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Many problems arising in image processing and signal recovery with multi-regularization and constraints can be formulated as minimization of a sum of three convex separable functions. Typically, the objective function involves a smooth function with Lipschitz continuous gradient, a linear composite nonsmooth function, and a nonsmooth function. In this paper, we propose a primal-dual fixed point (PDFP) scheme to solve the above class of problems. The proposed algorithm for three-block problems is a symmetric and fully splitting scheme, only involving an explicit gradient, a linear transform, and the proximity operators which may have a closed-form solution. We study the convergence of the proposed algorithm and illustrate its efficiency through examples on fused LASSO and image restoration with non-negative constraint and sparse regularization.

Background Atherosclerosis is a chronic immune-inflammatory disorder and one of the leading causes responsible for cardiovascular morbidity and mortality. Traditional Chinese medicine treatment with multi-targets has shown prospects for the therapeutic effect on atherosclerosis. Thus, this study aims to investigate whether xiaoxianggou has benefit for reducing the atherosclerotic plaque area in endogenous high Ang II ApoE−/− mice and investigated the underlying mechanisms. Methods Endogenous high Ang II ApoE−/− mice model was generated by using two kidney one clip (2K1C). All mice were treated by intragastric administration with xiaoxianggou two times a week for 16 weeks. En face plaque area was analyzed by oil-red O staining. Serum anti-OxLDL antibodies were measured by ELISA assay. Expression of miR-203 and Ets-2 were evaluated using qRT-RCR and western blotting analysis, respectively. Results This study revealed that xiaoxianggou treatment dose-dependently reduced the atherosclerotic plaque area and serum autoantibodies against oxLDL, elevated miR-203 expression and reduced Ets-2 expression in endogenous high Ang II ApoE−/− mice. In primary arterial ECs, Xiaoxianggou reverses the reduced miR-203 expression and the elevated Ets-2 expression induced by AngII, which was further recovered by miR-203 inhibitor. Additionally, miR-203 regulated the expression of Ets-2 by targeting Ets-2-3′ UTR. Moreover, miR-203 inhibitor reversed the reduction of atherosclerotic lesion area induced by Xiaoxianggou. Conclusions These findings present that xiaoxianggou plays an anti-atherosclerotic role in endogenous high Ang II ApoE−/− mice model, which is partly due to its antioxidant actions against atherosclerosis and the inhibition of miR-203 on the expression of Ets-2 in endothelial cells.

An elderly male patient with coronary heart disease underwent coronary angiography, which revealed bilateral severe coronary artery stenosis. Four stents were implanted, and at 5 h post-surgery, typical hemorrhagic shock appeared. Echocardiography verified heavy bleeding in the right thoracic cavity. Emergency angiography excluded injury or perforation of the coronary artery, aorta, right subclavian artery and brachiocephalic artery. Considering the patient's history of chronic obstructive pulmonary disease and severe cough during the operation, it was suspected that hemothorax was induced by a blood vessel rupture in the pleura. Video-assisted thoracic examination confirmed the tearing of pleural adhesion bands and bleeding at three sites in the pulmonary pleura and parietal pleura. According to the reported case, bleeding as a result of the laceration of pleural adhesions is an important cause of hemothorax that should be considered after exclusion of other common causes of pleural hemorrhage.

We extend a primal-dual fixed point algorithm (PDFP) proposed in [5] to solve two kinds of separable multi-block minimization problems, arising in signal processing and imaging science. This work shows the flexibility of applying PDFP algorithm to multi-block problems and illustrate how practical and fully decoupled schemes can be derived, especially for parallel implementation of large scale problems. The connections and comparisons to the alternating direction method of multiplier (ADMM) are also present. We demonstrate how different algorithms can be obtained by splitting the problems in different ways through the classic example of sparsity regularized least square model with constraint. In particular, for a class of linearly constrained problems, which are of great interest in the context of multi-block ADMM, can be solved by PDFP with a guarantee of convergence. Finally, some experiments are provided to illustrate the performance of several schemes derived by the PDFP algorithm.

The reduced movement repertoire of Parkinson's disease (PD) is mainly due to degeneration of nigrostriatal dopamine neurons. Restoration of dopamine transmission by levodopa (L-DOPA) relieves motor symptoms of PD but often causes disabling dyskinesias. Subchronic L-DOPA increases levels of adaptor protein p11 (S100A10) in dopaminoceptive neurons of the striatum. Using experimental mouse models of Parkinsonism, we report here that global p11 knockout (KO) mice develop fewer jaw tremors in response to tacrine. Following L-DOPA, global p11KO mice show reduced therapeutic responses on rotational motor sensitization, but also develop less dyskinetic side effects. Studies using conditional p11KO mice reveal that distinct cell populations mediate these therapeutic and side effects. Selective deletion of p11 in cholinergic acetyltransferase (ChAT) neurons reduces tacrine-induced tremor. Mice lacking p11 in dopamine D2R-containing neurons have a reduced response to L-DOPA on the therapeutic parameters, but develop dyskinetic side effects. In contrast, mice lacking p11 in dopamine D1R-containing neurons exhibit tremor and rotational responses toward L-DOPA, but develop less dyskinesia. Moreover, coadministration of rapamycin with L-DOPA counteracts L-DOPA-induced dyskinesias in wild-type mice, but not in mice lacking p11 in D1R-containing neurons. 6-OHDA lesioning causes an increase of evoked striatal glutamate release in wild type, but not in global p11KO mice, indicating that altered glutamate neurotransmission could contribute to the reduced L-DOPA responsivity. These data demonstrate that p11 located in ChAT or D2R-containing neurons is involved in regulating therapeutic actions in experimental PD, whereas p11 in D1R-containing neurons underlies the development of L-DOPA-induced dyskinesias.

Compressive sensing and sparse approximation have many emerging applications, and are a relatively new driving force for the development of splitting methods in optimization. Many sparse coding problems are well described by variational models with l1-norm penalties and constraints that are designed to promote sparsity. Successful algorithms need to take advantage of the separable structure of potentially complicated objectives by “splitting” them into simpler pieces and iteratively solving a sequence of simpler convex minimization problems. In particular, isolating l1 terms from the rest of the objective leads to simple soft thresholding updates or l1 ball projections. A few basic splitting techniques can be used to design a huge variety of relevant algorithms. This chapter will focus on operator splitting strategies that are based on proximal operators, duality, and alternating direction methods. These will be explained in the context of basis pursuit variants and through compressive sensing applications.

This work deals with the reconstruction of dynamic images that incorporate characteristic dynamics in certain subregions, as arising for the kinetics of many tracers in emission tomography (SPECT, PET). We make use of a basis function approach for the unknown tracer concentration by assuming that the region of interest can be divided into subregions with spatially constant concentration curves. Applying a regularised variational framework reminiscent of the Chan-Vese model for image segmentation we simultaneously reconstruct both the labelling functions of the subregions as well as the subconcentrations within each region. Our particular focus is on applications in SPECT with the Poisson noise model, resulting in a Kullback–Leibler data fidelity in the variational approach. We present a detailed analysis of the proposed variational model and prove existence of minimisers as well as error estimates. The latter apply to a more general class of problems and generalise existing results in literature since we deal with a nonlinear forward operator and a nonquadratic data fidelity. A computational algorithm based on alternating minimisation and splitting techniques is developed for the solution of the problem and tested on appropriately designed synthetic data sets. For those we compare the results to those of standard EM reconstructions and investigate the effects of Poisson noise in the data.

