510 results on '"John B. Davis"'
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152. Where Economics and Philosophy Meet: Review of the Elgar Companion to Economics and Philosophy with Responses from the Authors
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Alain Marciano, Jochen Runde, Margaret Schabas, Peter J. Boettke, Francesco Guala, John B. Davis, Christopher J. Coyne, and History and Methodology of Economics (ASE, FEB)
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Value (ethics) ,Economics and Econometrics ,Computational economics ,Philosophy and economics ,Sociology ,Experimental economics ,Philosophy of psychology ,Neuroeconomics ,Positive economics ,Positivism ,Social theory - Abstract
Although Adam Smith’s 1776 Wealth of Nations is often cited as marking the birth of economics, it was really not until after the second world war that economics became the distinctive, more or less unified, and largely separate discipline summarised in the textbooks of today. Even a mere fifty years ago, it was possible for the intelligent reader to move with relative ease between economics on the one hand and political economy, sociology and social theory, psychology and philosophy on the other. This is now no longer the case, and most young economists are taught to think of their discipline, not primarily in terms of the particular economic social phenomena it was once taken to be about, but as a sophisticated and largely self-contained analytical approach to the investigation of social phenomena of any kind. Even so, economics has never been able to separate itself entirely from its sister disciplines, even at the high tide of mathematical economics and positivism during the 1970s and 1980s, and many of the most active new areas in economics currently involve some form of boundary crossing (e.g. experimental economics, neuroeconomics and computational economics to name just three). With respect to the philosophy of economics in particular, the last fifty years or so have seen a steady expansion in scholarly investigation into different connections between economics and philosophy, with the emergence of new journals, professional associations, research networks and the like. There has been a great deal of work on epistemological questions in the wake of the decline of positivism, on boundary issues and the question of whether or not economics constitutes a science, and on the rhetoric of economics, ethics, value and, latterly, the ontology of economics (Hands, 2001). It is against this background that, in 2004, three of us published the Elgar Companion to Economics and Philosophy (Davis, Marciano and Runde, 2004, henceforth the Companion), an edited collection aimed at documenting the current state of play in three important areas of the philosophy of economics
- Published
- 2006
153. Discovery of SB-705498: A potent, selective and orally bioavailable TRPV1 antagonist suitable for clinical development
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Jeffrey C. Jerman, Darren Smart, Andrew D. Randall, Becky Sargent, Steve Fell, Geoffrey Stemp, Harshad Kantilal Rami, Alexander J. Stevens, Dominic Sanderson, Martin J. Gunthorpe, John B. Davis, and Mervyn Thompson
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Pyrrolidines ,Guinea Pigs ,Clinical Biochemistry ,TRPV1 ,Administration, Oral ,TRPV Cation Channels ,Pharmaceutical Science ,Biochemistry ,Chemical synthesis ,Cell Line ,Structure-Activity Relationship ,chemistry.chemical_compound ,In vivo ,Drug Discovery ,Animals ,Humans ,Urea ,Structure–activity relationship ,Receptor ,Molecular Biology ,Molecular Structure ,Organic Chemistry ,Antagonist ,Small molecule ,Rats ,chemistry ,Capsaicin ,Drug Design ,Molecular Medicine - Abstract
Small molecule antagonists of the vanilloid receptor TRPV1 (also known as VR1) are disclosed. Pyrrolidinyl ureas such as 8 and 15 (SB-705498) emerged as lead compounds following optimisation of the previously described urea SB-452533. Pharmacological studies using electrophysiological and FLIPR-Ca2+-based assays showed that compounds such as 8 and 15 were potent antagonists versus the multiple chemical and physical modes of TRPV1 activation (namely capsaicin, acid and noxious heat). Furthermore, 15 possessed suitable developability properties to enable progression of this compound into in vivo studies and subsequently clinical development.
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- 2006
154. The effect of neurotrophic factors on morphology, TRPV1 expression and capsaicin responses of cultured human DRG sensory neurons
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Uma Anand, C. Bountra, Maria A Casula, John B. Davis, Nicola C. Day, W.R. Otto, Praveen Anand, and Rolfe Birch
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Adult ,Male ,medicine.medical_specialty ,TRPV3 ,medicine.medical_treatment ,TRPV1 ,TRPV Cation Channels ,Sodium Channels ,NAV1.8 Voltage-Gated Sodium Channel ,Potassium Channels, Calcium-Activated ,chemistry.chemical_compound ,Neurotrophin 3 ,Neurotrophic factors ,Ganglia, Spinal ,Internal medicine ,Nerve Growth Factor ,medicine ,Glial cell line-derived neurotrophic factor ,Humans ,Glial Cell Line-Derived Neurotrophic Factor ,Nerve Growth Factors ,Neurons, Afferent ,Cells, Cultured ,Cell Size ,biology ,business.industry ,General Neuroscience ,Growth factor ,Sensory neuron ,Endocrinology ,medicine.anatomical_structure ,Nerve growth factor ,nervous system ,chemistry ,Capsaicin ,biology.protein ,business - Abstract
We have studied the effect of key neurotrophic factors (NTFs) on morphology, levels of the vanilloid receptor-1 (TRPV1) and responses to capsaicin in adult human sensory neurons in vitro. Avulsed dorsal root ganglia (DRG, n = 5) were cultured with or without a combination of nerve growth factor (NGF), glial cell (line)-derived growth factor (GDNF) and neurotrophin3 (NT3) for 5 days. In the absence of NTFs, the diameter of neurons ranged from 20 to 100 microm (mean 42 +/- 4 microm). Adding NTFs caused a significant increase in neuronal sizes, up to 120 microm (mean diameter 62 +/- 5 microm, P < 0.01, t-test), an overall 35% increase of TRPV1-positive neurons (P < 0.003), and notably of large TRPV1-positive neurons > 80 microm (P < 0.05). Responses to capsaicin were significantly enhanced with calcium ratiometry (P < 0.0001). Short duration (1h) exposure of dissociated sensory neurons to NTFs increased numbers of TRPV1-positive neurons, but not of TRPV3, Nav 1.8 and IK1 and the morphological size-distribution remained similar to intact post-mortem DRG neurons. NTFs thus increase size, elevate TRPV1 levels and enhance capsaicin responses in cultured human DRG neurons; these changes may relate to pathophysiology in disease states, and provide an in vitro model to study novel analgesics.
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- 2006
155. The turn in economics: neoclassical dominance to mainstream pluralism?
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John B. Davis and History and Methodology of Economics (ASE, FEB)
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Human development theory ,Applied economics ,Managerial economics ,Economics ,Mainstream economics ,Schools of economic thought ,Complexity economics ,New institutional economics ,Positive economics ,Neoclassical economics ,General Economics, Econometrics and Finance ,Heterodox economics - Abstract
This paper investigates whether since the 1980s neoclassical economics has been in the process of being supplanted as the dominant research programme in economics by a collection of competing research approaches which share relatively little in common with each other or with neoclassical economics. A shortlist of the new approaches in recent economics includes game theory, experimental economics, behavioral economics, evolutionary economics, neuroeconomics, and non-linear complexity theory. Two hypotheses are advanced – one regarding the relation between economics instruction and economics research and one regarding the nature of the economics research frontier – to describe social-institutional practices that contribute to the replication of economics as a field. Two further hypotheses are advanced – one regarding the boundaries of the field and one regarding how the field appraises itself – to create a historical–methodological framework for evaluating the question of change in economics and change in recent economics in particular. Finally, the paper distinguishes three leading explanations – the ‘breakdown’ view, the ‘takeover’ view, and the ‘maturity’ view – of why neoclassical economics no longer dominates a mainstream economics.
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- 2006
156. The London Drug Scene and the Making of Drug Policy, 1965-73
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John B. Davis
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Drug ,History ,media_common.quotation_subject ,Political science ,Law ,Public administration ,Making-of ,media_common - Published
- 2005
157. Continuously variable mixing-ratio micromixer with elastomer valves
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John B Davis, M.C. Tracey, C. K. L. Tan, and I. D. Johnston
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Control valves ,Materials science ,Mechanical Engineering ,Acoustics ,Microfluidics ,Micropump ,Micromixer ,Context (language use) ,Elastomer ,Electronic, Optical and Magnetic Materials ,Mechanics of Materials ,Electronic engineering ,Fluidics ,Electrical and Electronic Engineering ,Mixing (physics) - Abstract
We report a self-contained microfluidic alternate flow injection mixer (AFIM) employing piezoelectrically actuated, PDMS seal-valves to control injection. AFIMs employ pulsatile injection of liquids to enhance interface surface generation. By allowing control of pulse-volume proportionality by variation of the duty-cycle of the valve control signals, continuously variable ratio mixing is achieved without external fluid control components. Mixing is discussed in the context of 'rate of new surface generation', thus allowing comparison with laminating mixer designs. The prototype mixer employs a simple micromould fabrication technique to minimize reversible elastomer valve-seal adhesion and hence allow correct valve operation. The resulting device has been characterized over a range of mixing ratios.
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- 2005
158. Neoclassicism, artificial intelligence, and the marginalization of ethics
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John B. Davis
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Philosophy of mind ,Economics and Econometrics ,Emotivism ,business.industry ,Philosophy and economics ,Economic methodology ,Functionalism (philosophy of mind) ,General Social Sciences ,Contemporary philosophy ,Multiple realizability ,Normative ,Artificial intelligence ,Sociology ,business - Abstract
PurposeThe paper examines the dependence of the positivist and welfarist preference satisfaction paradigm of neoclassical economics upon an implicit functionalist philosophy of mind. Functionalism is the doctrine that mental states are strictly materialistic and understandable in cause‐effect terms. An important aspect of functionalism is the multiple realizability thesis, namely, that mental states can be realized in any type of hardware, whether human brain or computer.Design/methodology/approachThe approach used involves investigating the fact‐value distinction after Robbins in terms of the positivist meta‐ethical view known as emotivism, and then explaining emotivism as inherently functionalist. Functionalist thinking itself is explained in terms of contemporary philosophy of mind.FindingsAn important finding is that the preference satisfaction paradigm can be shown to be as suitable to artificial intelligence systems as to human beings. A consequence of this is that normative concerns are increasingly difficult to address in connection with the neoclassical thinking about economic agents.Research limitations/implicationsThe paper does not investigate more recent research programs in economics (such as behavioural economics) that depart from basic neoclassical assumptions.Practical implicationsA practical implication of the paper is that it shifts attention to previously un‐emphasized aspects of neoclassical thinking.Originality/valueThe paper's value to explain the relation of economics to ethics in neoclassical economics in connection with functionalist philosophy of mind.
