Joseph Rudinger memorial lecture: Discovery and applications of cyclotides

Cyclotides are plant‐derived peptides of approximately 30 amino acids that have the characteristic structural features of a head‐to‐tail cyclized backbone and a cystine knot arrangement of their three conserved disulfide bonds. This article gives a personal account of the discovery of cyclotides, their characterization and their applications, based on work carried out in my laboratory over the last 20 years. It describes some of the background to their discovery and focuses on how their unique structural features lead to exceptional stability. This stability and their amenability to chemical synthesis have made it possible to use cyclotides as templates in protein engineering and drug design applications. These applications complement the interest in cyclotides deriving from their unique structures and natural function as host defense molecules. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd.     

Joseph Rudinger memorial lecture: Unexpected functions of angiotensin converting enzyme,beyond its enzymatic activity

Angiotensin converting enzyme (ACE) is a well‐known enzyme, largely studied for its action on hypertension, as it produces angiotensin II from angiotensin I. This paper describes two original behaviours of ACE. We showed that ACE could hydrolyse gastrin, a neuropeptide from the gastrointestinal tract, releasing the C‐terminal amidated dipeptide H‐Asp‐Phe‐NH₂. This dipeptide is believed to be involved in the gastrin‐induced acid secretion in the stomach. This hypothetic mechanism of action of gastrin resulted in a strategy to rationally design gastrin receptor antagonists. Beyond, we showed that the brain renin angiotensin system (RAS) could be activated by a new characterized peptide named acein, resulting in stimulation of dopamine release within the striatum. This new and original ‘receptor‐like’ activity for brain membrane‐bound ACE is quite significant taking into account the role of dopamine in the brain, particularly in neurodegenerative diseases. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.     

Failla memorial lecture. Risk, research, and radiation protection

Radiation protection concerns the risk of stochastic late effects, especially cancer, and limits on radiation exposure both occupationally and for the public tend to be based on these risks. The risks are determined, mainly by expert committees, from the steadily growing information on exposed human populations, especially the survivors of the atomic bombs dropped in Japan in 1945. Risks of cancer estimated up to the early 1980s were in the range 1 to 5 X 10(-2)/Sv, but recent revisions in the dosimetry of the Japanese survivors and additional cycles of epidemiological information suggest values now probably at the high end of this range. These are likely to require an increase in the values used for radiation protection. A major problem with risk estimation is that data are available only for substantial doses and must be extrapolated down to the low-dose region of interest in radiation protection. Thus the shape of the dose-response curve is important, and here we must turn to laboratory research. Of importance are studies involving (1) dose rate, which affects the response to low-LET radiation and often to high-LET radiation as well; (2) radiation quality, since the shapes of the dose-response curves for high- and low-LET radiation differ and thus the RBE, the ratio between them, varies, reaching a maximum value RBEM at low doses; and (3) modifiers of the carcinogenic response, which either enhance or reduce the effect of a given dose. Radiation protection depends both on risk information, and especially also on comparisons with other occupational and public risks, and on research, not only for extrapolations of risk to low doses but also in areas where human information is lacking such as in the effects of radiation quality and in modifications of response.     

Spatial Segregation of Congeneric Invaders in Central Pennsylvania, USA

Carduus acanthoides and Carduus nutans (plumeless and musk thistles) are among the most noxious weeds in the United States of America, presenting a serious challenge in cropping and pasture systems. Unfortunately, a lack of detailed spatial distribution information hampers both our ability to understand the factors affecting their invasive success, and the effectiveness of monitoring and management efforts. To examine patterns of distribution and co-occurrence at a local level, we sampled a 5000 km² area of central Pennsylvania that cut a transect across known areas of C. acanthoides and C. nutans infestation. A number of potential environmental explanatory variables were recorded and analyzed to examine whether they correlated with observed species distribution patterns. Patterns of forest density and spatial aggregation of the thistles were the primary covariates that significantly impacted both species’ distributions. The survey established that the frequency of sightings for each species diminished as the ranges converged, with only brief overlap: the two species are strongly negatively correlated in space. Understanding environmental correlates of infestation and the pattern of spatial dissociation of these two invasive species is an important step towards an improved understanding of the mechanisms underlying their invasive potential, and hence towards effective weed control.     

Failla memorial lecture. Contrarian concepts in the progress of radiotherapy

Radiobiology concepts relevant to radiotherapy have undergone continued revision, suggesting that a continuing skeptical if not completely contrarian view of current concepts is also warranted. Some such revisions are revisited, and some present applications of radiobiology to radiotherapy are discussed before they, too, require revision.     

The Seiji memorial lecture: the melanosome: an ideal model to study cellular differentiation

Melanosomes provide an intriguing model for study at many levels. In part this is due to their unique structure and function, but also in part to their involvement in pigmentary diseases and as a model to study basic cellular mechanisms of organelle biogenesis. Recent studies have elucidated the full proteome of the melanosome and the metabolic and molecular lesions involved in a number of pigmentary diseases have been resolved. This paper summarizes recent advances in the field in these areas.     

Chemistry,clones, and circadian control of the dinoflagellate bioluminescent system. The Marlene DeLuca memorial lecture

Bioluminescence in the dinoflagellate Gonyaulax polyedra occurs as brief bright flashes, originating from many (～400) small (～0.5 μm) cytoplasmic organelles which protrude into the acidic vacuole, and are thus surrounded by the tonoplast. Biochemically, the substrate is unusual; it is an open chain tetrapyrrole, highly unstable to air but protected in the cell at pH? 8 by virtue of a luciferin binding protein (LBP). This molecule is a dimer of 72 kDa subunits which, upon a decrease in pH, releases luciferin to react with oxygen in the luciferase (～140 kDa) catalysed luminescent reaction. cDNAs for both luciferase and LBP have been isolated and cloned, and the identity of LBP was confirmed by hybrid selection and in vitro translation of the message. The tenfold circadian (day to night) change in the amount of LBP, which parallels the in vivo rhythm of luminescence, is due to de novo synthesis and subsequent degradation of the protein each day. The LBP mRNA levels, as determined by in vitro translations and by Northern hybridizations, do not vary over the daily cycle, indicating that circadian control of bioluminescence in this species is mediated at the level of translation.     

Hammond memorial lecture. New concepts of the control of corpus luteum function

Five new concepts concerning the control of corpus luteum function in the cow have been developed in recent years. Prostacyclin (PGI-2) plays a luteotrophic role. Conversely, products of the lipoxygenase pathway of arachidonic acid metabolism, particularly 5 hydroxyeicosatetraenoic acid (5-HETE), play luteolytic roles. Luteal cells arise from two sources. The small luteal cells are all of theca cell origin; the large cells found early in the cycle (Days 2-6) are mainly of granulosa cell origin. However, a population of large cells found after Day 10 of the cycle are of theca cell origin. Oxytocin of luteal cell origin plays a role in development of the corpus luteum and possibly in its regression. The recently described Ca2+-polyphosphoinositol-protein kinase C second messenger system, as well as the LH-cAMP system, is involved in control of progesterone synthesis in the bovine corpus luteum. Progesterone synthesis in the small theca-derived luteal cells is primarily controlled by the cAMP system. However, elevated intracellular calcium diminishes cAMP-mediated progesterone synthesis in these cells. These findings modify our current concepts of the mechanisms of control of progesterone secretion by the corpus luteum and suggest several new lines of research.