibuchi Kozo , Ming Guo-li , Song Hongjun , Sawamoto Kazunobu , Takahashi Masahide
Published: June 2011

In postnatally developing and adult brains, interneurons of the olfactory bulb (OB) are continuously generated at the subventricular zone of the forebrain. The newborn neuroblasts migrate tangentially to the OB through a well defined pathway, the rostral migratory stream (RMS), where the neuroblasts undergo collective migration termed “chain migration.” The cell-intrinsic regulatory mechanism of neuroblast chain migration, however, has not been uncovered. Here we show that mice lacking the actin-binding Akt substrate Girdin (a protein that interacts with Disrupted-In-Schizophrenia 1 to regulate neurogenesis in the dentate gyrus) have profound defects in neuroblast chain migration along the RMS. Analysis of two gene knock-in mice harboring Girdin mutants identified unique amino acid residues in Girdin's C-terminal domain that are responsible for the regulation of neuroblast chain migration but revealed no apparent requirement of Girdin phosphorylation by Akt. Electron microscopic analyses demonstrated the involvement of Girdin in neuroblast cell–cell interactions. These findings suggest that Girdin is an important intrinsic factor that specifically governs neuroblast chain migration along the RMS.
Protein Kinase CK2 Increases Glutamatergic Input in the Hypothalamus and Sympathetic Vasomotor Tone in Hypertension
Authors: Ye Zeng-You , Li De-Pei , Li Li , Pan Hui-Lin
Published: June 2011

Increased glutamatergic input in the paraventricular nucleus (PVN) is important for high sympathetic outflow in hypertension, but the associated molecular mechanisms remain unclear. Here, we determined the role of protein kinase CK2 (formerly casein kinase II) in increasedN-methyl-d-aspartate receptor (NMDAR) activity in spinally projecting PVN neurons and sympathetic vasomotor tone in spontaneously hypertensive rats (SHRs). The selective CK2 inhibitors 5,6-dichloro-1-β-d-ribofuranosylbenzimidazole (DRB) or 4,5,6,7-tetrabromobenzotriazole (TBB) significantly decreased the frequency of miniature EPSCs (mEPSCs) of labeled PVN neurons in SHRs but not in Wistar-Kyoto (WKY) normotensive rats. Also, DRB abolished the inhibitory effect of the NMDAR antagonist AP5 on the frequency of mEPSCs in SHRs. Treatment with DRB or TBB significantly reduced the amplitude of evoked NMDA-EPSCs but not AMPA-EPSCs in SHRs. Furthermore, DRB significantly decreased the firing activity of PVN neurons in SHRs but not in WKY rats. The membrane protein level of CK2α in the PVN, but not brainstem and prefrontal cortex, was significantly higher in SHRs than in WKY rats. Lowering blood pressure with celiac ganglionectomy in SHRs did not alter the increased CK2α level and the effects of DRB on mEPSCs and NMDA-EPSCs. In addition, intracerebroventricular injection of DRB not only significantly reduced blood pressure and lumbar sympathetic nerve discharges but also eliminated the inhibitory effect of AP5 microinjected into the PVN on sympathetic nerve activity in SHRs. Our findings suggest that augmented CK2 activity critically contributes to increased presynaptic and postsynaptic NMDAR activity in the PVN and elevated sympathetic vasomotor tone in essential hypertension.
Synchronized Bilateral Synaptic Inputs toDrosophila melanogasterNeuropeptidergic Rest/Arousal Neurons
Authors: McCarthy Ellena v. , Wu Ying , deCarvalho Tagide , Brandt Christian , Cao Guan , Nitabach Michael N.
Published: June 2011