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- 2005
159. Capsaicin receptor TRPV1 in urothelium of neurogenic human bladders and effect of intravesical resiniferatoxin
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Apostolos Apostolidis, Praveen Anand, Yiangos Yiangou, John B. Davis, Clare J. Fowler, and Ciaran Brady
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Adult ,Male ,medicine.medical_specialty ,Biopsy ,Urology ,Urinary Bladder ,Resiniferatoxin ,TRPV1 ,TRPV Cation Channels ,Ion Channels ,Immunoenzyme Techniques ,Basal (phylogenetics) ,chemistry.chemical_compound ,Nerve Fibers ,Image Processing, Computer-Assisted ,Humans ,Medicine ,Single-Blind Method ,Urinary Bladder, Neurogenic ,Urothelium ,Receptor ,Urinary bladder ,business.industry ,musculoskeletal, neural, and ocular physiology ,Cell Polarity ,Cystoscopy ,Middle Aged ,Administration, Intravesical ,medicine.anatomical_structure ,nervous system ,chemistry ,Capsaicin ,Female ,lipids (amino acids, peptides, and proteins) ,Diterpenes ,business ,psychological phenomena and processes ,Immunostaining - Abstract
Objectives To study TRPV1 immunoreactivity in the urothelium of patients with neurogenic detrusor overactivity (NDO) before and after treatment with resiniferatoxin (RTX) and controls. Functional capsaicin TRPV1 receptors have been demonstrated in urothelial cells of rodent urinary bladder, and TRPV1-knockout mice exhibit diminished nitric oxide and stretch-evoked adenosine triphosphate release from urothelial cells. In patients with NDO, TRPV1 suburothelial nerve density is increased, which is reversed by successful treatment with intravesical RTX. However, the role of urothelial TRPV1 in human bladder disorders is unknown. Methods Flexible cystoscopic bladder biopsies were obtained from 14 patients with NDO before and after treatment with RTX and from 8 control patients. Using a specific antibody for immunostaining, TRPV1 immunoreactivity in the urothelium was quantified by image analysis. Results TRPV1 immunoreactivity was observed in basal and apical urothelial cells. Basal cell layer TRPV1 immunoreactivity was significantly increased in NDO compared with control bladders ( P = 0.003). In 5 patients who responded clinically to RTX, basal cell layer and total urothelial TRPV1 immunoreactivity decreased significantly after treatment ( P = 0.032 and P = 0.016, respectively). The decreases in the basal cell layer TRPV1 immunoreactivity after RTX were comparable to the decreases in suburothelial TRPV1 nerve fibers in the biopsies previously studied from the same patients. Conclusions Increased urothelial TRPV1 in patients with NDO may play a role in the pathophysiology, in concert with increased TRPV1 nerve fibers. Although it is not known whether similar pathogenic mechanisms are involved in the increase of urothelial and neuronal TRPV1, both may be targeted by successful RTX therapy.
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- 2005
160. Robbins, textbooks, and the extreme value neutrality view
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John B. Davis and History and Methodology of Economics (ASE, FEB)
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Economics and Econometrics ,History ,Economics ,Neutrality ,Positive economics ,Criminology ,Extreme value theory - Published
- 2005
161. Jejunal afferent nerve sensitivity in wild-type and TRPV1 knockout mice
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Weifang Rong, Wendy J. Winchester, Gareth A. Hicks, John B. Davis, K. Hillsley, and David Grundy
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medicine.medical_specialty ,Physiology ,Chemistry ,musculoskeletal, neural, and ocular physiology ,Antagonist ,TRPV1 ,Bradykinin ,Anatomy ,Distension ,chemistry.chemical_compound ,Endocrinology ,Capsaicin ,Internal medicine ,Knockout mouse ,medicine ,lipids (amino acids, peptides, and proteins) ,Mechanosensitive channels ,Capsazepine - Abstract
The aim of this study was to investigate the contribution of the TRPV1 receptor to jejunal afferent sensitivity in the murine intestine. Multiunit activity was recorded in vitro from mesenteric afferents supplying segments of mouse jejunum taken from wild-type (WT) and TRPV1 knockout (TRPV1−/−) animals. In WT preparations, ramp distension of the gut (up to 60 mmHg) produced biphasic changes in afferent activity so the pressure–response curve had an initial rapid increase in afferent discharge followed by a second phase of slower increase in activity. Afferent response to distension was significantly lower in TRPV1−/− than in WT mice. Single-unit analysis revealed three functional types of afferent fibres: (1) low-threshold fibres (2) wide dynamic range fibres and (3) high-threshold fibres. There was a marked downward shift of the pressure–response curve for wide dynamic range fibres in the TRPV1−/− mice as compared to the WT controls. The afferent response to intraluminal hydrochloric acid (20 mm) was also attenuated in the TRPV1−/− mice. In contrast, the response to bath application of bradykinin (1 μm, 3 ml) was not significantly different between the two groups. The TRPV1 antagonist capsazepine (10 μm) significantly attenuated the nerve responses to distension, intraluminal acid and bradykinin, as well as the spontaneous discharge in WT mice. The WT jejunal afferents responded to capsaicin with rapid increases in afferent activity, whereas TRPV1−/− afferents were not at all sensitive to capsaicin. Previous evidence indicates that TRPV1 is not mechanosensitive, so the results of the present study suggest that activation of TRPV1 may sensitize small intestinal afferent neurones.
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- 2004
162. Increased capsaicin receptor TRPV1 nerve fibres in the inflamed human oesophagus
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Paul Facer, John B. Davis, Qasim Aziz, Philip J Matthews, Praveen Anand, and David G. Thompson
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Adult ,Male ,medicine.medical_specialty ,Pathology ,Adolescent ,Receptors, Drug ,TRPV1 ,Nerve fiber ,Gastroenterology ,chemistry.chemical_compound ,Esophagus ,Nerve Fibers ,Internal medicine ,Biopsy ,medicine ,Esophagitis ,Humans ,Aged ,Aged, 80 and over ,Lamina propria ,Mucous Membrane ,Hepatology ,medicine.diagnostic_test ,business.industry ,musculoskeletal, neural, and ocular physiology ,Heartburn ,Peripherin ,Middle Aged ,medicine.anatomical_structure ,nervous system ,chemistry ,Capsaicin ,Female ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,business ,Sensory nerve - Abstract
Background Gastro-oesophageal reflux disease (GORD) patients commonly describe symptoms of heartburn and chest pain. The capsaicin receptor vanilloid receptor 1 (TRPV1) (VR1) is a cation channel expressed by sensory neurones and activated by heat, acid pH and ethanol, which may trigger burning pain. Aim To study the distribution of TRPV1-expressing nerve fibres in oesophageal mucosal biopsies from patients with symptomatic oesophagitis and in control subjects. Methods Biopsies were taken at gastroscopy from the distal oesophagus of seven symptomatic oesophagitis patients and seven asymptomatic patients undergoing investigation for iron-deficiency anaemia. These biopsies were studied by immunohistochemistry using affinity-purified antibodies to TRPV1 and to the neuronal marker peripherin. The density of oesophageal epithelial TRPV1 innervation was assessed by calculating the proportion of papillae in each oesophageal epithelium biopsy specimen containing TRPV1-immunoreactive fibres. Results TRPV1-immunoreactive nerves were distributed within the lamina propria in healthy subjects and in oesophagitis patients. The percentage of papillae positive for TRPV1 was elevated in oesophagitis patients compared with controls. Peripherin fibre density was not significantly different between the groups. Conclusions TRPV1-immunoreactive sensory nerve fibres are expressed in human oesophageal mucosa both in health and in disease. Increased TRPV1 expression in the inflamed oesophagus may mediate the heartburn in oesophagitis, and TRPV1 blockers may provide novel treatment.
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- 2004
163. Daily body temperature rhythm and heat tolerance in TRPV1 knockout and capsaicin pretreated mice
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John B. Davis, Z. Hummel, J. Szolcsányi, and Zoltán Szelényi
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Mice, Knockout ,medicine.medical_specialty ,Hot Temperature ,Chemistry ,Receptors, Drug ,General Neuroscience ,TRPV1 ,Body Temperature ,Circadian Rhythm ,Mice, Inbred C57BL ,Heat tolerance ,Mice ,Transient receptor potential channel ,Temperature rhythm ,chemistry.chemical_compound ,Endocrinology ,In vivo ,Capsaicin ,Internal medicine ,medicine ,Deficient mouse ,Animals ,lipids (amino acids, peptides, and proteins) ,Receptor - Abstract
Daily body temperature (DBT) rhythm of mice lacking one of the transient receptor potential (TRP) family of proteins, the capsaicin receptor or TRPV1, was recorded by biotelemetry and found to have significantly higher amplitude than that of wild-type mice. Capsaicin-desensitized wild-mice exhibited an even higher DBT amplitude than did TRPV1 deficient mice. A standard heat load (radiant temperature of 36-37 degrees C) resulted in similar rises in body core temperature in wild-type mice and in TRPV1 deficient mice, while capsaicin-desensitized wild-type mice exhibited a robust heat-intolerance. The lack of TRPV1 slightly modifies amplitude of daily body temperature rhythm but does not seem to influence physiological heat defence in mice. In vivo evidence for a TRP protein functioning in the physiological heat-defence range is still lacking.
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- 2004
164. Identification and characterisation of SB-366791, a potent and selective vanilloid receptor (VR1/TRPV1) antagonist
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S. Nasir, Angela Worby, Catherine H. Gill, Harshad Kantilal Rami, Wyman Paul Adrian, Jeffrey C. Jerman, Andrew D. Randall, John B. Davis, Mervyn Thompson, Darren Smart, Julie Egerton, Ellen M. Soffin, Davina E. Owen, Graham D Smith, Ceri H. Davies, Sarah C. Lappin, Martin J. Gunthorpe, L. Howett, and S. Luis Hannan
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Hot Temperature ,N-Methylaspartate ,Patch-Clamp Techniques ,Receptors, Drug ,TRPV1 ,Pharmacology ,Kidney ,TRPV ,Cell Line ,Membrane Potentials ,Norepinephrine ,Radioligand Assay ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Excitatory Amino Acid Agonists ,medicine ,Animals ,Humans ,Anilides ,Drug Interactions ,Receptor ,alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid ,8-Hydroxy-2-(di-n-propylamino)tetralin ,Orexins ,Aniline Compounds ,Dose-Response Relationship, Drug ,Neuropeptides ,Intracellular Signaling Peptides and Proteins ,Antagonist ,Excitatory Postsynaptic Potentials ,Embryo, Mammalian ,Rats ,Serotonin Receptor Agonists ,Xanthenes ,Mechanism of action ,chemistry ,Discovery and development of TRPV1 antagonists ,Cinnamates ,Capsaicin ,Calcium ,medicine.symptom ,Carrier Proteins ,Capsazepine ,Acids ,Protein Binding - Abstract
Vanilloid receptor-1 (TRPV1) is a non-selective cation channel, predominantly expressed by peripheral sensory neurones, which is known to play a key role in the detection of noxious painful stimuli, such as capsaicin, acid and heat. To date, a number of antagonists have been used to study the physiological role of TRPV1; however, antagonists such as capsazepine are somewhat compromised by non-selective actions at other receptors and apparent modality-specific properties. SB-366791 is a novel, potent, and selective, cinnamide TRPV1 antagonist isolated via high-throughput screening of a large chemical library. In a FLIPR-based Ca(2+)-assay, SB-366791 produced a concentration-dependent inhibition of the response to capsaicin with an apparent pK(b) of 7.74 +/- 0.08. Schild analysis indicated a competitive mechanism of action with a pA2 of 7.71. In electrophysiological experiments, SB-366791 was demonstrated to be an effective antagonist of hTRPV1 when activated by different modalities, such as capsaicin, acid or noxious heat (50 degrees C). Unlike capsazepine, SB-366791 was also an effective antagonist vs. the acid-mediated activation of rTRPV1. With the aim of defining a useful tool compound, we also profiled SB-366791 in a wide range of selectivity assays. SB-366791 had a good selectivity profile exhibiting little or no effect in a panel of 47 binding assays (containing a wide range of G-protein-coupled receptors and ion channels) and a number of electrophysiological assays including hippocampal synaptic transmission and action potential firing of locus coeruleus or dorsal raphe neurones. Furthermore, unlike capsazepine, SB-366791 had no effect on either the hyperpolarisation-activated current (I(h)) or Voltage-gated Ca(2+)-channels (VGCC) in cultured rodent sensory neurones. In summary, SB-366791 is a new TRPV1 antagonist with high potency and an improved selectivity profile with respect to other commonly used TRPV1 antagonists. SB-366791 may therefore prove to be a useful tool to further study the biology of TRPV1.
