Prize In Physiology Research Articles

Roger Guillemin, Andrew Victor Schally, Rosalyn Sussman Yalow

Research into the physiology of active substances in the 50s of the last century led to the discovery of new peptides, which were named releasing factors, or releasing hormones. The nature of these substances was studied by Roger Guillemin and Andrew Victor Schally. Within a few years, the luteinizing hormone-releasing hormone was isolated, sequenced and synthesized. This discovery laid the ground for modern research on the hypothalamus. Results of animal studies were quickly translated to humans and found their use in clinical practice. The American researcher Rosalyn Sussman Yalow used radioisotopes to measure the volume of circulating blood and to study the distribution of serum proteins in body tissues, as well as to diagnose diseases of the thyroid. Subsequently, a radioimmunological method was developed, including the use of radioactive agents to track various substances in the blood plasma and other tissues. In 1977, Rosalyn Yalow was awarded half of the Nobel Prize in Physiology and Medicine “for the development of radio-immunological methods for the determination of peptide hormones”. Another part of this award was shared by Roger Guillemin and Andrew Schally for a similar research on brain hormones related to “the production of peptide hormones in the brain”. Doctors around the world use the discoveries of these outstanding scientists to improve the quality of life and increase the life expectancy in millions of patients with prostate cancer.

Discovery of temperature and touch receptors: An introduction of the 2021 Nobel Prize in Physiology or Medicine

<p indent=0mm>Human has five senses, including vision, touch, hearing, taste, smell and taste, as well as temperature (including heat and cold) and pain sensation. How humans perceive the physical world through somatic sensation has fascinated us for centuries. The 2021 Nobel Prize in Physiology or Medicine was awarded to David Julius from the University of California, San Francisco (UCSF) and Ardem Patapoutian from Scripps Institute for their thermal and mechanical transducers discoveries. David Julius pursued a project to identify the receptor for capsaicin in the late 1990s. He screened a cDNA library from rodent dorsal root ganglia, identified a cDNA encoding a novel ion channel belonging to the superfamily of transient receptor potential (TRP) cation channels (now called TRPV1). In subsequent studies, TRPV1 demonstrated a pronounced activation by heat (especially above 40°C) and led to cellular calcium influx. Patch-clamp recordings revealed a heat-evoked membrane current similar to those of sensory neurons. Furthermore, high temperatures above 40°C have already been harmful to the human body. Because mice lacking Trpv1 showed only a minor loss of acute noxious heat sensation, other heat-sensitive receptors must exist. In 2011, Voets and his team identified TRPM3 as a second heat-sensitive receptor. In 2004, Julius noticed TRPA1, another superfamily of transient receptor potential (TRP) cation channels, can be activated by various chemical substances, as well as by cold and heat. In 2002, Julius and Patapoutian identified TRPM8 and found it can be activated by low temperature, which humans perceive as innocuous cold. At present, important roles for TRPV1, TRPA1, TRPM3, and TRPM8 in temperature sensing have been experimentally established. Thus, the discovery of TRPV1 by David Julius opened the door and represented a landmark achievement to a molecular understanding of thermosensation. Future studies will likely provide additional insights into this active research field. Ardem Patapoutian mainly focuses on the research of mechanosensitive ion channels. He identified a mechanosensitive Neuro2A cell line by using brief and rapid indentation of the plasma membrane in combination with patch-clamp recording. Ardem Patapoutian screened 72 candidate genes, including known ion channels and proteins of unknown function. The candidate genes were silenced by RNA interference one by one. Knockdown of the FAM38A, eliminated the mechanically activated current and the protein was named Piezo1. A second mechanosensitive channel Piezo2, was discovered by sequence homology. Piezo1 and Piezo2 represent an entirely novel class of ion channels as mechanical sensors. In 2014, Patapoutian found mice lacking Piezo2 in neither Merkel cells nor sensory neurons deficient in light touch sensation. Patapoutian also demonstrated that Piezo2 is the principal transduction channel for proprioception in mice. In further work, Patapoutian and his group found central roles of Piezo1 and Piezo2 for many physiological functions. The mutations in the <italic>Piezo2</italic> gene cause several genetic disorders manifested by altered sensations of touch, vibration and proprioception in humans. The discovery of Piezo proteins provides insights into how humans perceive internal and external environments. This review focuses on the 2021 Nobel Prize in Physiology or Medicine. Recent other research on sensory perceptions is also briefly introduced.

From sense of touch to tactile intelligence: Thoughts from the 2021 Nobel Prize in Physiology or Medicine

<p indent=0mm>Human beings have highly developed sense of touch. Through touching we can perceive heat, pain, mechanical stimuli, recognize features of an object such as texture and hardness, and even understand emotion of a person. Hence, human touch is one of the most important ways to sense and adapt to the world around us. However, we had little understanding of how cutaneous perception was formed in our nervous system, until the groundbreaking discoveries were made by this year’s Nobel Prize laureates in Physiology or Medicine, David Julius from University of California, San Francisco, and Ardem Patapoutian from Scripps Research. They found that heat and mechanical stimuli can initiate specific nerve impulses for temperature, pain, and touch sensations. The quest to understand temperature sensation and pain spans millennia. In the early 20th century, the Greek physician Galen proposed that sensations were transmitted along pathways that connect the organs to the brain. It was not until 1997 that the true underlying molecular mechanism was revealed by Julius in a breakthrough work. Julius and his team found that a receptor on the cell’s membrane arranges itself from one side to the other, so that it creates a passage called a transient receptor potential (TRP) channel. This ion channel opens or closes in response to heat. Inspired by Julius’s work, Patapoutian in the early 21st century explored a mechanosensitive ion channel, called the Piezo channel, and identified that it is essential for the sense of touch. Patapoutian and his team also found that the Piezo channel is responsible for the sensing of position and motion of our body, which explains why we can balance on a steep stair. Not only did these discoveries elucidate the physiological understanding of human somatosensory, they also enlightened the researchers who work on reproducing such human functions in robotics and prosthetics. The molecular mechanisms of thermo-sensation and mechano-sensation provided a new paradigm for designing artificial cutaneous perception and constructing electronic skin for robots. Once fully armed by tactile perception and haptic feedback, smart robots and artificial intelligence may start to have consciousness and feel emotions like we humans do. With the awarding of the 2021 Nobel Prize in Physiology or Medicine to research in how humans perceive touch and pain, the research in tactile intelligence now has a clearer roadmap and gains a greater momentum. We foresee many exciting breakthroughs in this field in the near future.