Cognitive impairments are common in depression and involve dysfunctional serotonin neurotransmission. The 5-HT1B receptor (5-HT(1B)R) regulates serotonin transmission, via presynaptic receptors, but can also affect transmitter release at heterosynaptic sites. This study aimed at investigating the roles of the 5-HT(1B)R, and its adapter protein p11, in emotional memory and object recognition memory processes by the use of p11 knockout (p11KO) mice, a genetic model for aspects of depression-related states. 5-HT(1B)R agonist treatment induced an impairing effect on emotional memory in wild type (WT) mice. In comparison, p11KO mice displayed reduced long-term emotional memory performance. Unexpectedly, 5-HT(1B)R agonist stimulation enhanced memory in p11KO mice, and this atypical switch was reversed after hippocampal adeno-associated virus mediated gene transfer of p11. Notably, 5-HT(1B)R stimulation increased glutamatergic neurotransmission in the hippocampus in p11KO mice, but not in WT mice, as measured by both pre- and postsynaptic criteria. Magnetic resonance spectroscopy demonstrated global hippocampal reductions of inhibitory GABA, which may contribute to the memory enhancement and potentiation of pre- and post-synaptic measures of glutamate transmission by a 5-HT(1B)R agonist in p11KO mice. It is concluded that the level of hippocampal p11 determines the directionality of 5-HT(1B)R action on emotional memory processing and modulates hippocampal functionality. These results emphasize the importance of using relevant disease models when evaluating the role of serotonin neurotransmission in cognitive deficits related to psychiatric disorders.

Background Long-term changes in the efficacy of glutamatergic synaptic transmission in reward-related brain regions such as the nucleus accumbens (NAc) are proposed to contribute to neuroadaptations that lead to drug addiction. Although alcohol is a widely used addictive substance, the cellular mechanisms by which it influences synaptic plasticity in the NAc are not elucidated. We therefore examined whether acute ethanol (EtOH) alters long-term potentiation (LTP) in the core region of the NAc and investigated the possible underlying mechanisms. Methods We measured field excitatory postsynaptic potential/population spike (fEPSP/PS) amplitude in mouse brain slices containing the NAc. We also used amperometry to detect, with carbon fiber electrode, evoked dopamine release in brain slices. Results In control slices, high-frequency stimulation (HFS) induced a stable LTP. LTP was reduced in slices perfused with EtOH (50 mM). Given that induction of LTP is dependent on glutamate acting on N-methyl-d-aspartate (NMDA) receptors and group I metabotropic glutamate receptors (mGluRs), we studied the ability of EtOH to modulate these 2 classes of receptors. NMDA (20 μM) depressed the amplitude of the fEPSP/PS, but this effect was not altered by EtOH in our experimental conditions. However, EtOH reversed the ability of the group I mGluR agonist (S)-3,5-Dihydroxyphenylglycine (DHPG) (50 μM) to potentiate the depressant action of NMDA on the fEPSP/PS. We also examined whether EtOH could modulate dopamine release given that dopamine plays important roles in mediating the reinforcing actions of abused drugs and in the induction of LTP in the NAc. We found that EtOH reversibly decreased action potential-dependent dopamine release evoked by single stimulation pulses and by HFS trains in NAc slices. Conclusions These results show that EtOH impairs the induction of LTP possibly through several mechanisms that include inhibition of group I mGluR-mediated potentiation of NMDA receptor function and of evoked dopamine release. This study provides additional support for a key role of glutamatergic and dopaminergic neurotransmission in the NAc in mediating the reinforcing effects of acute alcohol.

With neurological processes involving multiple neurotransmitters and neuromodulators, it is important to have the ability to directly map and quantify multiple signaling molecules simultaneously in a single analysis. By utilizing a molecular-specific approach, namely desorption electrospray ionization mass spectrometry imaging (DESI-MSI), we demonstrated that the technique can be used to image multiple neurotransmitters and their metabolites (dopamine, dihydroxyphenylacetic acid, 3-methoxytyramine, serotonin, glutamate, glutamine, aspartate,gamma-aminobutyric acid, adenosine) as well as neuroactive drugs (amphetamine, sibutramine, fluvoxamine) and drug metabolites in situ directly in brain tissue sections. The use of both positive and negative ionization modes increased the number of identified molecular targets. Chemical derivatization by charge-tagging the primary amines of molecules significantly increased the sensitivity, enabling the detection of low abundant neurotransmitters and other neuroactive substances previously undetectable by MSI. The sensitivity of the imaging approach of neurochemicals has a great potential in many diverse applications in fields such as neuroscience, pharmacology, drug discovery, neurochemistry, and medicine.

In this paper, we consider 3D Bioluminescence tomography (BLT) source reconstruction from Poisson data in three dimensional space. With a priori information of sources sparsity and MAP estimation of Poisson distribution, we study the minimization of Kullback-Leihbler divergence with ? 1 and ? 0 regularization. We show numerically that although several ? 1 minimization algorithms are efficient for compressive sensing, they fail for BLT reconstruction due to the high coherence of the measurement matrix columns and high nonlinearity of Poisson fitting term. Instead, we propose a novel greedy algorithm for ? 0 regularization to reconstruct sparse solutions for BLT problem. Numerical experiments on synthetic data obtained by the finite element methods and Monte-Carlo methods show the accuracy and efficiency of the proposed method.

Serotonin 5-HT6 receptors have been implicated in the regulation of cognition, locomotion, and mood, but the elucidation of their functions is complicated by conflicting data using various animal models. Here, a systematic evaluation showed that autoradiographic binding with the selective 5-HT6 receptor antagonist [125I]SB-258585 was similar in marmosets and rats. In both species, [125I]SB-258585 binding was enriched in the caudate-putamen. Various recently developed agonists and antagonists toward 5-HT6 receptors exhibited similarities in their abilities to displace [125I]SB-258585 binding in marmosets and rats. The rank order of pEC50 values were as follows: (+)EMDT-CR = EMD386088>MS-245 = 5-HT>EMDT>>(−)EMDT-CR; and (+)EMDT-CR = EMD386088>5-HT = MS-245 = EMDT>>(−)EMDT-CR, in marmosets and rats, respectively. Unilateral 6-hydroxydopamine lesioning of dopaminergic axons caused a significant decrease of [125I]SB-258585 binding in the caudate-putamen of both marmosets and rats. Nonetheless, acute administration of the 5-HT6 receptor agonist EMDT to unilaterally 6-hydroxydopamine-lesioned rats, caused an induction of egr-1, homer, and enkephalin mRNAs in the dopamine-depleted hemisphere, indicating a supersensitization of 5-HT6 receptors following dopamine depletion. In conclusion, this study provides evidence for significant similarities in the distribution, level, pharmacology, and regulation of 5-HT6 receptors between rats and marmosets. J. Comp. Neurol. 519:1815–1827, 2011. © 2011 Wiley-Liss, Inc.

In this paper, we propose a unified primal-dual algorithm framework for two classes of problems that arise from various signal and image processing applications. We also show the connections to existing methods, in particular Bregman iteration (Osher et al., Multiscale Model. Simul. 4(2):460---489, 2005) based methods, such as linearized Bregman (Osher et al., Commun. Math. Sci. 8(1):93---111, 2010; Cai et al., SIAM J. Imag. Sci. 2(1):226---252, 2009, CAM Report 09-28, UCLA, March 2009; Yin, CAAM Report, Rice University, 2009) and split Bregman (Goldstein and Osher, SIAM J. Imag. Sci., 2, 2009). The convergence of the general algorithm framework is proved under mild assumptions. The applications to ? 1 basis pursuit, TV?L 2 minimization and matrix completion are demonstrated. Finally, the numerical examples show the algorithms proposed are easy to implement, efficient, stable and flexible enough to cover a wide variety of applications.