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- 2004
165. Brexit and the Agri-food Sector
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John B. Davis
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Food sector ,Brexit ,business.industry ,Geography, Planning and Development ,International trade ,business - Published
- 2016
166. Capsazepine Protects against Neuronal Injury Caused by Oxygen Glucose Deprivation by InhibitingIh
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Danniel P. Gitterman, Jenny C. Roberts, John B. Davis, Alison M. Ray, Ceri D. Benham, Mark H Harries, Christopher H. Davies, Catherine H. Gill, and Christophe Lanneau
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Agonist ,Programmed cell death ,Patch-Clamp Techniques ,Potassium Channels ,medicine.drug_class ,Receptors, Drug ,Cyclic Nucleotide-Gated Cation Channels ,Nerve Tissue Proteins ,In Vitro Techniques ,Pharmacology ,Hippocampus ,Neuroprotection ,Ion Channels ,Rats, Sprague-Dawley ,Mice ,chemistry.chemical_compound ,Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels ,medicine ,Animals ,Patch clamp ,Cells, Cultured ,Mice, Knockout ,Neurons ,Cell Death ,Dose-Response Relationship, Drug ,Chemistry ,General Neuroscience ,Neurodegeneration ,medicine.disease ,Cell Hypoxia ,Potassium channel ,Rats ,Glucose ,Neuroprotective Agents ,Biochemistry ,Cytoprotection ,NMDA receptor ,Capsaicin ,Capsazepine ,Cellular/Molecular - Abstract
Cell death mechanisms frequently involve the influx of extracellular calcium through voltage- and ligand-gated ion channels, e.g., the NMDA receptor (Greene, 1999). The vanilloid receptor (VR1) is present in regions of the brain (Mezey et al., 2000) that are highly susceptible to neurodegenerative insults, suggesting that this ion channel might contribute to the cellular processes involved in neuronal death. We tested the effects of VR1 ligands in the oxygen glucose deprivation (OGD) model of cell death in organotypic hippocampal slice cultures. The VR1agonist capsaicin at concentrations that are selective for VR1did not affect cell viability per se or the extent of neurodegeneration induced by the OGD insult. In contrast, the VR1antagonist capsazepine (0.1-10 μm) significantly reduced the amount of OGD-induced cell death. However, capsazepine was still neuroprotective in slices prepared from VR1knock-out mice, which exhibited the same degree of neurodegeneration to that observed in slices prepared from wild-type mice, excluding the possibility that it afforded neuroprotection through inhibition of VR1. Instead, capsazepine inhibited the hyperpolarization-activated nonspecific cation channel generated currentIhin a concentration range similar to that which was neuroprotective. Furthermore, the specificIhblocker ZD-7288 was also neuroprotective, mirroring the effects of capsazepine, in that it was effective at preventing cell death when applied either during or after the OGD insult. These results demonstrate that capsazepine affords neuroprotection through inhibition ofIhrather than inhibition of VR1.
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- 2003
167. Subscription Information Comment s'abonner Informationen für den Abonnenten
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John B. Davis
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Geography, Planning and Development - Published
- 2003
168. Reflexivity: curse or cure?
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Matthias Klaes and John B. Davis
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Curse ,Sociology of scientific knowledge ,Reflexivity ,Economics, Econometrics and Finance (miscellaneous) ,Economic methodology ,Self-reference ,Sociology ,Epistemology - Abstract
Reflexivity has been argued to be self‐defeating and potentially devastating for the sociology of scientific knowledge. We first survey various meanings associated with the concept of reflexivity and then provide an interpretation of Velazquez's Las Meninas to generate a three‐part taxonomy of reflexivity, distinguishing between ‘immanent’, ‘epistemic’ and ‘transcendent’ reflexivity. This provides the basis for engaging with reflexivity as a problem in the economic methodology literature, focusing on recent contributions to the topic by Hands, Sent, Maki and Mirowski. Employment of our taxonomy clarifies the similarities and differences between the various forms of reflexivity that can be identified or are addressed in these contributions. Our main argument is that a successful response to the malign aspects of reflexivity requires a simultaneous consideration of various levels of reflexivity and relies on social–historical perspectives.
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- 2003
169. TRPV channels as temperature sensors
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John B. Davis, Christopher D. Benham, and Martin J. Gunthorpe
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TRPV4 ,TRPV3 ,Physiology ,Receptors, Drug ,TRPV1 ,TRPV Cation Channels ,TRPV ,Ion Channels ,Mice ,Cations ,medicine ,Animals ,Humans ,Thermosensing ,Neurons, Afferent ,Cation Transport Proteins ,Molecular Biology ,Ion channel ,Chemistry ,Cell Biology ,Anatomy ,Stretch-activated ion channel ,medicine.anatomical_structure ,nervous system ,Biophysics ,Nociceptor ,Neuron - Abstract
The past year has seen a doubling in the number of heat-sensitive ion channels to six, and four of these channels are from the TRPV family. These channels characteristically have Q(10) values of >10 above the thermal threshold, very different from the Q(10) values of 1.5-2.0 seen in most ion channels. Cells expressing TRPV1 show similar temperature sensitivity to small capsaicin-sensitive nociceptor neurons, consistent with these neurons expressing homomers of TRPV1. A-delta fibres exhibit properties that may be explained by TRPV2 containing channels which is present in large diameter sensory neurons that do not express TRPV1. TRPV3 has a lower temperature threshold and may contribute to warm-sensitive channels together with TRPV1. Warm sensation may also be transduced by TRPV4 expressing sensory neurons and hypothalamic neurons. We can now look forward to further work defining the properties of the recombinant channels in more detail and a re-analysis of endogenous i(heat) currents in thermosensitive neurons and other cells. Data from the study of mice in which TRPV2, TRPV3 or TRPV4 have been deleted are also eagerly awaited.
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- 2003
170. Data Reduction Using a Discrete Wavelet Transform in Discriminant Analysis of Very High Dimensionality Data
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Mark D. Thornquist, Ziding Feng, Yinsheng Qu, John B. Davis, John D. Potter, Mary Ann Clements, Yutaka Yasui, Paul F. Schellhammer, George L. Wright, Bao Ling Adam, Lisa H. Cazares, and Mary Lou Thompson
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Male ,Statistics and Probability ,Discrete wavelet transform ,Linear classifier ,Mass Spectrometry ,General Biochemistry, Genetics and Molecular Biology ,Wavelet ,Statistics ,Humans ,Mathematics ,Principal Component Analysis ,Mahalanobis distance ,General Immunology and Microbiology ,business.industry ,Applied Mathematics ,Discriminant Analysis ,Prostatic Neoplasms ,Wavelet transform ,Pattern recognition ,General Medicine ,Data Compression ,Linear discriminant analysis ,Data point ,Principal component analysis ,Artificial intelligence ,General Agricultural and Biological Sciences ,business - Abstract
We present a method of data reduction using a wavelet transform in discriminant analysis when the number of variables is much greater than the number of observations. The method is illustrated with a prostate cancer study, where the sample size is 248, and the number of variables is 48,538 (generated using the ProteinChip technology). Using a discrete wavelet transform, the 48,538 data points are represented by 1271 wavelet coefficients. Information criteria identified 11 of the 1271 wavelet coefficients with the highest discriminatory power. The linear classifier with the 11 wavelet coefficients detected prostate cancer in a separate test set with a sensitivity of 97% and specificity of 100%.
- Published
- 2003
171. Neurogenic responses mediated by vanilloid receptor-1 (TRPV1) are blocked by the high affinity antagonist, iodo-resiniferatoxin
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Pierangelo Geppetti, Michele Tognetto, Christophe Créminon, Silvia Amadesi, Michela Rigoni, Selena Harrison, David Gazzieri, Barbara Campi, Marcello Trevisani, John B. Davis, and Riccardo Nadaletto
- Subjects
Pharmacology ,chemistry.chemical_compound ,Chemistry ,Capsaicin ,In vivo ,TRPV1 ,Resiniferatoxin ,Antagonist ,Stimulation ,Capsazepine ,Extravasation - Abstract
(1) Stimulation of the vanilloid receptor-1 (TRPV1) results in the activation of nociceptive and neurogenic inflammatory responses. Poor specificity and potency of TRPV1 antagonists has, however, limited the clarification of the physiological role of TRPV1. (2) Recently, iodo-resiniferatoxin (I-RTX) has been reported to bind as a high affinity antagonist at the native and heterologously expressed rat TRPV1. Here we have studied the ability of I-RTX to block a series of TRPV1 mediated nociceptive and neurogenic inflammatory responses in different species (including transfected human TRPV1). (3) We have demonstrated that I-RTX inhibited capsaicin-induced mobilization of intracellular Ca(2+) in rat trigeminal neurons (IC(50) 0.87 nM) and in HEK293 cells transfected with the human TRPV1 (IC(50) 0.071 nM). (4) Furthermore, I-RTX significantly inhibited both capsaicin-induced CGRP release from slices of rat dorsal spinal cord (IC(50) 0.27 nM) and contraction of isolated guinea-pig and rat urinary bladder (pK(B) of 10.68 and 9.63, respectively), whilst I-RTX failed to alter the response to high KCl or SP. (5) Finally, in vivo I-RTX significantly inhibited acetic acid-induced writhing in mice (ED(50) 0.42 micro mol kg(-1)) and plasma extravasation in mouse urinary bladder (ED(50) 0.41 micro mol kg(-1)). (6) In in vitro and in vivo TRPV1 activated responses I-RTX was approximately 3 log units and approximately 20 times more potent than capsazepine, respectively. This high affinity antagonist, I-RTX, may be an important tool for future studies in pain and neurogenic inflammatory models.
