Rats in each hormone group were treated with vehicle, sertraline (10 mg/kg) or imipramine (10 mg/kg), 24, 5 and 1 h before the FST. Immediately after the FST, midbrain, hippocampus and prefrontal cortex tissue was removed and frozen for analysis of gene expression via quantitative real-time PCR (midbrain tissue) and protein expression via Western blot (prefrontal cortex and hippocampal tissue). In the FST, sertraline decreased immobility and increased swimming in OVE rats, as well as increased swimming in OVW AG-14699 rats. In contrast, no sertraline effect was observed in OVX rats. Rats treated with imipramine showed increased climbing but no changes in immobility or swimming. No changes in protein expression were

detected in any treatment group. However, in vehicle-treated rats, E-2 increased midbrain SERT mRNA expression, with no effect on midbrain mRNA for the 5-HT receptors. In sertraline-treated rats, E-2 decreased 5-HT2A receptor mRNA, and E-2-withdrawal increased 5-HT1A, 5-HT2A and 5-HT2C receptor mRNA. In imipramine-treated rats, E-2 (and E-2-withdrawal) did not affect mRNA expression for any of the target genes. Thus, E-2 synergized behaviorally and neurochemically with an SSRI but not a tricyclic antidepressant. (c) 2008 Elsevier Ltd. All rights reserved.”
“The anti-inflammatory, antifibrotic, and antiproteinuric properties of vitamin D have been defined

Forskolin in studies using active vitamin D analogs. In this prospective observational study we determined whether nutritional vitamin D repletion can have additional beneficial effects in patients with type 2 diabetic nephropathy already established on renin-angiotensin-aldosterone system inhibition. During a 7-month period, 63 patients were enrolled and those with low levels of 25(OH) D were treated with

oral cholecalciferol for 4 months. Baseline serum 25(OH) D and 1,25(OH)(2)D showed no significant correlation with baseline urinary MCP-1, TGF-beta 1, or albuminuria measured as the urinary albumin-to-creatinine ratio. Of the 63 patients, 54 had insufficient or deficient levels of serum 25(OH) D and 49 complied with cholecalciferol therapy and follow-up. VX-661 Both 25(OH) D and 1,25(OH)(2)D were significantly increased at 2 and 4 months of treatment. Albuminuria and urinary TGF-beta 1 decreased significantly at both time points compared to their baseline values, while urinary MCP-1 did not change. Thus, in the short term, dietary vitamin D repletion with cholecalciferol had a beneficial effect in delaying the progression of diabetic nephropathy above that due to established renin-angiotensin-aldosterone system inhibition. Kidney International (2011) 80, 851-860; doi:10.1038/ki.2011.224; published online 10 August 2011″
“To establish axonal connections growth cones must navigate multiple intermediate targets before reaching their final target. During this journey growth cones are guided by extracellular repulsive and attractive signals.

Results suggest that relative to women with earlier DLMOs and MSTs, depressed peri- and post-menopausal women whose DLMOs and MSTs are phase-delayed may experience increases in appetite, hypersomnia, and BMI. These symptoms might be relieved by sleep or light manipulations that advance melatonin

and sleep timing parameters. (C) 2010 Elsevier Ireland Ltd. All rights reserved.”
“The Myb protein was first identified as an oncogene that causes leukemia in chickens. Since then, it has been widely associated with different types of cancers and studied in detail in myeloid leukemias. However, despite these studies, its role in the induction, pathogenesis CP673451 supplier and maintenance of AML, and other blood disorders, is still not well understood. Recent efforts to uncover its plethora of transcriptional targets have provided key insights into understanding its mechanism of action. This review evaluates our current knowledge of the role of Myb in leukemia, with AZD9291 price a particular focus on AML, from the vast literature spanning three decades, highlighting key studies that have influenced our understanding. We discuss recent insights into its role in leukemogenesis and how these could be exploited for the therapeutic

targeting of Myb, its associated co-regulators or its target genes, in order to improve outcomes in the treatment of a wide range of hematopoietic malignancies. Leukemia (2013) 27, 269-277; doi:10.1038/leu.2012.225″
“There exists an extensive terminology for defining the situation find more of children