CGRP: A New Endogenous Cell Stemness Maintenance Molecule.

Stem cells have the ability of self-replication and multidirectional differentiation, but the mechanism of how stem cells “maintain” this ability and how to “decide” to give up this state and differentiate into cells with specific functions is still unknown. The Nobel Prize in physiology and medicine in 2021 was awarded to “temperature and tactile receptor,” which made the pain receptor TRPV1-calcitonin gene-related peptide (CGRP) pathway active again. The activation and blocking technology of CGRP has been applied to many clinical diseases. CGRP gene has complex structure and transcription process, with multiple methylation and other modification sites. It has been considered as a research hotspot and difficulty since its discovery. Drug manipulation of TRPV1 and inhibition of CGRP might improve metabolism and prolong longevity. However, whether the TRPV1-neuropeptide-CGRP pathway is directly or indirectly involved in stem cell self-replication and multidirectional differentiation is unclear. Recent studies have found that CGRP is closely related to the migration and differentiation of tumor stem cells, which may be realized by turning off or turning on the CGRP gene expression in stem cells and activating a variety of ways to regulate stem cell niches. In this study, we reviewed the advances in researches concentrated on the biological effects of CGRP as a new endogenous switching of cell stemness.

Beyond Thermal Sensation: Roles of Transient Receptor Potential Vanilloid Subfamily Member 1 and Spicy Food in Cardiometabolic Diseases