- Published
- 2003
172. Activation of vanilloid receptor 1 by resiniferatoxin mobilizes calcium from inositol 1,4,5-trisphosphate-sensitive stores
- Author
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Davina E. Owen, Darren Smart, John B. Davis, Tim V Cripps, Shaun McNulty, and Ian C B Marshall
- Subjects
Pharmacology ,medicine.medical_specialty ,Thapsigargin ,Carbachol ,Phospholipase C ,Resiniferatoxin ,TRPV1 ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Capsaicin ,Internal medicine ,medicine ,Inositol ,Capsazepine ,medicine.drug - Abstract
1 Capsaicin and resiniferatoxin (RTX) stimulate Ca2+ influx by activating vanilloid receptor 1 (VR1), a ligand-gated Ca2+ channel on sensory neurones. We investigated whether VR1 activation could also trigger Ca2+ mobilization from intracellular Ca2+ stores. 2 Human VR1-transfected HEK293 cells (hVR1-HEK293) were loaded with Fluo-3 or a mixture of Fluo-4 and Fura Red and imaged on a fluorometric imaging plate reader (FLIPR) and confocal microscope respectively. 3 In Ca2+ -free media, RTX caused a transient elevation in intracellular free Ca2+ concentration in hVR1-HEK293 cells (pEC(50) 6.45+/-0.05) but not in wild type cells. Capsaicin (100 microM) did not cause Ca2+ mobilization under these conditions. 4 RTX-mediated Ca2+ mobilization was inhibited by the VR1 receptor antagonist capsazepine (pIC(50) 5.84+/-0.04), the Ca2+ pump inhibitor thapsigargin (pIC(50) 7.77+/-0.04), the phospholipase C inhibitor U-73122 (pIC(50) 5.35+/-0.05) and by depletion of inositol 1,4,5-trisphosphate-sensitive Ca2+ stores by pretreatment with the acetylcholine-receptor agonist carbachol (20 microM, 2 min). These data suggest that RTX causes Ca2+ mobilization from inositol 1,4,5-trisphosphate-sensitive Ca2+ stores in hVR1-HEK293 cells. 5 In the presence of extracellular Ca2+, both capsaicin-mediated and RTX-mediated Ca2+ rises were attenuated by U-73122 (10 microM, 30 min) and thapsigargin (1 microM, 30 min). We conclude that VR1 is able to couple to Ca2+ mobilization by a Ca2+ dependent mechanism, mediated by capsaicin and RTX, and a Ca2+ independent mechanism mediated by RTX alone.
- Published
- 2003
173. Regional Economic Integration, the Environment and Community: East Asia and APEC
- Author
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John B. Davis
- Subjects
Economic integration ,Economic cooperation ,Economics and Econometrics ,Asia pacific ,Economics ,Developing country ,East Asia ,Rationality ,Economic system ,Game theory ,Plural - Abstract
This paper argues that regional economic integration can be compatible with concern for the environment in rapidly industrializing parts of the developing world, but that this compatibility would be aided by reconceptualizing the collective decision-making process in regional economic communities in a manner that employs a plural subject concept of the decision-making agent. The focus of the paper is the environmental challenges faced by the East Asian members of the Asia Pacific Economic Cooperation (APEC) forum. The plural subject concept is applied to the problem of environmental 'super-externalities' faced by members of APEC. The argument of the paper distinguishes between two concepts of trust, one associated with non-cooperative game theory and instrumental rationality, and one associated with an alternative form of rationality, termed deontological rationality, developed in connection with the idea of the plural subject. Cooperation in connection with the former is highly fragile, but cooperation i...
- Published
- 2003
174. Capabilities and Personal Identity: Using Sen to explain personal identity in Folbre's 'structures of constraint' analysis
- Author
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John B. Davis
- Subjects
Constraint (information theory) ,Negotiation ,Collective identity ,media_common.quotation_subject ,Political Science and International Relations ,Economics, Econometrics and Finance (miscellaneous) ,Perspective (graphical) ,Constraint analysis ,Personal identity ,Economics ,media_common ,Epistemology - Abstract
Folbre's 'structures of constraint' analysis treats women as socially embedded in 'multiple, often contradictory positions, because they belong to multiple groups'. This paper addresses the problem of women's multiple collective identities by arguing that Sen's capability framework offers a means of explaining how women can maintain coherent personal identities. Using Sen's real opportunities sense of capabilities, the paper argues that women can acquire personal identities apart from their multiple collective identities if they acquire the specific capability of being able, freely and successfully, to negotiate their multiple group involvements. Folbre's list of policies for a more egalitarian family is reconsidered from this perspective.
- Published
- 2002
175. Gramsci, Sraffa, Wittgenstein: philosophical linkages
- Author
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John B. Davis
- Subjects
Hegemony ,Praxis ,General Arts and Humanities ,Philosophy ,media_common.quotation_subject ,Economics, Econometrics and Finance (miscellaneous) ,Caesarism ,Intellectual history ,Epistemology ,History and Philosophy of Science ,Philosophical thinking ,Set (psychology) ,Humanities ,media_common - Abstract
The paper assumes that since Gramsci influenced Sraffa and SraffA influenced Wittgenstein it may be possible to delineate a set of philosophical ideas which they shared in some degree. Gramsci's ideas are first reviewed on terms of his concept of hegemony, concept of caesarism and philosophy of praxis. On this basis three philosophical themes are identified in his thinking: the conept of emergence; catastrophic equilibrium; and the idea of a concrete universal. The thinking of Sraffa (both earlier and later) and the thinking of Wittgenstein (later) are then interpreted in terms of these same three themes. These links neither exhaust their philosophical thinking nor necessarily constitute the only links among the three. But these ideas provide one way of exploring connections among the three. The paper closes with brief remarks concerning two opposed philosophical traditions in modern European intellectual history at the turn of the century — one associated with thinking in Britain and one associated with ...
- Published
- 2002
176. Will Social Values Influence the Development of HMOs?
- Author
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John B. Davis
- Subjects
Health (social science) ,Quality Assurance, Health Care ,Social Values ,media_common.quotation_subject ,Decision Making ,Health Care Sector ,Social value orientations ,Health care ,Humans ,Socioeconomics ,Speculation ,health care economics and organizations ,media_common ,Economic Competition ,Public economics ,business.industry ,Health Policy ,Health Maintenance Organizations ,Insurance Pools ,Payment ,United States ,Issues, ethics and legal aspects ,Managed care ,Business ,Delivery of Health Care ,Medicaid ,Developed country - Abstract
Among industrialized nations the United States is relatively unique in relying on a mix of public and private financing and delivery of healthcare: federal and federal-state programs, such as Medicare and Medicaid; employment-based health insurance (primarily HMOs); and state-subsidized insurance pools for high-risk individuals. In recent years, however, there have been efforts to apply the principles of private employment-based health insurance to the other forms of healthcare, and there is speculation that rising healthcare costs can only be addressed by further extending capitated payment plans. This suggests that U.S. healthcare may increasingly be organized according to market principles. For some, this represents a historic departure from an emphasis on public responsibility for healthcare and a sacrifice of the value principles embodied in health relationships between patient and provider. But defenders of HMOs and a larger role for markets argue that managed care allows for a more rational allocation of scarce healthcare resources by minimizing inefficient low-benefit–high-cost care. More individuals receive essential care if inessential care is eliminated. HMOs are also said to encourage non-HMOs to provide lower priced healthcare.
- Published
- 2002
177. TRPV3 is a temperature-sensitive vanilloid receptor-like protein
- Author
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Rosemary E. Kelsell, Andrew D. Randall, K. J. Charles, Jeffrey C. Jerman, James Wright, P. Reilly, Darren Smart, Praveen Anand, Julie Egerton, Paul Facer, Lezanne Ooi, Graham D Smith, Philip David Hayes, John B. Davis, Martin J. Gunthorpe, and Jean-Philippe Walhin
- Subjects
TRPV3 ,Hot Temperature ,Receptors, Drug ,Molecular Sequence Data ,TRPV2 ,TRPV1 ,Sequence Homology ,TRPV Cation Channels ,Biology ,TRPP ,TRPV ,Ion Channels ,Cell Line ,chemistry.chemical_compound ,Dorsal root ganglion ,Ganglia, Spinal ,medicine ,Humans ,Amino Acid Sequence ,RNA, Messenger ,Cloning, Molecular ,Receptor ,Cation Transport Proteins ,Multidisciplinary ,Gene Expression Profiling ,Precipitin Tests ,Cell biology ,Electrophysiology ,Protein Subunits ,medicine.anatomical_structure ,nervous system ,chemistry ,Biochemistry ,Capsaicin ,Calcium ,lipids (amino acids, peptides, and proteins) ,Protons ,Ion Channel Gating ,Protein Binding - Abstract
Vanilloid receptor-1 (VR1, also known as TRPV1) is a thermosensitive, nonselective cation channel that is expressed by capsaicin-sensitive sensory afferents and is activated by noxious heat, acidic pH and the alkaloid irritant capsaicin. Although VR1 gene disruption results in a loss of capsaicin responses, it has minimal effects on thermal nociception. This and other experiments--such as those showing the existence of capsaicin-insensitive heat sensors in sensory neurons--suggest the existence of thermosensitive receptors distinct from VR1. Here we identify a member of the vanilloid receptor/TRP gene family, vanilloid receptor-like protein 3 (VRL3, also known as TRPV3), which is heat-sensitive but capsaicin-insensitive. VRL3 is coded for by a 2,370-base-pair open reading frame, transcribed from a gene adjacent to VR1, and is structurally homologous to VR1. VRL3 responds to noxious heat with a threshold of about 39 degrees C and is co-expressed in dorsal root ganglion neurons with VR1. Furthermore, when heterologously expressed, VRL3 is able to associate with VR1 and may modulate its responses. Hence, not only is VRL3 a thermosensitive ion channel but it may represent an additional vanilloid receptor subunit involved in the formation of heteromeric vanilloid receptor channels.
- Published
- 2002
178. The Emperor's Clothes
- Author
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John B. Davis
- Subjects
Formalism (philosophy) ,General Arts and Humanities ,media_common.quotation_subject ,Western thought ,Mainstream economics ,Enlightenment ,Demise ,Surprise ,History and Philosophy of Science ,Argument ,Contemporary society ,Sociology ,Positive economics ,General Economics, Econometrics and Finance ,media_common - Abstract
David Colander argued to this Society two years ago that the term “neoclassical economics” ought to be declared dead (Colander 2000). I concur with him on the verdict, but do so for different reasons. Colander's argument was that neoclassicism possessed six primary attributes, and much of mainstream economics cannot be characterized in these terms. My argument is simpler. It is that neoclassical economics was primarily a theory of the human individual in economic life (albeit a flawed one), but contemporary mainstream economics does not possess a theory of the human individual. This conclusion may not surprise those who have reflected on the rise of formalism in economics in the postwar period. But for two reasons I think it important to emphasize the disappearance of a theory of the individual from economics. First, because neoclassicism implemented and defended for nearly a century one particular philosophical conception of the individual central to western thought since the Enlightenment, the abandonment of this commitment by mainstream economics is an important part of our understanding of its evolution and its relation to social thinking generally. Second, the demise of the individual in mainstream economics is also significant because, having abandoned the individual, mainstream economics is no longer capable of offering a defense of the individual in contemporary society. Indeed its project, I will suggest, is in important respects anti-individualist. It may be naïve on my part to think contemporary society still engaged in a defense of the individual. Nonetheless, I hold that thinking about the individual remains fundamental to how many people think about the social world, and that consequently mainstream economics' abandonment of the individual may render it historically irrelevant, perhaps contributing to its fragmentation and dissolution as an identifiable approach in economics. Thus the important conclusion to draw may not be Colander's: that we have seen the death of neoclassical economics. It may be that at issue today is the death of mainstream economics.
