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Tyrosine phosphorylation of K(ir)3.1 in spinal cord is induced by acute inflammation, chronic neuropathic pain, and behavioral stress.

Tyrosine phosphorylation is an important means of regulating ion channel function. Our previous gene expression studies using the Xenopus laevis oocyte system suggested that tyrosine phosphorylation of G-protein-gated inwardly rectifying potassium channels (K(ir)3 or GIRK) suppressed basal channel conductance and accelerated channel deactivation. To assess whether similar mechanisms regulate K(ir)3 function in mammalian cells, we developed and characterized a phosphoselective antibody recognizing K(ir)3.1 phosphorylated at tyrosine 12 in the N-terminal domain and then probed for evidence of K(ir)3.1 phosphorylation in cultured mammalian cells and spinal cord. The antibody was found to discriminate between the phospho-Tyr(12) of K(ir)3.1 and the native state in transfected cell lines and in primary cultures of mouse atria. Following either mouse hindpaw formalin injection or sciatic nerve ligation, pY12-K(ir)3.1 immunoreactivity was enhanced unilaterally in the superficial layers of the spinal cord dorsal horn, regions previously described as expressing K(ir)3.1 channels. Mice lacking K 3.1 following targeted gene disruption did not show specific pY12-K(ir)3.1 immunoreactivity after sciatic nerve ligation. Further, mice exposed to repeatedly forced swim stress showed bilateral enhancement in pY12-K(ir)3.1 in the dorsal horn. This study provides evidence that K(ir)3 tyrosine phosphorylation occurred during acute and chronic inflammatory pain and under behavioral stress. The reduction in K(ir)3 channel activity is predicted to enhance neuronal excitability under physiologically relevant conditions and may mediate a component of the adaptive physiological response.

Animals↗

Digestion and absorption of food: usefulness and limitations of in vitro models.

The digestion and absorption of food is a spatiotemporal and dynamic process involving complex enzymatic and transport reactions, and it is illusive to try to reproduce in a single model all these biochemical and physiological events. A more practical and realistic approach is to separately evaluate the specific contributions of oral and gastric digestion, intestinal digestion by pancreatic enzymes, brush-border hydrolysis, and eventually intestinal absorption and enterocyte metabolism. The models proposed must be versatile enough to be able to modify their conditions of operation according to physiological adaptation to food. Enzymatic preparations must be kept close to physiological conditions in regard to their nature and their mode of operation. A digestion cell and a peptidase bioreactor were developed for this purpose. The challenge is to find a way to integrate all these data. This can be partially achieved by selecting techniques that allow the collection and isolation of reaction products from one step for use as substrates for the next event. Various models are presented to illustrate this concept as applied to food protein.

Animals↗

Physiological variation and adaptability in human populations.

This review traces some of the developments in population physiology based on contributions to the Annals over the last 25 years. Two broad themes are evident, physiological systems variation and adaptation, and by way of introduction an historical perspective of their relationship within human ecology is explored. Studies of physical fitness and work capacity, and the efforts to create standardized field procedures make up a number of the early papers. Longitudinal studies have provided reliable reference standards for Westernized populations, but are virtually non-existent for primitive groups. The relative importance of phenotypic and genotypic variations in working capacity have yet to be clearly defined. The level of habitual activity during childhood contributes to the development of ventilatory capacity though constitutional influences are of major importance. Variability in strength and motor performance of skeletal muscles are shown to have a direct bearing on aspects of growth, development and biological maturation. Physical and psychological stress in communities have been investigated. These and other studies contribute valuable data on the issue of stress, hypertension and cardiovascular morbidity and mortality. On the theme of human adaptability, high altitude populations, variations in thermal tolerance and adaptations in ageing populations have all received recent investigation. Highland people of all ages have considerably larger lung volumes than coastal dwellers. Haematological, biochemical and pulmonary function show adaptive phenomena that vary in different highland groups. In the tropical biome, more recent work includes the functional consequences of malnutrition, ethnic and cultural differences in work capacity, and the effects of endemic disease on physical performance. Annals of Human Biology papers have more recently contributed to investigations on morphological and physiological changes with human ageing. Though there is a decline in the ability to adapt to environmental stresses with age this may be met by changes in adaptational strategy in physiological systems.

Adaptation, Physiological↗

Psycho-physiological mechanisms of adaptation of rotation personnel in Arctic regions.

