Abstract: The study of diverse animal groups allows us to discern the evolution of the neurobiology of nociception. Nociception functions as an important alarm system alerting the individual to potential and actual tissue damage. All animals possess nociceptors, and, in some animal groups, it has been demonstrated that there are consistent physiological mechanisms underpinning the nociceptive system. This review considers the comparative biology of nociception and pain from an evolutionary perspective.

Abstract: In addition to regulating the ingestion and digestion of food, sensory feedback from gut to brain modifies emotional state and motivated behavior by subconsciously shaping cognitive and affective responses to events that bias behavioral choice This focused review highlights evidence that gut-derived signals impact motivated behavior by engaging vagal afferents and central neural circuits that generally serve to limit or terminate goal-directed approach behaviors, and to initiate or maintain behavioral avoidance

Abstract: Mammals are characterized by a stable core body temperature. When maintenance of core temperature is challenged by ambient or internal heat loads, mammals increase blood flow to the skin, sweat and/or pant, or salivate. These thermoregulatory responses enable evaporative cooling at moist surfaces to dissipate body heat. If water losses incurred during evaporative cooling are not replaced, body fluid homeostasis is challenged. This article reviews the way mammals balance thermoregulation and osmoregulation.

Abstract: Mitophagy, a process that selectively removes damaged organelles by autolysosomal degradation, is an early cellular response to ischemia. Mitophagy is activated in both cardiomyocytes and platelets during ischemia/reperfusion (I/R) and heart disease conditions. We focus on the molecular regulation of mitophagy and highlight the role of mitophagy in cardioprotection.

Abstract: The functions of sleep remain a mystery. Yet they must be important since sleep is highly conserved, and its chronic disruption is associated with various metabolic, psychiatric, and neurodegenerat...

Abstract: This review compares two states that lower energy expenditure: non-rapid eye movement (NREM) sleep and torpor. Knowledge on mechanisms common to these states, and particularly on the role of adenosine in NREM sleep, may ultimately open the possibility of inducing a synthetic torpor-like state in humans for medical applications and long-term space travel. To achieve this goal, it will be important, in perspective, to extend the study to other hypometabolic states, which, unlike torpor, can also be experienced by humans.

Abstract: Life is shaped by circadian clocks. This review focuses on how behavioral genetics in the fruit fly unveiled what is known today about circadian physiology. We will briefly summarize basic properties of the clock and focus on some clock-controlled behaviors to highlight how communication between central and peripheral oscillators defines their properties.

Abstract: In this review, we focus on the processes guiding human pancreas development and provide an update on methods to efficiently generate pancreatic progenitors (PPs) and β-like cells in vitro from hum...

Abstract: Until recently, astrocyte processes were thought to be too small to contain mitochondria However, it is now clear that mitochondria are found throughout fine astrocyte processes and are mobile with neuronal activity resulting in positioning near synapses In this review, we discuss evidence that astrocytic mitochondria confer selective resiliency to astrocytes during ischemic insults and the functional significance of these mitochondria for normal brain function

Abstract: Autophagy is a cellular digestion process that contributes to cellular homeostasis and adaptation by the elimination of proteins and damaged organelles. Evidence suggests that dysregulation of autophagy plays a role in neurodegenerative diseases, including motor neuron disorders. Herein, we review emerging evidence indicating the roles of autophagy in physiological motor neuron processes and its function in specific compartments. Moreover, we discuss the involvement of autophagy in the pathogenesis of motor neuron diseases, including spinal cord injury and aging, and recent developments that offer promising therapeutic approaches to mitigate effects of dysregulated autophagy in health and disease.

Abstract: Blood platelets are involved in a wide range of physiological responses and pathological processes. Recent studies have considerably advanced our understanding of the mechanisms of platelet production and clearance, revealing new connections between the birth and death of these tiny, abundant cells. Key insights have also been gained into how physiological challenges such as inflammation, infection, and chemotherapy can affect megakaryocytes, the cells that produce platelets.