- Published
- 2002
179. Activation of TRPV4 Channels (hVRL-2/mTRP12) by Phorbol Derivatives
- Author
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Veit Flockerzi, Jeff C. Jerman, Phil Hayes, Darren Smart, Guy Droogmans, John B. Davis, Ullrich Wissenbach, William Cairns, Graham D Smith, Christopher D. Benham, Joris Vriens, Hiroyuki Watanabe, Bernd Nilius, and Jean Prenen
- Subjects
TRPV4 ,Ruthenium red ,Stereochemistry ,Receptors, Drug ,TRPV Cation Channels ,Gating ,Transfection ,Biochemistry ,TRPV ,Ion Channels ,Cell Line ,Mice ,chemistry.chemical_compound ,Tumor Cells, Cultured ,Animals ,Humans ,Coloring Agents ,Protein kinase A ,Cation Transport Proteins ,Molecular Biology ,Cells, Cultured ,Ion channel ,Dose-Response Relationship, Drug ,Chemistry ,Cell Biology ,Phorbols ,Ruthenium Red ,Recombinant Proteins ,Electrophysiology ,Kinetics ,Biophysics ,Phorbol ,Calcium ,Endothelium, Vascular - Abstract
We have studied activation by phorbol derivatives of TRPV4 channels, the human VRL-2, and murine TRP12 channels, which are highly homologous to the human VR-OAC, and the human and murine OTRPC4 channel. 4alpha-Phorbol 12,13-didecanoate (4alpha-PDD) induced an increase in intracellular Ca(2+) concentration, [Ca(2+)](i), in 1321N1 cells stably transfected with human VRL-2 (hVRL-2.1321N1) or HEK-293 cells transiently transfected with murine TRP12, but not in nontransfected or mock-transfected cells. Concomitantly with the increase in [Ca(2+)](i), 4alpha-PDD activated an outwardly rectifying cation channel with an Eisenman IV permeation sequence for monovalent cations that is Ca(2+)-permeable with P(Ca)/P(Na) = 5.8. Phorbol 12-myristate 13-acetate also induced an increase in [Ca(2+)](i) but was approximately 50 times less effective than 4alpha-PDD. EC(50) for Ca(2+) increase and current activation was nearly identical (pEC(50) approximately 6.7). Similar effects were observed in freshly isolated mouse aorta endothelial cells which express TRP12 endogenously. By using 4alpha-PDD as a tool to stimulate TRP12, we showed that activation of this channel is modulated by [Ca(2+)](i); an increase in [Ca(2+)](i) inhibits the channel with an IC(50) of 406 nm. Ruthenium Red at a concentration of 1 microm completely blocks inward currents at -80 mV but has a smaller effect on outward currents likely indicating a voltage dependent channel block. We concluded that the phorbol derivatives activate TRPV4 (VR-OAC, VRL-2, OTRPC4, TRP12) independently from protein kinase C, in a manner consistent with direct agonist gating of the channel.
- Published
- 2002
180. Cloning and Functional Expression of Human Short TRP7, a Candidate Protein for Store-operated Ca2+ Influx
- Author
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Antonio Riccio, Andrew D. Randall, Cesar Mattei, Christopher D. Benham, Rosemary E. Kelsell, Andrew R. Calver, John B. Davis, Andrew D. Medhurst, and Menelas N. Pangalos
- Subjects
Central Nervous System ,Male ,Time Factors ,Kidney ,Biochemistry ,Ion Channels ,Calcium in biology ,Epitopes ,Transient receptor potential channel ,chemistry.chemical_compound ,Tissue Distribution ,Cloning, Molecular ,Enzyme Inhibitors ,Phylogeny ,Reverse Transcriptase Polymerase Chain Reaction ,Imidazoles ,Brain ,Exons ,Calcium Channel Blockers ,Pituitary Gland ,Thapsigargin ,Female ,Signal transduction ,Protein Binding ,medicine.drug ,DNA, Complementary ,Carbachol ,Molecular Sequence Data ,TRPM Cation Channels ,Biology ,Transfection ,Cell Line ,Complementary DNA ,medicine ,Humans ,Amino Acid Sequence ,RNA, Messenger ,Molecular Biology ,Gene Library ,Manganese ,Sequence Homology, Amino Acid ,Calcium channel ,T-type calcium channel ,Membrane Proteins ,Cell Biology ,Oligonucleotides, Antisense ,Molecular biology ,chemistry ,Calcium - Abstract
The regulation and control of plasma membrane Ca(2+) fluxes is critical for the initiation and maintenance of a variety of signal transduction cascades. Recently, the study of transient receptor potential channels (TRPs) has suggested that these proteins have an important role to play in mediating capacitative calcium entry. In this study, we have isolated a cDNA from human brain that encodes a novel transient receptor potential channel termed human TRP7 (hTRP7). hTRP7 is a member of the short TRP channel family and is 98% homologous to mouse TRP7 (mTRP7). At the mRNA level hTRP7 was widely expressed in tissues of the central nervous system, as well as some peripheral tissues such as pituitary gland and kidney. However, in contrast to mTRP7, which is highly expressed in heart and lung, hTRP7 was undetectable in these tissues. For functional analysis, we heterologously expressed hTRP7 cDNA in an human embryonic kidney cell line. In comparison with untransfected cells depletion of intracellular calcium stores in hTRP7-expressing cells, using either carbachol or thapsigargin, produced a marked increase in the subsequent level of Ca(2+) influx. This increased Ca(2+) entry was blocked by inhibitors of capacitative calcium entry such as La(3+) and Gd(3+). Furthermore, transient transfection of an hTRP7 antisense expression construct into cells expressing hTRP7 eliminated the augmented store-operated Ca(2+) entry. Our findings suggest that hTRP7 is a store-operated calcium channel, a finding in stark contrast to the mouse orthologue, mTRP7, which is reported to enhance Ca(2+) influx independently of store depletion, and suggests that human and mouse TRP7 channels may fulfil different physiological roles.
- Published
- 2002
181. The History of Ecoonomics as a Sub-Discipline:The Role of the History of Economics Society Meetings
- Author
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John B. Davis and History and Methodology of Economics (ASE, FEB)
- Subjects
Economics and Econometrics ,History ,Economy ,Sociology ,Social science - Published
- 2002
182. Brexit and Implications for the Agri‐food Sector
- Author
-
John B. Davis
- Subjects
Food sector ,Brexit ,business.industry ,Geography, Planning and Development ,International trade ,business - Published
- 2017
183. Die Konzeption des sozial eingebetteten Individuums
- Author
-
John B. Davis
- Abstract
Die Soziookonomik begreift das menschliche Individuum als sozial eingebettet statt als atomistisch, und das ist eine der grundlegendsten Differenzen zu der in vielerlei Hinsicht anders gearteten ublichen Mainstream-Okonomik. Das Konzept des sozial eingebetteten Individuums ist tatsachlich eines der entscheidenden Merkmale der Soziookonomik, ganz wie die atomistische Auffassung zu den charakteristischen Eigenschaften der Mainstream-Okonomik gehort. Der Unterschied zwischen diesen beiden Konzepten beruht im Grosen und Ganzen darauf, dass die Individuen und ihr Verhalten im einen Fall ‚von ausen‘, das heist mit Blick auf ihre sozialen Beziehungen, erklart werden und im anderen Fall ‚von innen‘, also von ihren personlichen Vorlieben und Praferenzen her.
- Published
- 2014
184. Economists’ Odd Stand on the Positive–Normative Distinction
- Author
-
John B. Davis
- Subjects
Loss aversion ,Economics ,Normative ,Neoclassical economics ,Value neutrality - Abstract
This chapter examines economists’ indefensible attachment to the positive–normative distinction, and suggests a behavioral economics explanation of their behavior on the subject. It traces the origins of the distinction to Hume’s guillotine and logical positivism, and argues they contributed to Robbins’ understanding of value neutrality. It connects philosophers’ rejection of logical positivism and their rejection of the positive-normative distinction, explains and modifies Putnam’s view of fact–value entanglement, and identifies four main ethical value judgments that contemporary economists employ. The behavioral explanation of economists’ denial of these value judgments emphasizes loss aversion and economists’ social identity as economists.
- Published
- 2014
185. Situating Care in Mainstream Health Economics: An Ethical Dilemma?
- Author
-
Robert McMaster and John B. Davis
- Subjects
Health economics ,Embeddedness ,business.industry ,media_common.quotation_subject ,Rationality ,Altruism ,Health care ,Consequentialism ,Ethical dilemma ,Sociology ,Positive economics ,business ,Externality ,media_common - Abstract
Standard health economics concentrates on the provision of care by medical professionals. Yet ‘care’ receives scant analysis; it is portrayed as a spillover effect or externality in the form of interdependent utility functions. In this context care can only be conceived as either acts of altruism or as social capital. Both conceptions are subject to considerable problems stemming from mainstream health economics’ reliance on a reductionist social model built around instrumental rationality and consequentialism. Subsequently, this implies a disregard for moral rules and duties and the compassionate aspects of behaviour. Care as an externality is a second-order concern relative to self-interested utility maximization, and is therefore crowded out by the parameters of the standard model. We outline an alternative relational approach to conceptualising care based on the social embeddedness of the individual that emphasises the ethical properties of care. The deontological dimension of care suggests that standard health economics is likely to undervalue the importance of care and caring in medicine.
- Published
- 2014
186. The vanilloid receptor (VR1)-mediated effects of anandamide are potently enhanced by the cAMP-dependent protein kinase
- Author
-
T. Ines Brandi, Pierangelo Geppetti, Luciano De Petrocellis, Michele Tognetto, Tiziana Bisogno, Graham D Smith, Cristophe Creminon, Vincenzo Di Marzo, Selena Harrison, and John B. Davis
- Subjects
Agonist ,medicine.medical_specialty ,Forskolin ,medicine.drug_class ,HEK 293 cells ,Neuropeptide ,Anandamide ,Biology ,Biochemistry ,Cell biology ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Capsaicin ,Internal medicine ,medicine ,lipids (amino acids, peptides, and proteins) ,Protein kinase A ,Receptor - Abstract
The endogenous cannabinoid receptor ligand, anandamide (AEA), is a full agonist of the vanilloid receptor type 1 (VR1) for capsaicin. Here, we demonstrate that the potency and efficacy of AEA at VR1 receptors can be significantly increased by the concomitant activation of protein kinase A (PKA). In human embryonic kidney (HEK) cells over-expressing human VR1, AEA induces a rise in cytosolic Ca2+ concentration that is mediated by this receptor. The EC50 for this effect was decreased five-fold in the presence of forskolin (FRSK, 1–5 µm) or the cAMP analogue, 8-Br-cAMP (10–100 µm). The effects of 8-Br-cAMP and FRSK were blocked by a selective PKA inhibitor. The FRSK (10 nm) also potently enhanced the sensory neurone- and VR1-mediated constriction by AEA of isolated guinea-pig bronchi, and this effect was abolished by a PKA inhibitor. In rat dorsal root ganglia slices, AEA-induced release of substance P, an effect mediated by VR1 activation, was enhanced three-fold by FRSK (10 nm). Thus, the ability of AEA to stimulate sensory VR1, with subsequent neuropeptide release, appears to be regulated by the state of activation of PKA. This observation supports the hypothesis that endogenous AEA might stimulate VR1 under certain pathophysiological conditions.