Neuropeptide PDF (pigment-dispersing factor)-secreting large ventrolateral neurons (lLNvs) in theDrosophilabrain regulate daily patterns of rest and arousal. These bilateral wake-promoting neurons are light responsive and integrate information from the circadian system, sleep circuits, and light environment. To begin to dissect the synaptic circuitry of the circadian neural network, we performed simultaneous dual whole-cell patch-clamp recordings of pairs of lLNvs. Both ipsilateral and contralateral pairs of lLNvs exhibit synchronous rhythmic membrane activity with a periodicity of ∼5–10 s. This rhythmic lLNvactivity is blocked by TTX, voltage-gated sodium blocker, or α-bungarotoxin, nicotinic acetylcholine receptor antagonist, indicating that action potential-dependent cholinergic synaptic connections are required for rhythmic lLNvactivity. Since injecting current into one neuron of the pair had no effect on the membrane activity of the other neuron of the pair, this suggests that the synchrony is attributable to bilateral inputs and not coupling between the pairs of lLNvs. To further elucidate the nature of these synaptic inputs to lLNvs, we blocked or activated a variety of neurotransmitter receptors and measured effects on network activity and ionic conductances. These measurements indicate the lLNvs possess excitatory nicotinic ACh receptors, inhibitory ionotropic GABAAreceptors, and inhibitory ionotropic GluCl (glutamate-gated chloride) receptors. We demonstrate that cholinergic input, but not GABAergic input, is required for synchronous membrane activity, whereas GABA can modulate firing patterns. We conclude that neuropeptidergic lLNvs that control rest and arousal receive synchronous synaptic inputs mediated by ACh.
Corticospinal Beta-Range Coherence Is Highly Dependent on the Pre-stationary Motor State
Authors: Omlor Wolfgang , Patino Luis , Mendez-Balbuena Ignacio , Schulte-Mönting Jürgen , Kristeva Rumyana
Published: June 2011

During steady muscle contractions, the human sensorimotor cortex generates oscillations in the beta-frequency range (15–30 Hz) that are coherent with the activity of contralateral spinal motoneurons. This corticospinal coherence is thought to favor stationary motor states, but its mode of operation remains elusive. We hypothesized that corticospinal beta-range coherence depends on the sensorimotor processing state before a steady force task and may thus increase after sensorimotor tuning to dynamic force generation. To test this hypothesis we instructed 16 human subjects to compensate static force after rest as well as after compensating predictable or unpredictable dynamic force with their right index finger. We calculated EEG-EMG coherence, cortical motor spectral power, and the motor performance during the force conditions. Corticospinal beta-coherence during stationary force was excessively elevated if the steady-state contraction was preceded by predictable dynamic force instead of rest, and was highest after unpredictable dynamic force. The beta-power decreased from rest to predictable dynamic force, and was lowest during unpredictable dynamic force. The increase in corticospinal beta-coherence showed a significant negative correlation with the preceding change in beta-power. The tuning to dynamic force did not entail an inferior motor performance during static force. The results imply a correlation between corticospinal beta-range coherence and the computational load of the preceding isometric motor engagement. We suggest beta-range coherence provides a functional corticospinal gateway for steady force-related processing that can override cortical states tuned to dynamic force. The modulation of corticospinal beta-range coherence might thus ensure comparable precision of static force in various motor contexts.
Suppressive Mechanisms in Monkey V1 Help to Solve the Stereo Correspondence Problem
Authors: Tanabe Seiji , Haefner Ralf M. , Cumming Bruce G.
Published: June 2011

Neurons encode the depth in stereoscopic images by combining the signals from the receptive fields in the two eyes. Local variations in single images can activate neurons that do not signal the correct disparity (false matches), giving rise to the stereo correspondence problem. We used binocular white-noise stimuli to decompose the responses of monkey primary visual cortex V1 neurons into the elements of a linear–nonlinear model (via spike-triggered covariance analysis). In our population of disparity-selective neurons, we find both excitatory and suppressive elements in many of the neurons. Their binocular receptive fields were aligned in a specific push–pull manner for disparity. We demonstrate that this arrangement reduces the responses to false matches but preserves the responses to true matches. The responses of the cells to the noise stimuli were well explained by a linear summation of the elements, followed by a nonlinearity. This model also explained the shape of independently measured disparity-tuning curves, although it overestimated the response magnitude. This study constitutes the first direct physiological evidence for the contribution of suppressive mechanisms to disparity selectivity. This new mechanism contributes to solving the stereo correspondence problem.
Cav1.3 Calcium Channels Are Required for Normal Development of the Auditory Brainstem
Authors: Hirtz Jan J. , Boesen Michael , Braun Nadine , Deitmer Joachim W. , Kramer Florian , Lohr Christian , Müller Britta , Nothwang Hans Gerd , Striessnig Jörg , Löhrke Stefan , Friauf Eckhard
Published: June 2011

