The demonstration by Bayliss and Starling that acid liberates a chemical messenger from the cells of the duodenal and jejunal mucosa and that this, by traveling through the blood, excites the pancreas to secrete revolutionized physiology. It subsequently provided the impetus to establish endocrinology as a specialist field in medicine. Together, their contributions to physiology covered a vast sphere of knowledge, ranging from hormones to the heart and from enzymes to osmotic forces. Every subject that they studied was augmented by their efforts, and their lucid scientific writing brought both clarity and organization to the field of physiological endeavor throughout the world. Both contributed in a very definite way to crystallizing physiology into a rigorous scientific discipline and their respective texts the "Principles of General Physiology" (Bayliss) and the "Principles of Human Physiology" (Starling) established a framework of thought that for decades remained the lodestar of physiological science. As mentors, they devoted themselves to aspirant physiologists from all parts of the world, and their dedication to the activities of the Physiological Society in London was legendary. Indeed from 1896, when Starling became secretary, until the death of Bayliss in 1924, the two ran this august body in one capacity or another for more than a quarter of a century. There is little doubt that the felicitous collaboration that led to the discovery of secretin and the introduction of the concept of chemical messengers represents an advance that not only revolutionized physiological thought but the entire face of clinical medicine.
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http://dx.doi.org/10.1097/00004836-200103000-00001 | DOI Listing |
Nat Commun
October 2024
Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT, 06536, USA.
Type IV pili (T4P) produced by the pathogen Pseudomonas aeruginosa play a pivotal role in adhesion, surface motility, biofilm formation, and infection in humans. Despite the significance of T4P as a potential therapeutic target, key details of their dynamic assembly and underlying molecular mechanisms of pilus extension and retraction remain elusive, primarily due to challenges in isolating intact T4P machines from the bacterial cell envelope. Here, we combine cryo-electron tomography with subtomogram averaging and integrative modelling to resolve in-situ architectural details of the dynamic T4P machine in P.
View Article and Find Full Text PDFSLAS Discov
September 2024
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ, USA. Electronic address:
Agonists of the secretin receptor have potential applications for diseases of the cardiovascular, gastrointestinal, and metabolic systems, yet no clinically-active non-peptidyl agonists of this receptor have yet been developed. In the current work, we have identified a new small molecule lead compound with this pharmacological profile. We have prepared and characterized a systematic structure-activity series around this thiadiazole scaffold to better understand the molecular determinants of its activity.
View Article and Find Full Text PDFJ Med Chem
July 2024
Gubra, Ho̷rsholm Kongevej 11B, Ho̷rsholm 2970, Denmark.
Peptide-based drug discovery has surged with the development of peptide hormone-derived analogs for the treatment of diabetes and obesity. Machine learning (ML)-enabled quantitative structure-activity relationship (QSAR) approaches have shown great promise in small molecule drug discovery but have been less successful in peptide drug discovery due to limited data availability. We have developed a peptide drug discovery platform called streaMLine, enabling rigorous design, synthesis, screening, and ML-driven analysis of large peptide libraries.
View Article and Find Full Text PDFJ Physiol
June 2024
Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
William Bayliss and Ernest Starling are not only famous as pioneers in cardiovascular physiology, but also responsible for the discovery of the first hormone (from the Greek 'excite or arouse'), the intestinal signalling molecule and neuropeptide secretin in 1902. Our research group focuses on neuropeptides and neuromodulators that influence cardiovascular autonomic control as potential biomarkers in disease and tractable targets for therapeutic intervention. Acute myocardial infarction (AMI) and chronic heart failure (CHF) result in high levels of cardiac sympathetic stimulation, which is a poor prognostic indicator.
View Article and Find Full Text PDFNat Commun
May 2024
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ, USA.
Class B G protein-coupled receptors can form dimeric complexes important for high potency biological effects. Here, we apply pharmacological, biochemical, and biophysical techniques to cells and membranes expressing the prototypic secretin receptor (SecR) to gain insights into secretin binding to homo-dimeric and monomeric SecR. Spatial proximity between peptide and receptor residues, probed by disulfide bond formation, demonstrates that the secretin N-terminus moves from adjacent to extracellular loop 3 (ECL3) at wild type SecR toward ECL2 in non-dimerizing mutants.
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