Regulation of Akt and Wnt signalling by the dopamine D2 receptor and metabotropic glutamate receptor 2/3

Akt and the Wnt pathway, two cascades that regulate GSK-3, have been implicated in schizophrenia and antipsychotic drug action. Although it is known that antipsychotic drugs alleviate psychosis by blocking the dopamine D2 receptor (D2DR) and that metabotropic glutamate receptor 2/3 (mGluR2/3) agonists may improve some of the symptoms of schizophrenia, it is unclear if both classes of drugs exert their effects through Akt, GSK-3 and/or the Wnt pathway or if changes in these pathways are mediated through the D2DR and mGluR2/3 respectively. In addition to antipsychotics, mood stabilizers and antidepressants also target GSK-3, suggesting that there must be something unique in the way GSK-3 is targeted by antipsychotics since neither mood stabilizers nor antidepressants alleviate psychosis. The current study examined whether Akt and the Wnt pathway are regulated by the D2DR and mGluR2/3 and investigated the role of Akt and Dvl-3, a key activator in the Wnt pathway, in regulating GSK-3 in the rat brain. The study also compared the effects of antipsychotic, mood stabilizers and antidepressants on Akt and Wnt pathway proteins to determine if antipsychotics have unique effects on these signalling proteins. Results showed that raclopride (D2DR antagonist) regulated Akt and the Wnt pathway via Dvl-3 and the response was identical to antipsychotic treatment. Administration of the mGluR2/3 agonist, LY379268 also targeted Akt and the Wnt pathway and induced a similar response as antipsychotics. In addition, repeated amphetamine treatment, an established animal model for the positive symptoms of schizophrenia, quinpirole (D2DR agonist) and LY341495 (mGluR2/3 antagonist) induced similar changes in Akt and Wnt signalling that parallel alterations reported in schizophrenia. Furthermore, systemic inhibition of GSK-3 was able to attenuate the increase in locomotion induced by LY341495, a behavioural measure that models the positive symptoms of schizophrenia. The study also showed that clozapine and haloperidol (antipsychotics) induced a common Wnt response that was not mimicked by the mood stabilizers or antidepressants tested but that all neuropsychiatric drugs tested induced changes in Akt. Collectively the data shows that the Wnt pathway is regulated specifically by drugs with antipsychotic properties and may represent a novel target for pharmaceutical intervention

Children and young people's participation in planning and regeneration: a final report to the Ecorys Research Programme 2010-11

This briefing paper summarises the findings from research carried out by Ecorys (formerly ECOTEC) and Loughborough University. The study set out to examine children and young people's roles in planning, design and regeneration in the UK and internationally; to map and assess different models of practice, and to locate these practices within wider debates about children's participation and citizenship. It also aimed to review the methods used to measure impact and outcomes in this area. The work was carried out between June 2010 and January 2011, and funded through the 2010-11 Round of the Ecorys Research Programme1. The methodology comprised a review of UK and international research literature, adopting the principles of a Rapid Evidence Assessment (REA)2; an analysis of selected UK policy and strategy documents, and a small number of exploratory stakeholder interviews. The research team was supported by an Advisory Group with representatives from policy and academia. The report concludes that the spatial aspects of children's participation crosscut the wider participation agenda, but have too often been overlooked within a service-driven approach to policymaking. There is evidence from research and practice that children and young people can play a significant role within planning and regeneration processes, with potential benefits at individual, peer group and community levels. A stronger evidence base is clearly needed to understand the longer-term impacts in this area. The recent change in government and emerging policies present both opportunities and challenges for children and young people's participation within the UK. There has been a renewed focus on citizenship of sorts, whilst the Localism agenda and Big Society place an emphasis on municipal leadership, which is a characteristic feature of many rights-based programmes worldwide. However, public sector funding cuts, coupled with the dismantlement of the national planning framework arguably run the risk of leaving children more vulnerable to exclusion from local planning decisions that affect their lives. The authors argue that developing a more outward-facing approach, and engaging with the various transnational networks of good practice that have been established around the CRC agenda should be a priority