Within the Cav1 family of voltage-gated calcium channels, Cav1.2 and Cav1.3 channels are the predominant subtypes in the brain. Whereas specific functions for each subtype were described in the adult brain, their role in brain development is poorly understood. Here we assess the role of Cav1.3 subunits in the activity-dependent development of the auditory brainstem. We used Cav1.3-deficient (Cav1.3−/−) mice because these mice lack cochlea-driven activity that deprives the auditory centers from peripheral input. We found a drastically reduced volume in all auditory brainstem centers (range 25–59%, total 35%), which was manifest before hearing onset. A reduction was not obvious outside the auditory system. The lateral superior olive (LSO) was strikingly malformed in Cav1.3−/−mice and had fewer neurons (1/3 less). The remaining LSO neurons displayed normal dendritic trees and received functional glutamatergic input, yet they fired action potentials predominantly with a multiple pattern upon depolarization, in contrast to the single firing pattern prevalent in controls. The latter finding appears to be due to a reduction of dendrototoxin-sensitive potassium conductances, presumably mediated through the Kv1.2 subtype. Fura2 imaging provided evidence for functional Cav1.3 channels in the LSO of wild-type mice. Our results imply that Cav1.3 channels are indispensable for the development of the central auditory system. We propose that the unique LSO phenotype in Cav1.3−/−mice, which hitherto was not described in other hereditary deafness models, is caused by the synergistic contribution of two factors: on-site loss of Cav1.3 channels in the neurons plus lack of peripheral input.
The Cross-Modal Spread of Attention Reveals Differential Constraints for the Temporal and Spatial Linking of Visual and Auditory Stimulus Events
Authors: Donohue Sarah E. , Roberts Kenneth C. , Grent-‘t-Jong Tineke , Woldorff Marty G.
Published: June 2011

The integration of multisensory information has been shown to be guided by spatial and temporal proximity, as well as to be influenced by attention. Here we used neural measures of the multisensory spread of attention to investigate the spatial and temporal linking of synchronous versus near-synchronous auditory and visual events. Human participants attended selectively to one of two lateralized visual-stimulus streams while task-irrelevant tones were presented centrally. Electrophysiological measures of brain activity showed that tones occurring simultaneously or delayed by 100 ms were temporally linked to an attended visual stimulus, as reflected by robust cross-modal spreading-of-attention activity, but not when delayed by 300 ms. The neural data also indicated a ventriloquist-like spatial linking of the auditory to the attended visual stimuli, but only when occurring simultaneously. These neurophysiological results thus provide unique insight into the temporal and spatial principles of multisensory feature integration and the fundamental role attention plays in such integration.
Superior Colliculus Inactivation Alters the Weighted Integration of Visual Stimuli
Authors: Nummela Samuel U. , Krauzlis Richard J.
Published: June 2011

The primate superior colliculus (SC) is important for the winner-take-all selection of targets for orienting movements. Such selection takes time, however, and the earliest motor responses typically are guided by a weighted vector average of the visual stimuli, before the winner-take-all selection of a single target. We tested whether SC activity plays a role in this initial stage of orienting by inactivating the SC in two macaques (Macaca mulatta) with local muscimol injections. After SC inactivation, initial orienting responses still followed a vector average, but the contribution of the visual stimulus inside the affected field was decreased, and the contribution of the stimulus outside the affected field was increased. These results demonstrate that the SC plays an important role in the weighted integration of visual signals for orienting, in addition to its role in the winner-take-all selection of the target.
Brain Modularity in Arthropods: Individual Neurons That Support “What” But Not “Where” Memories
Authors: Sztarker Julieta , Tomsic Daniel
Published: June 2011

Experiments with insects and crabs have demonstrated their remarkable capacity to learn and memorize complex visual features (Giurfa et al., 2001; Pedreira and Maldonado, 2003; Chittka and Niven, 2009). Such abilities are thought to require modular brain processing similar to that occurring in vertebrates (Menzel and Giurfa, 2001). Yet, physiological evidence for this type of functioning in the small brains of arthropods is still scarce (Liu et al., 1999, 2006; Menzel and Giurfa, 2001). In the crabChasmagnathus granulatus, the learning rate as well as the long-term memory of a visual stimulus has been found to be reflected in the performance of identified lobula giant neurons (LGs) (Tomsic et al., 2003). The memory can only be evoked in the training context, indicating that animals store two components of the learned experience, one related to the visual stimulus and one related to the visual context (Tomsic et al., 1998; Hermitte et al., 1999). By performing intracellular recordings in the intact animal, we show that the ability of crabs to generalize the learned stimulus into new space positions and to distinguish it from a similar but unlearned stimulus, two of the main attributes of stimulus memory, is reflected by the performance of the LGs. Conversely, we found that LGs do not support the visual context memory component. Our results provide physiological evidence that the memory traces regarding “what” and “where” are stored separately in the arthropod brain.
Attention Improves Encoding of Task-Relevant Features in the Human Visual Cortex
Authors: Jehee Janneke F. M. , Brady Devin K. , Tong Frank
Published: June 2011

