1,646 research outputs found
Antagonists of Ionotropic Receptors for the Inhibitory Neurotransmitter GABA: Therapeutic Indications
Agents that antagonize the action of GABA on ionotropic receptors are widely used to probe the function of this neurotransmitter. Three such agents are in common use: bicuculline, gabazine, and picrotoxinin. These three agents produce convulsions on systemic administration but act in significantly different ways. Bicuculline is a competitive antagonist of GABAA receptors. Gabazine is also a competitive antagonist of GABAA receptors, interacting with different residues on the receptors. Picrotoxinin is a noncompetitive antagonist acting on the chloride channel of GABAA and several other ionotropic CYS-loop receptors including glycine, GABAC, and 5-HT3 receptors. Many other structurally diverse agents are now known to act as GABA receptor antagonists, providing opportunities for the discovery of agents with selectivity for the myriad of ionotropic GABA receptors. TPMPA is a selective antagonist for GABAC receptors, which are insensitive to bicuculline. Like TPMPA, many antagonists of ionotropic GABA receptors are not convulsants, indicating that there is still much to be learnt about GABA function in the brain from the study of such agents and their possible therapeutic uses. The most recently discovered GABAA receptor nonconvulsive antagonist is S44819, which is subtype selective for α5-containing receptors, and is arousing much interest in relation to cognition
Muscimol as an Ionotropic GABA Receptor Agonist
Abstract Muscimol, a psychoactive isoxazole from Amanita muscaria and related mushrooms, has proved to be a remarkably selective agonist at ionotropic receptors for the inhibitory neurotransmitter GABA. This historic overview highlights the discovery and development of muscimol and related compounds as a GABA agonist by Danish and Australian neurochemists. Muscimol is widely used as a ligand to probe GABA receptors and was the lead compound in the development of a range of GABAergic agents including nipecotic acid, tiagabine, 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol, (Gaboxadol Ò ) and 4-PIOL
Timing of daily calorie loading affects appetite and hunger responses without changes in energy metabolism in healthy subjects with obesity
Acknowledgments The authors gratefully acknowledge Sylvia Stephen, Jean Bryce, Nina Lamza, Karen Taylor, Melanie Hudson, Kat Niblock, Ewa Wojtaczka, Aimee Sutherland, David Bremner, Claire Kidd, and Alicia Bryce at the Human Nutrition Unit of the Rowett Institute for their support in meal preparation and participant assessment. The authors acknowledge the contribution of NIHR Core Biochemistry Assay Laboratory, Cambridge Biomedical Research Centre (gut hormone analysis), and Loek Wouters at Maastricht University, Netherlands (DLW analysis). The authors also gratefully acknowledge Claus-Dieter Mayer for statistical analysis and modeling of the gastric emptying data. The authors gratefully acknowledge funding from the Medical Research Council (grant MR/P012205/1, The Big Breakfast study). A.M.J., P.J.M., G.W.H., and J.A.N.F. also acknowledge funding support from the Scottish Government, Rural and Environment Science and Analytical Services Division. Author contributions Conceptualization, design, and funding acquisition, A.M.J., P.J.M., and J.D.J.; investigation, L.C.R.-C. and C.L.F.; DLW analysis and modeling, K.R.W.; statistical analysis, G.W.H. and J.A.N.F.; writing – original draft, L.C.R.-C. and A.M.J.; writing – review & editing, all authors.Peer reviewedPublisher PD
Timing of daily calorie loading affects appetite and hunger responses without changes in energy metabolism in healthy subjects with obesity
Acknowledgments The authors gratefully acknowledge Sylvia Stephen, Jean Bryce, Nina Lamza, Karen Taylor, Melanie Hudson, Kat Niblock, Ewa Wojtaczka, Aimee Sutherland, David Bremner, Claire Kidd, and Alicia Bryce at the Human Nutrition Unit of the Rowett Institute for their support in meal preparation and participant assessment. The authors acknowledge the contribution of NIHR Core Biochemistry Assay Laboratory, Cambridge Biomedical Research Centre (gut hormone analysis), and Loek Wouters at Maastricht University, Netherlands (DLW analysis). The authors also gratefully acknowledge Claus-Dieter Mayer for statistical analysis and modeling of the gastric emptying data. The authors gratefully acknowledge funding from the Medical Research Council (grant MR/P012205/1, The Big Breakfast study). A.M.J., P.J.M., G.W.H., and J.A.N.F. also acknowledge funding support from the Scottish Government, Rural and Environment Science and Analytical Services Division.Peer reviewedPublisher PD
Identification of Melatonin-Regulated Genes in the Ovine Pituitary Pars Tuberalis, a Target Site for Seasonal Hormone Control
