Ferid Murad (1936-2023).

Physician-scientist who discovered NO signaling.

[Johannes Müller (1801-1858) and his school: pioneer and giant of German physiology]. / Johannes Müller (1801­1858) und seine Schule ­ Wegbereiter und Gigant der deutschen Physiologie.

Johannes Müller was indisputably the most versatile and brilliant physiologist in the mid-nineteenth century. Müller was born in Koblenz in 1801 as the eldest of five children. He received an excellent education in mathematics and the ancient languages and was thus able to read with ease the writings of Aristotle in the original.He served a year with the Pioneers after graduating from high school in 1818. In 1819 he enrolled at the University of Bonn. In 1821, while still a student, he was awarded the scientific university prize for his work on foetal respiration. Müller received his doctorate at the university of Bonn in 1822. He moved to Berlin, where he continued to attend lectures by the anatomist Karl Asmund Rudolphi.He obtained his habilitation in physiology and comparative anatomy in 1824. After his years in Bonn, he accepted a chair at the University of Berlin in 1833 as Rudolphi's successor. His famous "Handbuch der Physiologie" (1833-1840) was published in Berlin. Müller's main areas of interest were physiology, human anatomy, comparative anatomy and anatomical pathology.Müller has numerous publications in addition to his famous book on physiology. He and his distinguished students (Emil du Bois-Reymond, Ernst Haeckel, Hermann von Helmholtz, Friedrich Gustav Jakob Henle, Carl Ludwig, Theodor Schwann and Rudolf Virchow amongst others) made the Berlin Physiological Institute world famous. The natural-philosophical approach to medicine that was still dominant at the beginning of the 19th century was increasingly replaced by a scientifically oriented methodology by Müller.

Claude Bernard and life in the laboratory.

Much has been written on Claude Bernard as a relentless promoter of the experimental method in physiology. Although the paper will touch Bernard's experimental intuitions and his experimental practice as well, its focus is slightly different. It will address the laboratory, that is, the space in which experimentation in the life sciences takes place, and it will analyze the scattered remarks that Bernard made on the topic both in his books and in his posthumously published writings. The paper is divided into four parts. The introduction briefly sketches the coming into being of the physiological laboratory in the first half of the nineteenth century. The second section will give an overview of Claude Bernard's own itinerary in physiology and his personal laboratory experience. The third part of the paper will have a look at the image of the laboratory that Claude depicted in his Introduction to Experimental Medicine. In the subsequent section and by contrast, the image of the laboratory will come into focus as it can be reconstructed from Bernard's notebook that he kept between 1850 and 1860, the Cahier rouge. Finally, the fifth part of the paper will spotlight Claude Bernard's comparison of the sciences and the arts and their respective practices. A brief concluding statement tries to summarize Bernard's epistemological position toward experimentally practiced science.

Kresimir Krnjevic (1927-2021) and GABAergic inhibition: a lifetime dedication.

After over seven decades of neuroscience research, it is now well established that γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. In this paper dedicated to Kresimir Krnjevic (1927-2021), a pioneer and leader in neuroscience, we briefly highlight the fundamental contributions he made in identifying GABA as an inhibitory neurotransmitter in the brain and our personal interactions with him. Of note, between 1972 and 1978 Dr. Krnjevic was a highly reputed Chief Editor of the Canadian Journal of Physiology and Pharmacology.

[Unfairly Forgotten: Carl Ludwig: The Founder of Modern Physiology]. / Zu Unrecht vergessen: Carl Ludwig, Begründer der modernen Physiologie.

Cardiovascular physiology was the dominant area of research for Ludwig. He developed instruments to record hemodynamic and other physiologic events accurately, allowing him to identify previously unrecognized physiologic relationships.His classical textbook of physiology challenged traditional scientific theories and suggested new concepts. His ultimate aim was to describe nature in a mathematic manner "that in the organism no other forces are active but the common physicochemical". ("Organic physicist").His scientific program attracted medical graduates from Europe, Asia and America. Ludwig's scientific ability and personality were the major factors for the success of his research program. His intellectual generosity and unselfishness in order to promote the careers of his pupils is legendary. He put scientific research and results ahead of personal recognition. He mentored his colleagues and pupils without ever putting himself or his own interests ahead of everybody else. He decided to forgo academic recognition and did not play political games.

Brain capillary pericytes and neurovascular coupling.

The neurovascular coupling ensures that cerebral activity is matched by the relevant blood flow. The control of the blood flow is mediated by capillaries and by the precapillary aterioles. It is the tone of the mural cells, which include pericytes, smooth muscle cells and cells with intermediate phenotypes between pericytes and smooth muscle cells, that determine the the diameter of the blood vessels and consequently the flow. Here we discuss the structure of these blood vessels and the excitationcontraction coupling of the mural cells.

The largest of August Krogh animals: Physiology and biomechanics of the blue whale revisited.

The blue whale is the largest animal ever. This gigantism probably evolved to exploit seasonal krill blooms, where massive feasts allow for accumulation of large blubber reserves that can fuel their low mass specific metabolism during prolonged periods of fasting. Until recently, the physiology and biomechanics of blue whales could only be inferred from anatomical inspections, but the recent development of biologging tags now provide unique insights into how these ocean giants function and interact with their environment. Their mandibles, the largest bones ever to evolve, along with a highly expandable buccal cavity, enable an extreme and dynamic bulk feeding behavior. During a lunge feeding event, blue whales accelerate up to 5 m/s to engulf a volume prey laden water that is commensurate with the whale's gigantic body size. Perhaps due to the costs of such extreme foraging, their dive times of 10-15 min are much shorter than scaling would predict for their size. Like other diving animals, blue whales display a dive response with heart rates down to 4 BPM to prolong dive times and perhaps mitigate decompression sickness. Blue whales make the lowest and most energetic calls of any mammal with ocean traversing potential under natural ambient noise conditions. However, communication space may be severely reduced due to pervasive shipping noise. We hope that an increasing ability to study the physiology and behavior of blue whales and other marine megafauna will enable informed decisions and ensure our permanent co-existence in the face of increasing human encroachment into marine habitats.