Driven by recent developments of PET-MRI scanners, simultaneous reconstruction of dual-modality has gained considerable research interest. The purpose of this paper is to propose a joint reconstruction model by utilizing complementary information of dual-modality to improve reconstruction quality of individual images. We propose a total variation based joint regularization with an adaptively estimated common edge indicator function as a weight. The common edge function takes into account the shared structures of two modalities in a flexible way. A proximal alternating algorithm is adopted to recover dual-modality images and the common edge, and the convergence of the overall numerical scheme is established. Finally, numerical tests for PET and MRI under different noise levels and subsampling patterns show that the proposed approach obtains favorable results compared to some existing methods.

Wavelet inpainting problem consists of filling in missed data in the wavelet domain. In [17], Chan, Shen, and Zhou proposed an efficient method to recover piecewise constant or smooth images by combining total variation regularization and wavelet representations. In this paper, we extend it to nonlocal total variation regularization in order to recover textures and local geometry structures simultaneously. Moreover, we apply an efficient algorithm framework for both local and nonlocal regularizers. Extensive experimental results on a variety of loss scenarios and natural images validate the performance of this approach.

Bregman methods introduced in [S. Osher, M. Burger, D. Goldfarb, J. Xu, and W. Yin, Multiscale Model. Simul., 4 (2005), pp. 460-489] to image processing are demonstrated to be an efficient optimization method for solving sparse reconstruction with convex functionals, such as the $\ell^1$ norm and total variation [W. Yin, S. Osher, D. Goldfarb, and J. Darbon, SIAM J. Imaging Sci., 1 (2008), pp. 143-168; T. Goldstein and S. Osher, SIAM J. Imaging Sci., 2 (2009), pp. 323-343]. In particular, the efficiency of this method relies on the performance of inner solvers for the resulting subproblems. In this paper, we propose a general algorithm framework for inverse problem regularization with a single forward-backward operator splitting step [P. L. Combettes and V. R. Wajs, Multiscale Model. Simul., 4 (2005), pp. 1168-1200], which is used to solve the subproblems of the Bregman iteration. We prove that the proposed algorithm, namely, Bregmanized operator splitting (BOS), converges without fully solving the subproblems. Furthermore, we apply the BOS algorithm and a preconditioned one for solving inverse problems with nonlocal functionals. Our numerical results on deconvolution and compressive sensing illustrate the performance of nonlocal total variation regularization under the proposed algorithm framework, compared to other regularization techniques such as the standard total variation method and the wavelet-based regularization method.

We generalize the primal-dual hybrid gradient (PDHG) algorithm proposed by Zhu and Chan in [An Efficient Primal-Dual Hybrid Gradient Algorithm for Total Variation Image Restoration, CAM Report 08-34, UCLA, Los Angeles, CA, 2008] to a broader class of convex optimization problems. In addition, we survey several closely related methods and explain the connections to PDHG. We point out convergence results for a modified version of PDHG that has a similarly good empirical convergence rate for total variation (TV) minimization problems. We also prove a convergence result for PDHG applied to TV denoising with some restrictions on the PDHG step size parameters. We show how to interpret this special case as a projected averaged gradient method applied to the dual functional. We discuss the range of parameters for which these methods can be shown to converge. We also present some numerical comparisons of these algorithms applied to TV denoising, TV deblurring, and constrained $l_1$ minimization problems.

FKBP-12, a 12 kDa FK506-binding protein (neuroimmunophilin), acts as a receptor for the immunosuppressant drug FK506. Neuroimmunophilins, including FKBP-12, are abundant in the brain and have been shown to be involved in reversing neuronal degeneration and preventing cell death. In this report, we have utilized several analytical techniques, such as in situ hybridization, Western blotting, two-dimensional gel electrophoresis, and liquid chromatography electrospray tandem mass spectrometry to study the transcriptional expression as well as protein levels of FKBP-12 in the unilateral 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease. The FKBP-12 protein was also detected directly on brain tissue sections using mass spectrometry profiling. We found increased levels of FKBP-12 mRNA and protein in the dorsal and middle part of the 6-OHDA lesioned striatum. Thus, these studies clearly demonstrate that FKBP-12 is increased in the brain of a common animal model of Parkinson's disease (PD). Additionally, we have identified potential binding partners to FKBP-12 that may be implicated in the pathophysiology of Parkinson's disease, such as alpha-enolase, 14-3-3 zeta/delta, pyruvate kinase isozymes, and heat shock protein 70, using surface plasmon resonance sensor technology in combination with mass spectrometry. In conclusion, these data strongly suggests that FKBP-12 is altered in an experimental model of PD.

Changes on 5-HT2 receptor mRNAs in striatum and subthalamic nucleus in Parkinson's disease model. PHYSIOL. BEHAV. 00(0), 000-000, 2006. Abnormal interactions between the serotonin and dopamine systems may underlie the high prevalence of non-motor complications in Parkinson's disease (PD). Here, we demonstrate that the genes encoding serotonin 5-HT2A and 5-HT2C receptors are differently regulated by dopamine in the 6-hydroxydopamine (6-OHDA) rat model of PD. Nigrostriatal cell loss causes an up-regulation of 5-HT2AR mRNA, but a down-regulation of 5-HT2CR mRNA, in striatum. Repeated injections with L-DOPA/benserazide reverse the effect of 6-OHDA lesioning on 5-HT2AR, but not on 5-HT2CR, gene expression. Neither 6-OHDA-lesioning nor L-DOPA/benserazide treatment had any effect on 5-HT2AR mRNA in cortex or on 5-HT2CR mRNA in nucleus subthalamicus. These data suggest that the regulation of 5-HT2AR in striatum, in the 6-OHDA rat model of PD, is mainly dependent upon alterations in dopamine levels. 5-HT2CR, on the other hand, are regulated by nigrostriatal cell loss and by the accompanied reduction of factor(s), other than dopamine, that are normally co-expressed with dopamine. The apparent imbalance between 5-HT2AR and 5-HT2CR levels in this PD model indicates a potential role for these receptors in the pathophysiology of neuropsychiatric symptoms, such as depression and L-DOPA-induced hallucinations, which are co-morbid with PD. The fact that 5-HT2CR are differentially regulated as compared to 5-HT2AR to alterations in the dopamine tone predicts that pharmacological manipulations at 5-HT2CR, but not at 5-HT2AR, will result in similar effects in PD patients whether they are treated or not with dopamine replacement.