who, in varying circumstances, suffer from affective deprivation (AD), within an unsatisfactory family situation or in institutions. Nevertheless, the neuroendocrine mechanisms (if they exist) determining it have yet to be identified. Our objective was to determine if specific neuroendocrine markers, all of them previously implicated in affective disorders, could be modified, and in which sense, in affective deprivation syndrome of the child. For this purpose, we studied three separate groups of children: (1) control group (CG); (2) children suffering from AD; and (3) children with non-organic failure to thrive (NOFT). In every case, we studied the serum levels of melatonin, serotonin, beta-endorphins and adrenocorticotropic hormone (ACTH); and kynurenine pathway tryptophan metabolites (both during the day and at night). Significantly, there was a conspicuous reduction in the levels of each of the neuroendocrine markers (melatonin, serotonin, beta-endorphins and ACTH) in the group suffering from affective deficiency, a diminution which was even more noticeable in the group of patients presenting delayed growth. Furthermore, as also occurs in other affective disorders, there were corresponding modifications in the metabolisation of tryptophan.

In contrast, the only areas activated by TMT were the internal granular layer of the main olfactory bulb and central amygdala, while both cat odor and TIVIT activated the glomeruli of the main olfactory bulb, piriform

cortex, ventral orbital cortex and anterior cortical amygdala. Results indicate that the effects of cat odor and TIVIT are easily distinguished both behaviorally and at a neural level, and suggest that TIVIT lacks the “”pheromone-like”" quality of cat odor that engages key hypothalamic sites involved in defensive behavior. (c) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.”
“Hepatitis https://www.selleckchem.com/products/emricasan-idn-6556-pf-03491390.html C virus (HCV) infection is a common cause of chronic hepatitis and is currently treated with alpha interferon (IFN-alpha)-based therapies. However, the underlying mechanism of IFN-alpha therapy remains to be elucidated. To identify the cellular proteins that mediate the antiviral effects of IFN-alpha, we created a HEK293-based cell culture system to inducibly express individual interferon-stimulated genes (ISGs) and determined their antiviral Anlotinib molecular weight effects against HCV. By screening 29 ISGs that are induced in Huh7 cells by IFN-alpha and/or up-regulated in HCV-infected livers, we discovered

that viperin, ISG20, and double-stranded RNA-dependent protein kinase (PKR) noncytolytically inhibited the replication of HCV replicons. Mechanistically, inhibition of HCV replication by ISG20 and PKR depends on their 3′-5′ exonuclease and protein kinase activities, respectively. Moreover, our work, for the first time, provides strong evidence suggesting learn more that viperin is a putative radical S-adenosyl-L-methionine (SAM) enzyme. In addition to demonstrating that the antiviral

activity of viperin depends on its radical SAM domain, which contains conserved motifs to coordinate [4Fe-4S] cluster and cofactor SAM and is essential for its enzymatic activity, mutagenesis studies also revealed that viperin requires an aromatic amino acid residue at its C terminus for proper antiviral function. Furthermore, although the N-terminal 70 amino acid residues of viperin are not absolutely required, deletion of this region significantly compromises its antiviral activity against HCV. Our findings suggest that viperin represents a novel antiviral pathway that works together with other antiviral proteins, such as ISG20 and PKR, to mediate the IFN response against HCV infection.”
“The medial thalamus contains abundant mu-opi-oid receptors and is activated by acute morphine administration. However, the role of the medial thalamus in the rewarding effects of morphine is unclear.

“
“The relationship between the blood lead concentration and cognitive function in children and adults with different VDR genotypes who participated in the third National Health and Nutrition Examination Survey was investigated. The relationship between blood lead and serum homocysteine concentrations was also investigated. In children 12 to 16 years old, performance on the Belnacasan digit span and arithmetic tests as a function of the blood lead concentration varied by VDR rs2239185 and VDR rs731236 genotypes. Decreases in performance occurred in some genotypes, but

not in others. In adults 20 to 59 years old, performance on the symbol-digit substitution test as a function of the blood lead concentration varied by VDR rs2239185-rs731236 haplotype. In the 12 to 16 year old children and adults 60 or more years old, the relationship between the serum homocysteine and blood lead concentrations varied by VDR genotype. The mean blood lead concentrations of the children and adults