- Published
- 2001
187. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide
- Author
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John B. Davis, Aniello Schiano Moriello, Ines Brandi, Vincenzo Di Marzo, Tiziana Bisogno, Susanna Tchilibon, Datta E. Ponde, Luciano De Petrocellis, Raphael Mechoulam, and Lumir Hanus
- Subjects
Pharmacology ,Cannabinoid receptor ,Stereochemistry ,medicine.medical_treatment ,Anandamide ,Endocannabinoid system ,digestive system diseases ,chemistry.chemical_compound ,surgical procedures, operative ,Mechanism of action ,chemistry ,Fatty acid amide hydrolase ,medicine ,Cannabinoid receptor type 2 ,lipids (amino acids, peptides, and proteins) ,Cannabinoid ,medicine.symptom ,Cannabidiol ,medicine.drug - Abstract
(−)-Cannabidiol (CBD) is a non-psychotropic component of Cannabis with possible therapeutic use as an anti-inflammatory drug. Little is known on the possible molecular targets of this compound. We investigated whether CBD and some of its derivatives interact with vanilloid receptor type 1 (VR1), the receptor for capsaicin, or with proteins that inactivate the endogenous cannabinoid, anandamide (AEA). CBD and its enantiomer, (+)-CBD, together with seven analogues, obtained by exchanging the C-7 methyl group of CBD with a hydroxy-methyl or a carboxyl function and/or the C-5′ pentyl group with a di-methyl-heptyl (DMH) group, were tested on: (a) VR1-mediated increase in cytosolic Ca2+ concentrations in cells over-expressing human VR1; (b) [14C]-AEA uptake by RBL-2H3 cells, which is facilitated by a selective membrane transporter; and (c) [14C]-AEA hydrolysis by rat brain membranes, which is catalysed by the fatty acid amide hydrolase. Both CBD and (+)-CBD, but not the other analogues, stimulated VR1 with EC50=3.2 – 3.5 μM, and with a maximal effect similar in efficacy to that of capsaicin, i.e. 67 – 70% of the effect obtained with ionomycin (4 μM). CBD (10 μM) desensitized VR1 to the action of capsaicin. The effects of maximal doses of the two compounds were not additive. (+)-5′-DMH-CBD and (+)-7-hydroxy-5′-DMH-CBD inhibited [14C]-AEA uptake (IC50=10.0 and 7.0 μM); the (−)-enantiomers were slightly less active (IC50=14.0 and 12.5 μM). CBD and (+)-CBD were also active (IC50=22.0 and 17.0 μM). CBD (IC50=27.5 μM), (+)-CBD (IC50=63.5 μM) and (−)-7-hydroxy-CBD (IC50=34 μM), but not the other analogues (IC50>100 μM), weakly inhibited [14C]-AEA hydrolysis. Only the (+)-isomers exhibited high affinity for CB1 and/or CB2 cannabinoid receptors. These findings suggest that VR1 receptors, or increased levels of endogenous AEA, might mediate some of the pharmacological effects of CBD and its analogues. In view of the facile high yield synthesis, and the weak affinity for CB1 and CB2 receptors, (−)-5′-DMH-CBD represents a valuable candidate for further investigation as inhibitor of AEA uptake and a possible new therapeutic agent. Keywords: Cannabinoid, endocannabinoid, vanilloid, receptors, FAAH, anandamide transporter Introduction Among the bioactive constituents of Cannabis sativa, (−)-cannabidiol (CBD, Figure 1) is one of those with the highest potential for therapeutic use (Mechoulam, 1999). Although the pharmacological properties of the other major Cannabis component, (−)-Δ9-tetrahydrocannabinol (THC), have been more thoroughly investigated (Mechoulam, 1999; Pertwee, 1999, for reviews), THC, unlike CBD, exhibits potent psychotropic effects, which have complicated the full assessment of its therapeutic potential. Little is known of the molecular mechanism(s) of action of CBD, which, unlike THC, has very little affinity for either cannabinoid receptor subtypes identified so far, the CB1 and CB2 receptors (Pertwee, 1997, for review). Recent studies, together with the earlier finding of the anti anxiety (Guimaraes et al., 1994), neuro-protective and anti-convulsive activity of CBD and some of its analogues (Consroe et al., 1981; Martin et al., 1987), indicate that CBD may also exert cyto-protective effects by inhibiting the release of inflammatory cytokines from blood cells (Srivastava et al., 1998; Malfait et al., 2000), thus producing an anti-inflammatory action, for example against rheumatoid arthritis (Malfait et al., 2000). These effects of CBD may be due to its anti-oxidant properties (Hampson et al., 1998), to its direct interaction with cytochrome p450-enzymes (Bornheim & Correia, 1989) and other enzymes of the ‘arachidonate cascade' (Burstein et al., 1985), or to an action at a specific receptor. Recent studies have investigated whether CBD interacts with proteins of the ‘endocannabinoid signalling system' other than the CB1/CB2 receptors. These proteins are: (i) fatty acid amide hydrolase (FAAH) (Cravatt et al., 1996), the intracellular enzyme catalysing the hydrolysis of the endogenous cannabinoid ligand, anandamide (arachidonoylethanolamide, AEA) (Ueda et al., 2000, for review); and (ii) the ‘anandamide membrane transporter' (AMT) (Di Marzo et al., 1994), which facilitates the transport of AEA across the cell membrane and, subsequently, its intracellular degradation (Hillard & Jarrahian, 2000, for review). It was found that CBD inhibits both AEA hydrolysis by FAAH-containing membrane preparations (Watanabe et al., 1996), and AEA uptake by RBL – 2H3 cells via the AMT (Rakhshan et al., 2000). Although these effects were observed at high μM concentrations, these findings raised the possibility that some of the pharmacological actions of CBD might be due to inhibition of AEA degradation, with subsequent enhancement of the endogenous levels of this mediator, for which neuroprotective (Hansen et al., 1998) and anti-inflammatory (Di Marzo et al., 2000a) properties have been previously suggested. Figure 1 Chemical structures of cannabidiol and capsaicin. The numbering for cannabidiol carbon atoms, and a possible cannabidiol-like conformation for capsaicin are shown. Many pharmacological activities of CBD have been established only in vivo, hence some of them may be due to CBD metabolites. The metabolism of CBD is well established. The primary step is hydroxylation on C-7, leading to (−)-7-hydroxy-CBD, followed by further oxidation to (−)-7-carboxy-CBD (Agurell et al., 1986). Although the metabolism of the dimethyl-heptyl homologue of CBD and of the (+) enantiomer of CBD has not been investigated, it is reasonable to assume that it follows the same pathways. Hence we prepared these CBD metabolites, their DMH homologues and some of the respective metabolites in the unnatural (+) series. In particular, in the present study we have examined whether the stereochemistry and the presence of certain chemical groups on the C-5′ and C-1 of CBD affect its capability of influencing AEA inactivation via the AMT and FAAH. Furthermore, we have addressed the question of the possible molecular transducer of CBD by studying the possibility that this natural compound, its (+)-enantiomer and some of its synthetic analogues, interact with another proposed target for AEA, i.e. the vanilloid receptor type 1 (VR1) for capsaicin (Holzer, 1991, Figure 1). This protein is a ligand-, heat- and proton-activated non-specific cation channel acting as a molecular integrator of nociceptive stimuli (Tominaga et al., 1998). Recently, it was discovered that AEA is a full, albeit weak, VR1 agonist (Zygmunt et al., 1999; Smart et al., 2000) and that synthetic capsaicin analogues can interact with either CB1 receptors or the AMT, or both (Di Marzo et al., 1998). Thus, there appears to be some overlap between the ligand recognition properties of VR1 and CB1 receptors and, in particular, of VR1 and the AMT (de petrocellis et al., 2000; Szallasi & Di Marzo, 2000). Although VR1, via the release of inflammatory and algesic peptides, is involved in inflammatory hyperalgesia (Davis et al., 2000; Caterina et al., 2000), the stimulation of this receptor by capsaicin and some of its analogues leads to rapid desensitization, with subsequent paradoxical analgesic and anti-inflammatory effects (Holzer, 1991; Szallasi & Blumberg, 1999). As a consequence of this tachyphylactic effect, capsaicin, like CBD, has been used to treat arthritis (Lorton et al., 2000) and convulsions (Dib & Falchi, 1996). We report data suggesting that VR1 is a possible molecular target for CBD, and that inhibitors of the AMT can be developed by chemical modification of this natural product.
- Published
- 2001
188. Palmitoylethanolamide enhances anandamide stimulation of human vanilloid VR1 receptors
- Author
-
John B. Davis, Luciano De Petrocellis, and Vincenzo Di Marzo
- Subjects
medicine.medical_specialty ,Polyunsaturated Alkamides ,Receptors, Drug ,medicine.medical_treatment ,Biophysics ,Resiniferatoxin ,Arachidonic Acids ,Palmitic Acids ,capsaicin ,Biochemistry ,Cell Line ,chemistry.chemical_compound ,Structural Biology ,Internal medicine ,Genetics ,medicine ,Humans ,Vanilloid ,Bovine serum albumin ,Receptor ,Molecular Biology ,Palmitoylethanolamide ,calcium ,biology ,food and beverages ,Drug Synergism ,endocannabinoid ,Cell Biology ,Anandamide ,cannabinoid ,Amides ,Endocannabinoid system ,Endocrinology ,chemistry ,Ethanolamines ,Capsaicin ,biology.protein ,lipids (amino acids, peptides, and proteins) ,vanilloid receptor ,Cannabinoid ,Diterpenes ,Endocannabinoids - Abstract
In human embryonic kidney cells over-expressing the human vanilloid receptor type 1 (VR1), palmitoylethanolamide (PEA, 0.5-10 microM) enhanced the effect of arachidonoylethanolamide (AEA, 50 nM) on the VR1-mediated increase of the intracellular Ca2+ concentration. PEA (5 microM) decreased the AEA half-maximal concentration for this effect from 0.44 to 0.22 microM. The PEA effect was not due to inhibition of AEA hydrolysis or adhesion to non-specific sites, since bovine serum albumin (0.01-0.25%) potently inhibited AEA activity, and PEA also enhanced the effect of low concentrations of the VR1 agonists resiniferatoxin and capsaicin. PEA (5 microM) enhanced the affinity of AEA for VR1 receptors as assessed in specific binding assays. These data suggest that PEA might be an endogenous enhancer of VR1-mediated AEA actions.