Between two stools? Pharmacologists nominated for Nobel prizes in "physiology or medicine" and "chemistry" 1901-1950 with a focus on John Jacob Abel (1857-1938).

Since the early stages of its academic professionalization, pharmacology has been an interdisciplinary field strongly influenced by the natural sciences. Using the Nobel Prize as a lens to study the history of pharmacology, this article analyzes nominations of pharmacologists for two Nobel Prize categories, namely "chemistry" and "physiology or medicine" from 1901 to 1950. Who were they? Why were they proposed, and what do the Nobel dossiers say about excellence in pharmacology and research trends? This paper highlights the evaluation of "shortlisted" candidates, i.e., those candidates who were of particular interest for the members of the Nobel Committee in physiology or medicine. We focus on the US scholar John Jacob Abel (1857-1938), repeatedly referred to as the "Founder of American Pharmacology." Nominated 17 times in both categories, Abel was praised by his nominators for both basic research as well as for his influential positions as editor and his work as chair at Johns Hopkins University. The Abel nominations were evaluated for the Nobel Committee in chemistry by the Swedish professor of chemistry and pharmaceutics Einar Hammarsten (1889-1968), particularly interested in Abel's work on hormones in the adrenal glands and in the pituitary gland. Eventually, Hammarsten did not view Abel's work prizeworthy, partly because other scholars had done-according to Hammarsten-more important discoveries in the same fields. In conclusion, analyses of Nobel Prize nominations help us to better understand various meanings of excellence in pharmacology during the twentieth century and beyond.

John Hill (1714?-1775) on 'Plant Sleep': experimental physiology and the limits of comparative analysis.

The phenomenon of 'plant sleep' - whereby vegetables rhythmically open and close their leaves or petals in daily cycles - has been a continual source of fascination for those with botanical interests, from the Portuguese physician Cristóbal Acosta and the Italian naturalist Prospero Alpini in the sixteenth century to Percy Bysshe Shelley and Charles Darwin in the nineteenth. But it was in 1757 that the topic received its earliest systemic treatment on English shores with the prodigious author, botanist, actor, and Royal Society critic John Hill's The Sleep of Plants, and Cause of Motion in the Sensitive Plant. As the present article aims to illustrate, Hill and his respondents used this remarkable behaviour, exhibited by certain plants, as a lens through which to reassess the nature of vegetables, and to address pressing questions of wider natural philosophical import, particularly the degree of continuity between the structures and functions of plants and animals and whether similar mechanisms necessarily account for related movements in different life forms. These disputes, this paper contends, also had profound methodological implications regarding the proper way to conduct experiments, the extent to which it was acceptable to extrapolate from observations, and the status of causal explanations.

Robert Furchgott (1916-2009): A scientist with a mission.

Robert Furchgott was first noted for research on drug-receptor theory, autonomic neuroeffector mechanisms, and vascular pharmacology/physiology. His studies on drug-receptor interactions provided important knowledge about the properties of drug receptors long before methodologies were developed to study them directly. However, Furchgott achieved an enduring legacy for recognizing the importance of endothelial cells for the relaxation of vascular smooth muscle. On the basis of his own experiments and those of others, he proposed that acetylcholine interacted with muscarinic receptors at the surface of endothelial cells to release a substance called endothelium relaxing factor. Endothelium relaxing factor was later identified as nitric oxide, a colorless, odorless gas. Furchgott's discovery of an entirely new mechanism by which blood vessels dilate revolutionized studies on the physiology of the vascular system. His work also suggested new treatments for hypertension and heart disease, and was a key factor in the development of the anti-impotence drug sildenafil. In 1998, Robert Furchgott shared the Nobel Prize in Physiology or Medicine with Ferid Murad and Louis Ignarro.

The magnitude of the Bohr effect profoundly influences the shape and position of the blood oxygen equilibrium curve.

For the past century, the importance of the Bohr effect for blood oxygen delivery has been deemed secondary to the influence of the uptake of carbon dioxide when the blood is deoxygenated (the Haldane effect). This is, however, not the case. The simultaneous oxygen and proton binding to hemoglobin can be modelled by a two-ligand, two-state formulation, while the resulting changes in acid-base status of the surrounding solution can be assessed according to Stewart's model for strong ion difference. This approach shows that an abolishment of the Bohr effect (by either equalizing pKa values of the Bohr groups of T and R states, or by removing the Bohr groups in the calculations) dramatically increases oxygen affinity, and that the Bohr effect plays a crucial role in determining the overall position and shape of the oxygen equilibrium curve. Thus, the magnitude of the Bohr effect (the Bohr factor) and oxygen affinity are directly related, and any change in hemoglobin structure that affects the Bohr factor will inevitably influence hemoglobin oxygen affinity. The modelling approach also emphasizes that pH, PCO2 and PO2 in capillaries are dependent variables, determined by arterial blood gases, the Bohr effect, the respiratory quotient (RQ) of tissue metabolism and the buffer capacity of blood. Thus, the full extent of the Bohr effect cannot be appreciated by comparing oxygen equilibrium curves made at constant PCO2 or pH, but only by comparing curves at constant proton saturation of the Bohr groups. This is because, it is the protons bound to the Bohr groups that directly influence hemoglobin­oxygen binding.