Parkinson's disease (PD) is a movement disorder characterized by a progressive loss of nigrostriatal dopaminergic neurons. Restoration of dopamine transmission byl-DOPA relieves symptoms of PD but causes dyskinesia. Trace Amine-Associated Receptor 1 (TAAR1) modulates dopaminergic transmission, but its role in experimental Parkinsonism andl-DOPA responses has been neglected. Here, we report that TAAR1 knock-out (KO) mice show a reduced loss of dopaminergic markers in response to intrastriatal 6-OHDA administration compared with wild-type (WT) littermates. In contrast, the TAAR1 agonist RO5166017 aggravated degeneration induced by intrastriatal 6-OHDA in WT mice. Subchronicl-DOPA treatment of TAAR1 KO mice unilaterally lesioned with 6-OHDA in the medial forebrain bundle resulted in more pronounced rotational behavior and dyskinesia than in their WT counterparts. The enhanced behavioral sensitization tol-DOPA in TAAR1 KO mice was paralleled by increased phosphorylation of striatal GluA1 subunits of AMPA receptors. Conversely, RO5166017 counteracted bothl-DOPA-induced rotation and dyskinesia as well as AMPA receptor phosphorylation. Underpinning a role for TAAR1 receptors in modulating glutamate neurotransmission, intrastriatal application of RO5166017 prevented the increase of evoked corticostriatal glutamate release provoked by dopamine deficiency after 6-OHDA-lesions or conditional KO of Nurr1. Finally, inhibition of corticostriatal glutamate release by TAAR1 showed mechanistic similarities to that effected by activation of dopamine D2receptors. These data unveil a role for TAAR1 in modulating the degeneration of dopaminergic neurons, the behavioral response tol-DOPA, and presynaptic and postsynaptic glutamate neurotransmission in the striatum, supporting their relevance to the pathophysiology and, potentially, management of PD.SIGNIFICANCE STATEMENTParkinson's disease (PD) is characterized by a progressive loss of nigrostriatal dopaminergic neurons. Restoration of dopamine transmission byl-DOPA relieves symptoms of PD but causes severe side effects. Trace Amine-Associated Receptor 1 (TAAR1) modulates dopaminergic transmission, but its role in PD andl-DOPA responses has been neglected. Here, we report that TAAR1 potentiates the degeneration of dopaminergic neurons and attenuates the behavioral response tol-DOPA and presynaptic and postsynaptic glutamate neurotransmission in the striatum, supporting the relevance of TAAR1 to the pathophysiology and, potentially, management of PD.

Background: The adolescent brain is sensitive to experience-dependent plasticity and might be more vulnerable than the adult brain to the effects of some drugs of abuse. The factors that contribute to these differences are not fully identified. We have examined the ability of cannabinoids to induce a form of synaptic plasticity, long-term depression, in the nucleus accumbens and dorsolateral striatum of adolescent and adult mice. Methods: We measured field excitatory postsynaptic potentials/population spikes in brain slices. Results: We found that the cannabinoid receptor agonist WIN 55,212-2 ( R) -(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate) induced long-term depression in the nucleus accumbens of adolescent but not adult mice and failed to induce long-term depression in the dorsolateral striatum of adolescent or adult mice. Similar results were obtained with the group I metabotropic glutamate receptor agonist ( S )-3,5- dihydroxyphenylglycine, which has previously been shown to promote the release of endocannabinoids. These age-related differences were associated with reduced protein levels of the cannabinoid type 1 receptor and metabotropic glutamate receptor 1 in adult nucleus accumbens and dorsolateral striatum and with an increased tone of endocannabinoids in the dorsolateral striatum of adult mice. We also found that N -methyl-d-aspartate receptor-dependent long-term depression, which was induced in the nucleus accumbens of adolescent mice, was blunted in adult mice, possibly because of decreased levels of GluN1, the obligatory subunit of N -methyl-d-aspartate receptors. Conclusions: This study identifies region- and age-specific differences in the ability of endogenous and exogenous cannabinoids, and of N -methyl-d-aspartate receptors, to induce long-term depression in the striatal complex. These observations might contribute to a better understanding of the increased sensitivity of the adolescent brain to drug induced-plasticity.

The Regularized D-bar method for Electrical Impedance Tomography provides a rigorous mathematical approach for solving the full nonlinear inverse problem directly, i.e. without iterations. It is based on a low-pass filtering in the (nonlinear) frequency domain. However, the resulting D-bar reconstructions are inherently smoothed leading to a loss of edge distinction. In this paper, a novel approach that combines the rigor of the D-bar approach with the edge-preserving nature of Total Variation regularization is presented. The method also includes a data-driven contrast adjustment technique guided by the key functions (CGO solutions) of the D-bar method. The new TV-Enhanced D-bar Method produces reconstructions with sharper edges and improved contrast while still solving the full nonlinear problem. This is achieved by using the TV-induced edges to increase the truncation radius of the scattering data in the nonlinear frequency domain thereby increasing the radius of the low pass filter. The algorithm is tested on numerically simulated noisy EIT data and demonstrates significant improvements in edge preservation and contrast which can be highly valuable for absolute EIT imaging.

The subthalamic nucleus and the striatum are input regions of the basal ganglia. This study used the unilateral 6-OHDA rat model of Parkinson's disease to examine effects of l-DOPA on the expression of c-fos and BDNF mRNAs in these nuclei. Dopamine depletion per se did not affect c-fos or BDNF. Both a single and repeated injections of l-DOPA induced c-fos, but not BDNF, in the dopamine-depleted striatum. However, repeated l-DOPA treatment increased c-fos and BDNF in the dopamine-depleted subthalamic nucleus. These molecular adaptations may reflect changes in neuronal plasticity that underlie some therapeutic actions and/or side effects of l-DOPA in Parkinson's disease.

INTRODUCTION From 1995 to the present, the interstate motor carrier industry in the United States has seen growth in the number of companies offering web-enhanced services (WES). These services range from limited tracking and tracing to transactions that are completely Internet-based. New technologies such as automatic vehicle location systems (AVLS), automatic vehicle identification (AVI), and satellite and radio based communication (SRC), make value added real-time service to shippers possible. Several publications have highlighted this growth. Lancioni et al. (2000) noted that throughout the supply chain, the sector that most widely uses the Internet is the transportation sector. Hickey (2001) reported that most trucking companies are involved in one or more Internet projects aimed at improving customer service. The Inbound Logistics' 2000 Annual Top 100 Trucking issue identified specific web-enhanced technologies commonly found in the motor carrier industry--real time tracking and tracing (RTT), electronically available bills of lading, POD's, etc.--and ranked the breadth of each of "the Top 100 Company's" web-enhanced capabilities. While success stories abound (e.g., Shulman, 1999) and lead to the assumption that WES capabilities add financial value to a motor carrier, motor carriers are hesitant to embark on a full-scale adoption of WES. According to a study by Nagarajan et al. (2000), motor carrier spending on Internet development has been small, accounting for only 12 percent of their investment in new technology. Implementation is still in its infancy with respect to both breadth and depth (Ellinger et al., 2001). With the recent difficulties that many Internet companies have experienced, some are questioning the cost advantages of WES for motor carriers (Chakraborty and Kazarosian, 2000; Graham, 2001; Nagarajan et al., 1999; Nagarajan et al., 2000). These concerns reflect the lack of actual knowledge and the scarcity of research regarding relationships between WES and their impact on profitability. Some authors have theorized that companies offering WES would be able to advantage themselves competitively (Chan and Artmangkorn, 2002; Kleindl 2000; Watson et al., 2000), that effective implementation would separate the successful trucking companies from the struggling ones (Panza, 2000), and that web-enhanced capabilities would even the playing field between large establishments and smaller startups (Rodriguez, 2001). However, others have noted that there are no well-established ways to estimate or measure the value of a website (King, 1999), or to accurately account for development costs (Stout and Marden, 2001). Still others have suggested that investment in WES may not be as profitable as other investment opportunities (e.g., Chakraborty and Kazarosian, 2000; Graham, 2001; Nagarajan et al., 2000). This study clarifies some of these issues by investigating relationships between adoption of WES and a motor carrier's financial performance. In particular, this study measures the financial results that firms should expect from offering WES in the motor carrier industry. This study also identifies distinguishing characteristics of companies that offer WES and addresses the issue of whether recent technological advancements have allowed smaller companies to compete more effectively with larger companies in service levels. Due to significant website development and maintenance costs and the lack of ability to clearly measure the financial value of WES, motor carriers are incurring substantial risks in committing resources for implementing and maintaining WES. This research provides empirical evidence that establishes a clear relationship between the offering of various web-enhanced services and their impact on profitability. This increased understanding offers great value and allows firms to allocate resources to WES with greater understanding of the likely effect of these investments. …

A set in ℝd is called regular if its Hausdorff dimension coincides with its upper box counting dimension. It is proved that a random graph-directed self-similar set is regular a.e..