- Published
- 2001
189. Characterisation of a human acid-sensing ion channel (hASIC1a) endogenously expressed in HEK293 cells
- Author
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Andrew D. Randall, Graham D Smith, Martin J. Gunthorpe, and John B. Davis
- Subjects
Patch-Clamp Techniques ,Physiology ,Receptors, Drug ,Clinical Biochemistry ,TRPV Cation Channels ,Nerve Tissue Proteins ,Endogeny ,Sensory system ,Biology ,Sodium Channels ,Cell Line ,Amiloride ,Physiology (medical) ,Humans ,Diuretics ,Receptor ,Ion channel ,Acid-sensing ion channel ,Reverse Transcriptase Polymerase Chain Reaction ,HEK 293 cells ,Membrane Proteins ,Nociceptors ,Anatomy ,Hydrogen-Ion Concentration ,Cell biology ,Acid Sensing Ion Channels ,Electrophysiology ,Cell culture ,Protons ,Ion Channel Gating - Abstract
Acid-sensing ion channels (ASICs) are a new and expanding family of proton-gated cation (Na+/Ca2+) channels that are widely expressed in sensory neurons and the central nervous system. Their distribution suggests that they may play a critical role in the sensation of the pain that accompanies tissue acidosis and may also be important in detecting the subtle pH variations that occur during neuronal signalling. Here, using whole-cell patch-clamp electrophysiology and reverse transcriptase-polymerase chain reaction (RT-PCR), we show that HEK293 cells, a commonly used cell line for the expression and characterisation of many ion channels, functionally express an endogenous proton-gated conductance attributable to the activity of human ASIC1a. These data therefore represent the first functional characterisation of hASIC1 and have many important implications for the use of HEK293 cells as a host cell system for the study of ASICs, vanilloid receptor-1 and any other proton-gated channel. With this latter point in mind we have devised a simple desensitisation strategy to selectively remove the contribution of hASIC1a from proton-gated currents recorded from HEK293 cells expressing vanilloid receptor-1.
- Published
- 2001
190. The Activity of Anandamide at Vanilloid VR1 Receptors Requires Facilitated Transport across the Cell Membrane and Is Limited by Intracellular Metabolism
- Author
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Mauro Maccarrone, Tiziana Bisogno, Vincenzo Di Marzo, John B. Davis, Alessandro Finazzi-Agrò, and Luciano De Petrocellis
- Subjects
Nitroprusside ,Cannabinoid receptor ,Polyunsaturated Alkamides ,Receptors, Drug ,Organophosphonates ,TRPV1 ,Resiniferatoxin ,receptors ,Arachidonic Acids ,Transfection ,Biochemistry ,Cell Line ,chemistry.chemical_compound ,Cytosol ,Fatty acid amide hydrolase ,anandamide ,Humans ,Enzyme Inhibitors ,Receptor ,Molecular Biology ,Cannabinoids ,Reverse Transcriptase Polymerase Chain Reaction ,Cell Membrane ,Biological Transport ,Cell Biology ,Anandamide ,cannabinoid ,Recombinant Proteins ,Kinetics ,chemistry ,vanilloid ,Capsaicin ,Calcium ,Diterpenes ,Intracellular ,Endocannabinoids - Abstract
The endogenous ligand of CB(1) cannabinoid receptors, anandamide, is also a full agonist at vanilloid VR1 receptors for capsaicin and resiniferatoxin, thereby causing an increase in cytosolic Ca(2+) concentration in human VR1-overexpressing (hVR1-HEK) cells. Two selective inhibitors of anandamide facilitated transport into cells, VDM11 and VDM13, and two inhibitors of anandamide enzymatic hydrolysis, phenylmethylsulfonyl fluoride and methylarachidonoyl fluorophosphonate, inhibited and enhanced, respectively, the VR1-mediated effect of anandamide, but not of resiniferatoxin or capsaicin. The nitric oxide donor, sodium nitroprusside, known to stimulate anandamide transport, enhanced anandamide effect on the cytosolic Ca(2+) concentration. Accordingly, hVR1-HEK cells contain an anandamide membrane transporter inhibited by VDM11 and VDM13 and activated by sodium nitroprusside, and an anandamide hydrolase activity sensitive to phenylmethylsulfonyl fluoride and methylarachidonoyl fluorophosphonate, and a fatty acid amide hydrolase transcript. These findings suggest the following. (i) Anandamide activates VR1 receptors by acting at an intracellular site. (ii) Degradation by fatty acid amide hydrolase limits anandamide activity on VR1; and (iii) the anandamide membrane transporter inhibitors can be used to distinguish between CB(1) or VR1 receptor-mediated actions of anandamide. By contrast, the CB(1) receptor antagonist SR141716A inhibited also the VR1-mediated effect of anandamide and capsaicin on cytosolic Ca(2+) concentration, although at concentrations higher than those required for CB(1) antagonism.
- Published
- 2001
191. Mark Blaug on the historiography of economics
- Author
-
John B. Davis
- Subjects
History of economic thought ,Competition (economics) ,Sociology of scientific knowledge ,Argument ,Marketplace of ideas ,Economic methodology ,Economics ,Historiography ,Positive economics ,Cultural economics - Abstract
This paper discusses how Mark Blaug reversed his thinking about the historiography of economics, abandoning 'rational' for 'historical' reconstruction, and using an economics of scientific knowledge argument against Paul Samuelson and others that rational reconstructions of past ideas and theories in the "marketplace of ideas" were Pareto inefficient. Blaug's positive argument for historical reconstruction was built on the concept of "lost content" and his rejection of the end-state view of competition in favor of a process view. He used these ideas to emphasize path dependency in the development of economic thinking, thereby advancing an evolutionary view of economics that has connections to a Lakatosian understanding of economic methodology. The paper argues that Blaug was essentially successful in criticizing the standard rational reconstructionist view of the history of economic thought in economics, and that this is borne out by the nature of the change in recent economics.
- Published
- 2013
192. Economics for the Common Good: Two Centuries of Social Economic Thought in the Humanistic Tradition
- Author
-
John B. Davis
- Subjects
Human development theory ,Economics and Econometrics ,Applied economics ,Philosophy and economics ,Economic methodology ,Mainstream economics ,General Social Sciences ,Sociology ,Schools of economic thought ,Positive economics ,Heterodox economics ,Cultural economics - Published
- 2000
193. Cloning and functional expression of a human orthologue of rat vanilloid receptor-1
- Author
-
Paul R. Murdock, Graham D Smith, Isro S Gloger, John Terrett, Kathryn Ellington, D.Malcolm Duckworth, Andrew D. Medhurst, Amanda J. L. Barton, Mark H Harries, Christopher D. Benham, Martin J. Gunthorpe, Andrew D. Randall, Helen J. Meadows, Simon Topp, David C. Harrison, Rab K. Prinjha, William Cairns, Catherine E. Clarke, Gareth J. Sanger, Owen Jenkins, John B. Davis, and Philip David Hayes
- Subjects
Genotype ,Receptors, Drug ,Xenopus ,Molecular Sequence Data ,Resiniferatoxin ,TRPV1 ,TRPV Cation Channels ,Biology ,Molecular cloning ,Chromosomes ,Cell Line ,chemistry.chemical_compound ,Complementary DNA ,Gene expression ,Animals ,Humans ,Amino Acid Sequence ,RNA, Messenger ,Cloning, Molecular ,Cloning ,Polymorphism, Genetic ,Base Sequence ,Temperature ,Nociceptors ,DNA ,Hydrogen-Ion Concentration ,Molecular biology ,Rats ,Anesthesiology and Pain Medicine ,Neurology ,chemistry ,Capsaicin ,Expression cloning ,Oocytes ,lipids (amino acids, peptides, and proteins) ,Neurology (clinical) - Abstract
Capsaicin, resiniferatoxin, protons or heat have been shown to activate an ion channel, termed the rat vanilloid receptor-1 (rVR1), originally isolated by expression cloning for a capsaicin sensitive phenotype. Here we describe the cloning of a human vanilloid receptor-1 (hVR1) cDNA containing a 2517 bp open reading frame that encodes a protein with 92% homology to the rat vanilloid receptor-1. Oocytes or mammalian cells expressing this cDNA respond to capsaicin, pH and temperature by generating inward membrane currents. Mammalian cells transfected with human VR1 respond to capsaicin with an increase in intracellular calcium. The human VR1 has a chromosomal location of 17p13 and is expressed in human dorsal root ganglia and also at low levels throughout a wide range of CNS and peripheral tissues. Together the sequence homology, similar expression profile and functional properties confirm that the cloned cDNA represents the human orthologue of rat VR1.
- Published
- 2000
194. Overlap between the ligand recognition properties of the anandamide transporter and the VR1 vanilloid receptor: inhibitors of anandamide uptake with negligible capsaicin-like activity
- Author
-
Vincenzo Di Marzo, Luciano De Petrocellis, John B. Davis, Roger G. Pertwee, and Tiziana Bisogno
- Subjects
Agonist ,Polyunsaturated Alkamides ,medicine.drug_class ,Receptors, Drug ,medicine.medical_treatment ,Biophysics ,TRPV Cation Channels ,Arachidonic Acids ,Transporter ,Ligands ,Binding, Competitive ,Biochemistry ,Cell Line ,chemistry.chemical_compound ,Structural Biology ,Tumor Cells, Cultured ,Genetics ,medicine ,Cannabinoid receptor type 2 ,Animals ,Humans ,Vanilloid ,Receptors, Cannabinoid ,Receptor ,Cannabinoid ,Molecular Biology ,Dose-Response Relationship, Drug ,Chemistry ,Biological Transport ,Anandamide ,Cell Biology ,Endocannabinoid system ,Rats ,Capsaicin ,AM404 ,Calcium ,lipids (amino acids, peptides, and proteins) ,Endocannabinoids - Abstract
Some synthetic agonists of the VR1 vanilloid (capsaicin) receptor also inhibit the facilitated transport into cells of the endogenous cannabinoid anandamide (arachidonoylethanolamide, AEA). Here we tested several AEA derivatives containing various derivatized phenyl groups or different alkyl chains as either inhibitors of the AEA membrane transporter (AMT) in intact cells or functional agonists of the VR1 vanilloid receptor in HEK cells transfected with the human VR1. We found that four known AMT inhibitors, AM404, arvanil, olvanil and linvanil, activate VR1 receptors at concentrations 400–10 000-fold lower than those necessary to inhibit the AMT. However, we also found three novel AEA derivatives, named VDM11, VDM12 and VDM13, which inhibit the AMT as potently as AM404 but exhibit little or no agonist activity at hVR1. These compounds are weak inhibitors of AEA enzymatic hydrolysis and poor CB1/CB2 receptor ligands. We show for the first time that, despite the overlap between the chemical moieties of AMT inhibitors and VR1 agonists, selective inhibitors of AEA uptake that do not activate VR1 (e.g. VDM11) can be developed.