When spatial attention is directed toward a particular stimulus, increased activity is commonly observed in corresponding locations of the visual cortex. Does this attentional increase in activity indicate improved processing of all features contained within the attended stimulus, or might spatial attention selectively enhance the features relevant to the observer's task? We used fMRI decoding methods to measure the strength of orientation-selective activity patterns in the human visual cortex while subjects performed either an orientation or contrast discrimination task, involving one of two laterally presented gratings. Greater overall BOLD activation with spatial attention was observed in visual cortical areas V1–V4 for both tasks. However, multivariate pattern analysis revealed that orientation-selective responses were enhanced by attention only when orientation was the task-relevant feature and not when the contrast of the grating had to be attended. In a second experiment, observers discriminated the orientation or color of a specific lateral grating. Here, orientation-selective responses were enhanced in both tasks, but color-selective responses were enhanced only when color was task relevant. In both experiments, task-specific enhancement of feature-selective activity was not confined to the attended stimulus location but instead spread to other locations in the visual field, suggesting the concurrent involvement of a global feature-based attentional mechanism. These results suggest that attention can be remarkably selective in its ability to enhance particular task-relevant features and further reveal that increases in overall BOLD amplitude are not necessarily accompanied by improved processing of stimulus information.
Olfactory Cortex Generates Synchronized Top-Down Inputs to the Olfactory Bulb during Slow-Wave Sleep
Authors: Manabe Hiroyuki , Kusumoto-Yoshida Ikue , Ota Mizuho , Mori Kensaku
Published: June 2011

The olfactory cortex is functionally isolated from the external odor world during slow-wave sleep. However, the neuronal activity pattern in the olfactory cortex and its functional roles during slow-wave sleep are not well understood. Here, we demonstrate in freely behaving rats that the anterior piriform cortex, a major area of the olfactory cortex, repeatedly generates sharp waves that are accompanied by synchronized discharges of numerous cortical neurons. Olfactory cortex sharp waves occurred relatively independently of hippocampal sharp waves. Current source density analysis showed that sharp wave generation involved the participation of recurrent association fiber synapses to pyramidal cells in the olfactory cortex. During slow-wave sleep, the olfactory bulb showed sharp waves that were in synchrony with olfactory cortex sharp waves, indicating that olfactory cortex sharp waves drove synchronized top-down inputs to the olfactory bulb. Based on these results, we speculate that the olfactory cortex sharp waves may play a role in the reorganization of bulbar neuronal circuits during slow-wave sleep.
TLR4 gene polymorphisms: evidence for protection against type 2 diabetes but not for diabetes-associated ischaemic heart disease
Authors: Manolakis A C , Kapsoritakis A N , Tiaka E K , Sidiropoulos A , Gerovassili A , Satra M , Vamvakopoulou D , Tsiopoulos F , Papanas N , Skoularigis I , Potamianos S P , Vamvakopoulos N
Published: June 2011

Objective

Several factors either predisposing or protecting from the onset of diabetes mellitus type 2 (DM2) have been proposed. Two specific polymorphisms of toll-like receptor 4 (TLR4; Asp299Gly and Thr399Ile) have recently been identified either as candidate protector genes against DM2 and associated neuropathy or risk alleles for the manifestation of diabetic retinopathy. The impact of these alleles on the risk for ischaemic heart disease (IHD) is controversial while their role in diabetes-associated IHD has never been studied.

Design and methods

In order to clarify the potential impact of TLR4 polymorphisms on the predisposition for DM2 as well as on diabetes-related IHD vulnerability, the distribution of the mutant TLR4 Asp299Gly and Thr399Ile alleles in 286 DM2 patients and 413 non-DM2 controls with or without IHD, was examined.