Abstract: Pulmonary hypertension is a complex and fatal disease that lacks treatments. Its pathophysiology involves pulmonary artery hyperreactivity, endothelial dysfunction, wall remodelling, inflammation, and thrombosis, which could all depend on ORAI Ca2+ channels. We review the knowledge about ORAI channels in pulmonary artery and discuss the interest to target them in the treatment of pulmonary hypertension.

Abstract: Foraging hummingbirds and nectar bats oxidize both glucose and fructose from nectar at exceptionally high rates. Rapid sugar flux is made possible by adaptations to digestive, cardiovascular, and metabolic physiology affecting shared and distinct pathways for the processing of each sugar. Still, how these animals partition and regulate the metabolism of each sugar and whether this occurs differently between hummingbirds and bats remain unclear.

Abstract: T-cell function in female animal models of hypertension is poorly understood since most research is conducted in males. Our findings in Dahl-salt-sensitive and Dahl salt-resistant rats support prio...

Abstract: I am becoming keenly aware that aging is a process of life: it is part of our own personal physiology. As with Benjamin Button, it may have been better to start the aging process with old age and accumulated wisdom to help guide our path as we become younger. But we are stuck with the aging process as it exists, and as we encounter it with time. Betty Friedan wisely advised that we should think that “aging is not lost youth but a new stage of opportunity and strength.” As he became older, Mark Twain noted “wrinkles should merely indicate where the smiles have been.” For me, these quotes are uplifting, especially during the past week, as I spent quality time with my 96-yr-old mother who has many wrinkles but continues to smile and make others smile. Looking into the mirror, there is no doubt that I am aging myself, and I ask myself, “What did my mother do to age so well?” Am I so lucky to have inherited her genes? Am I eating right? Do I exercise enough? Aging research is helping to unravel this very complex physiological process. Perhaps by identifying common features of successful aging, we can further extend life expectancy or at the very least help improve the quality of life as we age. The first article in this issue of Physiology explores the aging process in women and how sex hormones impact aging. Cessation or diminution of reproductive capacity is a key manifestation of aging. Sex hormones are potent mediators of homeostasis in our bodies throughout life, but their impact is particularly evident in women after menopause. This perturbation of naturally occurring sex hormones may accelerate age-related processes and may cause subsequent decline in physical and cognitive health. Yet, we know very little about the effects of menopause. For decades, basic scientists have used ovariectomized animals to study the effects of ovarian hormones across the entire body. Women who undergo bilateral oophorectomy, which causes premature natural menopause, provide a unique opportunity to study the effects of ovarian hormones, primarily estrogen, on the pace of aging in humans. In their review (4), Rocca et al. discuss animal and clinical studies that examine the effect of premature and abrupt disruption of ovarian function. These results help inform the decision to remove the ovaries for prophylaxis of ovarian and breast cancer. In addition, the biological mechanisms elucidated in women who have undergone bilateral oophorectomy may inform the development of interventions that also apply to the aging processes also in men. Understanding the aging process at the cellular, tissue, organ, and system levels is crucial to develop novel and effective interventions to stem the negative effects of aging. We have known for decades (if not longer) that exercise is essential for our health, but the mechanisms by which regular exercise keeps us healthy are not entirely known. It has long been thought that regular exercise increases the number of calories we burn each day and that this is one of the major ways that exercise improves our health. But, surprisingly, recent work in this area indicates this isn’t the case. Instead, the body adjusts dynamically to changes in daily physical activity to keep the number of calories burned per day within a narrow window— being more active does not result in burning more calories per day. This constraint in our daily energy expenditure suggests a previously unrecognized mechanism by which regular exercise improves health: if daily energy expenditure is capped, then increasing the energy spent on exercise must reduce energy expenditure in other physiological activities. These reductions could be the key to improved health. In his review (3), Pontzer suggests that regular exercise has suppressive effects throughout the body, reducing immune system activity (namely inflammation), reactivity of the stress response (cortisol and norepinephrine release), and reproductive hormone production—all of which have beneficial effects on our health. The “constrained” view of energy expenditure also predicts that extreme levels of physical activity will have negative effects on health, since energy needed for essential functions is reduced due to large exercise expenditures. Again, the published data support this view, with a range of negative health outcomes, including the female athlete triad, which involves low energy availability (due to eating disorders), amenorrhea/oligomenorrhoea, and decreased bone mineral density (osteoporosis and osteopenia), and overtraining syndrome associated with extreme exercise workloads. Constrained energy expenditure is thus a promising and powerful novel framework for understanding the health effects of exercise. A thorough understanding of pathways governing the development of the human pancreas and -cells will facilitate the optimization of methods to generate pancreatic cells from pluripotent stem cells (PSC). Strengths and weaknesses of cell manufacturing, engrafting, functionality, and safety must be assessed when using pancreatic progenitors and -like cells for cell replacement therapy in Type 1 diabetes. In their review (5), Sambathkumar et al. discuss the processes guiding human pancreas development and review methods to efficiently generate pancreatic progenitors and -like cells from PSCs. It is important to be able to identify and use specific cell surface markers to generate safer populations of pancreatic progenitors for clinical translation and to study the development of pancreatic progenitors in vivo and in vitro. Understanding and evaluating the strengths and weaknesses of using these two different cell types for clinical translation is critical as is evaluating the physiological properties of stem cell-derived -like cells generated in vivo using various transplantation approaches. Advances in stem cell and developmental biology are leading to cell products that are being considered for clinical application. Delta cells ( -cells), located in the stomach, intestine, and pancreatic islets release somatostatin, which inhibits insulin secretion. An important input to -cells is Urocortin3, a peptide hormone secreted by pancreatic -cells, which is EDITORIAL Gary C. Sieck, Editor-in-Chief Mayo Clinic, Rochester, Minnesota PHYSIOLOGY 33: 372–373, 2018.

