So far in this course we have dealt entirely with the evolution of characters that are controlled by simple Mendelian inheritance at a single locus. There are notes on the course website about gametic disequilibrium and how allele frequencies change at two loci simultaneously, but we didn’t discuss them. In every example we’ve considered we’ve imagined that we could understand something about evolution by examining the evolution of a single gene. That’s the domain of classical population genetics. For the next few weeks we’re going to be exploring a field that’s actually older than classical population genetics, although the approach we’ll be taking to it involves the use of population genetic machinery. If you know a little about the history of evolutionary biology, you may know that after the rediscovery of Mendel’s work in 1900 there was a heated debate between the “biometricians” (e.g., Galton and Pearson) and the “Mendelians” (e.g., de Vries, Correns, Bateson, and Morgan). Biometricians asserted that the really important variation in evolution didn’t follow Mendelian rules. Height, weight, skin color, and similar traits seemed to

Human biochemical genetics

Well-being : the foundations of hedonic psychology

Flavonoids are nearly ubiquitous in plants and are recognized as the pigments responsible for the colors of leaves, especially in autumn. They are rich in seeds, citrus fruits, olive oil, tea, and red wine. They are low molecular weight compounds composed of a three-ring structure with various substitutions. This basic structure is shared by tocopherols (vitamin E). Flavonoids can be subdivided according to the presence of an oxy group at position 4, a double bond between carbon atoms 2 and 3, or a hydroxyl group in position 3 of the C (middle) ring. These characteristics appear to also be required for best activity, especially antioxidant and antiproliferative, in the systems studied. The particular hydroxylation pattern of the B ring of the flavonoles increases their activities, especially in inhibition of mast cell secretion. Certain plants and spices containing flavonoids have been used for thousands of years in traditional Eastern medicine. In spite of the voluminous literature available, however, Western medicine has not yet used flavonoids therapeutically, even though their safety record is exceptional. Suggestions are made where such possibilities may be worth pursuing.

The Effects of Plant Flavonoids on Mammalian Cells:Implications for Inflammation, Heart Disease, and Cancer

Objective: This article presents a new formulation of the relationship between stress and the processes leading to disease. It emphasizes the hidden cost of chronic stress to the body over long time periods, which act as a predisposing factor for the effects of acute, stressful life events. It also presents a model showing how individual differences in the susceptibility to stress are tied to individual behavioral responses to environmental challenges that are coupled to physiologic and pathophysiologic responses. Data Sources: Published original articles from human and animal studies and selected reviews. Literature was surveyed using MEDLINE. Data Extraction: Independent extraction and cross-referencing by us. Data Synthesis: Stress is frequently seen as a significant contributor to disease, and clinical evidence is mounting for specific effects of stress on immune and cardiovascular systems. Yet, until recently, aspects of stress that precipitate disease have been obscure. The concept of homeostasis has failed to help us understand the hidden toll of chronic stress on the body. Rather than maintaining constancy, the physiologic systems within the body fluctuate to meet demands from external forces, a state termed allostasis . In this article, we extend the concept of allostasis over the dimension of time and we define allostatic load as the cost of chronic exposure to fluctuating or heightened neural or neuroendocrine response resulting from repeated or chronic environmental challenge that an individual reacts to as being particularly stressful. Conclusions: This new formulation emphasizes the cascading relationships, beginning early in life, between environmental factors and genetic predispositions that lead to large individual differences in susceptibility to stress and, in some cases, to disease. There are now empirical studies based on this formulation, as well as new insights into mechanisms involving specific changes in neural, neuroendocrine, and immune systems. The practical implications of this formulation for clinical practice and further research are discussed. (Arch Intern Med. 1993;153:2093-2101)

https://jamanetwork.com/journals/INTEMED/articlepdf/617820/archinte_153_18_004.pdf

Stress and the Individual: Mechanisms Leading to Disease

Introduction and Background Modern glucocorticoid endocrinology is a colorful, richly varied, but formless discipline—a profusion of cellular, physiological and pharmacological effects, seemingly unrelated through any central hormonal function. A current list of glucocorticoid effects might include such disparate items as stimulation of hepatic gluconeogenesis, inhibition of glucose uptake by peripheral tissues, suppression of inflammation, enhanced excretion of a water load, induction in various cells of tryptophan oxygenase and glutamine synthetase, suppression of numerous immune reactions, inhibition of secretion of several hormones and neuropeptides, and inhibition of activity of plasminogen activator and other neutral proteinases. Judging from recent writings on glucocorticoid physiology, an item that might be low on the list or missing altogether is “increased resistance to stress”.