Results

Mutant alleles were predominantly detected in 79/413 non-diabetic individuals versus 15/286 DM2 patients (P<0.0001). The rates of positivity for mutant alleles were similar among diabetic patients with or without IHD (7/142 vs 8/144, P>0.1), whereas they proved different among non-diabetic individuals with or without IHD (39/145 vs 40/268, P=0.004). Following multivariate analysis, the difference between diabetic and non-diabetic subjects, with regard to TLR4 mutations alone, remained significant (P=0.04).

Conclusions

Mutant TLR4 alleles confer protection against DM2. However, their presence does not seem to play any role, protective or aggravating, in the manifestation of IHD either in diabetic or in non-diabetic individuals.
Aromatase promoter I.f is regulated by progesterone receptor in mouse hypothalamic neuronal cell lines
Authors: Yilmaz M Bertan , Wolfe Andrew , Zhao Hong , Brooks David C , Bulun Serdar E
Published: June 2011

Aromatase catalyzes the conversion of C19steroids to estrogens. Aromatase and progesterone, both of which function at different steps of steroidogenesis, are crucial for the sexually dimorphic development of the fetal brain and the regulation of gonadotropin secretion and sexual interest in adults. The aromatase gene (Cyp19a1) is selectively expressed in distinct neurons of the mouse hypothalamus through a distal brain-specific promoter, I.f, located ∼40 kb upstream of the coding region. However, the regulation of aromatase expression in the brain is not well understood. In this study, we investigated a short feedback effect of progesterone analogues on aromatase mRNA expression and enzyme activity in estrogen receptor α (Esr1)-positive or -negative mouse embryonic hypothalamic neuronal cell lines that express aromatase via promoter I.f. In a hypothalamic neuronal cell line that highly expresses aromatase, progesterone receptor (Pgr), and Esr1, a progesterone agonist, R5020, inhibited aromatase mRNA level and enzyme activity. The inhibitory effect of R5020 was reversed by its antagonist, RU486. Deletion mutants of promoter I.f suggested that inhibition of aromatase expression by progesterone is conferred by the nt −1000/−500 region, and R5020 enhanced binding of Pgr to the nt −800/−600 region of promoter I.f. Small interfering RNA knockdown ofPgreliminated progesterone-dependent inhibition of aromatase mRNA and enzyme activity. Taken together, progesterone enhances recruitment of Pgr to specific regions of the promoter I.f ofCyp19a1and regulates aromatase expression in hypothalamic neurons.
Capital accumulation and growth in Hungary, 1924–2006
Authors: Leeuwen B. , Földvári P.
Published: June 2011

The objective of this paper is to analyse the role of both human and physical capital in economic growth in Hungary during the 20thcentury by extending the already available data on physical and human capital. Besides the standard measure for the volume of human capital, we develop a simple method to estimate the value of the human capital stock in Hungary between 1924 and 2006. While the volume index slowly grows over time, the value of human capital shows a decline during the late socialist period. Applying the value of human capital in a growth accounting analysis, we find that the Solow residual has no long-run effect on economic growth anymore.
Diagonal cumulation of origin as an institutional incentive mechanism for cost optimisation in contemporary international business
Authors: Jurše M. , Logožar K. , Ključevšek M. , Korez-Vide R.
Published: June 2011

In the emerging process of market globalisation, firms’ strategic options for optimising their cross-border operations have broadened. This paper presents a strategic framework for developing an appropriate strategic response of firms by relocating their production facilities and framing their operational procedures in such a way that they may, as eligible beneficiaries, exploit institutional incentive mechanisms available in a specific region or a host country. More specifically, in the paper we explore a strategic option for lowering firms’ operational costs through international operations by using the mechanism of diagonal cumulation of origin introduced by the European Union (EU) in its Common Commercial Policy towards selected non-member countries. Despite extensive discussions in theoretical literature on the conception of the rules of origin, only a few studies have explored the implications of this mechanism from the perspective of a firm’s transaction costs in international business. This paper shows that the ‘SAP+ diagonal cumulation of origin,’ when properly conceived and implemented by a firm, can positively affect its financial performance. By analysing the cost-effect simulation of a selected household appliance producer in the presented case study, we then discuss the key strategic and operational implications for firms wishing to take advantage of offered supranational institutional incentive mechanisms.
THE EFFECTS OF EXERGAMING ON PHYSICAL ACTIVITY AMONG INACTIVE CHILDREN IN A PHYSICAL EDUCATION CLASSROOM
Authors: Fogel Victoria A. , Miltenberger Raymond G. , Graves Rachel , Koehler Shannon
Published: June 2011

