Tribute to Prof. Geoffrey Burnstock: transition of purinergicsignaling to drug discovery

Purinergic Signalling - Geoffrey Burnstock made a chance observation early in his research career that did not fit the conventional scientific dogma—non-noradrenergic, non-cholinergic (NANC)...     

The history of the Purine Club: a tribute to Prof. Geoffrey Burnstock

The international purinergic scientific community has lost its pioneer. Geoffrey Burnstock, born on the 10th of May 1929 in London, died on the 2nd of June 2020, aged 91, in Melbourne (Australia). Geoff was one of the most highly regarded scientists of his generation. In the 1960s and 1970s, he developed a radical and somehow heretical new theory and opened an entire new field of science, signalling via extracellular nucleotides (the “purinergic theory”), which revolutionized our understanding of how cells communicate between each other. Initially, his unconventional theory found a lot of resistance in the scientific community. Once, one scientist even threatened to devote his entire life to disproving Burnstock’s theory. Undeterred, Geoff went further on, and continued to accumulate evidence in favour of his hypothesis, and led the field ever since. He struggled to attract new scientists to this new field of research and, in the early 1990s, due to new molecular biology techniques making it possible to isolate and identify cell surface receptors for ATP and its breakdown product adenosine, did evidence emerge that eventually convinced the doubters. The number of spontaneous obituaries and messages honouring Geoff’s memory that have appeared on specialized Journals and in the public press throughout the world since last June indicates that many people are clearly affected by his death. Besides being a rigorous, ethical and extremely brilliant scientist, Geoff was an extraordinary human being, always eager to collaborate and share data, never jealous of his findings and capable of learning things even from young people. He was known for his enthusiasm, empathy and ability to motivate young scientists and promote their careers. After the establishment of the Purine Club back in the 1990s, numerous Purine Club Chapters have been formed around the world with Geoff’s help and encouragement. He has obviously also been the inspirator and founder of our Journal, Purinergic Signalling (PUSI). For this reason, Charles Kennedy, the current Editor of the Journal, and myself thought that it might be nice to invite representatives from all known Purine Clubs to send a few notes to be published in PUSI on the history of their club and how Geoff inspired, aided or supported them. Here, I have collected all their contributions and I share with the entire purinergic community my personal memories on how the Purine Club was born and developed thanks to the invaluable mentoring of Geoffrey Burnstock. I apologize in advance if I am missing some information or forgot to mention somebody, and I strongly encourage all readers to submit memories and additional information that I shall gather for future writing. Keeping alive the history of how the field developed will be the best tribute that we can play to celebrate Geoff’s work along the years.

     

Correction to: The history of the purine Club: a tribute to prof. Geoffrey Burnstock

Purinergic Signalling - A Correction to this paper has been published: https://doi.org/10.1007/s11302-021-09787-6     

Preface: A Tribute to Prof. John B. Clark

Neurochemical Research -     

Neuropeptides and Neuropeptide Receptors: Drug Targets,and Peptide and Non‐Peptide Ligands: a Tribute to Prof. Dieter Seebach