The 2021 Nobel Prize in Physiology or Medicine was awarded to David Julius for his discovery of capsaicin receptors in 1997.[1] The capsaicin receptor is also called transient receptor potential vanilloid subfamily member 1 (TRPV1) and belongs to the transient receptor potential channels family. TRPV1 possesses a tetrameric structure consisting of 6 transmembrane regions, a pore-shaped region between the fifth (S5) and sixth transmembrane regions (S6), a cytoplasmic amino group, and a carboxyl terminus, which is selectively permeable for cations such as H+, Na+, and Ca2+.[1] TRPV1 can be activated by nociceptive thermal stimulation (temperature > 43°C), pH values less than 5.96, and capsaicin, a pungent component of chili peppers, and other factors including free oxygen radicals, 12-lipoxygenase, 20-hydroxyeicosatetraenoic acid, etc. Activation of TRPV1-induced neuronal depolarization transmitted to the central nervous system creates thermal and pain sensations.[2] In addition, activation of TRPV1 can also promote the release of calcitonin gene-related peptide (CGRP), substance P (SP), and other neurotransmitters.[3,4] The discovery of TRPV1 has increased our understanding of how temperature triggers nerve impulses, because our ability to perceive ambient temperature is essential for survival and the basis of our interaction with the world around us. This perspective focuses on the actions of TRPV1 in the regulation of cardiometabolic function and beneficial effects of spicy food on the prevention of cardiometabolic diseases. TRPV1 and regulation of cardiometabolic function TRPV1 is distributed not only in the nervous system, but also in non-neuronal tissues and organs such as the heart, liver, pancreas, vasculature, kidney, intestine, skeletal muscle, and fat tissues.[2] In addition to sensing temperature, TRPV1 may impact cardiometabolic function. In 2004, our team began to focus on the role of TRPV1 in the regulation of cardiometabolic function and its relevance to cardiometabolic diseases because epidemiological data in China revealed a remarkable difference in the prevalence of cardiometabolic diseases between subjects who prefer spicier food and those who prefer less spicy food. Role of TRPV1 in vascular function and heart function The TRPV1 channel is expressed in myocardium, epicardial surface, vascular endothelial cells, vascular smooth muscle cells (VSMCs), and peripheral sensory nerves of the heart.[4,5] Activation of endothelial TRPV1 by capsaicin relaxes blood vessels by modulating the potassium channel and the Ca2+ dependent potassium channel.[6] Our study showed that activation of endothelial TRPV1 by capsaicin promotes Ca2+ influx, which increases the phosphorylation of protein kinase A (PKA) and endothelial nitric oxide synthase (eNOS), thereby promoting nitric oxide (NO) production in endothelial cells.[7] Activation of TRPV1 also increases the intracellular calcium level and promotes the adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway, which affects VSMC proliferation and migration.[8] Activation of TRPV1 in perivascular sensory neurons can promote the release of CGRP, SP, and other neuropeptides, thus leading to vasodilatation.[5] TRPV1 in afferent neuronal baroreceptors maintains blood pressure homeostasis.[9] TRPV1 expressed in cardiac nodes and sympathetic afferent fibers, cardiomyocytes, and fibroblasts affects cardiac structure and function.[10] After coronary artery ligation in TRPV1 knockout mice, the cardiac infarction area, inflammatory cell infiltration, capillary density, and collagen content of myocardium as well as mortality significantly increased.[8] Knockout of TRPV1 in mice increased the expression of transforming growth factor-β1, Smad2, vascular endothelial growth factor, and matrix metalloproteinase 2 (MMP2) in myocardium and promoted cardiac fibrosis as well as reduced the production of CGRP and SP.[10] Role of TRPV1 in metabolic regulation TRPV1 has been detected in several key metabolic organs, but its roles in these organs remain elusive. We reported the expression of TRPV1 in adipocytes and white adipose tissue. Activation of TRPV1 by capsaicin can increase adipocyte calcium levels and reduce triglyceride production through inhibition of peroxisome proliferator-activated receptor γ (PPAR γ) and fatty acid synthase.[11] Reduction off at accumulation by TRPV1 activation is also associated with an increased gap junction protein 43 (Cx43)-mediated Ca2+ influx.[12] The expression of TRPV1 is rich in brown fat. TRPV1 activation by capsaicin promoted sirtuin-1 (SIRT-1) expression and its acetylation as well as the interaction between PPAR γ and PR/SET Domain-16 (PRDM-16).[13] TRPV1 also regulates the glucose homeostasis through several pathways. Capsaicin can increase insulin secretion in a dose-dependent manner via TRPV1 in rodent islet β cells and β cell lines.[14] TRPV1 regulates insulin secretion by stimulating the afferent sensory nerves that innervate islet cells.[14] TRPV1 has also been localized in secretion tumor cell-1 (STC-1) cells and ileum.[15] TRPV1 activation by capsaicin stimulated glucagon-like peptide-1 (GLP-1) secretion from STC-1 cells in a calcium-dependent manner and also increased GLP-1 and insulin secretion, thus improving glucose tolerance.[15] Hepatic TRPV1 activation by capsaicin reduced lipid accumulation in the liver[16] and up-regulated the expression of uncoupling protein 2 (UCP2) and PPAR δ to prevent fatty liver.[17] TRPV1 in skeletal muscle is associated with more mitochondrial biogenesis, oxidative fiber production, and enhanced exercise endurance.[18] In addition, activation of TRPV1 also increased AMPK expression and promoted glucose oxidation and ATP production in skeletal muscle.[19] TRPV1 dysfunction and cardiometabolic diseases Dysfunction of TRPV1 is associated with pathogenesis of cardiometabolic diseases. Lower TRPV1 expression in visceral adipose tissue from obese mice and obese humans was accompanied by reduced capsaicin-induced calcium influx.[11] Capsaicin treatment prevented high-fat diet-induced obesity in mice by increasing lipolysis via Cx43-mediated Ca2+ influx that enhanced the expression of phospho-calmodulin (p-CaM), calmodulin-dependent protein kinase II (CaMK II), PPAR δ, and hormone sensitive lipase (HSL) in adipose tissues.[11,12] The inhibitory effect of capsaicin on obesity-related brown adipose tissue (BAT) whitening was mediated by SIRT3 that prevented mitochondrial calcium overload.[20] The low expression of TRPV1 in BAT caused glucose intolerance and hypercholesterolemia and decreased the plasma GLP-1 level; in contrast, TRPV1 activation by dietary capsaicin ameliorated abnormal glucose homeostasis and increased GLP-1 levels in plasma and ileum.[15] In diabetic mice, hyperglycemia decreased TRPV1 expression and PKA phosphorylation in endothelial cells, which was reversed by capsaicin in a UCP2-dependent manner.[21] In addition, activation of TRPV1 potently improved diabetic nephropathy by inhibition of hyperglycemia-induced mitochondrial dysfunction in podocytes.[22] Also, TRPV1 prevented the development of fatty liver through stimulating lipolysis by increasing UCP2, phosphorylated HSL, carnitine palmitoyl transferase 1, and PPAR δ.[17] In skeletal muscle, TRPV1 activation promoted mitochondrial biogenesis, increased oxidative fibers, and enhanced exercise endurance.[18] In addition to ameliorating metabolic disorders, TRPV1 activation also benefits cardiovascular diseases (CVDs). Long-term stimulation of TRPV1 by dietary capsaicin activates PKA that increases NO synthase phosphorylation, improves vasorelaxation, and lowers blood pressure in genetically hypertensive rats.[7] Activation of TRPV1 in mesenteric arteries also reduces high-salt-diet-induced endothelial dysfunction and nocturnal hypertension by restoring NO production.[23] In the kidneys, TRPV1 activation promoted urinary sodium excretion by inhibiting epithelial sodium channel α subunit-mediated sodium reabsorption.[24] Activation of TRPV1 by dietary capsaicin mediated increases in phosphorylation of eNOS delayed the onset of stroke and increased the survival time in stroke-prone spontaneously hypertensive rats.[25] In addition, activation of TRPV1 also increased the ATP-binding cassette transporter A1 and reduced low-density lipoprotein (LDL) receptor-related protein 1 expression in the aorta, thus inhibiting atherosclerotic lesions by reducing foam cell formation from VSMCs.[26] The upregulation of PKA/UCP2 via TRPV1 activation ameliorates coronary dysfunction and prolongs the lifespan of atherosclerotic mice by ameliorating endothelial mitochondrial dysfunction.[27] In the heart, activation of TRPV1 by capsaicin attenuated high-salt-diet-induced cardiac hypertrophy and fibrosis by restoring mitochondrial complex I oxidative phosphorylation and sirtuin 3 expression.[28,29] Spicy food consumption and prevention of cardiometabolic diseases TRPV1 agonists and antagonists are mainly used for analgesia, and their side effects include temperature changes, among others.[30] The protective effect of TRPV1 in cardiometabolic disease is mainly based on the population observation of spicy food intake. Capsaicin is a major pungent component of chili peppers and can specifically activate TRPV1.[2] Currently, the Dietary Approaches to Stop Hypertension diet in the United States and Mediterranean Diet in the Europe are recommended as dietary therapies for the prevention of cardiometabolic diseases.[31] Although basic studies have provided a large amount of evidence that dietary capsaicin-activating TRPV1 can ameliorate the pathogenesis of cardiometabolic diseases [Figure 1], it remains unclear whether spicy food is beneficial in clinical studies.[32]Figure 1: Roles of TRPV1 and spicy food in the amelioration of cardiometabolic diseases. ABCA1: ATP-binding cassette transporter A1; ARD: Ankyrin repeating domain; eNaC: Epithelial sodium channel; eNOS: Endothelial nitric oxide synthase; FAS: Fatty acid synthase; GLP-1: Glucagon-like peptide 1; LRP1: Low-density lipoprotein receptor-related protein 1; NO: Nitric oxide; PGC-1α: Peroxisome proliferator-activated receptor-gamma coactivator 1 α; PKA: Protein kinase A; PPAR δ: Peroxisome proliferator-activated receptor δ; PPAR γ: Peroxisome proliferator-activated receptor γ; ROS: Reactive oxygen species; TRP: Transient receptor potential domain; TRPV1: Transient receptor potential vanilloid subfamily member 1; UCP2: Uncoupling protein 2.Effect of spicy food on blood pressure A systematic review and meta-analysis of randomized controlled trials showed that supplementation with fermented red pepper paste (FRPP) improved systolic blood pressure and diastolic blood pressure.[33] Nine years of data from the China Health and Nutrition Survey (CHNS) showed that chili intake is inversely associated with the risk of developing hypertension in Chinese adults aged 20 to 75 years.[34] The China Kadoorie Biobank (CKB) prospective study and CHNS showed that frequency of spicy food consumption was inversely associated with risk of hypertension in females but not males.[35,36] We also reported that consuming spicy foods significantly reduced individual salt preference, daily salt intake, and blood pressure by modifying the neural processing of salty taste in the brain.[37] Use of spicy flavors may be a promising behavioral intervention for reducing high salt intake and blood pressure. Effect of spicy food on glycolipids and obesity In 1549 participants aged 65 years in the CHNS, the frequency and the average amount of spicy food intake were both inversely associated with LDL-cholesterol and LDL-cholesterol:HDL-cholesterol ratio after adjustment for potential confounders and cluster effects.[38] A 4-week intervention with chili peppers, equivalent to 5 mg/day capsaicin, successfully improved fasting blood lipid profiles compared with placebo in women with gestational diabetes mellitus (GDM).[39] Consumption of 30 g/day chopped chili peppers for 4 weeks also increased the resistance of serum LDL to oxidation in healthy subjects.[40] A clinical trial conducted in 28 females for 12 weeks revealed that treatment with FRPP evoked a greater cholesterol-modulating effect.[41] The consumption of chili peppers has a potential immediate thermogenic effect and a potential hypoglycemic effect in sedentary people.[42] Capsaicin-containing chili supplementation regularly improved postprandial hyperglycemia and hyperinsulinemia as well as decreased the incidence of large-for-gestational-age newborns in women with GDM.[39] The CKB prospective study showed that spicy food consumption was inversely associated with the risks of death due to diabetes in the whole cohort after multivariate adjustment.[43] A large-scale longitudinal, household based survey in China showed that subjects without chili intake had higher insulin resistance compared with subjects with chili intake.[44] In healthy individuals, taking capsicum capsules lowered plasma glucose levels and increased plasma insulin levels.[39] In a randomized, double-blind, placebo-controlled, 8-week trial with a combination of nutrients including capsaicin, there was a decrease in insulin resistance and inflammatory adipokines.[45] Epidemiological data revealed that the consumption of foods containing capsaicin was associated with a lower prevalence of obesity. The CKB study recruited a total of 434,556 adults aged 30 to 79 years. It showed that the prevalence of daily intake of spicy food rate was dramatically geographically diverse. In areas with increased frequency, intensity and duration of spicy food consumption, the obesity parameters decreased significantly after covariate adjustment.[46] Another double-blind, randomized, placebo-controlled trial indicated that treatment of overweight or obese subjects with capsinoid for 12 weeks reduced abdominal fat.[47] In moderately overweight subjects, 12-week administration of noninvamide, a non-pungent capsaicin analogue, prevented diet-induced systemic fat gain.[48] Capsaicin treatment caused sustained fat oxidation during weight maintenance compared with placebo.[49] A randomized double-blind study showed that subjects treated with capsinoid for 4 weeks increased their oxygen consumption and resting energy expenditure.[50] Effect of spicy food on fatty liver and muscle endurance Dietary factors including spicy foods were associated with fatty liver in an Indian study.[51] The occurrence of fatty liver was inversely associated with frequent consumption of spicy foods in a cross-sectional study including 9378 participants in China.[52] A population-based cross-sectional study found a positive correlation between frequency of chili consumption and muscle strength in adult males.[53] Healthy young men taking capsaicin analog supplementation produced higher maximal isometric force and delayed fatigue compared to those taking placebo.[54] Spicy food consumption and CVD risk The CKB study revealed that spicy food consumption was inversely associated with the risks of death due to ischemic heart diseases in the whole cohort after multivariate adjustment.[43] In the Molisani cohort study, regular consumption of chili pepper was associated with decreased risk of ischemic heart disease (hazard ratio (HR): 0.56; 95% confidence interval (CI): 0.35–0.87) and cerebrovascular death (HR: 0.39; 95% CI: 0.20–0.75).[55] A meta-analysis of 4 studies (from the United States, China, Italy, and Iran) that recruited more than a half million participants showed that spicy food consumption was associated with significant reduction of total mortality and CVD death risk.[56] In conclusion, a consumption of spicy food recommendation has been written into China's guidelines for prevention of cardiometabolic diseases through a healthy lifestyle.[57,58] If more prospective and randomized clinical trials can further validate the cardiometabolic benefits of spicy food, it would be a low-cost, widespread, and easy to implement dietary therapy to prevent cardiometabolic diseases. The discovery of TRPV1 not only illuminates the principle of temperature and pain perception but also provides a promising strategy for the prevention of cardiometabolic diseases in the population. Funding This work was supported by grants from the National Basic Research Program of China (2006CB503905) and the National Natural Science Foundation of China (81721001, 31701023, 81900380). Conflicts of interest None.