Physiological Functions of Glucocorticoids in Stress and Their Relation to Pharmacological Actions

Stimulation at several mesencephalic and diencephalic sites abolished responsiveness to intense pain in rats while leaving responsiveness to other sensory modes relatively unaffected. The peripheral field of analgesia was usually restricted to one-half or to one quadrant of the body, and painful stimuli applied outside this field elicited a normal reaction. Analgesia outlasted stimulation by up to 5 minutes. Most electrode placements that produced analgesia also supported self-stimulation. One placement supported self-stimulation only in the presence of pain.

https://science.sciencemag.org/content/sci/174/4016/1351.full.pdf

Analgesia from Electrical Stimulation in the Brainstem of the Rat

Inescapable foot shock in rats caused profound analgesia that was antagonized by naloxone or dexamethasone when shock was delivered intermittently for 30 minutes, but not when it was delivered continuously for 3 minutes. Thus, depending only on its temporal characteristics, foot-shock stress appears to activate opioid or nonopioid analgesia mechanisms. Certain forms of stress may act as natural inputs to an endogenous opiate analgesia system.

https://science.sciencemag.org/content/sci/208/4444/623.full.pdf

Opioid and nonopioid mechanisms of stress analgesia

Analgesia produced by focal electrical stimulation of the brain is partially reversed by the narcotic antagonist naloxone. The absence of complete reversal does not appear to be caused by inadequate doses of naloxone since doses higher than 1 milligram per kilogram of body weight did not increase the antagonism. It is suggested that stimulation-produced analgesia may result, at least in part, from release of an endogenous, narcotic-like substance, such as that recently reported by other investigators.

https://science.sciencemag.org/content/sci/191/4230/961.full.pdf

Antagonism of stimulation-produced analgesia by naloxone, a narcotic antagonist

The cytotoxic activity of natural killer cells was investigated in rats subjected to one of two inescapable footshock stress paradigms, both of which induce analgesia, but only one via activation of opioid mechanisms. Splenic natural killer cell activity was suppressed by the opioid, but not the nonopioid, form of stress. This suppression was blocked by the opioid antagonist naltrexone. Similar suppression of natural killer activity was induced by high doses of morphine. These results suggest that endogenous opioid peptides mediate the suppressive effect of certain forms of stress on natural killer cell cytotoxicity.

https://science.sciencemag.org/content/sci/223/4632/188.full.pdf

Opioid peptides mediate the suppressive effect of stress on natural killer cell cytotoxicity

Portions of the brain stem seem normally to inhibit pain. In man and laboratory animals these brain areas and pathways from them to spinal sensory circuits can be activated by focal stimulation. Endogenous opioids appear to be implicated although separate nonopioid mechanisms are also evident. Stress seems to be a natural stimulus triggering pain suppression. Properties of electric footshock have been shown to determine the opioid or nonopioid basis of stress-induced analgesia. Two different opioid systems can be activated by different footshock paradigms. This dissection of stress analgesia has begun to integrate divergent findings concerning pain inhibition and also to account for some of the variance that has obscured the reliable measurement of the effects of stress on tumor growth and immune function.

https://science.sciencemag.org/content/sci/226/4680/1270.full.pdf

John C. Liebeskind

Papers

Analgesia from Electrical Stimulation in the Brainstem of the Rat

Opioid and nonopioid mechanisms of stress analgesia

Antagonism of stimulation-produced analgesia by naloxone, a narcotic antagonist

Opioid peptides mediate the suppressive effect of stress on natural killer cell cytotoxicity

Intrinsic Mechanisms of Pain Inhibition: Activation by Stress