Childhood obesity, which is due in part to lack of physical activity, is a serious concern that requires the attention of the behavioral community. Although excessive video game play has been noted in the literature as a contributor to childhood obesity, newer video gaming technology, called exergaming, has been designed to capitalize on the reinforcing effects of video games to increase physical activity in children. This study evaluated the effects of exergaming on physical activity among 4 inactive children in a physical education (PE) classroom. Results showed that exergaming produced substantially more minutes of physical activity and more minutes of opportunity to engage in physical activity than did the standard PE program. In addition, exergaming was socially acceptable to both the students and the PE teacher. Exergaming appears to hold promise as a method for increasing physical activity among inactive children and might be a possible intervention for childhood obesity.
USING THE STIMULUS EQUIVALENCE PARADIGM TO TEACH COURSE MATERIAL IN AN UNDERGRADUATE REHABILITATION COURSE
Authors: Walker Brooke D. , Rehfeldt Ruth Anne , Ninness Chris
Published: June 2011

In 2 experiments, we examined whether the stimulus equivalence instructional paradigm could be used to teach relations among names, definitions, causes, and common treatments for disabilities using a selection‐based intraverbal training format. Participants were pre‐ and posttested on vocal intraverbal relations and were trained using multiple‐choice worksheets in which selection‐based intraverbal relations were taught and feedback was delivered until mastery. Most participants in Experiment 1 showed the emergence of vocal intraverbal relations, but responding did not generalize to final written intraverbal tests. Participants in Experiment 2 showed the emergence of not only vocal intraverbal relations but also written intraverbal relations on final tests. Results suggest that the stimulus equivalence paradigm can be effectively implemented using a selection‐based intraverbal training format, the protocol may be an effective means of emphasizing important concepts in a college course, and emergent skills may generalize to novel response topographies.
DEVELOPMENT AND MODIFICATION OF A RESPONSE CLASS VIA POSITIVE AND NEGATIVE REINFORCEMENT: A TRANSLATIONAL APPROACH
Authors: Mendres Amber E. , Borrero John C.
Published: June 2011

When responses function to produce the same reinforcer, a response class exists. Researchers have examined response classes in applied settings; however, the challenges associated with conducting applied research on response class development have recently necessitated the development of an analogue response class model. To date, little research has examined response classes that are strengthened by negative reinforcement. The current investigation was designed to develop a laboratory model of a response class through positive reinforcement (i.e., points exchangeable for money) and through negative reinforcement (i.e., the avoidance of scheduled point losses) with 11 college students as participants and clicks as the operant. Results of both the positive and negative reinforcement evaluations showed that participants usually selected the least effortful response that produced points or the avoidance of point losses, respectively. The applied implications of the findings are discussed, along with the relevance of the present model to the study of punishment and resurgence.
SPOON DISTANCE FADING WITH AND WITHOUT ESCAPE EXTINCTION AS TREATMENT FOR FOOD REFUSAL
Authors: Rivas Kristi D. , Piazza Cathleen C. , Patel Meeta R. , Bachmeyer Melanie H.
Published: June 2011

Little is known about the characteristics of meals that serve as motivating operations (MOs) for escape behavior. In the current investigation, we showed that the distance at which a therapist held a spoon from a child's lips served as an MO for escape behavior. Based on these results, we implemented spoon distance fading, compared fading with and without escape extinction (EE), and compared fading plus EE to EE alone. Initially, inappropriate mealtime behavior decreased during fading, but this effect was not maintained as fading progressed. Inappropriate mealtime behavior was lower initially when we combined fading and EE relative to EE alone, but acceptance increased more rapidly with EE than with fading plus EE. These results suggest that a number of mealtime characteristics might function as MOs for escape behavior and that analyses of MOs may be useful for developing treatments for food refusal.
INCREASING THE VOCAL RESPONSES OF CHILDREN WITH AUTISM AND DEVELOPMENTAL DISABILITIES USING MANUAL SIGN MAND TRAINING AND PROMPT DELAY
Authors: Carbone Vincent J. , Sweeney‐Kerwin Emily J. , Attanasio Vivian , Kasper Tamara
Published: June 2011