Abstract: Recent trials in Type 2 diabetes (T2D) have shown cardiovascular benefits with specific GLP-1 receptor agonists and SGLT2 inhibitors. We discuss the landscape of outcome trials in T2D from a pathophysiology viewpoint, review current knowledge gaps in underlying mechanisms, propose a caloric fuel routing hypothesis, and highlight areas of future research.

Abstract: The award of the Nobel Prize in Physiology 2017 to Hall, Rosbash, and Young for their groundbreaking discoveries into mechanisms regulating circadian rhythms has contributed to greater scientific appreciation and recognition for the field of circadian physiology. The origins of circadian physiology certainly date back multiple decades and even centuries. First demonstrations of controlled endogenous circadian rhythms in plants by Mairan and Candolle in the 18th century paved the way for more recent groundbreaking discoveries into regulation of mammalian circadian function made by pioneering 20th-century physiologists Pittendrigh and Aschoff (10). In the 21st century, research into circadain physiology has been fueled by discoveries into the genetic mechanisms of the circadian rhythm generation deemed essential for organismal adaption to the 24-h environmental cycles in nearly all living organisms (14). More recently, circadian research has been further fueled by circadian etiology of common chronic diseases such as diabetes, cancer, heart disease, and neurodegeneration. In mammals, the circadian system is organized as a multi-level hierarchical oscillator network. The “central clock” of the circadian system in mammals is localized in the suprachiasmatic nucleus (SCN) of the hypothalamus, where it functions to synchronize cell-autonomous circadian oscillators present in a wide array of peripheral tissues via a combination of neuronal, humoral, and behavioral cues. The composition of the molecular clock in the SCN and peripheral tissues consists of transcriptional activators CLOCK and its heterodimer BMAL1, and repressor genes that encode period (PER1,2) and cryptochrome (CRY1,2) proteins, in addition to secondary regulatory loops that provide molecular stabilization by acting as respective repressors and activators of Bmal1 (14). The CLOCK:BMAL1 heterodimer is essential for the generation of circadian rhythms of transcription through DNA binding to conserved promoter regions along with concurrent recruitment of cell-specific enhancers and repressors for regulation of cell-specific target genes (14). Importantly, this complex regulatory mechanism ensures the generation of robust 24-h cycles of transcription and translation with varying phases of expression, which are optimal for cell-specific functionality, proliferation, and survival. Thus numerous essential cellular physiological functions (e.g., mitochondrial function, ion channel activation, inflammatory responses, substrate metabolism, and many more) display robust circadian rhythmicity due to transcriptional control by the circadian clock. In recent years, biomedical research reproducibility has been one of the most discussed topics in the scientific community. In 2014, Director of the National Institutes of Health (NIH) Francis Collins issued a set of initiatives designed to address specific factors contributing to lack of reproducibility in biomedical research (2). Importantly, preclinical animal research has been specifically singled out as an area most susceptible to concerns related to scientific reproducibility and rigor (2). Since then, numerous corrective actions have been put forward to improve reproducibility of animal-based experimentation, which include (but are not limited to) enhanced transparency and consideration of the experimental design, statistical methodologies and randomization, sex and strain characterizations, and many others. Despite these efforts, consideration for the role of circadian rhythms and circadian timing as an important factor in preclinical research reproducibility has received limited attention. This is particularly troublesome given widespread use in preclinical research of nocturnal rodents, which characteristically display circadian rhythms that are out-of-phase from typical work schedules of researchers. Indeed, classic studies performed more than four decades ago by Hallberg and colleagues demonstrated that the timing of nearly 50 key physiological parameters in the laboratory mouse exhibits distinct circadian periodicity (12). So what are some potential solutions for improved consideration for circadian physiology in preclinical animal research? Objective quantification of circadian periodicity in a given physiological parameter requires collection of data spanning at least two circadian cycles (i.e., at least 48 h). This degree of biological sampling is obviously prohibitive for the majority of researchers; however, timing of physiological sampling should be consistent and clearly defined in the experimental design. Furthermore, investigators should consider an optimal time window to detect maximal physiological response in a tested biological parameter. For example, in metabolic research, it is now well documented that rodents exhibit optimal glucose tolerance at the onset of the “dark” or “active” circadian cycle, which is associated with maximal stimulation of the insulin secretory response from the pancreas and the peak in the activation of insulin-stimulated glucose disposal in skeletal muscle (7). Similarly, mouse tolerance to lipopolysaccharide (LPS) (common way to induce global inflammatory response) is significantly greater during the active (nocturnal) phase of the circadian cycle compared with the inactive (light) period (11). Consistent with these observations, Zhang and colleagues recently developed a comprehensive circadian gene expression atlas of 12 different mouse organs (15). Investigators reported that nearly half of all protein coding genes exhibited distinct circadian rhythmicity in one of the main organs. Most notably, the majority of circadian genes were organspecific, with only 10 commonly oscillating transcripts observed in all 12 studied organs (15). Taken together, these studies highlight the importance for consideration of circadian timing in measuring molecular and physiological parameters in animal experimentation to optimize data reproducibility and rigor. Consideration for the duration, intensity, and timing of circadian light exposure is another critical factor essential for optimal experimental design in animal research. Light is the most salient stimulus responsible for the entrainment of the SCN PHYSIOLOGY’S IMPACT Aleksey V. Matveyenko Mayo Clinic, Rochester, Minnesota PHYSIOLOGY 33: 250–251, 2018.