An inspiration to the studies on mechanisms of acupuncture and moxibustion action derived from 2021 Nobel Prize in Physiology or Medicine

Abstract The editorial board of Acupuncture and Herbal Medicine recently convened an academic seminar with a focus on studies regarding the mechanisms mediating acupuncture efficacy and moxibustion action inspired by the 2021 Nobel Prize in Physiology or Medicine. Specifically, Professor Bailong Xiao introduced the Nobel Prize for research on the mechanically activated Piezo ion channel, evaluating the structure of the Piezo channel and its physiological and pathological functions, and proposed a possible role for the Piezo channel in acupuncture mechanical stimulation. Professor Michael Xi Zhu introduced the discovery of the transient receptor potential (TRP) family, reporting that the therapeutic effects of Chinese medicine and acupuncture may be achieved via the TRP family, and that information regarding associations between the meridian and lymphatic systems may have important research and medical value. In addition, Professor Tianle Xu reviewed the history of ion channel research, particularly the physiological and pharmacological effects of non-classical ion channels (eg, the acid sensing ion channel family) and pointed out that the characterization and neural circuits of acupuncture deqi manipulation are important for elucidating the mechanisms of acupuncture actions. Professor Yongming Li similarly proposed that the 2021 Nobel Prize may open the door to disclosing the histological basis of acupuncture and moxibustion and analyzing the main scientific concerns regarding the clinical translation of acupuncture and moxibustion from basic to translational research. Finally, Professor Yi Guo summarized the study progress of the acupoint microenvironment induced by acupuncture over the course of nearly 30 years and put forward the hypothesis that acupuncture may initiate the physical-chemical coupling network by activating ion channel receptors in acupoints via physical and mechanical stimulation. Therefore, we conclude that a primary achievement of the 2021 Nobel Prize in Physiology or Medicine is in helping interpret how acupuncture and moxibustion adjust homeostasis (ie, by activating mechanical and thermal sensation), which is conducive to validating and promoting the clinical efficacy of acupuncture modalities.