Purpose Researchers developed multiple measures to assess media reputation, which is believed to be a driving force of corporate reputation. This study compared six measures that were used to measure seven attributes of media reputation. Design/methodology/approach This study conducted the content analysis of 2,817 news articles from both elite newspapers and local newspapers about nine big food corporations. Six measures were used to measure the media reputations of these corporations. Paired samples t-test was used to examine whether these measures are significantly different from each other. Findings Significant differences between measures of media reputation were found in seven attributes for elite and local newspapers. Using different news samples, elite newspapers vs. local newspapers, would also lead to significantly different assessments of media reputation in seven attributes. Originality/value No published research examines whether these measures are significantly different when they are used to measure multiple attributes of media reputation. The findings suggest that the six measures of media reputation cannot substitute one another. Researchers should provide rationales when they use any of them to measure the attributes of media reputation.

International audience; Current neuroimaging techniques have very limited abilities to directly identify and quantify neurotransmitters from brain sections. We have developed a molecular-specific approach for the simultaneous imaging and quantitation of multiple neurotransmitters, precursors, and metabolites, such as tyrosine, tryptamine, tyramine, phenethylamine, dopamine, 3-methoxytyramine, serotonin, GABA, glutamate, acetylcholine, and L-alpha-glycerylphosphorylcholine, in histological tissue sections at high spatial resolutions. The method is employed to directly measure changes in the absolute and relative levels of neurotransmitters in specific brain structures in animal disease models and in response to drug treatments, demonstrating the power of mass spectrometry imaging in neuroscience.

The GluN2B subunit of NMDA receptors (NMDARs) is an attractive drug target for therapeutic intervention in Parkinson's disease (PD). We have used whole-cell patch clamp recordings in brain slices to examine the contribution of GluN2B and GluN2D to functional NMDARs in the striatum of the unilateral 6-hydroxydopamine-lesioned mouse model of PD. We found that current/voltage relationships of NMDAR-mediated excitatory post synaptic currents were altered in a population of medium spiny projection neurons (MSNs) in the dopamine-depleted striatum. Using antagonists for GluN2B- and GluN2D-containing NMDARs, we found that GluN2B contributes to functional NMDARs in MSNs in the intact striatum and in the striatum of control mice. The function of GluN2B-containing NMDARs is however reduced in MSNs from the dopamine-depleted striatum. GluN2D is absent in MSNs from intact striatum and from control mice, but the contribution of this subunit to functional NMDARs is increased in the dopamine-depleted striatum. These changes in the subunit composition of NMDARs are associated with a decreased protein level of GluN2B and an increased level of GluN2D in the dopamine-depleted striatum. In cholinergic interneurons from the intact striatum and control mice, both GluN2B and GluN2D contribute to functional NMDARs. The functions of GluN2D, and to some extent GluN2B, are reduced in the dopamine-depleted striatum. Our findings demonstrate a cell-type specific reorganization of GluN2B and GluN2D in a mouse model of PD and suggest GluN2D as a potential target for the management of the disease.

Renal denervation is a novel method for hypertension treatment. In this study, we aimed to investigate the safety and efficacy of radiofrequency ablation (RFA) at ablation temperatures of 45 °C or 50 °C and its possible mechanisms.A hypertensive canine model was established by abdominal aortic constriction in 20 healthy hybrid dogs. These dogs were then randomly assigned to the treatment and the control groups, with dogs in the treatment group further randomly assigned to receive RFA at ablation temperatures of 45 °C or 50 °C. In the treatment group, RFA was performed at 1 month after modeling; renal angiography was performed at 2 months after ablation. The arterial vessels of the dogs were examined histologically with hematoxylin and eosin staining. Changes in blood pressure in the foreleg and whole-body norepinephrine spillover rate were also assessed.No arterial stenosis, dissection, thrombosis or other abnormalities were detected in the treated vessels by renal angiography, yet histology results showed minimal to mild renal arterial injury. Renal denervation resulted in a marked decrease in the whole-body norepinephrine spillover rate (p0.05) in addition to significantly reducing blood pressure (p0.05), with no significant differences detected between the 45 °C and 50 °C subgroups for both (p0.05).Renal denervation can be performed without acute major adverse events, using catheter-based RFA with temperature control. The procedure was feasible in reducing blood pressure by at least partially inhibiting sympathetic drive and systemic sympathetic outflow.

The intellectual property (IP) law has been forcefully challenged by scholars and multiple anti-IP movementshave been pushed by activists in recent years. The critiques from scholars mainly focused on the enclosure ofinformation and knowledge enforced by IP law. And the activists of anti-IP movements argued for the openaccess to knowledge to promote creation.This study proposes an endogenous economic growth model highlighting the role of open-access knowledge ineconomic growth. The solution of the model shows that the production efficiency of knowledge, the convertingefficiency from knowledge products into human capital, and the externality of knowledge products, will haveimpacts on the economic growth rate. The policy implication of this study is that government’s intervention,such as the subsidy to the knowledge production, investment in the open-access knowledge, and regulation onthe quality of knowledge products, will have positive effects on economic growth.

The PDZ domain-containing proteins, such as PSD-95 and GRIP, have been suggested to be involved in the targeting of glutamate receptors, a process that plays a critical role in the efficiency of synaptic transmission and plasticity. To address the molecular mechanisms underlying AMPA receptor synaptic localization, we have identified several GRIP-associated proteins (GRASPs) that bind to distinct PDZ domains within GRIP. GRASP-1 is a neuronal rasGEF associated with GRIP and AMPA receptors in vivo. Overexpression of GRASP-1 in cultured neurons specifically reduced the synaptic targeting of AMPA receptors. In addition, the subcellular distribution of both AMPA receptors and GRASP-1 was rapidly regulated by the activation of NMDA receptors. These results suggest that GRASP-1 may regulate neuronal ras signaling and contribute to the regulation of AMPA receptor distribution by NMDA receptor activity.