Abstract: In the November issue of Physiology, Sun et al (12) published a review describing the role of lactate as a multi-tissue autocrine regulatory molecule influencing multiple cellular and systemic physiological functions Such functions included transmembrane H+ transport, enzyme regulation, downregulation of multi-tissue lipolysis, anti-inflammation, improved immune tolerance, stimulation of long-term memory, and improved wound healing including ischemic tissue injury, while deleteriously supporting cancer growth and metastasis We acknowledge the detail and quality of the presentation of the contemporary evidence for the involvement of lactate in the regulation of these processes Nevertheless, it is unfortunate that the authors referred to cellular lactate production as lactic acid, repeatedly associated cellular lactic acid production as a cause of acidosis, and used the term lactic acid within their title Such repeated use, totaling 50 occurrences of “lactic acid” throughout the entirety of the manuscript, severely detracts from the scientitic quality of their work

Abstract: In their editorial on the lactic acid paper ([10][1]), Robergs et al. claim the non-existence of lactic acid in the body and that lactate is not an acid-related anion but rather a buffer that minimizes acidosis. They also assert that, in traditionally viewed lactic acidosis, protons (H+) are

Abstract: The 38th World Congress of IUPS in Rio de Janeiro marks the beginning of my tenure as the President of IUPS for 2017–2021. It is indeed an honor that, together with the stellar group of physiologists on the Executive Committee and Council, I am bestowed with the privilege to provide service to the

Abstract: In 1859, Charles Darwin expressed his concept of evolution: “It’s not the strongest of the species that survive, nor the most intelligent, but the one most responsive to change.” Later, in 1865, the French physiologist, Claude Bernard extended this concept to physiology, proposing that our internal environment is tightly regulated in response to change or perturbations. Bernard’s concept was further refined by the American physiologist Walter Cannon, who coined the term homeostasis to describe the dynamic equilibrium that the body (or cell) attempts to achieve when perturbed to survive. Much of what we study in physiology today fits within the rubric of homeostasis as we unravel its complex biological manifestations. In this issue of Physiology, the six review articles explore variations of homeostasis at different levels, from processes mediating organelle repair (e.g., mitophagy), to cell-cell interactions (astrocytes and neurons) in response to ischemia. We examine the neurophysiology of breathing as we control the levels of O2 and CO2 in our blood and tissues. We examine the challenges of a sugar-rich diet in vertebrate nectarivores, in the context of high energy demand and the need to control blood glucose levels, and the influence of disrupting the circadian system in Type 2 diabetes. Finally, we explore the role of gut-brain interactions in mediating motivated approach and avoidance behaviors critical for survival. Life and survival depend on energy, and mitochondria are the cellular powerhouses that produce ATP at the expense of oxygen. In this process, mitochondria are also major sources and targets of reactive oxygen species, thus highly sensitive to changes in oxygen tension in conditions such as hypoxia and ischemia followed by reperfusion. Mitochondrial dysfunction underlies heart diseases arising from ischemia/reperfusion injury and other heart disease conditions. Mitochondrial autophagy (mitophagy) is a cellular process that selectively removes the damaged or superfluous mitochondria by autolysosomal degradation under (patho-)physiological conditions. Mitophagy has been described in both cardiomyocytes and platelets during conditions of hypoxia and prolonged ischemia/ reperfusion. In their review, Zhang et al. (6) focus on recent progress in our understanding of the molecular regulation of mitophagy in response to hypoxia and ischemia/reperfusion injury. Furthermore, they highlight the role of mitophagy in both platelets and cardiomyocytes as a major mechanism for cardioprotection against ischemia/reperfusion injury. Indeed, hypoxic activation of mitophagy may explain the beneficial effect of ischemic preconditioning, and it may also provide a new strategy to protect cardiac function and fight cardiovascular diseases. Monitoring mitochondrial quality and mitochondrial functional status may serve as a useful and convenient approach before the application of ischemic and pharmacological preconditioning. Astrocytes were once believed to be only passive-supportive glue for neural networks but are now known to be essential for all aspects of brain homeostasis and normal functioning. Within astrocytes, mitochondria were thought to be spatially restricted to the cell bodies due to the small size of distal processes. However, recent work from multiple laboratories has shown that mitochondria are present throughout fine astrocytic processes as well as enriched in vascular endfeet, the structures that physically connect astrocytes to capillary walls. Their very presence at these highly dynamic sites of interface with neuronal synapses and blood vessels has opened up an entire realm of possibilities for heretofore unknown functions of astrocytic mitochondria in the modulation of synaptic activity and vascular response. In their review, Shih and Robinson (4) discuss the idea that astrocytic mitochondria may be central to how specific astrocytes respond to and withstand ischemia. In fact, astrocytic mitochondria may confer the potential to rescue neighboring neurons during ischemia. Such a new and exciting role for astrocytic mitochondria opens up novel approaches to stroke therapeutics, which to date have largely been neuron-centric. Since stroke is one of the leading causes of human morbidity and mortality, research in this area has high potential for impacting the nearly 1 million patients who suffer strokes annually in the U.S. Several times during every minute of every day of our lives we take a breath, typically without conscious effort, unfailingly whether awake or asleep. Breathing is essential for life, and in mammals it is achieved by activating the diaphragm muscle—the major inspiratory pump muscle. Breathing is controlled by a complex neural network, with phrenic motor neurons, located in the cervical spinal cord, as the final common output of neural control. Each phrenic motor neuron innervates a group of diaphragm muscle fibers, which is collectively called a motor unit, which vary in their mechanical and fatigue properties. In their review, Fogarty and colleagues (1) explore how different diaphragm motor unit types are recruited to generate the forces required for breathing as well as the forces necessary to achieve higher force, non-respiratory expulsive maneuvers of the diaphragm. Different motor behaviors of the diaphragm muscle may have unique pattern generators and neural circuits, but motor unit recruitment is always the final common output of neural control. The mechanical properties of diaphragm muscle fibers change during our lifespan from birth to old age as well as under disease conditions. With these changes in muscle fiber properties, neural control of the diaphragm though motor unit recruitment is affected, and the repertoire of motor behaviors is limited. Importantly, despite marked age-related and diseaserelated changes in diaphragm muscle strength, the ability to breathe and its neural control is remarkably resilient. In contrast, the ability to generate forces required for expulsive behaviors of the PHYSIOLOGY IN PERSPECTIVE Gary C. Sieck, Editor-in-Chief Mayo Clinic, Rochester, Minnesota PHYSIOLOGY 33: 84–85, 2018.