The purpose of this study was to determine the effect of manual sign mand training combined with prompt delay and vocal prompting on the production of vocal responses in nonvocal children with developmental disabilities. A multiple baseline design across participants verified the effectiveness of this intervention. All participants showed increases in vocal responses following the implementation of the independent variables.
THE EFFECTS OF RESPONSE EFFORT ON SAFE PERFORMANCE BY THERAPISTS AT AN AUTISM TREATMENT FACILITY
Authors: Casella Sarah E. , Wilder David A. , Neidert Pamela , Rey Catalina , Compton Megan , Chong Ivy
Published: June 2011

The effects of response effort on safe behaviors (i.e., glove wearing, hand sanitizing, and electrical outlet replacement) exhibited by therapists at an autism treatment center were examined. Participants were exposed to 2 or 3 levels of effort (i.e., high, medium, low) for each dependent variable. Results showed increased safe performance during the low‐effort conditions relative to other conditions across all dependent variables for all participants.
THE EFFECTS OF BEHAVIORAL SKILLS TRAINING ON MAND TRAINING BY STAFF AND UNPROMPTED VOCAL MANDS BY CHILDREN
Authors: Nigro‐Bruzzi Darlene , Sturmey Peter
Published: June 2011

We evaluated the effects of a training package, including instructions, modeling, rehearsal, and feedback, for training staff members to conduct mand training with children. Experimenters collected data on staff performance on each step of a task analysis of mand training and on unprompted child vocal mands. Training resulted in increases in staff performance in mand training and in unprompted mands by children. We observed replication of these effects across settings for all staff and for 3 of the children.
Chemical Libraries for Virtual Screening
Authors: Lagorce David , Sperandio Olivier , A. Miteva Maria , O. Villoutreix Bruno
Published: June 2011

The number of new drug approvals per year has been decreasing over the past decade for numerous
reasons including an increase in regulatory requirements and lack of sufficient knowledge on the pathophysiological
processes being targeted. Also, many compounds fail in development because they lack efficacy and
safety. One strategy, among many, to circumvent this high attrition rate is through improving the quality of the
compound collections as libraries have usually grown in size with little or inadequate attention about the quality.
There are many different ways to prepare a compound collection, the process can involve increasing diversity but
it can also imply the creation of focused collection dedicated to a specific disease-type and/or target. In parallel,
ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) properties have to be considered and the
parameters assessed tuned according to the project, stage of the project and disease type. In this chapter, in silico
methods facilitating the creation of a generic target-independent compound collections are explored and several in
silico ADMET prediction tools are discussed. Key concepts are described to build a compound collection
appropriate for hit finding. Overall, this procedure involves several steps: database cleaning, compound filtering
step using drug-likeness or lead-likeness criteria, removal of undesirables chemical structures, and structural and
chemical quality control. Because for in silico screening studies the collection has to be in 3D, a paragraph
exposes some recently developed methods for 3D structure generations, and a list of commercial and free
standalone packages as well as online tools is provided.
Structure-Based Virtual Screening
Authors: Sperandio Olivier , O. Villoutreix Bruno , A. Miteva Maria
Published: June 2011

The number of promising macromolecular targets involved in drug discovery programs has
considerably increased because of the recent advances in human genomics and proteomics. In this respect, modern
techniques like virtual screening in combination with high-throughput screening are well established approaches
to assist identification of novel lead compounds. In particular, structure-based virtual screening is widely applied
to search for new hit molecules among a large number of chemical compounds against therapeutically relevant
protein targets with known three-dimensional structures. Here, we introduce the main techniques and programs
applied for structure-based virtual screening with a focus on the molecular docking–scoring methodology and we
discuss key issues that still need to be improved. In addition, we give recent examples of successful applications
of hierarchical structure-based virtual screening methods combined with ligand-based ones.
Fragment-Based Methods for Lead Discovery
Authors: R. Pitt Will , P. Higueruelo Alicia , P. Todorov Nikolay
Published: June 2011