Transit workers (240 oil industry workers, aged 19-50) living in the European part of Russia and flying to work in the northern regions of West Siberia (Tyumen district) were observed. Psychological status was determined by the method of Taylor. Biological rhythms, chemical control of ventilation, oxygen (O2) and carbon dioxide (CO2) consumption, body temperature, and hormone-metabolic data were assessed. The analysis of illness for the Nadymgazprom Enterprise was carried out in accordance with the medical charts. One may notice a certain cyclic recurrence of the adaptation process. Thus, the first stage of vigorous rearrangement of the psycho-physiological regulation system is followed by a period of relative stability, the result of initiation of compensatory processes. Compensation mechanisms, however, may become disabled, triggering development of a disadaptive state. Results of these scientific investigations were used to introduce new transit work regimens at Nadymgazprom Enterprise.

Adaptation, Physiological↗

On the nature of enduring modifications induced in cells and organisms.

The clarity of Mendelian genetics and the elegance of the molecular mechanisms of replication and readout of DNA have tended to obscure a solid body of evidence demonstrating that nongenetic, enduring modifications can be induced in the behavior of cells, modifications that continue to be expressed for many divisions after withdrawal of the inducing stimulus. The most prosaic case is the differentiated state of metazoan cells, which persists throughout the lifetime of the organism. Much less widely known but well-characterized examples are also cited for bacteria, protozoa, and cultured cells of higher plants and animals. The spontaneous neoplastic transformation of cultured mouse NIH 3T3 cells is introduced as an enduring adaptive response to moderate growth constraints. Evidence in support of the thesis that physiological adaptation is the driving force for chemically induced carcinogenesis in the intact animal is also presented. The cases described here involve integrated responses of many if not all of the regulatory components of the cell, rather than singular molecular mechanisms. The continuous generation of phenotypic heterogeneity, a process observed readily in cell culture, provides the basis for a model that accounts for enduring modifications. This model, designated progressive state selection, makes no attempt at a detailed biochemical explanation of heterogeneity, but uses it as a fundamental postulate to represent the adaptive behavior of the cells.

Animals↗

Physiological characterization of adaptive clones in evolving populations of the yeast, Saccharomyces cerevisiae.

Populations of a diploid strain of S. cerevisiae were grown in glucose-limited continuous culture for more than 260 generations. A series of seven sequential adaptive changes were identified by monitoring the frequency of cycloheximide resistance in these populations. Samples were taken from the continuous cultures following each adaptive shift and characterized physiologically to determine (1) the range of phenotypes that can be selected in a precisely defined constant environment and (2) the order and predictability of the occurrence of the adaptive mutations in evolving populations. The clones were characterized with respect to the growth parameters, maximum growth rate, saturation coefficient and yield, as well as for changes in cell size and geometry and rate of glucose uptake. The maximum growth rates of the seven adaptive clones were very similar, but in contrast the saturation coefficients differed substantially. Surprisingly, not all clones showed reductions in the saturation coefficients, in comparison to the immediately preceding clones, as would be predicted from classical continuous culture kinetics. In addition, yield estimates first increased and then decreased for later isolated adaptive clones. In general, the results suggest epistatic interactions between the adaptive clones, consistent with earlier published results. The rate of glucose uptake, as measured by 14C-xylose uptake, increased dramatically after the selection and fixation of seven adaptive clones. Progressive decreases in cell volume and changes in cell geometry, resulting in increased surface area to volume ratios, were also observed in the adaptive clones, but these changes were not always seen in other haploid and diploid yeast populations evolving under the same conditions. Such changes may be easily explainable in terms of the characteristics of the glucose-limited environment. The significance of the results to the evolution of microorganisms under nutrient-limiting conditions is discussed.

Biological Transport↗

Behavior and body weight changes under intermittent exposure to cold in C57BL/6J mice.

This experiment examined effects of the intermittent exposure to cold. C57BL/6J mice were exposed to cold (4-5 degrees C) for six hours in light (L-cold group) or dark (D-cold group) period and their wheel-running and drinking activities, daily amounts of food and water intake, and body weight were analyzed. Wheel running and drinking decreased during cold exposure, while they increased in postcold period. These behavioral changes were more clearly found in the D-cold group. Body weight of the D-cold group was kept constant for all days of cold exposure, while that of the L-cold group tended to increase. These results are discussed from the view points of adaptive significance of postcold behaviors and the relationship between behavioral and physiological adaptations.

Animals↗

Chronic cold exposure increases skeletal muscle oxidative structure and function in Monodelphis domestica, a marsupial lacking brown adipose tissue.

