History of Geoff Burnstock's research on P2 receptors.

Geoffrey Burnstock is a purinergic signalling legend who's discoveries and conceptualisation created and shaped the field. His scientific achievements were extraordinary and sustained. They included his demonstration that ATP can act as a neurotransmitter and hence extracellular signalling molecule, which he championed despite considerable initial opposition to his proposal that ATP acts outside of its role as an energy source inside cells. He led on purine receptor classification: initially of the P1 and P2 receptor families, then the P2X and P2Y receptor families, and then subtypes of P2X and P2Y receptors. This was achieved across several decades as he conceptualised and made sense of the emerging and growing evidence that there were multiple receptor subtypes for ATP and other nucleotides. He made discoveries about short term and long term/trophic purinergic signalling. He was a leader in the field for over 50 years. He inspired many and was a great colleague and mentor. I had the privilege of spending over 10 years (from 1985) with Geoff at the Department of Anatomy and Developmental Biology, University College London. This review is a personal perspective of some of Geoff's research on P2 receptors carried out during that time. It is a tribute to Geoff who I regarded with enormous respect and admiration.

Perspectives on Geoff Burnstock as researcher, teacher and friend.

Geoffrey Burnstock, one of the most talented and brilliant scientists of his generation, was born on the 10th of May 1929 in London and died on the 2ndof June 2020, aged 91, in Melbourne (Australia). Geoffrey Burnstock started his research studies with an interest in the nerves controlling the guts of guinea pigs, and discovered a completely unexpected and ubiquitous signalling system mediated via extracellular nucleotides (the "purinergic theory"), which revolutionized our understanding of how cells communicate between each other. He made the highly controversial discovery that ATP (adenosine triphosphate), a molecule well known to biochemists for its role as a source of energy inside cells, could also transmit signals between them. Initially, his somewhat heretical theory, that did not fit conventional views, found considerable resistance in the scientific community. However, he continued to accumulate evidence in favor of his hypothesis, extending it to a variety of organs and systems and demonstrating a role for purinergic signaling in the cardiovascular, respiratory and nervous systems, and in the pathophysiology of pain, blood clotting, cell proliferation and differentiation, and immunity. For his entire life, he struggled to attract scientists to this new field and, finally, in the early 1990s, did evidence emerge that convinced the doubters, due to new molecular biology techniques making it possible to isolate and identify the cell surface receptors for ATP and its breakdown product, adenosine. His death clearly impacted a huge number of scientists who have lost their pioneering leader. In this Review, I will not talk of the many discoveries made by Professor Burnstock, nor of his enormous scientific contributions to the field and of the incredible number of prizes and public recognitions that he has received after his theory was accepted worldwide. Instead, I will share some personal memories on him as a teacher and scientist, and, most of all, as a loyal and reliable friend. Geoff was an extraordinary human being, always eager to collaborate and share data, never jealous of his findings and capable of learning even from young people. He was known for his enthusiasm, empathy and ability to motivate young scientists. I was lucky to meet him when I was still very young, and the collaboration and friendship that we established and maintained across the years has profoundly conditioned my professional and personal life. For me, Geoff was what in Italy we call a "Maestro", one of those leading figures who are fundamental not only for mentoring an individual's career but also their growth as a scientist and as a human being.

A historical perspective on the development of modern concepts of tissue perfusion: prehistory to the twentieth century.

The historical development of the concept of perfusion is traced, with particular focus on the development of the modern clinical concepts of perfusion through the fields of anatomy, physiology, and biochemistry. This article reviews many of the significant contributors to the changing ideas of perfusion up through the twentieth century that have influenced the modern physiologic circulatory and metabolic models. The developments outlined have provided the modern model of perfusion, linking the cardiopulmonary circulation, tissue oxygen utilization and carbon dioxide production, food intake, tissue waste production and elimination, and ultimately the production and utilization of ATP in the body.

ATP and acetylcholine, equal brethren.