did not vary by VDR genotype. Published by Elsevier Inc.”
“During conventional mRNA cap formation, two separate methyltransferases sequentially modify the cap structure, first at the guanine-N-7 (G-N-7) position and subsequently at the ribose 2′-O position. For vesicular stomatitis www.selleckchem.com/products/AC-220.html virus (VSV), a prototype of the nonsegmented negative-strand RNA viruses, the two methylase activities share a binding site for the methyl donor S-adenosyl-L-methionine and are inhibited by individual amino acid substitutions within the C-terminal domain of the large (L) polymerase protein. This led to the suggestion that a single methylase domain functions for both 2′-O and G-N-7 methylations. MK-1775 price Here we report a trans-methylation assay that recapitulates both ribose 2′-O and G-N-7 modifications by using purified recombinant L and in vitro-synthesized RNA. Using this assay, we demonstrate that VSV L typically modifies the 2′-O position of

the cap prior to the G-N-7 position and that G-N-7 methylation is diminished by pre-2′-O methylation of the substrate RNA. Amino acid substitutions in the C terminus of L that prevent all cap methylation in recombinant VSV (rVSV) partially retain the ability to G-N-7 methylate a pre-2′-O-methylated RNA, therefore uncoupling the effect of substitutions in the C terminus of the L protein on the two methylations. In addition, we show that the 2′-O and G-N-7 methylase activities act specifically on RNA substrates that contain the conserved elements of a VSV mRNA start at the 5′ terminus. This study provides new mechanistic insights into the mRNA cap methylase activities of VSV L, demonstrates that 2′-O methylation precedes and facilitates subsequent G-N-7 methylation, and reveals an RNA sequence and length requirement for the two methylase activities. We propose a model of regulation of the activity of the C terminus of L protein in 2′-O and G-N-7 methylation of the cap structure.

Design and Methods:

Eligible studies were identified by searching 14 databases using standardized terms. Experts, study authors and manufacturers were also contacted. Hand-searching was not undertaken. PD-1/PD-L1 inhibitor Selection criteria for inclusion in the review were controlled human trials of vanadium vs. placebo in adults with type 2 diabetes of minimum 2 months duration, and a minimum of 10 subjects per arm. Data extraction, assessment of study quality and outcome analysis were undertaken by two independent reviewers.

Results: One hundred and fifty one studies were found but none met the inclusion criteria. We proceeded to summarize the state of existing evidence and plan for a future clinical trial by applying revised, less restrictive criteria to our search, for clinical trials of 30150 mg daily oral vanadium supplementation in diabetic humans. Only five were identified. These demonstrated significant treatment-effects, but due to poor study quality, must be interpreted with caution. Treatment with vanadium often results in gastrointestinal side-effects.

Conclusion: There is no rigorous evidence that oral vanadium supplementation improves glycaemic

control in type 2 diabetes. Buparlisib The routine use of vanadium for this purpose cannot be recommended. A large-scale randomized controlled trial is needed to address this clinical question.”
“Purpose: We characterized prostate cancer focality in regard to clinicopathological features, prognostic value and impact on biochemical outcome.

Materials and Methods: We retrospectively reviewed the records of 1,366 patients in our prospective database who underwent radical prostatectomy between VE-822 research buy 1999 and 2010 for clinically localized prostate cancer with pathological evaluation using whole mount sectioning techniques and tumor mapping. Unifocal disease was

defined as the identification of a solitary cancer focus in the prostate without additional tumor foci or satellite lesions, ie multifocal disease, on histopathological evaluation. Cox regression modeling was used to identify predictors of biochemical progression among groups.

Results: A total of 184 patients (13%) fulfilled our unifocal tumor criteria. Unifocal tumors tended to be smaller in volume and in greatest diameter than multifocal tumors (p <0.0001 and <0.005, respectively). Of patients with pathologically insignificant disease the relative proportion with unifocal tumors increased to 28% from 13% in the overall cohort (p <0.0005). Also, tumor focality failed to predict biochemical recurrence in univariate and multivariate models. Accordingly we noted no significant differences in 5-year biochemical recurrence-free survival for unifocal and multifocal tumors (66% and 61%, respectively, p = 0.76). Limitations of this study include its retrospective nature.

Conclusions: In this study tumor focality failed to predict patients likely to experience biochemical failure.