Abstract: such as neural networks, cell signaling pathways, critical periods during development, and gender differences of hypoxia on blood pressure. On-going

Abstract: I was catapulted into my first International Union of Physiological Sciences (IUPS) Congress held in Leiden, Holland, in 1962. The metaphorical catapult arose from the fact that my PhD thesis under Otto Hutter at University College London had produced two letters to Nature and a few articles in the

Abstract: Stem cells are the basic building blocks of life and determine differentiation into all cell types within the body. Our first attempts to harness the potential of stem cells occurred in the late 1960s with the introduction of bone marrow transplantation. Excitement, debate, and controversy then

Abstract: The role of beta and α-cells to glucose control are established, but the physiological role of δ-cells is poorly understood. Delta-cells are ideally positioned within pancreatic islets to modulate insulin and glucagon secretion at their source. We review the evidence for a negative feedback loop between delta and β-cells that determines the blood glucose set point and suggest that local δ-cell-mediated feedback stabilizes glycemic control.

Abstract: The successful rollout of anti-retroviral therapy ensured that HIV is increasingly managed as a chronic condition. HIV-positive persons are therefore exhibiting increased cardiovascular complicatio...

Abstract: Recent observations in laminopathy patient cells and cancer cells have revealed that the nuclear envelope (NE) can transiently rupture during interphase. NE rupture leads to an uncoordinated exchange of nuclear and cytoplasmic material, thereby deregulating cellular homeostasis. Moreover, concurrently inflicted DNA damage could prime rupture-prone cells for genome instability. Thus, NE rupture may represent a novel pathogenic mechanism that has far-reaching consequences for cell and organism physiology.

Abstract: Humans and other species adapt dynamically to changes in daily physical activity, maintaining total energy expenditure within a narrow range. Chronic exercise thus suppresses other physiological ac...