In order to further investigate the interaction between the octapeptide cholecystokinin and opioid analgesia in the spinal cord we used double-colour immunofluorescence to examine the anatomical distribution of cholecystokinin and μ-opioid receptors in the dorsal horn, as well as the effect of morphine on cholecystokinin- and μ-opioid receptor-like immunoreactivities following peripheral nerve injury and inflammation. μ-opioid receptor-like immunoreactivity was present in 65.6% of cholecystokinin-positive neurons in laminae I and II of rat spinal cord. Conversely, 40.4% of μ-opioid receptor-positive neurons contained cholecystokinin-like immunoreactivity. Systemic application of morphine (1, 3 or 10 mg/kg; i.v.) after sciatic nerve section significantly, but reversibly, decreased μ-Opioid receptor-like immunoreactivity in the medial half of lamina II in segment L5 of the ipsilateral dorsal horn, and cholecystokinin-like immunoreactivity was also markedly reduced in the same region. These effects were dose- and time-dependent and could be prevented by naloxone preadministration. In contrast, no significant change in the pattern of distribution or intensity of μ-opioid receptor- and cholecystokinin-like immunoreactivities was observed in intact rats or during peripheral inflammation. These results provide a cellular basis for the interaction of μ-opioid receptors and cholecystokinin at the spinal level by showing a high degree of co-existence of these two molecules in local interneurons, and also show that morphine can induce rapid and short lasting effects on μ-opioid receptors after peripheral nerve injury. The results contribute to our understanding of how endogenous cholecystokinin reduces the analgesic effect of morphine.

Synaptic clustering of neurotransmitter receptors is crucial for efficient signal transduction and integration in neurons. PDZ domain–containing proteins such as PSD-95/SAP90 interact with the intracellular C termini of a variety of receptors and are thought to be important in the targeting and anchoring of receptors to specific synapses. Here, we show that PICK1 (protein interacting with C kinase), a PDZ domain–containing protein, interacts with the C termini of α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptors in vitro and in vivo. In neurons, PICK1 specifically colocalizes with AMPA receptors at excitatory synapses. Furthermore, PICK1 induces clustering of AMPA receptors in heterologous expression systems. These results suggest that PICK1 may play an important role in the modulation of synaptic transmission by regulating the synaptic targeting of AMPA receptors.

Many excitatory synapses are thought to be postsynaptically 'silent', possessing functional NMDA but lacking functional AMPA glutamate receptors. The acquisition of AMPA receptors at silent synapses may be important in synaptic plasticity and neuronal development. Here we characterize a possible morphological correlate of silent synapses in cultured hippocampal neurons. Initially, most excitatory synapses contained NMDA receptors, but only a few contained detectable AMPA receptors. Synapses progressively acquired AMPA receptors as the cultures matured. AMPA receptor blockade increased the number, size and fluorescent intensity of AMPA receptor clusters and rapidly induced the appearance of AMPA receptors at 'silent' synapses. In contrast, NMDA receptor blockade increased the size, intensity and number of NMDA receptor clusters and decreased the number of AMPA receptor clusters, resulting in an increase in the proportion of 'silent' synapses. These results suggest that the number of silent synapses is regulated during development and by changes in synaptic activity.

Strong serologic and molecular probe correlations indicate that the newly discovered gamma herpesvirus KSHV or HHV8 is the likely etiologic agent of all forms of Kaposi’s sarcoma as well as BCBL/PEL and MCD in patients with acquired immunodeficiency syndrome (AIDS). Two large segments of HHV8 DNA from an AIDS-associated BCBL tumor covering genomic positions 0‐52 kilobase [kb] and 108‐140 kb have been cloned, mapped, and partially sequenced. Our studies have focused on novel viral proteins encoded within a 13-kb divergent locus (DL-B) by nine captured homologues of cellular genes, including vIL-6, vDHFR, vTS, vBcl-2, three C-C beta chemokines (vMIP-1A, vMIP1B, and vBCK), and two LAP/PHD subclass zinc finger proteins (IE1A and IE1B). The HHV-8 vIL-6, vDHFR, vTS, and vBcl-2 proteins have all been shown to be active in a variety of appropriate functional assays, and transcripts from vIL-6, vMIP-1B, vIE1-A, vIE1-B, and vDHFR genes are all expressed as abundant single messenger RNA species after butyrate or phorbol ester (TPA) induction of the lytic cycle in HHV8-positive BCBL cell lines. All of these genes lie within a divergent transcriptional domain that contains a single central enhancer and associated untranslated leader region plus seven distinct proximal promoters, some of which are negatively regulated through AP-1 and ZRE motifs by the EBV ZTA transactivator. This region also encompasses a predicted complex oriLyt domain of 1050 bp that is duplicated in inverted orientation adjacent to the T0.7 latency RNA in another large divergent locus (DL-E). We have previously described three distinct subtypes of the HHV8 genome that differ by 1.0%‐1.5% at the nucleotide level within the ORF26 and ORF75 genes. Certain strains or clades appear to have preferential geographic distributions, but it is not known as yet whether there are any specific disease associations. Interestingly, the A, B, and C subtypes of HHV-8 also proved to differ dramatically in coding content at both the extreme left and right ends of the unique segment of the genome as well as in the positions of the junctions with the terminal repeats. On the left-hand side, the receptor-like ORF-K1 protein is highly variable with A-strain subtypes displaying 15% amino acid differences from C strains and up to 30% differences from B strains. On the right-hand side, two unrelated alternative types of the putative multiple membrane spanning ORF-K15 protein are found. [Monogr Natl Cancer Inst 1998:23:79‐88]

To understand the role of opioids and their receptors in chronic pain following peripheral nerve injury, we have studied the mu-opioid receptor in rat and monkey lumbar 4 and 5 dorsal root ganglion neurons and the superficial dorsal horn of the spinal cord under normal circumstances and after peripheral axotomy. Our results show that many small neurons in rat and monkey dorsal root ganglia, and some medium-sized and large neurons in rat dorsal root ganglia, express mu-opioid receptor-like immunoreactivity. Most of these neurons contain calcitonin gene-related peptide. The mu-opioid receptor was closely associated with the somatic plasmalemma of the dorsal root ganglion neurons. Both mu-opioid receptor-immunoreactive nerve fibers and cell bodies were observed in lamina II of the dorsal horn. The highest intensity of mu-opioid receptor-like immunoreactivity was observed in the deep part of lamina II. Most mu-opioid receptor-like immunoreactivity in the dorsal horn originated from spinal neurons. A few mu-opioid receptor-positive peripheral afferent terminals in the rat and monkey dorsal horn were calcitonin gene-related peptide-immunoreactive. In addition to pre- and post-junctional receptors in rat and monkey dorsal horn neurons, mu-opioid receptors were localized on the presynaptic membrane of some synapses of primary afferent terminals in the monkey dorsal horn. Peripheral axotomy caused a reduction in the number and intensity of mu-opioid receptor-positive neurons in the rat and monkey dorsal root ganglia, and of mu-opioid receptor-like immunoreactivity in the dorsal horn of the spinal cord. The decrease in mu-opioid receptor-like immunoreactivity was more pronounced in the monkey than in the rat dorsal root ganglia and spinal cord. It is probable that there was a parallel trans-synaptic down-regulation of mu-opioid-like immunoreactivity in local dorsal horn neurons of the monkey. These data suggest that one factor underlying the well known insensitivity of neuropathic pain to opioid analgesics could be due to a marked reduction in the number of mu-opioid receptors in the axotomized sensory neurons and in interneurons in the dorsal horn of the spinal cord.

How to extract information intensively from ECGs for the diagnosis of cardiovascular diseases and assessment of heart function is a topical subject. Using a method based on the wavelet transform to calculate the irregularity of the QRS complex, which may relate to inotropy, the QRS complex irregularity time series is successfully extracted from original ECG signals. This provides a new approach to studies of ECG dynamics. With the help of non-linear dynamics theory, the QRS complex irregularity time series of eight subjects, from the MIT/BIH arrhythmia database are studied qualitatively and quantitatively, and the characteristics of ECG dynamics are analysed extensively. The power spectrum, phase portrait, correlation dimension, largest Lyapunov exponent, time-dependent divergence exponent and complexity measure all verify the fact that ECG dynamics are dominated by an underiying 5–6-dimensional non-linear chaotic system, whose complexity measure is about 0.7. The QRS complex irregularity time series contains abundant information about all parts of the heart and the regulation of the autonomic nervous system, and so further analyses are of great potential theoretical and clinical significance to patho-physiology studies and ambulatory monitoring.