Fragment-based drug discovery (FBDD) has received much attention in recent years by the
pharmaceutical industry and academia. Here published FBDD methods are reviewed with a particular focus on in
silico methods and theoretical approaches. Included are techniques useful at each stage of the process, from
fragment library design, to virtual fragment screening and on to fragment growth and lead generation. The
strengths and weaknesses of FBDD approaches are presented and the benefits of the complementary use of
experimental and computational methods are discussed.
Protein-Protein Interaction Inhibition (2P2I): Mixed Methodologies for the Acceleration of Lead Discovery
Authors: Roche Philippe , Morelli Xavier
Published: June 2011

Protein–Protein Interactions (PPIs) constitute a promising class of targets for drug discovery. Inhibitors
of these original interactions are certainly the next generation of highly innovative drugs that will reach the market
in the next decade. However, the in silico design of such compounds still remains challenging. This review
describes this particular protein-protein interaction chemical space and the main biophysical reasons that make
them challenging targets for the drug discovery process. A state of the art of protein databases and servers
dedicated to PPIs, their analysis and inhibition is also surveyed. It then presents some innovative methodologies
that led to the development of new inhibitors. Finally, different families of protein-protein interactions for which
an inhibitor is known are briefly introduced and potential tracks for the future are proposed such as a new
classification based on protein-protein interfaces with known inhibitors into specific families, with a subsequent
notion of focused databases dedicated to each specific class.
Application of In Silico Methods to Study ABC Transporters Involved in Multidrug Resistance
Authors: Pajeva Ilza , Wiese Michael
Published: June 2011

ABC transporters are involved in variety of processes of physiological and clinical significance.
Besides their function as natural physiological protectors of the living organisms against xenobiotics, they play a
crucial role in drug pharmacokinetics and for the multidrug resistance in tumor cells. The in silico modeling of
ABC transporters is extensively developing in the recent years making use of increasing data about 3D structures
of transport proteins. The chapter describes the most recent achievements in the computational studies starting
from ligand-based design approaches and classification algorithms to homology modeling and docking of ligands.
Many of the models show a satisfying performance shading light on the structure-function relationships of the
proteins and their substrates and inhibitors, as well as generating hypotheses of ligand-protein interactions and
helping in design of further experimental studies. However, a number of problems related to reliability of the
experimental data used for modeling and computational methodologies applied limit the applicability of these
methods for virtual ligand screening. First attempts towards docking of ligands into transporter binding sites are
discussed to illustrate these limitations.
Successful Applications of In Silico Approaches for Lead/Drug Discovery
Authors: Bortolato Andrea , Perruccio Francesca , Moro Stefano
Published: June 2011

Rational drug design approaches represent an important alternative strategy to the discovery of new
therapeutics based on simply serendipity. Computational chemists have to understand the peculiar aspects linked
to the biological system in study and on this basis choose the right collection of complementary in silico
approaches to tackle in the better way the medicinal chemistry problem in study. In this chapter several examples
of successful applications of in silico approaches for lead/drug discovery are presented. In the first paragraph are
discussed interesting structure based methods to design inhibitors of protein kinases, while in the second both
structure and ligand based techniques are exploited in a consensus fashion to develop novel Adenosine A3 receptor
antagonists. The last paragraph presents an overview of ligand based virtual screening and an example of a
successful application of this approach to identify a small molecule agonist of the NTS1 receptor. Even if the
cases reported cannot cover completely the complexity of the computational techniques available nowadays, they
embody different interesting examples useful to understand the potentialities, limits and pitfalls of modern
molecular modeling approaches.
Visualisation and Efficient Communication in Structure-Based Lead Discovery
Authors: Bortolato Andrea , Perruccio Francesca , Moro Stefano
Published: June 2011

A key aspect of efficient scientific research is the efficient accumulation, exchange and
presentation of relevant information. Multi-disciplinary fields of research, such as structure-based lead
discovery (SBLD), depend upon many different data types and require the concurrent capture and
display of such heterogeneous types of data. The visualisation of such data in a more intuitive and
accessible format than the underlying data capture method is often extended to provide the viewer
context within a wider range of data types. In the field of SBLD, experimental protein structure
determination presents a need to visualise three-dimensional data and to further annotate such
visualisations with additional information. The use of high-throughput methods in both chemistry and
biology has resulted in a rapid accumulation of relevant information to support and prioritise SBLD.
The appropriate integration and visualisation of this data maximises the impact of the underlying
information within the context of a project both not only for computational chemists and structural
biologists but also for biologists and medicinal chemists. In this chapter we will discuss current
approaches and outstanding issues associated with this particular challenge in the context of SBLD.