Monodelphis domestica (Marsupialia: Didelphidae) was used as a model animal to investigate and compare muscle adaptation to exercise training and cold exposure. The experimental treatment consisted of four groups of animals: either warm or cold acclimation temperature and with or without endurance exercise training. Maximal aerobic capacity during a running VO2max test in the warm-exercised or cold-exposed (with or without exercise) groups was about 130 mL O(2)/kg/min, significantly higher than the warm-acclimated controls at 113.5 mL O(2)/kg/min. Similarly, during an acute cold challenge (VO2summit), maximal aerobic capacity was higher in these three experimental groups at approximately 95 mL O(2)/kg/min compared with 80.4 mL O(2)/kg/min in warm-acclimated controls. Respiratory exchange ratio was significantly lower (0.89-0.68), whereas relative heart mass (0.52%-0.73%) and whole-body muscle mitochondrial volume density (2.59 to 3.04 cm(3)) were significantly higher following cold exposure. Chronic cold exposure was a stronger stimulus than endurance exercise training for tissue-specific adaptations. Although chronic cold exposure and endurance exercise are distinct challenges, physiological adaptations to each overlap such that the capacities for aerobic performance in response to both cold exposure and running are increased by either or both treatments.

Acclimatization↗

Preweaning intake and postweaning dietary energy effects on intake and metabolism of calves weaned at 26 days of age.

Holstein calves (n = 48) were used to evaluate whether preweaning feeding management affects postweaning DMI and metabolism after abrupt weaning at 26 d of age. Calves were fed only whole milk until d 19 of age. From d 19 to 26, calves were provided one of three isocaloric and isonitrogenous diets: milk at 15% of d-1 BW, milk at 12% of d-1 BW plus a grain-based supplement added to the pail, or milk at 12% of d-1 BW and drenched (force-fed) with the supplement. After weaning, calves were offered a low or high energy (1.7 or 5.8% ether extract) starter. From d 26 to 36, starter intake was similar between calves fed the supplement in the pail and those fed only milk but lower than for calves drenched with supplement. Plasma NEFA increased threefold from d 26 to 27, and calves fed only milk had higher NEFA than drenched calves. From d 26 to 42, plasma VFA of drenched calves were higher than those fed only milk. Except for an increase in plasma NEFA at d 36 and 42, high energy starter did not affect any variable. Preweaning drenching of calves stimulated postweaning adaptation to dry diets. Intake postweaning appears to depend more on physiological adaptation to dry diets than a preweaning feeding management.

Animal Feed↗

A uterine decidual cell cytokine ensures pregnancy-dependent adaptations to a physiological stressor.

In the mouse, decidual cells differentiate from uterine stromal cells in response to steroid hormones and signals arising from the embryo. Decidual cells are crucially involved in creating the intrauterine environment conducive to embryonic development. Among their many functions is the production of cytokines related to prolactin (PRL), including decidual prolactin-related protein (DPRP). DPRP is a heparin-binding cytokine, which is abundantly expressed in uterine decidua. In this investigation, we have isolated the mouse Dprp gene, characterized its structure and evaluated its biological role. Dprp-null mice were made by replacing exons 2 to 6 of the Dprp gene with an in-frame enhanced green fluorescent protein (EGFP) gene and a neomycin (neo) resistance cassette. Heterozygous intercross breeding of the mutant mice yielded the expected mendelian ratio. Pregnant heterozygote females expressed EGFP within decidual tissue in locations identical to endogenous Dprp mRNA and protein expression. Homozygous Dprp-null mutant male and female mice were viable, exhibited normal postnatal growth rates, were fertile and produced normal litter sizes. A prominent phenotype was observed when pregnant Dprp-null mice were exposed to a physiological stressor. DPRP deficiency interfered with pregnancy-dependent adaptations to hypoxia resulting in pregnancy failure. Termination of pregnancy was associated with aberrations in mesometrial decidual cells, mesometrial vascular integrity, and disruptions in chorioallantoic placenta morphogenesis. The observations suggest that DPRP participates in pregnancy-dependent adaptations to a physiological stressor.

Adaptation, Physiological↗

The biological aspects of physiological anthropology with reference to its five keywords.

The methodology of physiological anthropology has been defined in the capacity of an independent academic field by five keywords: environmental adaptability, technological adaptability, physiological polymorphism, whole-body coordination and functional potentiality, clearly suggesting the direction of approach to human beings in the field of physiological anthropology. Recently, these keywords have attracted a great deal of attention from physiological anthropologists in Japan. Physiological anthropology is based on a biological framework. From the viewpoint of biology, it is essential to discuss the biological function of human behavior. In this brief conceptual manuscript, the biological aspects of physiological anthropology are discussed in relation to the five keywords.