Isolation of a highly active Photosystem II preparation from Synechocystis 6803 using a histidine-tagged mutant of CP 47

Site-directed mutagenesis was used to produce a Synechocystis mutant containing a histidine tag at the C terminus of the CP 47 protein of Photosystem II. This mutant cell line, designated HT-3, exhibited slightly above normal rates of oxygen evolution and appeared to accumulate somewhat more Photosystem II reaction centers than a control strain. A rapidly isolatable (\u3c7 \u3eh) oxygen-evolving Photosystem II preparation was prepared from HT-3 using dodecyl-β-d-maltoside solubilization and Co2+ metal affinity chromatography. This histidine-tagged Photosystem II preparation stably evolved oxygen at a high rate (2440 μmol O2 (mg chl)-1 h-1), exhibited an α-band absorption maximum at 674 nm, and was highly enriched in a number of Photosystem II components including cytochrome c550. Fluorescence yield analysis using water or hydroxylamine as an electron donor to the Photosystem II preparation indicated that virtually all of the Photosystem II reaction centers were capable of evolving oxygen. Proteins associated with Photosystem II were highly enriched in this preparation. 3,3\u27,5,5\u27-Tetramethylbenzidine staining indicated that the histidine-tagged preparation was enriched in cytochromes c550 and b559 and depleted of cytochrome f. This result was confirmed by optical difference spectroscopy. This histidine-tagged Photosystem II preparation may be very useful for the isolation of Photosystem II preparations from mutants containing lesions in other Photosystem II proteins. Copyright (C) 1998 Published by Elsevier Science B.V

Metabolic state alters economic decision making under risk in humans

Background: Animals' attitudes to risk are profoundly influenced by metabolic state (hunger and baseline energy stores). Specifically, animals often express a preference for risky (more variable) food sources when below a metabolic reference point (hungry), and safe (less variable) food sources when sated. Circulating hormones report the status of energy reserves and acute nutrient intake to widespread targets in the central nervous system that regulate feeding behaviour, including brain regions strongly implicated in risk and reward based decision-making in humans. Despite this, physiological influences per se have not been considered previously to influence economic decisions in humans. We hypothesised that baseline metabolic reserves and alterations in metabolic state would systematically modulate decision-making and financial risk-taking in humans. Methodology/Principal Findings: We used a controlled feeding manipulation and assayed decision-making preferences across different metabolic states following a meal. To elicit risk-preference, we presented a sequence of 200 paired lotteries, subjects' task being to select their preferred option from each pair. We also measured prandial suppression of circulating acyl-ghrelin (a centrally-acting orexigenic hormone signalling acute nutrient intake), and circulating leptin levels (providing an assay of energy reserves). We show both immediate and delayed effects on risky decision-making following a meal, and that these changes correlate with an individual's baseline leptin and changes in acyl-ghrelin levels respectively. Conclusions/Significance: We show that human risk preferences are exquisitely sensitive to current metabolic state, in a direction consistent with ecological models of feeding behaviour but not predicted by normative economic theory. These substantive effects of state changes on economic decisions perhaps reflect shared evolutionarily conserved neurobiological mechanisms. We suggest that this sensitivity in human risk-preference to current metabolic state has significant implications for both real-world economic transactions and for aberrant decision-making in eating disorders and obesity

Regulators of G protein Signaling (RGS) proteins (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Regulators of G protein signalling (RGS) proteins display a common RGS domain that interacts with the GTP-bound Gα subunits of heterotrimeric G proteins, enhancing GTP hydrolysis by stabilising the transition state [29, 419, 418], leading to a termination of GPCR signalling. Interactions through protein:protein interactions of many RGS proteins have been identified for targets other than heteromeric G proteins. Sequence analysis of the 20 RGS proteins suggests four families of RGS: RZ, R4, R7 and R12 families. Many of these proteins have been identified to have effects other than through targetting G proteins. Included here is RGS4 for which a number of pharmacological inhibitors have been described

