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Sample records for endocannabinoid-dependent homeostatic regulation

  1. Calcineurin mediates homeostatic synaptic plasticity by regulating retinoic acid synthesis.

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    Arendt, Kristin L; Zhang, Zhenjie; Ganesan, Subhashree; Hintze, Maik; Shin, Maggie M; Tang, Yitai; Cho, Ahryon; Graef, Isabella A; Chen, Lu

    2015-10-20

    Homeostatic synaptic plasticity is a form of non-Hebbian plasticity that maintains stability of the network and fidelity for information processing in response to prolonged perturbation of network and synaptic activity. Prolonged blockade of synaptic activity decreases resting Ca(2+) levels in neurons, thereby inducing retinoic acid (RA) synthesis and RA-dependent homeostatic synaptic plasticity; however, the signal transduction pathway that links reduced Ca(2+)-levels to RA synthesis remains unknown. Here we identify the Ca(2+)-dependent protein phosphatase calcineurin (CaN) as a key regulator for RA synthesis and homeostatic synaptic plasticity. Prolonged inhibition of CaN activity promotes RA synthesis in neurons, and leads to increased excitatory and decreased inhibitory synaptic transmission. These effects of CaN inhibitors on synaptic transmission are blocked by pharmacological inhibitors of RA synthesis or acute genetic deletion of the RA receptor RARα. Thus, CaN, acting upstream of RA, plays a critical role in gating RA signaling pathway in response to synaptic activity. Moreover, activity blockade-induced homeostatic synaptic plasticity is absent in CaN knockout neurons, demonstrating the essential role of CaN in RA-dependent homeostatic synaptic plasticity. Interestingly, in GluA1 S831A and S845A knockin mice, CaN inhibitor- and RA-induced regulation of synaptic transmission is intact, suggesting that phosphorylation of GluA1 C-terminal serine residues S831 and S845 is not required for CaN inhibitor- or RA-induced homeostatic synaptic plasticity. Thus, our study uncovers an unforeseen role of CaN in postsynaptic signaling, and defines CaN as the Ca(2+)-sensing signaling molecule that mediates RA-dependent homeostatic synaptic plasticity.

  2. Stromal cell regulation of homeostatic and inflammatory lymphoid organogenesis

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    Kain, Matthew J W; Owens, Benjamin M J

    2013-01-01

    Summary Secondary lymphoid organs function to increase the efficiency of interactions between rare, antigen-specific lymphocytes and antigen presenting cells, concentrating antigen and lymphocytes in a supportive environment that facilitates the initiation of an adaptive immune response. Homeostatic lymphoid tissue organogenesis proceeds via exquisitely controlled spatiotemporal interactions between haematopoietic lymphoid tissue inducer populations and multiple subsets of non-haematopoietic stromal cells. However, it is becoming clear that in a range of inflammatory contexts, ectopic or tertiary lymphoid tissues can develop inappropriately under pathological stress. Here we summarize the role of stromal cells in the development of homeostatic lymphoid tissue, and assess emerging evidence that suggests a critical role for stromal involvement in the tertiary lymphoid tissue development associated with chronic infections and inflammation. PMID:23621403

  3. Bio-responsive polymer hydrogels homeostatically regulate blood coagulation.

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    Maitz, Manfred F; Freudenberg, Uwe; Tsurkan, Mikhail V; Fischer, Marion; Beyrich, Theresa; Werner, Carsten

    2013-01-01

    Bio-responsive polymer architectures can empower medical therapies by engaging molecular feedback-response mechanisms resembling the homeostatic adaptation of living tissues to varying environmental constraints. Here we show that a blood coagulation-responsive hydrogel system can deliver heparin in amounts triggered by the environmental levels of thrombin, the key enzyme of the coagulation cascade, which--in turn--becomes inactivated due to released heparin. The bio-responsive hydrogel quantitatively quenches blood coagulation over several hours in the presence of pro-coagulant stimuli and during repeated incubation with fresh, non-anticoagulated blood. These features enable the introduced material to provide sustainable, autoregulated anticoagulation, addressing a key challenge of many medical therapies. Beyond that, the explored concept may facilitate the development of materials that allow the effective and controlled application of drugs and biomolecules.

  4. A cerebellar framework for predictive coding and homeostatic regulation in depressive disorder

    NARCIS (Netherlands)

    Schutter, D.J.L.G.

    2016-01-01

    Depressive disorder is associated with abnormalities in the processing of reward and punishment signals and disturbances in homeostatic regulation. These abnormalities are proposed to impair error minimization routines for reducing uncertainty. Several lines of research point towards a role of the

  5. Glycogen metabolism and the homeostatic regulation of sleep

    KAUST Repository

    Petit, Jean-Marie

    2014-11-16

    In 1995 Benington and Heller formulated an energy hypothesis of sleep centered on a key role of glycogen. It was postulated that a major function of sleep is to replenish glycogen stores in the brain that have been depleted during wakefulness which is associated to an increased energy demand. Astrocytic glycogen depletion participates to an increase of extracellular adenosine release which influences sleep homeostasis. Here, we will review some evidence obtained by studies addressing the question of a key role played by glycogen metabolism in sleep regulation as proposed by this hypothesis or by an alternative hypothesis named “glycogenetic” hypothesis as well as the importance of the confounding effect of glucocorticoïds. Even though actual collected data argue in favor of a role of sleep in brain energy balance-homeostasis, they do not support a critical and direct involvement of glycogen metabolism on sleep regulation. For instance, glycogen levels during the sleep-wake cycle are driven by different physiological signals and therefore appear more as a marker-integrator of brain energy status than a direct regulator of sleep homeostasis. In support of this we provide evidence that blockade of glycogen mobilization does not induce more sleep episodes during the active period while locomotor activity is reduced. These observations do not invalidate the energy hypothesis of sleep but indicate that underlying cellular mechanisms are more complex than postulated by Benington and Heller.