Adaptation, Biological↗

The role of mitochondrial respiration in physiological and evolutionary adaptation.

Aerobic mitochondria serve as the power sources of eukaryotes by producing ATP through oxidative phosphorylation (OXPHOS). The enzymes involved in OXPHOS are multisubunit complexes encoded by both nuclear and mitochondrial DNA. Thus, regulation of respiration is necessarily a highly coordinated process that must organize production, assembly and function of mitochondria to meet an organism's energetic needs. Here I review the role of OXPHOS in metabolic adaptation and diversification of higher animals. On a physiological timescale, endocrine-initiated signaling pathways allow organisms to modulate respiratory enzyme concentration and function under changing environmental conditions. On an evolutionary timescale, mitochondrial enzymes are targets of natural selection, balancing cytonuclear coevolutionary constraints against physiological innovation. By synthesizing our knowledge of biochemistry, physiology and evolution of respiratory regulation, I propose that we can now explore questions at the interface of these fields, from molecular translation of environmental cues to selection on mitochondrial haplotype variation.

Adaptation, Physiological↗

Sudden death in athletes: an update.

The athlete projects the ultimate image of well-being in the health status spectrum. Nevertheless, exercise-related sudden cardiac death (SCD) is an uncommon, yet tragic, occurrence. Exercise-related SCD is defined by symptoms that arise within 1 hour of participation in sport. The major mechanisms involved in exercise-related SCD are related to haemodynamic and electrophysiological changes brought about by exercise in the susceptible individual. Fatal arrhythmia seems to be the most common mechanism of death. Between 1 and 5 cases of SCD per 1 million athletes occur annually. In young athletes (<35 years old), the majority of these cases are caused by defined and hereditary cardiovascular disorders. Among other aetiologies, hypertrophic cardiomyopathy and coronary artery anomalies are most common in this group. In older athletes (>35 years old), sudden death is usually associated with atherosclerotic cardiac disease. A problem for identifying athletes at risk for SCD is that the athlete's heart undergoes adaptive changes in response to regular physical exercise. Alterations in cardiac function influence the physical examination, the electrocardiogram and the echocardiogram. Because of these characteristic 'abnormalities' of the athlete's heart, it is often difficult to distinguish physiological adaptations from pathophysiological processes. Although studies and observations have helped to clarify the cardiovascular pathology responsible for SCD in young, apparently healthy individuals, effective methods for preventing SCD and identifying and screening athletes at risk remain elusive. Problems with routine comprehensive screening of athletes include the limitations inherent in the predictive value of available diagnostic procedures and the cost of testing large populations. The variation from normal cardiac physiology found within the athletic population and the rarity of SCD in athletes means that elaborate screening to determine individuals at risk is neither practical nor cost effective. A thorough assessment of pertinent family and medical histories, cardiac auscultation of young athletes, evaluation of exercise-induced symptoms and education of older athletes to the symptoms of cardiac ischaemia are all essential to primary prevention of SCD in the athletic population. Until reliable methods can accurately identify those athletes at risk for SCD, broad recommendations are available to help guide the management and participation in sports of athletes with cardiovascular disease.

Adaptation, Physiological↗

Adaptation of bone to physiological stimuli.

The ability of bone to alter its morphology in response to local physical stimuli is predicated upon the appropriate recruitment of bone cell populations. In turn, the ability to initiate cellular recruitment is influenced by numerous local and systemic factors. In this paper, we discuss data from three ongoing projects from our laboratory that examine how physiological processes influence adaptation and growth in the skeleton. In the first study, we recorded in vivo strains to quantify the locomotion-induced distribution of two parameters closely related to bone fluid flow strain rate and strain gradients. We found that the magnitude of these parameters (and thus the implied fluid flow) varies substantially within a given cross-section, and that while strain rate magnitude increases uniformly with elevated speed, strain gradients increase focally as gait speed is increased. Secondly, we examined the influence of vascular alterations on bone adaptation by assessing bone blood flow and bone mechanical properties in an in vivo model of trauma-induced joint laxity. A strong negative correlation (r2 = 0.8) was found between increased blood flow (76%) in the primary and secondary spongiosa and decreased stiffness (-34%) following 14 weeks of joint laxity. These data suggest that blood flow and/or vascular adaptation may interact closely with bone adaptation initiated by trauma. Thirdly, we examined the effect of a systemic influence upon skeletal health. After 4 weeks old rats were fed high fat-sucrose diets for 2 yr, their bone mechanical properties were significantly reduced. These changes were primarily due to interference with normal calcium absorption. In the aggregate, these studies emphasize the complexity of bone's normal physical environment, and also illustrate the potential interactions of local and systemic factors upon the process by which bone adapts to physical stimuli.