In older adults, it was related to higher life satisfaction only among working individuals, although the difference from nonworking individuals

was not significant. Volunteer work was associated with higher positive affect in both age groups. In younger adults, it had no relation to life satisfaction and depressive symptoms. In older adults, Obeticholic research buy it was related to higher life satisfaction among nonworking individuals and to fewer depressive symptoms among those without a steady partner.

Volunteer work but not participation in voluntary organizations yielded compensatory effects on mental health among older adults.”
“Background

Whether closure of a patent foramen ovale is effective in the prevention of recurrent ischemic stroke in patients who have had a cryptogenic stroke is unknown. We conducted a trial to evaluate whether closure is superior to medical therapy alone in preventing recurrent ischemic stroke or early death in patients 18 to 60 years of age.

Methods

In this prospective, multicenter, randomized, event-driven

trial, we randomly assigned patients, in a 1:1 ratio, to medical therapy alone or closure of the patent foramen ovale. The primary results of the trial were analyzed when the target of 25 primary end-point events had been observed and adjudicated.

Results

We enrolled 980 patients mean age, 45.9 years) at 69 sites. The medical-therapy www.selleckchem.com/products/cl-amidine.html group received one or more antiplatelet medications 74.8%) or warfarin 25.2%). Treatment exposure between the two groups was unequal 1375 patient-years in the closure group vs. 1184 patient-years in the medical-therapy group, P=0.009) owing to a higher dropout rate in the medical-therapy group. In the intention-to-treat cohort, 9 patients in the closure group and

16 in the medical-therapy group had a recurrence of stroke hazard ratio with closure, 0.49; 95% confidence interval VE821 [CI], 0.22 to 1.11; P=0.08). The between-group difference in the rate of recurrent stroke was significant in the prespecified per-protocol cohort 6 events in the closure group vs. 14 events in the medical-therapy group; hazard ratio, 0.37; 95% CI, 0.14 to 0.96; P=0.03) and in the as-treated cohort 5 events vs. 16 events; hazard ratio, 0.27; 95% CI, 0.10 to 0.75; P=0.007). Serious adverse events occurred in 23.0% of the patients in the closure group and in 21.6% in the medical-therapy group P=0.65). Procedure-related or device-related serious adverse events occurred in 21 of 499 patients in the closure group 4.2%), but the rate of atrial fibrillation or device thrombus was not increased.

Conclusions

In the primary intention-to-treat analysis, there was no significant benefit associated with closure of a patent foramen ovale in adults who had had a cryptogenic ischemic stroke.

Results: Heparin coating did not decrease bacterial adhesion compared to its control. E. coli adhesion was limited by all check details stents tested. The Polaris stent showed significantly

greater resistance to bacterial adherence for Klebsiella, Pseudomonas and Enterococcus than the Endo-Sof and Radiance stents but was more susceptible to S. aureus adherence. The Triumph stent resisted all bacteria except Pseudomonas and Enterococcus. Mature biofilms were observed on all stents with lower viability on the Triumph stent. Radiance stents showed higher tensile and lower compression strength than its control.

Conclusions: Heparin coating does not decrease bacterial adherence to ureteral stents.

Drug eluting antimicrobials have an inhibitory effect on bacterial adherence and the Polaris stent showed the least bacterial adherence of the nondrug eluting ureteral stents tested.”
“The hippocampus plays an essential P5091 cell line role in learning and memory and is one of the major sites implicated in neural diseases. The proper organization of the hippocampus during development is important for its function. We found that draxin, a repulsive axon guidance cue, was widely expressed in the developing hippocampus and draxin deficient mice possessed a smaller hippocampus, particularly in the anterior part of the structure. Quantification of this reduction revealed that the volume of the dentate gyrus of the mutant was significantly smaller compared to the normal www.selleck.cn/products/MG132.html counterpart. This size reduction seemed to be dependent on apoptosis rather than due to a decrease in the rate of cell division. (C) 2009 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.”
“Purpose: Urinary macromolecules in children show stronger inhibition of Ca oxalate crystal growth, aggregation and adhesion than

in adults. To investigate the mechanism of Ca oxalate urolithiasis we evaluated the differences in inhibitory activity against oxalate induced renal cell injury between adults and children.