A tribute to Eddy Fischer (April 6, 1920–August 27, 2021): Passionate biochemist and mentor

Edmond (Eddy) Fischer was one of the great biochemists of the 20th and 21st centuries. He was also a gifted pianist, an avid mountain climber, and a pilot, a true man of the world who lived on three continents and spoke many languages fluently. Having spent his childhood in China and Europe, Eddy was formally schooled in Switzerland and began his studies at the University of Geneva in 1939, just as Hitler was invading Poland. After receiving his doctorate in Chemistry at the University of Geneva, he went to the California Institute of Technology, but was then quickly recruited to the fledgling Department of Biochemistry at the University of Washington in 1953 by Hans Neurath, where the mountains as well as the biochemistry were a big attraction. Seattle remained his home for the rest of his life, but the world was his home and his impact radiated across many continents. In Seattle he met Edwin Krebs, who had been recruited in 1948, and in the next few years these two young scientists changed the course of history for all of us. They laid the foundation for a community of scholars that extended across the world and Eddy, in particular, became a friend and mentor to all of us. His sphere of influence extended well beyond those who trained directly in his laboratory. In the 1950s, Ed and Eddy built quickly on the foundation that was laid at Washington University in St. Louis by Gerty and Carl Cori, two other earlier transplants from Europe, and made a discovery that changed the world of biology and won them the Nobel Prize in Physiology or Medicine in 1992 (1). They discovered that proteins in cells are dynamically regulated by the covalent addition of a phosphate moiety from ATP, and that two enzymes catalyze … [↵][1]1To whom correspondence may be addressed. Email: staylor{at}ucsd.edu. [1]: #xref-corresp-1-1

The Thiopurine Tale: An Unexpected Journey.

Exactly 70 years ago [1951] mercaptopurine was discovered by Gertrude Elion as a novel treatment option for acute leukaemia. A total of three thiopurines (also thioguanine [1950] and azathioprine [1957]) were developed over time. These immunosuppressive drugs were also successfully introduced a few decades later to prevent rejection of transplanted organs and to treat several autoimmune diseases. For her discovery of thiopurines and other antimetabolite drugs, in 1988 Elion was rewarded, together with George Hitchings and James Black, with the Nobel Prize in Physiology or Medicine. Important steps have been made in recent years to unravel its metabolism, mode of action and pharmacogenetics. Today thiopurine [based] therapy remains an essential immunosuppressive approach in treating patients with inflammatory bowel disease.

David Hunter Hubel, the 'Circe effect', and SARS-CoV-2 infection of the human visual system.

David Hunter Hubel (1926-2013) was an internationally recognized neurophysiologist and vision neuroscientist noted for his life-long studies on the columnar structure and highly integrated function of the brain's primary and secondary visual cortex. He was co-recipient with the American neuropsychologist and neurobiologist Roger Wolcott Sperry (1913-1994) and the Swedish neurophysiologist Torsten Nils Wiesel (1924-present) of the 1981 Nobel Prize in Physiology or Medicine, for their significant discoveries concerning the functional specialization of the cerebral hemispheres, the layered structure of the human cerebral visual cortex and information processing in the visual system, how the human visual cortex is organized into columns, and how this remarkable cellular organization and connectivity for the human visual system can be modified by lifestyle, experience, aging and disease. This commentary integrates these significant findings with current observations on SARS-CoV-2, the causative agent of COVID-19, and its invasion of the human visual system via the angiotensin converting enzyme 2 (ACE2) receptor.

Analyses of the 2021 Nobel Prize in Physiology or Medicine: Receptors for Temperature and Touch

ABSTRACT David Julius, a professor of physiology at the University of California, San Francisco, and Ardem Patapoutian, a molecular biologist at Scripps Research in La Jolla, California, share the 2021 Nobel Prize in Physiology or Medicine for their contributions to the identification of receptors for temperature and touch which are fundamental for an organism’s ability to sense and interact with the internal and external environment. The advancement of the molecular understanding of thermosensation and mechanotransduction can further our understanding of the regulation of biological processes. Following a general overview of temperature and touch receptors is a bibliometric analysis of each of this year’s laureates and their work.