The pars tuberalis (PT) of the pituitary gland expresses a high density of melatonin (MEL) receptors and is believed to regulate seasonal physiology by decoding changes in nocturnal melatonin secretion. Circadian clock genes are known to be expressed in the PT in response to the decline (Per1) and onset (Cry1) of MEL secretion, but to date little is known of other molecular changes in this key MEL target site. To identify transcriptional pathways that may be involved in the diurnal and photoperiod-transduction mechanism, we performed a whole genome transcriptome analysis using PT RNA isolated from sheep culled at three time points over the 24-h cycle under either long or short photoperiods. Our results reveal 153 transcripts where expression differs between photoperiods at the light-dark transition and 54 transcripts where expression level was more globally altered by photoperiod (all time points combined). Cry1 induction at night was associated with up-regulation of genes coding for NeuroD1 (neurogenic differentiation factor 1), Pbef / Nampt (nicotinamide phosphoribosyltransferase) , Hif1α (hypoxia-inducible factor-1α), and Kcnq5 (K channel) and down-regulation of Rorβ, a key clock gene regulator. Using in situ hybridization, we confirmed day-night differences in expression for Pbef / Nampt, NeuroD1, and Rorβ in the PT. Treatment of sheep with MEL increased PT expression for Cry1, Pbef / Nampt, NeuroD1, and Hif1α, but not Kcnq5. Our data thus reveal a cluster of Cry1-associated genes that are acutely responsive to MEL and novel transcriptional pathways involved in MEL action in the PT
Artificial Neural Network Inference (ANNI): A Study on Gene-Gene Interaction for Biomarkers in Childhood Sarcomas
Objective: To model the potential interaction between previously identified biomarkers in children sarcomas using artificial neural network inference (ANNI).
Method: To concisely demonstrate the biological interactions between correlated genes in an interaction network map, only 2 types of sarcomas in the children small round blue cell tumors (SRBCTs) dataset are discussed in this paper. A backpropagation neural network was used to model the potential interaction between genes. The prediction weights and signal directions were used to model the strengths of the interaction signals and the direction of the interaction link between genes. The ANN model was validated using Monte Carlo cross-validation to minimize the risk of over-fitting and to optimize generalization ability of the model.
Results: Strong connection links on certain genes (TNNT1 and FNDC5 in rhabdomyosarcoma (RMS); FCGRT and OLFM1 in Ewing’s sarcoma (EWS)) suggested their potency as central hubs in the interconnection of genes with different functionalities. The results showed that the RMS patients in this dataset are likely to be congenital and at low risk of cardiomyopathy development. The EWS patients are likely to be complicated by EWS-FLI fusion and deficiency in various signaling pathways, including Wnt, Fas/Rho and intracellular oxygen.
Conclusions: The ANN network inference approach and the examination of identified genes in the published literature within the context of the disease highlights the substantial influence of certain genes in sarcomas
Public opinion on energy crops in the landscape: considerations for the expansion of renewable energy from biomass
Public attitudes were assessed towards two dedicated biomass crops – Miscanthus and Short Rotation Coppice (SRC), particularly regarding their visual impacts in the landscape. Results are based on responses to photographic and computer-generated images as the crops are still relatively scarce in the landscape. A questionnaire survey indicated little public concern about potential landscape aesthetics but more concern about attendant built infrastructure. Focus group meetings and interviews indicated support for biomass end uses that bring direct benefits to local communities. Questions arise as to how well the imagery used was able to portray the true nature of these tall, dense, perennial plants but based on the responses obtained and given the caveat that there was limited personal experience of the crops, it appears unlikely that wide-scale planting of biomass crops will give rise to substantial public concern in relation to their visual impact in the landscape
Biographical interviews and imagined futures essay writing: users of two methods in conversation
This article reports on a conversation between users of two research methods, biographical interviews and imagined futures essay writing. A dialogue form is used to discuss these methods and their potential to be combined. The value of comparing research methods is discussed, and then the two methods are described and points of connection and contrast are explored. Although one method emphasises looking back while the other looks forward, the two have much in common, including the exercise of imagination, and discussion of individual agency and structural constraint. Both involve the construction of narratives that help understanding of people’s lives as individual trajectories set in broader social and historical contexts. The two methods are quite different but complementary, and possibilities for their combination in one project are identified. The article ends by reflecting on the benefits and drawbacks of using dialogue to consider how research methods sit alongside each other
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