Materials and Methods: Urine samples were collected from healthy men and their sons. The protective effects of urinary macromolecules against oxalate induced injury to Madin-Darby canine kidney cells (ATCC (R)) were examined by lactate dehydrogenase assay and immunostaining. Variations in the relative abundance of proteins involved in stone formation, such as osteopontin and calgranulin B, were analyzed.

Results: The urine of children had significantly higher urinary macromolecule and glycosaminoglycan concentrations than that of adults (p <0.01). Urinary macromolecules inhibited oxalate induced Madin-Darby canine kidney cell injury in a concentration dependent manner and stronger activity was observed in children (P <0.05).

Together, our results demonstrated that upregulation of E2F1 by potassium deprivation promotes apoptosis in C57 mouse CGNs but antagonizes apoptosis in SD rat CGNs, suggesting https://www.selleckchem.com/products/Pitavastatin-calcium(Livalo).html opposing roles for E2F1 in regulating CGN fate. (C) 2011 Elsevier Ireland Ltd. All rights reserved.”
“Ocean acidification (OA) resulting from anthropogenic emissions of carbon dioxide (CO2) has already lowered and is predicted to further lower surface ocean pH. There is a particular need to study effects of OA on organisms living in cold-water environments due to the higher solubility of CO2 at lower temperatures. Mussel larvae (Mytilus edulis) and shrimp larvae (Pandalus borealis) were kept under an ocean

acidification scenario predicted for the year 2100 (pH 7.6) and compared against identical batches of organisms held under the current oceanic pH of 8.1, selleck chemicals llc which acted as a control. The temperature was held at a constant 10 degrees C

in the mussel experiment and at 5 degrees C in the shrimp experiment. There was no marked effect on fertilization success, development time, or abnormality to the D-shell stage, or on feeding of mussel larvae in the low-pH (pH 7.6) treatment. Mytilus edulis larvae were still able to develop a shell in seawater undersaturated with respect to aragonite (a mineral form of CaCO3), but the size of low-pH larvae was significantly smaller than in the control. After 2 mo of exposure the mussels were 28% smaller in the pH 7.6 treatment than in the control. The experiment with

Pandalus borealis larvae ran from 1 through 35 days post hatch. Survival of shrimp larvae was not reduced after 5 wk of exposure to pH 7.6, but a significant delay in zoeal progression (development time) was observed.”
“Objective: Neurological Soft Signs (NSS) have been found to be more prevalent in schizophrenic patients. A breakdown in intracortical functional connectivity, including interhemispheric communication, has been suggested in the pathogenesis of schizophrenia. Indeed, problems with interhemispheric information transfer via the Corpus Callosum (CC) have been documented in schizophrenics. Our study goal was to relate NSS to CC morphology. Methods: CC Magnetic Resonance Imaging (MRI) measurements were VX-661 ic50 collected from 29 right-handed male schizophrenia inpatients. NSS were evaluated employing the Neurological Evaluation Scale (NES). We examined the scores obtained from the NES total and the three NES subscales: Integrative Sensory Function, Motor Coordination, and Sequencing Of Complex Motor Acts. We compared CC morphology of patients with “”high”" NSS with that of patients with “”low”" NSS. Correlation analyses were performed to further clarify the relationship between CC size, NSS, and total lifetime antipsychotic consumption.

(c) 2008 Elsevier Ltd. All rights reserved.”
“Passive transfer of neutralizing antibodies is effective in protecting rhesus macaques against simian/human immunodeficiency virus (SHIV) challenge. In addition to neutralization, effector functions of the crystallizable fragment (Fc) of antibodies are involved in antibody-mediated protection against a number of viruses. We recently showed that interaction between the Fc fragment of the broadly neutralizing antibody

IgG1 b12 and cellular Fc gamma receptors (Fc gamma Rs) plays an important role in protection against SHIV infection in rhesus macaques. The specific nature of this Fc-dependent protection is largely unknown. To investigate, we generated a panel of 11 IgG1 b12 antibody variants with selectively diminished or enhanced affinity I-BET151 in vitro for the two main activating Fc gamma Rs, Fc gamma RIIa and Fc gamma RIIIa. All 11 antibody variants bind gp120 and neutralize virus as effectively as does wild-type b12. Binding studies using monomeric (enzyme-linked immunosorbent assay [ELISA] and surface plasmon resonance [SPR]) and cellularly expressed Fc gamma receptors show decreased (up to 5-fold) and increased (up to 90-fold) binding to Fc gamma RIIa and Fc gamma RIIIa with this newly generated panel of antibodies. Erastin molecular weight In addition, there was generally a good correlation between b12 variant affinity for Fc gamma receptor and