The noble mission of Nobel Laureate Sir Ronald Ross

INTRODUCTION July 25 is a Historic Day. On that day in the year 1603, James VI of Scotland was crowned by James of England Uniting Kingdom of England and Scotland. Malaria and Yellow fever, The deadly Mosquito borne diseases, compelled England and Scotland to form the Kingdom of Great Britain through Union Act 1707, to conquer these diseases to set up and spread their Colonies’ business. MALARIA HUNTERS Two legendary Scots, Sir Ronald Ross [Figure 1] (13.05.1857-16.09.1932), inspired and guided by his mentor Sir Patrick Manson (03.10.1894-09.04.1922), made the breakthrough to combat Malaria and Mosquito-borne diseases and thus saving the humanity from this veritable scourge. A French Army Physician and Scientist (Father of Protozoa) Charles Louis Alphonse Laveran (18.06.1845-18.05.1924) discovered “oscillaria Malariae” (Plasmodium) on November 6, 1880 responsible for Malaria at Constantine, Algeria proving the “Germ Theory” of disease propounded by Louis Pasteur (27.12.1822-28.09.1885), in 1870. Thus, it was proved that Malaria (mal aria-bad air in Italian) or Paludism (“means Marshy” in French) is due to parasite, not due to bad air or marshy, i.e., Miasmatic origin. Sir Patrick Manson (Father of Tropical medicine) was the author of “Mosquito Malaria theory.”Figure 1: Sir Ronald Ross (1857–1932)EPIC STUDY Sir Ronald Ross made the landmark discovery that female Anopheles mosquito is the Vector of Malarial Parasite in Secundrabad (August 20, 1897, calling MOSQUITO DAY) and the lifecycle of Malarial Parasite (Bird to mosquito to the bird cycle of malaria) at the Presidency General Hospital, Calcutta (established on April 22, 1770) now, known as SSKM Hospital, Kolkata, at the present Sir Ronald Ross Laboratory on July 4, 1898 (MALARIA DAY). Calcutta (Once Mecca of Medicine in India) is the BIRTH PLACE OF MALARIA LOGY (Covell, 1932). Sir Ronald Ross is revered as FATHER OF MALARIALOGY for his “Great and Epoch making Discovery.” Sir Ronald Ross was awarded the Nobel Prize in physiology and Medicine on December 10, 1902 and he was recognized as “One of Greatest benefactors of mankind.” In Nobel Citation, it was mentioned “for his work on Malaria by which he has shown how it enters the organism and thereby he laid the foundation for successful research on this disease and methods of combating it.” BIOGRAPHY Sir Ronald Ross was born at Almora, India. He was the eldest son of the ten children of Sir Campbell Claye Grant Ross, a General in British Indian Army (Bengal Staff Corps) and Matilda Charlotte Elderton. At the age of 8 years, he was sent to England to study. He completed primary school and secondary education. During school life, he developed intense interest in poetry, literature, music, painting and mathematics and devoted to pursue his passion. He was not very much attentive to his academic study or playing. His father was very tough to his son to be a medical doctor. Hence, he was enrolled at St. Bartholomew’s Hospital Medical Collage in London on October 29, 1874 and passed in 1881. As a Medical Student, he did not show any brightness and also failed in examinations because he devoted to his Passions-not to be a Medical Doctor. INDIA - HIS DREAM Ronald Ross joined Indian Medical Service (IMS) on April 2, 1881, and worked from 25 years at different places such as Madras, Burma, Baluchistan, Andaman Islands, Bangalore, Secunderabad, Calcutta, and Assam. Wherever he went, two things – one iron frame upright Piano and one microscope – always were essential items of his luggage. STUDY ON MALARIA Ronald Ross used to suffer as a child seeing the malaria attack of his grandfather Lt. Col. Hugh Ross. Ross was determined to find a cure of the disease. During course of his Medical School, he saw a female patient presenting with muscle ache and high fever with chill and headache. That lady came from Essex marshes. Ronald Ross thoroughly examined her and provisionally diagnosed as a case of Malaria. However, malaria was very common in south America and India. The patient became frightened to see the exhaustive examination of Ronald Ross. She was lost to follow-up. Hence, Ross could not prove the diagnosis. Ronald Ross’s interest in Malaria began in 1892. He got a Laveran’s masterpiece on Malaria (translated from French to English). It was a great inspiration to him. From 1892 to 1894, he could not find Laveran’s “Oscillaria malariae” (Malarial Parasite). He met Sir Patrick Manson on April 10, 1894, at Cavendish Square, London, who taught him how to see the malarial parasite under microscope. During his leave from June 1888 to May 1889, he obtained D.P.H. (Diploma in Public Health) in London. He was first recipient of D.P.H. in the world. He was trained by Prof. Emanuel Edward Klein (Father of British Microbiology) on Bacteriology for 2 months. He married to Rosa Bessi Bloxam on 1889. From 1894 to 1898, Ronald Ross was under the constant guidance of his mentor Sir Patrick Manson. 173 letters were exchanged between them from 1895 to 1899. Ross observed early stages of Malarial Parasite in the stomach of a mosquito in May 1895. His total devotion was focused on mosquito and Malarial Parasite. It was interrupted when he was deputed to Bangalore as a Sanitary Officer to investigate the outbreak of Cholera. At Bangalore, there was no mosquito. Hence, Ronald Ross was very unhappy, but he worked hard to check cholera through proper massive sanitization (Drainages, Cleanliness, etc). Ross was an adroit environmentalist. Between 1895 and 1897, he made Bangalore in a clean and healthy city by dint of his meticulous planning and leadership. At Sigur Ghat, near Ooty, he saw “dappled winged” brown mosquitoes with peculiar posture. These dappled winged mosquitoes were species of the genus Anopheles. On August 20, 1897, he discovered that female anopheles mosquitoes were the vectors of Malarial Parasite at Secunderabad. He declared August 20, as Mosquito Day. He wrote a poem and sent to his wife Rosa Bessi Bloxam and Sir Patrick Manson On August 22: “This day relenting God Hath Placed Within My Hand A Wondrous thing, and God Be praised. At His command Seeking his secret deeds With tears and toiling breath, I find Thy cunning seeds 0 Million – murdering Death I know this little thing A myriad men will save 0 Death, where is Thy sting? Thy Victory, 0 Grave? This discovery was published in the Indian Medical Gazette on August 27, 1897, and subsequently on the December 18, 1897, Issue of British Medical Journal titled – ”on some peculiar pigmented cells found in two Mosquitoes fed on Malarial blood.” AGAIN INTERRUPTION IN RESEARCH WORK In September 1897, Ross was transferred to Malaria-free Kherwara in Rajputana (Rajasthan). He became angry and deeply frustrated. He threatened to resign from service, but due to Patrick Manson’s (Medical Advisor to Colonial Office) intervention, the Government arranged for his continued service and transferred to Calcutta “On a special duty” for 6 months under the Director General of IMS to investigate Malaria and Kala-azar (Visceral leishmaniasis). He joined the Presidency General Hospital (now SSKM Hospital) Calcutta on February 17, 1898. He was transferred to Calcutta on January 29, 1898. DISCOVERY OF LIFE CYCLE OF MALARIAL PARASITE At Presidency General Hospital, Calcutta Ross did his research on bird (purchased at his own cost) by grey Mosquitoes (Infected Culex Pipiens). His very obedient servant Mohammad Bux helped him a lot. His Laboratory Assistant was Dr. Kishori Mohan Bandhopadhyay. Due to plague in Calcutta at that time, human volunteers were not available; female Anopheles stephensi Mosquitoes do not cause Malaria in birds. Ross knew Danielewski’s studies on bird Malaria. Ross used birds as experimental model. ON July 4, 1898, he made the landmark discovery at D.D. Cunnigham’s Laboratory (at present Sir Ronald Ross Laboratory) of life cycle of Malarial Parasite proving the hypothesis of Laveran and Manson. RETIREMENT FROM INDIAN MEDICAL SERVICE Ronald Ross left Calcutta on August 13, 1898, to get rid of “Administrative Barbarism.” He submitted a report to the Government giving details of “Anti-Malarial weapons” including rational interventional strategies, as he thought to prevent, control, and eradicate malaria. WORK ON KALA-AZAR (VISCERAL LEISHMANIASIS) Ronald Ross submitted his report on the nature Kala-azar on January 30,1899, to the Director General of IMS. Ross named “Leishman-donovan bodies” as parasite of Kalaazar discovered by W. B. Leishman (06.11.1865-02.06.1926) and Charles Donovan (September 19, 1863–October, 29, 1951). Leishman discovered in 1903 but could not definitely identify; Donovan in 1903 in his research found the same but called it a parasite. Ronald Ross solved this dispute and named this parasite as “Leishman-Donovan Bodies.” ROSS JOINED LIVERPOOL SCHOOL OF TROPICAL MEDICINE, UK Returning from Calcutta, Ronald Ross joined as Lecturer with a very poor pay. He worked from 1899 to 1926 at different positions. He retired as Alfred Jones’ Professor and Director of Tropical Medicine. HEROIC EXPEDITIONS During his service at LSTM, he made expedition to Freetown, capital of Sierra Leona (1899 and 1901), Mian mir Lahore (1901), Lagos (1901), Ismailia at Egypt (1902), Panama (1904), Greece (1906), Mauritius (1907–1908), Alexandria (1914–18) to control, prevent, and eradicate Malaria. AWARDED NOBEL PRIZE IN PHYSIOLOGY AND MEDICINE (DECEMBER 10, 1902) Ronald Ross was the First Indian to get the Nobel Prize in Physiology and Medicine. Malaria known as Modern Plague or Deadly Fever (Mrityujwar by Sushruta, 800 BC-700 BCE) is now defeated by Ronald Ross. Sir Ronald Ross was a man of immense versatility; even within malaria, at least three streams of subsequent work flow from his original contribution; in parasitology-work on the life cycle, best known but perhaps not his greatest work, although crucial to all the rest; in epidemiological models which was 20 years ahead of his time and in sanitation or hygiene, in promoting the prevention of Malaria and other diseases by Environmental means. -David J Bradley Director, Ross Institute, London ROSS INSTITUTE AND HOSPITAL FOR TROPICAL DISEASES This institute was inaugurated in 1926 in Putney Heath by the Prince of Wales as a memorial to and in recognition of Ronald Ross’s work. It was dedicated to study of the nature and treatment, propagation and prevention of tropical diseases. In 1926, Ronald Ross became the Director-in-Chief of this institute till his death in 1932. After his death, it was incorporated by the London School of Hygiene and Tropical Medicine. HONOR TO SIR RONALD ROSS After his death on September 16, 1932, The Times, London, paid tribute to him “He slew the Dragon and delivered mankind from immortal bondage.” Dr. W. C. Gorgas said “Dr. Ronald Ross had dug the Panama canal with the help of microscope.” Calcutta honors Sir Ronald Ross. Barkley Bronze Medal by the Asiatic society of Calcutta on May 20, 1903 Gate of Commemoration unveiled by Lord Lytton, in the presence of Sir Ronald Ross at PG Hospital Campus on January 7, 1927. Ronald Ross Building was established at PG (SSKM) Hospital Kolkata in 1954. Ronald Ross oration (yearly) was established at IPGM and R (Institute of Post Graduate Medical Education and Research) in 1956. PG (SSKM) hospital was declared as a Heritage precinct and Sir Ronald Ross Laboratory Building as a Heritage Building by Calcutta Municipal Corporation on January 6,1991 due to appeal of Dr. Ranen Dasgupta. Sir Ronald Ross Sarani (Erstwhile Hospital Road) was declared by the Calcutta Municipal Corporation on the 09.01.2001, in response to appeal of Dr. Ranen Dasgupta Sir Ronald Ross Memorial Malaria Clinic (24 h) at Sir Ronald Ross Laboratory at SSKM Hospital was sanctioned by Government of West Bengal and Kolkata Municipal Corporation in response to appeal of Dr. Ranen Dasgupta, which was inaugurated on February 05, 2004. Sir Ronald Ross Park was established at SSKM Hospital on January 16, 2006. due to my endeavor. CONCLUSION Sir Ronald Ross was a remarkable man who contributed immensely not only in Malaria Research but also as a Mathematician, Epidemiologist, Sanitarian, Editor of Science Progress, Dramatist, Poet, Musician, Composer, Artist, and Author. He was a Polymath. Above all, he was a Medical Missionary. Earnest appeal To Commemorate his glorious attachment to PG SSKM Hospital Calcutta, The IPGME and R (Institute of Post Graduate Medical Education and Research) should be renamed as SIR RONALD ROSS INSTITUTE OF POST GRADUATE MEDICAL EDUCATION and RESEARCH. A MEDICAL MUSEUM should be established at the allotted land for the second campus of PG (SSKM) HOSPITAL at New Town, Kolkata, where foundation stone was laid on 11th November, 2010, to Showcase Calcutta, as MECCA OF MEDICINE and PG HOSPITAL AS PRIDE and GLORY OF BENGAL. The History of Malaria contains a good lesson for humanity. We should be more scientific in our habits of thought and more practical in our habits of Government. -Sir Ronald Ross Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Clinical application and future perspectives of HIF-PH inhibitors