The diagnosis of Parkinson's disease (PD) is solely based on movement disorders, but several non-motor deficits are common in PD. Depression often precedes the movement dysfunctions and continues to be a major concern during all stages of the disease. The pathophysiology of parkinsonian depression is largely unknown, but appears to partly differ from depression in patients without PD. Because of the increased awareness of the negative impact of depression on the quality of life of PD patients, there is a growing interest in developing animal models of parkinsonism that also recapitulate the depressive-like symptomatology. This review introduces paradigms for measurement of depression-like behaviors in rodents and summarizes data on behavioral, neurochemical and pharmacological changes in experimental PD models with relevance for depression-related states.

Anxiety and depression are highly prevalent and frequently co-morbid conditions. The ionotropic glutamate receptors N-methyl-d-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) mediate actions of monoaminergic antidepressants and have been directly targeted by novel fast-acting antidepressants. Less is known about the role of these receptors in anxiety-like states. Here we investigate how two distinct anxiolytic agents, buspirone, a partial 5-HT1A agonist, and diazepam, a benzodiazepine, influence phosphorylation of GluA1 subunits of AMPA receptors at the potentiating residue Ser845 and Ser831 in corticolimbic regions. To test the functional relevance of these changes, phosphomutant GluA1 mice lacking phosphorylatable Ser845 and Ser831 were examined in relevant behavioural paradigms. These mutant mice exhibited a reduced anxiety-like phenotype in the light/dark exploration task and elevated plus maze, but not in the novelty induced hypophagia paradigm. These data indicate that reduced potentiation of the AMPA receptor signalling, via decreased GluA1 phoshorylation, is specifically involved in approach–avoidance based paradigms relevant for anxiety-like behaviours.

We have previously reported that galanin message-associated peptide (GMAP), a fragment of galanin precursor protein, occurs in a limited number of dorsal root ganglion (DRG) cells in rats with intact sciatic nerves. In the present study, the localization of GMAP in dorsal root ganglia, dorsal roots and dorsal horn was analyzed immunohistochemically and compared between rats with intact and sectioned sciatic nerves. Furthermore, the effects of intrathecal (i.t.) GMAP on the flexor reflex in rats with intact and sectioned nerves were examined. In rats with intact sciatic nerves, i.t. GMAP elicited a moderate facilitation of the flexor reflex. The facilitation of the flexor reflex induced by conditioning stimulation (CS) of cutaneous C-fibers was strongly blocked by GMAP. GMAP also selectively antagonized the reflex facilitatory effect of i.t. substance P (SP), but not i.t. vasoactive intestinal peptide (VIP). Unilateral sciatic nerve section induced an upregulation of GMAP in the ipsilateral dorsal root ganglia 2 weeks after axotomy. The effect of GMAP on the baseline reflex was similar in normal and axotomized rats, but the blocking effect of GMAP on C-fiber CS-induced facilitation was significantly reduced after axotomy. GMAP did not antagonize the reflex facilitatory effect of SP after axotomy, whereas an antagonism on VIP-induced facilitation was observed. The possible role of GMAP in spinal transmission and comparison with the effects of galanin are discussed.

In this study co-localization of galanin- with calcitonin gene-related peptide (CGRP)-like immunoreactivity was examined in dorsal root ganglion neurons 14 days after sciatic nerve cut using a laser scanning confocal microscope. CGRP- and galanin-like immunoreactivities were also analysed in the dorsal horn of the spinal cord of these animals with immunofluorescence microscopy. The ultrastructural changes in galanin-immunoreactive, presumably primary afferent terminals in the superficial dorsal horn, were studied as well as the relationship between galanin-, substance P- and CGRP-like immunoreactivities in primary afferent terminals. Local galanin-positive neurons in lamina II were also analysed after peripheral axotomy. Under the confocal microscope, CGRP-like immunoreactivity was located in the perinuclear region, probably the Golgi complex, and in dot-like structures, probably representing large dense-core vesicles, in normal dorsal root ganglion neurons. However, after peripheral axotomy CGRP was mainly detected in dot-like structures. Only a slight decrease in percentage of CGRP neurons in dorsal root ganglion was seen after axotomy, and about 84% of the galanin-positive neurons contained CGRP. The field of galanin-positive nerve fibres in the superficial lumbar (L)4 and L5 dorsal horn expanded and the intensity of staining for CGRP was reduced in these regions 14 days after sciatic nerve cut. Using pre-embedding immunoelectron microscopy, several morphological changes were observed in galanin-positive terminals in laminae I and II ipsilateral to the lesion. Most importantly, the most frequently occurring type of galanin-positive terminals (type 1) showed distinct changes with a granular matrix, many immunoreactive, peripherally located large dense-core vesicles, empty large vesicles and synaptic vesicles which were displaced from the presynaptic zone. Other galanin-positive terminals underwent even more pronounced morphological changes, including extensive vesiculolysis, also of large dense-core vesicles, filamentous degeneration or formation of axonal labyrinths. An increased number of galanin-positive nerve terminals was observed in lamina III of the ipsilateral dorsal horn after axotomy. They did not form glomeruli and contained few large dense-core vesicles. Post-embedding immunocytochemistry combined with quantitative analysis revealed that significant changes occurred in a proportion of terminals also with regard to peptide content in large dense-core vesicles after axotomy. Thus, the percentage of galanin-positive large dense-core vesicles increased in several cases and that of substance P- and CGRP-immunoreactive ones decreased. With regard to galanin-positive local neurons in lamina II, they were in synaptic contact with presumable primary afferent terminals, and these terminals underwent the characteristic ultrastructural changes following the axotomy described above. Additionally, electron-dense bodies were found beneath the postsynaptic membrane of one type of galanin-immunoreactive local neuron [type B; Zhang et al. (1994) Neuroscience 64 , 875–891]. Taken together, these results demonstrate marked morphological changes in virtually all galanin-containing terminals of presumable afferent origin in laminae I and II in the dorsal horn after peripheral axotomy. In several terminals the perturbations were such that transmission via both the classic transmitter and peptides must be virtually abolished. In the majority of cases, however, the synaptic vesicles in the presynaptic zone were mainly affected, with many peptide-containing large dense-core vesicles remaining peripherally close to the axonal membrane, i.e. in a release position. Thus, transmission via the classic transmitter, e.g. glutamate, may become less significant after axotomy, whereas peptidergic transmission should gain in importance. The up-regulation of galanin [and vasoactive intestinal polypeptide; Zhang et al. (1994) Neuroscience 64 , 917–941] and down-regulation of substance P and CGRP suggest a shift in the types of peptides involved. This change in peptide phenotype is paralleled by changes in dorsal horn transmission.