variant function in antibody-dependent cell-mediated virus inhibition (ADCVI), phagocytosis, NK cell activation assays, and antibody-dependent cellular cytotoxicity (ADCC) assays. In future studies, these b12 variants will enable PI3K inhibitor the investigation of the protective role of individual Fc gamma Rs in HIV infection.”
“Langerhans cells (LCs) are myeloid cells of the epidermis, featured in immunology textbooks as bone marrow-derived antigen-presenting dendritic cells (DCs). A new picture of LC origin, homeostasis and function has emerged, however, after genetic labelling and conditional cell ablation models in mice. LC precursors

are recruited into the fetal epidermis, where they differentiate and proliferate in situ. In adults, LCs proliferate at steady state, and during inflammation, in response to signals from neighbouring cells. Here we review the experimental evidence that support either extra-embryonic yolk sac (YS) macrophages or hematopoietic stem cells (HSCs) as the origin of LCs. Beyond LC biology, we propose that YS and HSCs can contribute to the development of distinct subsets of macrophages and DCs.”
“3,4-methylenedioxymethamphetamine (MDMA) or “”Ecstasy”" is one of the most widely used illicit recreational drugs among young adults. MDMA is an indirect monoaminergic agonist and reuptake inhibitor that primarily affects the serotonin system. Preclinical studies in animals have found prenatal exposure related to neonatal tremors and long-term learning and memory impairments.

However, recent data from various neuroscience disciplines have questioned the major role of amines in the pathogenesis of depression. A considerable amount of evidence has accumulated that suggests that normalization of the hypothalamo-pituitary-adrenal (HPA) system might be the GW786034 clinical trial final step necessary for a remission of depression. In addition, an increasing body of clinical and postmortem evidence is pointing to a role played by gamma-aminobutyric acid (GABA) and glutamate in the etiology of depression. This review examines the evidence, mainly obtained from clinical studies or from postmortem brain material, for a major role of the HPA

axis, glutamatergic, and GABAergic systems in the pathogenesis of major and bipolar depression. The authors hope that these insights will stimulate further studies with the final aim of developing new types of antidepressants that combine increased efficacy with a shorter delay of the onset of action and reduced side-effect profiles.”
“Alcohol use disorders (AUDs) impact millions of individuals and there remain few effective treatment strategies. Despite evidence that neuronal nicotinic acetylcholine receptors

(nAChRs) have a role in AUDs, it has not been established which subtypes of the nAChR are involved. Recent human genetic association studies have implicated the gene cluster CHRNA3-CHRNA5-CHRNB4 encoding the alpha 3, alpha 5, and beta selleck chemical 4 subunits of the nAChR in susceptibility to develop nicotine and alcohol dependence; however, their role in ethanol-mediated behaviors is unknown due to the lack of suitable and selective research tools. To determine the role of the alpha 3, and beta 4 subunits of the nAChR in ethanol self-administration, we developed and characterized high-affinity partial agonists at alpha 3 beta 4 nAChRs, CP-601932, and PF-4575180. Both CP-601932 and PF-4575180 selectively decrease ethanol but not sucrose consumption and operant self-administration following long-term exposure. We show that the functional potencies of CP-601932 and PF-4575180 at a3b4 nAChRs correlate with their unbound

rat brain concentrations, suggesting that the effects ARN-509 mw on ethanol self-administration are mediated via interaction with alpha 3 beta 4 nAChRs. Also varenicline, an approved smoking cessation aid previously shown to decrease ethanol consumption and seeking in rats and mice, reduces ethanol intake at unbound brain concentrations that allow functional interactions with alpha 3 beta 4 nAChRs. Furthermore, the selective alpha 4 beta 2* nAChR antagonist, DH beta E, did not reduce ethanol intake. Together, these data provide further support for the human genetic association studies, implicating CHRNA3 and CHRNB4 genes in ethanol-mediated behaviors. CP-601932 has been shown to be safe in humans and may represent a potential novel treatment for AUDs. Neuropsychopharmacology (2011) 36, 603-615; doi:10.1038/npp.2010.