The number of neuropeptides and their corresponding receptors has increased steadily over the last fourty years: initially, peptides were isolated from gut or brain (e.g., Substance P, somatostatin), then by targeted mining in specific regions (e.g., cortistatin, orexin in the brain), or by deorphanization of G‐protein‐coupled receptors (GPCRs; orexin, ghrelin receptors) and through the completion the Human Genome Project. Neuropeptides (and their receptors) have regionally restricted distributions in the central and peripheral nervous system. The neuropeptide signaling is somewhat more distinct spatially than signaling with classical, low‐molecular‐weight neurotransmitters that are more widely expressed, and, therefore, one assumes that drugs acting at neuropeptide receptors may have more selective pharmacological actions with possibly fewer side effects than drugs acting on glutamatergic, GABAergic, monoaminergic, or cholinergic systems. Neuropeptide receptors, which may have a few or multiple subtypes and splice variants, belong almost exclusively to the GPCR family also known as seven‐transmembrane receptors (7TM), a favorite class of drug targets in the pharmaceutical industry. Most neuropeptides are co‐stored and co‐released with classic neurotransmitters, albeit often only at higher frequencies of stimulation or at bursting activity, thus restricting the neuropeptide signaling to specific circumstances, another reason to assume that neuropeptide drug mimics may have less side effects. Neuropeptides possess a wide spectrum of functions from neurohormone, neurotransmitter to growth factor, but also as key inflammatory mediators. Neuropeptides become ‘active’ when the nervous system is challenged, e.g., by stress, injury, drug abuse, or neuropsychiatric disorders with genetic, epigenetic, and/or environmental components. The unsuspected number of true neuropeptides and their cognate receptors provides opportunities to identify novel targets for the treatment of both central and peripheral nervous system disorders. Both, receptor subtype‐selective antagonists and agonists are being developed, as illustrated by the success of somatostatin agonists, angiotensin, and endothelin antagonists, and the expected clinical applications of NK‐1/2/3 (substance P) receptor antagonists, CRF, vasopressin, NPY, neurotensin, orexin antagonists, or neuropeptide receptor modulators; such ligands have efficacy in preclinical or clinical models of pain and neuropsychiatric diseases, such as migraine, chronic/neuropathic pain, anxiety, sleep disorders, depression, and schizophrenia. In addition, both positive and negative allosteric modulators have been described with interesting in vivo activities (e.g., at galanin receptors). The field has become more complex now that an increasing number of heteromeric neuropeptide receptors are described, e.g., ghrelin receptors with 5‐HT_2C or dopamine D₁, D₂ receptors. At long last, structure‐based drug discovery can now be envisaged with confidence, since crystal or solution structure of GPCRs and GPCR? ligand complexes, including peptide receptors, are published almost on a monthly basis. Finally, although most compounds acting at peptide receptors are still peptidomimetics, the last decade has seen the emergence of low‐molecular‐weight nonpeptide ligands (e.g., for orexin, ghrelin, or neurokinin receptors), and surprising progress has been made with β‐ and γ‐peptides as very stable and potent mimetics of, e.g., somatostatin (SRIF), where the native SRIF has a half‐life limited to 2–3 min. This last point will be illustrated more specifically, as we have had a long‐standing collaboration with Prof. D. Seebach to whom this review is dedicated at the occasion of his 75th birthday.     

Book review: Mammalian Evolutionary Morphology: A Tribute to Frederick S. Szalay

In this article, we evaluate the association between the Fort King George “skull” and two Franciscans who were killed during a Guale revolt in 1597 and whose remains were never recovered (Pedro de Corpa and Francisco de Veráscola). The history and historiography of the revolt is summarized to generate a forensic profile for the individuals. The calvaria is described in terms of preservation, taphonomy, possible trauma, age, and sex. Because these factors are consistent with the individuals in question, population affinity is assessed using comparative craniometric analysis. In response to recent criticism of the typological nature of forensic population affinity assessment, we use a population specific approach, as advocated by Alice Brues (1992). Archaeological and historical data inform the occupation history of the site, and data from those specific populations are used in the comparative analysis. Results of linear discriminant function analysis indicate a low probability that the calvaria is a Guale (the precontact inhabitants of southeastern Georgia) or an individual of African descent. Comparison among European and Euro‐American populations indicated poor discriminatory resolution; however, the closest match suggests a New World affinity rather than an Old World English, Scottish, or Iberian affinity for the specimen. Future analyses that will provide greater resolution about the identity of the calvaria are outlined. The case highlights the unique challenges of historical forensics cases relative to those of traditional jurisprudence, as well as the potential for using historiography to overcome those challenges in future analyses. Am J Phys Anthropol, 2009. © 2009 Wiley‐Liss, Inc.     

Hypertrophic cardiornyopathy: from gene defect to clinical disease

Major advances have been made over the last decade in our understanding of the molecular basis of several cardiac conditions. Hypertrophic cardiomyopathy (HCM) was the first cardiac disorder in which a genetic basis was identified and as such, has acted as a paradigm for the study of an inherited cardiac disorder. HCM can result in clinical symptoms ranging from no symptoms to severe heart failure and premature sudden death. HCM is the commonest cause of sudden death in those aged less than 35 years, including competitive athletes. At least ten genes have now been identified, defects in which cause HCM. All of these genes encode proteins which comprise the basic contractile unit of the heart, i.e. the sarcomere. While much is now known about which genes cause disease and the various clinical presentations, very little is known about how these gene defects cause disease, and what factors modify the expression of the mutant genes. Studies in both cell culture and animal models of HCM are now beginning to     

Tribute to Tinbergen: The Four Problems of Biology. A Critical Appraisal

Tinbergen's (1963, Z. Tierpsychol. 20 , 410–433) four questions have guided the conceptual thinking of behavioural biologists over five decades. This is partly based on a misunderstanding of the aims and virtue of this article. Tinbergen called attention to the fact that his classification of problems is somehow illogical. Here, an attempt is made to remove some of the inconsistency by reformulating the levels of analysis of biological (including behavioural) traits. Furthermore, important merits of Tinbergen's milestone paper that have remained largely unnoticed are put in perspective. Perhaps the most lasting of several functions of that article has been its pivotal role in establishing a new research discipline, behavioural ecology.     

R.B. Merrifield: European footnotes to his life and work.