Using light microscopic immunoperoxidase and immunofluorescence histochemistry, double-staining methodology, and electron microscopic pre-embedding and post-embedding immunocytochemistry, we studied galanin-immunoreactive neurons in the superficial dorsal horn of the rat spinal cord. Co-existence of galanin with other neuropeptides was also analysed. The lumbar 4 and 5 segments of normal rats and after rhizotomy or spinal cord transection were studied. Galanin-positive local neurons in lamina II were often islet cells and could be classified as type A, which had abundant electron-dense cytoplasm containing many large dense-core vesicles, and type B, which had electron-lucent cytoplasm with only a few large dense-core vesicles. Galanin-positive and -negative peripheral afferent terminals made synaptic contact mostly with galanin-negative dendrites and cell bodies, but also with type B galanin cell bodies and with galanin-positive dendrites of unidentified type. Galanin-immunoreactive terminals from local neurons could also be classified into two types. Type α terminals were most common; they contained densely packed synaptic vesicles and many large dense-core vesicles, were strongly immunostained and most frequently made synaptic contact with galanin-negative dendrites. Type β terminals contained loosely packed synaptic vesicles and a few large dense-core vesicles, and were weakly immunostained. Axosomatic synaptic contact were sometimes found between type β terminals and type B galanin-positive cell bodies, but were most often associated with galanin-negative dendrites. Double immunostaining showed that galanin-like immunoreactivity co-localized mainly with enkephalin-like, but sometimes also with neuropeptide Y-like immunoreactivity in some local neurons in lamina II. Galanin-like and substance P-like immunoreactivities were identified in the same neurons in deeper layers of the dorsal horn. Coexistence of these neuropeptides and neurotensin with galanin was demonstrated not only in terminals in lamina II but also in large dense-core vesicles, as revealed by post-embedding immunocytochemistry. These results show that galanin-immunoreactive neurons in lamina II receive inputs directly from primary afferents and frequently make synaptic contacts with other intrinsic neurons. Galanin in the superficial dorsal horn may be released both from primary afferents and local neurons to modulate sensory processing in many different ways, including interacting with enkephalin, neuropeptide Y, neurotensin and substance P released from the same and/or other local neurons.

Both oxidative stress and inflammation are involved in the pathogenesis of contrast-induced nephropathy (CIN). Epigallocatechin-3-gallate (EGCG), a purified catechin from green tea, has antioxidant and anti-inflammatory effects. However, it is unknown whether or not EGCG is effective in treating CIN. Our present study found that intravenous administration of EGCG, either before or just after the establishment of CIN, had a protective effect, determined by normalization of serum creatinine and blood urea nitrogen levels, improvement in renal histopathological scoring and alleviation of apoptosis, accompanied by decreased oxidative stress and inflammation. Because EGCG is a potent inducer of the antioxidant heme oxygenase-1 (HO-1), we studied HO-1 signaling in CIN. HO-1 levels were increased in CIN; treatment with EGCG further increased HO-1 levels, accompanied by an increase in Nrf2, a regulator of antioxidant proteins. Interestingly, blockade of HO-1 with protoporphyrin IX zinc(II) (ZnPP) prevented the protective effect of EGCG on CIN. ZnPP also blocked the ability of EGCG to increase the activity of an antioxidant (superoxide dismutase), and decrease markers of oxidative stress (myeloperoxidase and malondialdehyde) and inflammation (myeloperoxidase and IL-1β), indicating that HO-1 is the upstream molecule that regulates the EGCG-mediated protection. To determine further the role of HO-1 on the EGCG-mediated inhibition of inflammation, we studied the effect of EGCG on the NLRP3 inflammasome, an upstream signaling of IL-1β. EGCG down-regulated NLRP3 expression, which was blocked by ZnPP, indicating that HO-1 links EGCG with NLRP3. Therefore, EGCG, via up-regulation of HO-1, protects against CIN by amelioration of oxidative stress and inflammation.

Supplemental Digital Content is available in the text, To investigate long noncoding RNA NONHSAT112178 (LncPPARδ) as a biomarker for coronary artery disease (CAD) in peripheral blood monocyte cells, RT-qPCR was performed to validate the microarray results, receiver operating characteristic curve was applied to study the potential of LncPPARδ as a biomarker. Diagnostic models from LncPPARδ alone or combination of risk factors were constructed by Fisher criteria. The expression of genes neighboring the LncPPARδ gene was examined with RT-qPCR in THP-1 cell line treated with LncPPARδ siRNA. Using a diagnostic model by Fisher criteria, the consideration of risk factors increased the optimal sensitivity from 70.00% to 82.00% and decreased the specificity from 94.00% to 78.00%. The consideration of risk factors also increased area under the receiver operating characteristic curve from 0.727 to 0.785 (P = 0.001), from 0.712 to 0.768 (P = 0.01), and from 0.769 to 0.835 (P = 0.07), in the original, training, and test sets, respectively. Finally, we found that the expression of peroxisome proliferator-activated receptor δ (PPARδ), Adipose Differentiation-Related Protein (ADRP), and Angiopoietin-like 4 (ANGPTL4) were affected by LncPPARδ silencing. Our present study indicated that LncPPARδ, especially combined with risk factors, can be a good biomarker for CAD. LncPPARδ regulates the expression of neighboring protein-coding genes, PPARδ and its direct target genes ADRP and ANGPTL4.

Dopamine plays an important role in cellular processes controlling the functional and structural plasticity of neurons, as well as their generation and proliferation, both in the developing and the adult brain. The precise roles of individual dopamine receptors subtypes in adult neurogenesis remain poorly defined, although D3 receptors are known to be involved in neurogenesis in the subventricular zone. By contrast, very few studies have addressed the influence of dopamine and D3 receptors upon neurogenesis in the subgranular zone of the hippocampus, an issue addressed herein employing constitutive D3 receptor knockout mice, or chronic exposure to the preferential D3 receptor antagonist, S33138. D3 receptor knockout mice revealed increased baseline levels of cell proliferation and ongoing neurogenesis, as measured both using Ki-67 and doublecortin, whereas there was no difference in cell survival as measured by BrdU (5-bromo-2'-deoxyuridine). Chronic administration of S33138 was shown to be functionally active in enhancing levels of the plasticity-related molecule, delta-FosB, in the D3 receptor-rich nucleus accumbens. In accordance with the stimulated neurogenesis seen in D3 receptor knockout mice, S33138 increased proliferation in wild-type mice. These observations suggest that D3 receptors exert a tonic, constitutive inhibitory influence upon adult hippocampal neurogenesis.

The olfactory bulbs of young and adult normal rats and of colchicine-treated rats and of some other species were analysed for the presence of neuropeptide Y and neuropeptide Y messenger RNA, using immunohistochemistry at the light- and electron-microscopic levels and with in situ hybridization. In the rat and mouse, but not in monkey and guinea-pig, neuropeptide Y-like immunoreactivity and neuropeptide Y messenger RNA were observed in ensheathing cells in the olfactory nerve layer of the olfactory bulb and within nerve bundles in the olfactory mucosa. Double staining experiments revealed that neuropeptide Y-like immunoreactivity was often present in a restricted compartment, mainly the Golgi apparatus, of S-100 protein-positive ensheathing cells. After colchicine treatment a different distribution of neuropeptide Y-like immunoreactivity and neuropeptide Y messenger RNA was observed. Thus, in the outer olfactory nerve layer both neuropeptide Y-like immunoreactivity and neuropeptide Y messenger RNA disappeared, whereas in the inner part messenger RNA levels remained high and neuropeptide Y-like immunoreactivity was observed in many granule-like structures distributed diffusely in the cytoplasm. The present findings suggest that neuropeptide Y may be involved in the control of regeneration, growth and/or guiding of the axons of the olfactory sensory neurons, the only mammalian neurons known to have a continuous renewal and growth during adult life.