Comprehensive literature review and statistical considerations for GWAS meta-analysis

Over the last decade, genome-wide association studies (GWAS) have become the standard tool for gene discovery in human disease research. While debate continues about how to get the most out of these studies and on occasion about how much value these studies really provide, it is clear that many of the strongest results have come from large-scale mega-consortia and/or meta-analyses that combine data from up to dozens of studies and tens of thousands of subjects. While such analyses are becoming more and more common, statistical methods have lagged somewhat behind. There are good meta-analysis methods available, but even when they are carefully and optimally applied there remain some unresolved statistical issues. This article systematically reviews the GWAS meta-analysis literature, highlighting methodology and software options and reviewing methods that have been used in real studies. We illustrate differences among methods using a case study. We also discuss some of the unresolved issues and potential future directions

Regulators of G protein Signaling (RGS) proteins (version 2020.4) in the IUPHAR/BPS Guide to Pharmacology Database

Regulator of G protein Signaling, or RGS, proteins serve an important regulatory role in signaling mediated by G protein-coupled receptors (GPCRs). They all share a common RGS domain that directly interacts with active, GTP-bound Gα subunits of heterotrimeric G proteins. RGS proteins stabilize the transition state for GTP hydrolysis on Gα and thus induce a conformational change in the Gα subunit that accelerates GTP hydrolysis, thereby effectively turning off signaling cascades mediated by GPCRs. This GTPase accelerating protein (GAP) activity is the canonical mechanism of action for RGS proteins, although many also possess additional functions and domains. RGS proteins are divided into four families, R4, R7, R12 and RZ based on sequence homology, domain structure as well as specificity towards Gα subunits. For reviews on RGS proteins and their potential as therapeutic targets, see e.g. [160, 377, 411, 415, 416, 512, 519, 312, 6]

Regulators of G protein Signaling (RGS) proteins in GtoPdb v.2021.2

Regulator of G protein Signaling, or RGS, proteins serve an important regulatory role in signaling mediated by G protein-coupled receptors (GPCRs). They all share a common RGS domain that directly interacts with active, GTP-bound Gα subunits of heterotrimeric G proteins. RGS proteins stabilize the transition state for GTP hydrolysis on Gα and thus induce a conformational change in the Gα subunit that accelerates GTP hydrolysis, thereby effectively turning off signaling cascades mediated by GPCRs. This GTPase accelerating protein (GAP) activity is the canonical mechanism of action for RGS proteins, although many also possess additional functions and domains. RGS proteins are divided into four families, R4, R7, R12 and RZ based on sequence homology, domain structure as well as specificity towards Gα subunits. For reviews on RGS proteins and their potential as therapeutic targets, see e.g. [225, 529, 578, 583, 584, 742, 753, 444, 10]

Copy Number Variation Affecting the Photoperiod-B1 and Vernalization-A1 Genes Is Associated with Altered Flowering Time in Wheat (Triticum aestivum)

The timing of flowering during the year is an important adaptive character affecting reproductive success in plants and is critical to crop yield. Flowering time has been extensively manipulated in crops such as wheat (Triticum aestivum L.) during domestication, and this enables them to grow productively in a wide range of environments. Several major genes controlling flowering time have been identified in wheat with mutant alleles having sequence changes such as insertions, deletions or point mutations. We investigated genetic variants in commercial varieties of wheat that regulate flowering by altering photoperiod response (Ppd-B1 alleles) or vernalization requirement (Vrn-A1 alleles) and for which no candidate mutation was found within the gene sequence. Genetic and genomic approaches showed that in both cases alleles conferring altered flowering time had an increased copy number of the gene and altered gene expression. Alleles with an increased copy number of Ppd-B1 confer an early flowering day neutral phenotype and have arisen independently at least twice. Plants with an increased copy number of Vrn-A1 have an increased requirement for vernalization so that longer periods of cold are required to potentiate flowering. The results suggest that copy number variation (CNV) plays a significant role in wheat adaptation