Some reflections on the life and work of RB Merrifield in the European context are given.     

Evidence for the contribution of LTR retrotransposons to C. elegans gene evolution

LTR retrotransposons may be important contributors to host gene evolution because they contain regulatory and coding signals. In an effort to assess the possible contribution of LTR retrotransposons to C. elegans gene evolution, we searched upstream and downstream of LTR retrotransposon sequences for the presence of predicted genes. Sixty-three percent of LTR retrotransposon sequences (79/124) are located within 1 kb of a gene or within gene boundaries. Most gene-retrotransposon associations were located along the chromosome arms. Our results are consistent with the hypothesis that LTR retrotransposons have contributed to the structural and/or regulatory evolution of genes in C. elegans.     

A morphometric analysis of Scottish Athyrium distentifolium: a contribution to the BAP

Summary

A morphologically distinct variety of Athyrium distentifolium called A. distentifolium var. flexile has been found only in Scotland. Research was undertaken for aUK Biodiversity Action Plan. To confirm that this taxon has a definitely recognisable morphology, a morphometric analysis was used on the range of characters used to define this variety. It showed that it can be clearly differentiated.     

The contribution of spontaneous mutation to variation in environmental responses of Arabidopsis thaliana: responses to light

It has been hypothesized that new, spontaneous mutations tend to reduce fitness more severely in more stressful environments. To address this hypothesis, we grew plants representing 20 Arabidopsis thaliana mutation-accumulation (M-A) lines, advanced to generation 17, and their progenitor, in differing light conditions. The experiment was conducted in a greenhouse, and two treatments were used: full sun and shade, in which influx of red light was reduced relative to far-red. The shade treatment was considered the more stressful because mean absolute fitness was lower in that treatment, though not significantly so. Plants from generation 17 of M-A developed significantly faster than those from generation 0 in both treatments. A significant interaction between generation and treatment revealed that, counter to the hypothesis, M-A lines tended to have higher fitness on average relative to the progenitor in the shaded conditions, whereas, in full sun, the two generations were similar in fitness. A secondary objective of this experiment was to characterize the contribution of new mutations to genotype x environment interaction. We did not, however, detect a significant interaction between M-A line and treatment. Plots of the line-specific environmental responses indicate no tendency of new mutations to contribute to fitness trade-offs, between environments. They also do not support a model of conditionally deleterious mutation, in which a mutant reduces fitness only in a particular environment. These results suggest that interactions between genotype and light environment previously documented for A. thaliana are not explicable primarily as a consequence of steady input of spontaneous mutations having environment-specific effects.     

Food-associated calls in rhesus macaques (Macaca mulatta): I. Socioecological factors

Upon discovering food, free-living rhesus macaques (Macaca mulatta)on the island of Cayo Santiago, Puerto Rico, produce a complexof vocal signals consisting of five acoustically distinguishablecalls. This report examines the socioecological factors elicitingcall production and the information protentially conveyed toothers. The primary contexts for three vocalizations ("warbles," "harmonicarches, " and "chirps") are encounters with rareand highly preferred foods (e.g., coconut). Two other vocalizations("coos" and "grunts") are produced both in food (primarily provisionedchow) and in nonfood contexts, such as during mother-infantseparation and grooming interactions. Grunts given upon encounteringfood are acoustically distinct from those given in nonfood contexts.In contrast, coos associated with food are statistically indistinguishablefrom coos given in other contexts. When conspecitics hear thesefood-associated calls, they typically approach the caller. Coosare less likely to lead to approach than other food-associatedcalls, Results from all-day follows on adult males and adultfemales reveal that changes in hunger level influence call ratebut not call type; the different call types are produced throughoutthe day. We infer that the structure of food-associated callsprovides information about the quality of the food discovered,whereas call rate conveys information about the relative hungerlevel of the caller. In this population, adult males give fewerfood-associated calls than adult females. In addition, femaleswithin large matrilines call more than females within smallermatrilines, and males who are resident in a group are more vocalthan peripheral males.     

A sensitive fluorimetric microassay for the determination of glutathione peroxidase activity. Application to human blood platelets

The method proposed for measuring glutathione peroxydase (GSH-Px) activity is based on the determination of oxidized glutathione (GSSG) using o-phtalaldehyde (OPT) as a fluorescent reagent. This method makes it possible to study the kinetics of both substrates (peroxide and reduced glutathione, GSH), and allosteric kinetics were found for GSH, with human platelets as the source of GSH-Px. Different methods for platelet disruption were compared. The reference values obtained for GSH-Px activity in human blood platelets by this fluorimetric procedure and the conventional enzymatic method were very similar and significantly higher than those previously reported; the reasons for this difference are discussed.