Adaptation, Physiological↗

Tyrosine hydroxylase protein content in the medulla oblongata of the foetal sheep brain increases in response to acute but not chronic hypoxia.

We have investigated the effect of lowering foetal arterial PO(2) either acutely or chronically on tyrosine hydroxylase (TH) protein content in the dorsal and ventral medullary regions of the brainstem of the sheep foetus during late gestation. TH protein content increased in both the dorsal and ventral medullary regions of the foetal brainstem after exposure to acute hypoxia when compared to normoxia. In contrast there was no increase in the TH protein content of either the dorsal or ventral medullary regions in the brainstem of foetal sheep which were chronically hypoxaemic throughout late gestation as a consequence of experimental restriction of placental growth. The differences between the TH responses to acute and chronic hypoxaemia in the foetal sheep brainstem may be important in the mediation of physiological adaptations to these intrauterine stimuli and for the generation of an appropriate physiological response to hypoxia in the newborn period.

Acute Disease↗

WORK PHYSIOLOGY.

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Adaptation, Physiological↗

Promoting fetal stabilization during maternal hemodynamic instability or respiratory insufficiency.

Fetal oxygenation is primarily determined by maternal oxygenation and uterine blood flow. Several physiologic adaptations during pregnancy support uteroplacental perfusion and, thus, fetal oxygenation. However, the physiologic changes required to sustain the metabolic demands of pregnancy may also predispose the parturient to decompensation when critical illness is superimposed upon pregnancy. In general, the critically ill gravid woman is treated similarly to the nonpregnant adult, with the exception of accomodating the physiologic changes of pregnancy and evaluating fetal well-being. An overview of the physiology of fetal oxygenation, impact of critical care interventions upon the fetus, and evaluation of the fetus is provided.

Blood Flow Velocity↗

Temperature sensitivities of cytosolic malate dehydrogenases from native and invasive species of marine mussels (genus Mytilus): sequence-function linkages and correlations with biogeographic distribution.

The blue mussel Mytilus galloprovincialis, a native of the Mediterranean Sea, has invaded the west coast of North America in the past century, displacing the native blue mussel, Mytilus trossulus, from most of its former habitats in central and southern California. The invasive success of M. galloprovincialis is conjectured to be due, in part, to physiological adaptations that enable it to outperform M. trossulus at high temperatures. We have examined the structure and function of the enzyme cytosolic malate dehydrogenase (cMDH) from these species, as well as from the more distantly related ribbed mussel, Mytilus californianus, to characterize the effects of temperature on kinetic properties thought to exhibit thermal adaptation. The M. trossulus cMDH ortholog differs from the other cMDHs in a direction consistent with cold adaptation, as evidenced by a higher and more temperature-sensitive Michaelis-Menten constant for the cofactor NADH (Km(NADH)). This difference results from minor changes in sequence: the M. trossulus ortholog differs from the M. galloprovincialis ortholog by only two substitutions in the 334 amino acid monomer, and the M. californianus and M. trossulus orthologs differ by five substitutions. In each case, only one of these substitutions is non-conservative. To test the effects of individual substitutions on kinetic properties, we used site-directed mutagenesis to create recombinant cMDHs. Recombinant wild-type M. trossulus cMDH (rWT) has high Km(NADH) compared with mutants incorporating the non-conservative substitutions found in M. californianus and M. galloprovincialis - V114H and V114N, respectively - demonstrating that these mutations are responsible for the differences found in substrate affinity. Turnover number (kcat) is also higher in rWT compared with the two mutants, consistent with cold adaptation in the M. trossulus ortholog. Conversely, rWT and V114H appear more thermostable than V114N. Based on a comparison of Km(NADH) and kcat values among the orthologs, we propose that immersion temperatures are of greater selective importance in adapting kinetic properties than the more extreme temperatures that occur during emersion. The relative warm adaptation of M. galloprovincialis cMDH may be one of a suite of physiological characters that enhance the competitive ability of this invasive species in warm habitats.

Amino Acid Sequence↗