Acetylcholine was the first neurotransmitter identified and ATP is the hitherto final compound added to the list of small molecule neurotransmitters. Despite the wealth of evidence assigning a signaling role to extracellular ATP and other nucleotides in neural and non-neural tissues, the significance of this signaling pathway was accepted very reluctantly. In view of this, this short commentary contrasts the principal molecular and functional components of the cholinergic signaling pathway with those of ATP and other nucleotides. It highlights pathways of their discovery and analyses tissue distribution, synthesis, uptake, vesicular storage, receptors, release, extracellular hydrolysis as well as pathophysiological significance. There are differences but also striking similarities. Comparable to ACh, ATP is taken up and stored in synaptic vesicles, released in a Ca(2+)-dependent manner, acts on nearby ligand-gated or metabotropic receptors and is hydrolyzed extracellularly. ATP and acetylcholine are also costored and coreleased. In addition, ATP is coreleased from biogenic amine storing nerve terminals as well as from at least subpopulations of glutamatergic and GABAergic terminals. Both ACh and ATP fulfill the criteria postulated for neurotransmitters. More recent evidence reveals that the two messengers are not confined to neural functions, exerting a considerable variety of non-neural functions in non-innervated tissues. While it has long been known that a substantial number of pathologies originate from malfunctions of the cholinergic system there is now ample evidence that numerous pathological conditions have a purinergic component.

Purinergic signalling.

While there were early papers about the extracellular actions of purines, the role of ATP as a purinergic neurotransmitter in nonadrenergic, noncholinergic nerves in the gut and bladder in 1972 was a landmark discovery, although it met considerable resistance for the next 20 years. In the early 1990s, receptors for purines were cloned: four P1 receptor subtypes and seven P2X ionotropic and eight P2Y metabotropic receptor subtypes are currently recognized and characterized. The mechanisms underlying ATP release and breakdown are discussed. Purines and pyrimidines have major roles in the activities of non-neuronal cells as well as neurons. This includes fast signalling roles in exocrine and endocrine secretion, platelet aggregation, vascular endothelial cell-mediated vasodilation and nociceptive mechanosensory transduction, as well as acting as a cotransmitter and neuromodulator in most, if not all, nerve types in the peripheral and central nervous systems. More recently, slow (trophic) purinergic signalling has been implicated in cell proliferation, migration, differentiation and death in embryological development, wound healing, restenosis, atherosclerosis, ischaemia, cell turnover of epithelial cells in skin and visceral organs, inflammation, neuroprotection and cancer.

Development of liposomal polyene antibiotics: an historical perspective.

PURPOSE: The purpose of this review article is to review the development of a number of liposomal polyene antibiotics. BACKGROUND: In the past thirty years, the increase in life-threatening pre-systemic and systemic fungal infections within cancer, diabetic and AIDS patients have reached alarming proportions. A number of antifungal agents have been developed to combat this problem. In particular, polyene antibiotics such as Amphotericin B (AmB) and Nystatin (Nys) have remained the most effective and widely used agents in the treatment of these infections. However, their administration is limited by dose-dependent toxicities. One such dose-limiting toxicity is renal toxicity. Polyene antibiotic-induced renal toxicity is believed to be mediated by the drug anchoring to cholesterol within the mammalian cell membrane, resulting in pore formation, abnormal electrolyte flux, decrease in adenosine triphosphate (ATP), and eventually a loss of cell viability. CONCLUSION: In the 1980s and 90s a number of promising lipid-based AmB and Nys formulations were developed to overcome these toxicities. This article will review the development of these liposomal polyene antibiotics.

Historical review: mitochondria and calcium: ups and downs of an unusual relationship.

The discovery of Ca(2+) transport by mitochondria is conventionally credited to De Luca and Engstrom, and Vasington and Murphy, who showed in 1961-1962 that Ca(2+) was taken up by isolated mitochondria using respiratory or ATP energy. However, contributions had already appeared in the 1950s showing - albeit indirectly - that isolated mitochondria bound Ca(2+) actively. Somehow, however, these contributions failed to attract the attention that they undoubtedly deserved. The 1961-1962 findings started the ball rolling, initiating a topic that was to have a peculiar oscillatory history. It went from peaks of great enthusiasm to valleys of essential neglect, and from there to a final (hopefully permanent) robust revival.

Understanding "active" chromatin: a historical perspective of chromatin remodeling.

Two phenomena have long been observed to correlate with transcriptionally active chromatin: increased histone acetylation and increased sensitivity to nucleases, including specific patterns of nuclease hypersensitivity in the promoters of active or inducible genes. Work in recent years has at last identified protein complexes required to form these hallmarks of active chromatin: histone acetyltransferases (HATs) and ATP-dependent chromatin remodeling complexes. This review traces the history of these discoveries, including the development of essential tools that allowed the major advances in the field, and describes the current understanding of the interactions between HATs and ATP-dependent remodelers.