Hypoxia-inducible factor (HIF) is a transcription factor that serves as a master regulator of the adaptive response against hypoxia. The 2019 Nobel Prize in Physiology or Medicine was awarded to three physician scientists for their groundbreaking work revealing this pathway.

La découverte de l’insuline 1921–1922 : un saut dans la recherche biomédicale

Discovery of insulin. If the symptoms of diabetes have been known since Antiquity, it is at the end of the 19th century that several investigators searched for the active substance of the pancreas and endeavoured to produce extracts that lowered blood and urine glucose and decreased polyuria in pancreatectomized dogs. The breakthrough came 100 years ago when the team of Frederick Banting, Charles Best and James Collip, working in the Department of Physiology, headed by John MacLeod at the University of Toronto, managed to obtain pancreatic extracts that could be used to treat patients and rescue them from the edge of death by starvation, the only treatment then available. This achievement was quickly recognized by the Nobel Prize in Physiology or Medicine to Banting and MacLeod in 1923. The discovery has had important scientific, industrial and clinical developments still efficient nowadays.

[The Nobel Prize in Physiology or Medicine 2021: Temperature and touch sensors].

David Julius, 65 ans, professeur à l’université de Californie à Los Angeles (UCLA), et Ardem Patapoutian, 54 ans, professeur à l’institut de recherche Scripps à la Jolla (Californie), ont reçu le prix Nobel de physiologie ou médecine 2021 pour « leurs découvertes des récepteurs de la température et du toucher ». Leurs travaux sur la somesthésie, un sens global qui nous renseigne sur les forces physiques s’exerçant au sein de notre organisme et sur notre peau, ont permis de répondre à une question fondamentale : comment les stimulations thermiques et mécaniques sont-elles converties en signaux électriques dans le système nerveux ? Ces travaux ont conduit à l’identification des canaux ioniques qui sont à l’interface entre notre corps et son environnement.