- Published
- 2000
195. Characterization using FLIPR of rat vanilloid receptor (rVR1) pharmacology
- Author
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Rab K. Prinjha, Jeffrey C. Jerman, Mark H Harries, Darren Smart, John B. Davis, and Stephen J. Brough
- Subjects
Pharmacology ,Ruthenium red ,Thapsigargin ,Resiniferatoxin ,Calcium in biology ,chemistry.chemical_compound ,Mechanism of action ,chemistry ,Capsaicin ,medicine ,Ligand-gated ion channel ,medicine.symptom ,Capsazepine - Abstract
The vanilloid receptor (VR1) is a ligand-gated ion channel, which plays an important role in nociceptive processing. Therefore, a pharmacological characterization of the recently cloned rat VR1 (rVR1) was undertaken. HEK293 cells stable expressing rVR1 (rVR1-HEK293) were loaded with Fluo-3AM and then incubated at 25 degrees C for 30 min with or without various antagonists or signal transduction modifying agents. Then intracellular calcium concentrations ([Ca(2+)](i)) were monitored using FLIPR, before and after the addition of various agonists. The rank order of potency of agonists (resiniferatoxin (RTX)>capsaicin>olvanil>PPAHV) was as expected, and all were full agonists. The potencies of capsaicin and olvanil, but not RTX or PPAHV, were enhanced at pH 6.4 (pEC(50) values of 7.47+/-0.06, 7.16+/-0.06, 8.19+/-0.06 and 6.02+/-0.03 respectively at pH 7.4 vs 7.71+/-0.05, 7.58+/-0.14, 8.10+/-0.05 and 6.04+/-0.08 at pH 6.4). Capsazepine, isovelleral and ruthenium red all inhibited the capsaicin (100 nM)-induced Ca(2+) response in rVR1-HEK293 cells, with pK(B) values of 7.52+/-0.08, 6.92+/-0.11 and 8.09+/-0.12 respectively (n=6 each). The response to RTX and olvanil were also inhibited by these compounds. None displayed any agonist-like activity. The removal of extracellular Ca(2+) abolished, whilst inhibition of protein kinase C with chelerythrine chloride (10 microM) partially (approximately 20%) inhibited, the capsaicin (10 microM)-induced Ca(2+) response. However, tetrodotoxin (3 microM), nimodipine (10 microM), omega-GVIA conotoxin (1 microM), thapsigargin (1 microM), U73122 (3 microM) or H-89 (3 microM) had no effect on the capsaicin (100 nM)-induced response. In conclusion, the recombinant rVR1 stably expressed in HEK293 cells acts as a ligand-gated Ca(2+) channel with the appropriate agonist and antagonist pharmacology, and therefore is a suitable model for studying the effects of drugs at this receptor.
- Published
- 2000
196. Caspase inhibitors are functionally neuroprotective against oxygen glucose deprivation induced CA1 death in rat organotypic hippocampal slices
- Author
-
Christopher D. Benham, Davina E. Owen, Martyn L. Evans, Alison M. Ray, and John B. Davis
- Subjects
medicine.medical_specialty ,Central nervous system ,Hippocampus ,DNA Fragmentation ,Cysteine Proteinase Inhibitors ,Hippocampal formation ,Neuroprotection ,Amino Acid Chloromethyl Ketones ,Brain Ischemia ,Mice ,Organ Culture Techniques ,Internal medicine ,medicine ,Animals ,Molecular Biology ,Caspase ,Cell Line, Transformed ,Neurons ,chemistry.chemical_classification ,Cell Death ,biology ,General Neuroscience ,Hypoxia (medical) ,Caspase Inhibitors ,Cell Hypoxia ,Rats ,Electrophysiology ,Oxygen ,Stroke ,Glucose ,Neuroprotective Agents ,Enzyme ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Enzyme inhibitor ,biology.protein ,Neurology (clinical) ,medicine.symptom ,Developmental Biology - Abstract
We have explored the neuroprotective efficacy of the cell penetrant caspase inhibitor, Ac-YVAD-cmk, in a hippocampal slice model of neuronal cell death induced by oxygen and glucose deprivation. Organotypic hippocampal slice cultures were prepared from 8 to 10-day-old rats and maintained for 10 to 12 days in vitro. Pre-treatment with Ac-YVAD-cmk prior to 45 min oxygen and glucose deprivation was neuroprotective as measured by propidium iodide uptake, with an EC(50) between 1 and 10 micromol/l. Ac-YVAD-cmk was also able to preserve synaptic function in the organotypic hippocampal slice cultures 24 h after oxygen and glucose deprivation. Ac-YVAD-cmk prevented the increase in histone-associated DNA fragmentation induced by oxygen and glucose deprivation. Interleukin-1beta did not reverse the protective effect of Ac-YVAD-cmk, and interleukin-1 receptor antagonist alone was not protective. These results show that caspase inhibitors are neuroprotective in a hippocampal slice culture system, using structural, biochemical and electrophysiological endpoints, and that this effect is not a result of inhibition of interleukin-1beta production.
- Published
- 2000
197. Fractionation and characterization of oligomeric, protofibrillar and fibrillar forms of β-amyloid peptide
- Author
-
Robin V. Ward, Davina E. Owen, Eric Karran, David R. Howlett, Gary Christie, Julie Hawkins, Robert Jepras, John B. Davis, Ashley George, Kevin H. Jennings, and William Neville
- Subjects
chemistry.chemical_classification ,Amyloid ,Molecular mass ,Peptide ,Biological activity ,Cell Biology ,Fibril ,Biochemistry ,chemistry ,mental disorders ,Viability assay ,Senile plaques ,Molecular Biology ,Polyacrylamide gel electrophoresis - Abstract
The beta-amyloid (Abeta) peptide, a major component of senile plaques in Alzheimer's disease brain, has been shown previously to undergo a process of polymerization to produce neurotoxic forms of amyloid. Recent literature has attempted to define precisely the form of Abeta responsible for its neurodegenerative properties. In the present study we describe a novel density-gradient centrifugation method for the isolation and characterization of structurally distinct polymerized forms of Abeta peptide. Fractions containing protofibrils, fibrils, sheet structures and low molecular mass oligomers were prepared. The fractionated forms of Abeta were characterized structurally by transmission electron microscopy. The effects on cell viability of these fractions was determined in the B12 neuronal cell line and hippocampal neurons. Marked effects on cell viability in the cells were found to correspond to the presence of protofibrillar and fibrillar structures, but not to monomeric peptide or sheet-like structures of polymerized Abeta. Biological activity correlated with a positive reaction in an immunoassay that specifically detects protofibrillar and fibrillar Abeta; those fractions that were immunoassay negative had no effect on cell viability. These data suggest that the effect of Abeta on cell viability is not confined to a single conformational form but that both fibrillar and protofibrillar species have the potential to be active in this assay.
- Published
- 2000
198. The Millennium Survey: Variable/Institutional Framework Subsystems
- Author
-
John B. Davis
- Subjects
Macroeconomics ,Economics and Econometrics ,Sociology and Political Science ,media_common.quotation_subject ,Wage ,Globalization ,Economic inequality ,Economic indicator ,Economics ,Business cycle ,Household income ,Economic model ,Volatility (finance) ,media_common - Abstract
JOHN B. DAVIS [*] ABSTRACT. Pryor's Millennium Survey results need to be understood in the context of economists' different economic models appropriate to different institutional frameworks. These variable/institutional framework subsystems in turn may be distinguished according to whether the variables involved exhibit considerable deviation from trend and whether significant institutional change is anticipated. One such subsystem, involving globalization, financial volatility, and income inequality, seems to be relatively independent of a subsystem made up of the domestic economy as a whole. Frederic Pryor's Millennium Survey provides economists' predictions regarding ten major U.S. economic indicators over the next 50 years as well as their assessments regarding whether the predicted changes are likely to produce major changes in economic systems and their supporting institutions. Putting aside for a moment how the ten indicators compare with one another in degree of deviation from current trends and in degree of associated impacts on institutional change, note first that for economists obviously the different indicators/variables enter differently into different economic models, which in turn are often designed to investigate very different kinds of issues. Further, since for most economists institutions are understood to be frameworks in which different economic processes occur, the Survey's various indicators are also likely be associated with very different kinds of institutional change. To illustrate, consider recent debate among economists over how globalization causes increases in U.S. wage (and household income) inequality (e.g., Federal Reserve Bank of Kansas City, 1998). Three of the ten indicators/variables-the prices of raw materials and fuels, levels of air and water pollution, and global warming-are generally not argued to be factors involved in explaining the relationship between globalization and increasing income inequality. Nor does debate over possible institutional change in regard to the globalization-inequality relationship have much connection to debate over possible institutional change regarding, say, global warming. Thus in this case as in others it seems fair to say that Pryor's results really concern economists' opinions about sets of relatively separable issues, and we ought to accordingly approach the Survey results with an eye toward determining how economists distinguish and understand distinct variable/institutional framework subsystems. In this respect, the Survey naturally suggests that we might contrast variable/institutional framework subsystems in which all or most of the included variables exhibit considerable deviation from trend, and in which all or most of the variables are also expected to be associated with significant institutional change, from those subsystems in which neither is the case. Pryor points us towards one such separation when he comments on the unexpected difference between economists' views on volatility in the production and financial spheres. Economists expect little deviation from current trends in production/business cycle volatility, and thus not surprisingly expect relatively little institutional change in this regard. Yet they predict significant deviation from current trend in U.S. financial volatility, and rank financial volatility highly in terms of likely institutional change. Note then, that part of what is involved in financial volatility is the effects of floating exchange rates, and that an important dimension of globalization is international capital flows. In the case of globalization, as with financial volatility, economists expect indicators to deviate significantly from current trends and also produce significant institutional change. Thus we might hypothesize for economists that the processes linking globalization and U. …
- Published
- 2000
199. The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1)
- Author
-
Jeffrey C. Jerman, Darren Smart, A I Muir, J Gray, Andrew D. Randall, Martin J. Gunthorpe, S. Nasir, John B. Davis, and J K Chambers
- Subjects
Pharmacology ,Agonist ,medicine.drug_class ,medicine.medical_treatment ,TRPV1 ,Anandamide ,Endocannabinoid system ,chemistry.chemical_compound ,chemistry ,Capsaicin ,medicine ,Cannabinoid receptor antagonist ,Cannabinoid ,Capsazepine - Abstract
The endogenous cannabinoid anandamide was identified as an agonist for the recombinant human VR1 (hVR1) by screening a large array of bioactive substances using a FLIPR-based calcium assay. Further electrophysiological studies showed that anandamide (10 or 100 microM) and capsaicin (1 microM) produced similar inward currents in hVR1 transfected, but not in parental, HEK293 cells. These currents were abolished by capsazepine (1 microM). In the FLIPR anandamide and capsaicin were full agonists at hVR1, with pEC(50) values of 5. 94+/-0.06 (n=5) and 7.13+/-0.11 (n=8) respectively. The response to anandamide was inhibited by capsazepine (pK(B) of 7.40+/-0.02, n=6), but not by the cannabinoid receptor antagonists AM630 or AM281. Furthermore, pretreatment with capsaicin desensitized the anandamide-induced calcium response and vice versa. In conclusion, this study has demonstrated for the first time that anandamide acts as a full agonist at the human VR1.
- Published
- 2000
200. [Untitled]
- Author
-
John B. Davis
- Subjects
Estimation ,medicine.medical_specialty ,Health (social science) ,Actuarial science ,Operationalization ,Public economics ,business.industry ,Health Policy ,media_common.quotation_subject ,Public health ,Public policy ,Health informatics ,Key person insurance ,Issues, ethics and legal aspects ,Philosophy of medicine ,Unemployment ,medicine ,Economics ,business ,media_common - Abstract
This paper examines the lack of health insurance coverage in the US as a public policy issue. It first compares the problem of health insurance coverage to the problem of unemployment to show that in terms of the numbers of individuals affected lack of health insurance is a problem comparable in importance to the problem of unemployment. Secondly, the paper discusses the methodology involved in measuring health insurance coverage, and argues that the current method of estimation of the uninsured underestimates the extent that individuals go without health insurance. Third, the paper briefly introduces Amartya Sen's functioning and capabilities framework to suggest a way of representing the extent to which individuals are uninsured. Fourth, the paper sketches a means of operationalizing the Sen representation of the uninsured in terms of the disability-adjusted life year (DALY) measure.
- Published
- 2000
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