[The insulin receptor discovery is 50 years old - A review of achieved progress].

The isolation of insulin from the pancreas and its purification to a degree permitting its safe administration to type 1 diabetic patients were accomplished 100 years ago at the University of Toronto by Banting, Best, Collip and McLeod and constitute undeniably one of the major medical therapeutic revolutions, recognized by the attribution of the 1923 Nobel Prize in Physiology or Medicine to Banting and McLeod. The clinical spin off was immediate as well as the internationalization of insulin's commercial production. The outcomes regarding basic research were much slower, in particular regarding the molecular mechanisms of insulin action on its target cells. It took almost a half-century before the determination of the tri-dimensional structure of insulin in 1969 and the characterization of its cell receptor in 1970-1971. The demonstration that the insulin receptor is in fact an enzyme named tyrosine kinase came in the years 1982-1985, and the crystal structure of the intracellular kinase domain 10 years later. The crystal structure of the first intracellular kinase substrate (IRS-1) in 1991 paved the way for the elucidation of the intracellular signalling pathways but it took 15 more years to obtain the complete crystal structure of the extracellular receptor domain (without insulin) in 2006. Since then, the determination of the structure of the whole insulin-receptor complex in both the inactive and activated states has made considerable progress, not least due to recent improvement in the resolution power of cryo-electron microscopy. I will here review the steps in the development of the concept of hormone receptor, and of our knowledge of the structure and molecular mechanism of activation of the insulin receptor.

Progress on the discoveries of temperature and touch receptors: Interpretation of the 2021 Nobel Prize in Physiology or Medicine

Progress on the discoveries of temperature and touch receptors: Interpretation of the 2021 Nobel Prize in Physiology or Medicine

Profile of David Julius and Ardem Patapoutian: 2021 Nobel Laureates in Physiology or Medicine

Three apparently unrelated findings led to the discovery of the temperature receptors: a better understanding of pain-sensing, the molecular nature of the channels in charge of touch and proprioception, and the 2021 Nobel Prize in Physiology or Medicine bestowed to David Julius and Ardem Patapoutian. In 1953, state-of-the-art research in temperature sensing concluded that temperature afferent fibers came in two flavors, “cold” and “warm,” characterized by discharging by a lowering in temperature and an increase in temperature, respectively (1). Hensel and Zotterman had previously described the sensitizing effect of menthol upon cold receptors (2). It is also an old observation that acute application of capsaicin, the active component of chili peppers, causes intense pain, and that its repeated administration renders animals insensitive to the action of this vanilloid compound (3). The fact that capsaicin induces a depolarization of ventral root neurons from the isolated rat spinal cord suggested to Theriault et al. (4) that capsaicin’s acute and chronic effects on nociception could be explained by a direct action on primary sensory neurons. On the other hand, McCarter et al. (5) demonstrated the existence of mechanosensitive currents in rat dorsal root ganglion (DRG) cells, clearly pointing to the existence of mechanosensitive ion channels as being responsible for the sense of touch. David Julius. Image credit: University of California, San Francisco. Since temperature is an “intensive” thermodynamic parameter (i.e., one that does not depend on the size of the system), it was difficult to think of specialized temperature receptors. However, the seminal 1997 Nature paper from Julius’ laboratory demonstrated that living beings have evolved to transduce all stimuli coming from the external world using ion channels, including temperature (6). Caterina et al. (6) used an expression cloning strategy to search for the capsaicin receptor and found a single clone in which capsaicin induced a significant … [↵][1]1To whom correspondence may be addressed. Email: ramon.latorre{at}uv.cl. [1]: #xref-corresp-1-1

[The Nobel Prize in Physiology or Medicine 2021-capsaicin receptor: from thermal sensation to prevention of cardiovascular diseases].

2021年诺贝尔生理学或医学奖颁予辣椒素受体——瞬时受体电位香草酸亚型1（TRPV1）的发现者美国科学家David Julius，TRPV1的发现揭示了温度及痛觉感知的机制，丰富了人们对感知和适应周围环境的认识。除在感觉神经末梢外，TRPV1在心血管系统也有丰富的表达，但其生物学意义并不明了。为此，国内外学者对TRPV1调控心血管功能的作用、与心血管病发病机制的联系及膳食辣椒素的治疗效益进行了探索，拓展了TRPV1的作用，开辟了心血管病防治的新领域。.

TRPV1 and Piezo: the 2021 Nobel Prize in Physiology or Medicine.

The 2021 Nobel Prize in Physiology or Medicine honors the discoveries of the temperature or mechanically activated channels, whose structural studies provided insights of channel gating at atomic level.

[Touch Medicine - a complementary therapeutic approach exemplified by the treatment of depression].

ZusammenfassungHaut-zu-Haut-Berührung stellt die ursprünglichste Sinneserfahrung von Mensch und Tier dar. Ein Mangel an Berührung in der Kindheit ist mit negativen Folgen für die psychosoziale und körperliche Gesundheit verbunden. Für die Entdeckung von Rezeptoren für Temperatur und Berührung im Körper wurde 2021 der Medizin-Nobelpreis verliehen. Klinische Studien belegen den Nutzen von professionellen Berührungstechniken zur Prävention und Therapie verschiedener Erkrankungen. Der breiten Anwendung einer professionellen Berührungstherapie gilt jedoch bis heute nur ein geringes klinisches Interesse. Wir schlagen eine neue Fachdisziplin der „Berührungsmedizin“ vor und spannen nachstehend einen Bogen zwischen den Erkenntnissen moderner Berührungsforschung und der klinischen Medizin. Exemplarisch steht dabei die Behandlung der primär als Leibkrankheit konzipierten Depression im Vordergrund. Kontrollierte Studien und systematische Übersichten belegen die antidepressive, anxiolytische sowie analgetische Wirksamkeit spezieller Massagetechniken in dieser Indikation. Auch für die Neonatologie, Pädiatrie, Schmerzmedizin, Onkologie und Geriatrie konnte die Wirksamkeit heilsamer Berührung gezeigt werden. Die jeweiligen Wirkmechanismen werden auf verschiedenen Konstrukt-Ebenen diskutiert. Im Vordergrund des internationalen Forschungsinteresses stehen derzeit das Interozeptionskonzept, zum anderen endokrinologische, z. B. oxytocinerge Effekte und die Aktivierung sog. CT-Afferenzen.