  6. Homeostatic regulation of meiotic DSB formation by ATM/ATR

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    Cooper, Tim J.; Wardell, Kayleigh; Garcia, Valerie; Neale, Matthew J., E-mail: m.neale@sussex.ac.uk

    2014-11-15

    Ataxia–telangiectasia mutated (ATM) and RAD3-related (ATR) are widely known as being central players in the mitotic DNA damage response (DDR), mounting responses to DNA double-strand breaks (DSBs) and single-stranded DNA (ssDNA) respectively. The DDR signalling cascade couples cell cycle control to damage-sensing and repair processes in order to prevent untimely cell cycle progression while damage still persists [1]. Both ATM/ATR are, however, also emerging as essential factors in the process of meiosis; a specialised cell cycle programme responsible for the formation of haploid gametes via two sequential nuclear divisions. Central to achieving accurate meiotic chromosome segregation is the introduction of numerous DSBs spread across the genome by the evolutionarily conserved enzyme, Spo11. This review seeks to explore and address how cells utilise ATM/ATR pathways to regulate Spo11-DSB formation, establish DSB homeostasis and ensure meiosis is completed unperturbed.

  7. Homeostatic and toxic mechanisms regulating manganese uptake, retention, and elimination

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    JEROME A ROTH

    2006-01-01

    Full Text Available This review attempts to summarize and clarify our basic knowledge as to the various factors that potentially influence the risks imposed from chronic exposure to high atmospheric levels of manganese (Mn. The studies describe the interrelationship of the different systems in the body that regulate Mn homeostasis by characterizing specific, biological components involved in its systemic and cellular uptake and its elimination from the body. A syndrome known as manganism occurs when individuals are exposed chronically to high levels of Mn, consisting of reduced response speed, intellectual deficits, mood changes, and compulsive behaviors in the initial stages of the disorder to more prominent and irreversible extrapyramidal dysfunction resembling Parkinson's disease upon protracted exposure. Mn intoxication is most often associated with occupations in which abnormally high atmospheric concentrations prevail, such as in welding and mining. There are three potentially important routes by which Mn in inspired air can gain access the body to: 1 direct uptake into the CNS via uptake into the olfactory or trigeminal presynaptic nerve endings located in the nasal mucosa and the subsequent retrograde axonal transport directly into the CNS; 2 transport across the pulmonary epithelial lining and its subsequent deposition into lymph or blood; and/or 3 mucocilliary elevator clearance from the lung and the subsequent ingestion of the metal in the gastrointestinal tract. Each of these processes and their overall contribution to the uptake of Mn in the body is discussed in this review as well as a description of the various mechanisms that have been proposed for the transport of Mn across the blood-brain barrier which include both a transferrin-dependent and a transferrin-independent process that may involve store-operated Ca channels.

  8. Body weight homeostat that regulates fat mass independently of leptin in rats and mice

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    Jansson, John-Olov; Hägg, Daniel A.; Schéle, Erik; Dickson, Suzanne L.; Anesten, Fredrik; Bake, Tina; Montelius, Mikael; Bellman, Jakob; Johansson, Maria E.; Cone, Roger D.; Drucker, Daniel J.; Wu, Jianyao; Aleksic, Biljana; Törnqvist, Anna E.; Sjögren, Klara; Gustafsson, Jan-Åke; Windahl, Sara H.; Ohlsson, Claes

    2018-01-01

    Subjects spending much time sitting have increased risk of obesity but the mechanism for the antiobesity effect of standing is unknown. We hypothesized that there is a homeostatic regulation of body weight. We demonstrate that increased loading of rodents, achieved using capsules with different weights implanted in the abdomen or s.c. on the back, reversibly decreases the biological body weight via reduced food intake. Importantly, loading relieves diet-induced obesity and improves glucose tolerance. The identified homeostat for body weight regulates body fat mass independently of fat-derived leptin, revealing two independent negative feedback systems for fat mass regulation. It is known that osteocytes can sense changes in bone strain. In this study, the body weight-reducing effect of increased loading was lost in mice depleted of osteocytes. We propose that increased body weight activates a sensor dependent on osteocytes of the weight-bearing bones. This induces an afferent signal, which reduces body weight. These findings demonstrate a leptin-independent body weight homeostat (“gravitostat”) that regulates fat mass. PMID:29279372

  9. Emerging role of the brain in the homeostatic regulation of energy and glucose metabolism

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    Roh, Eun; Song, Do Kyeong; Kim, Min-Seon

    2016-01-01

    Accumulated evidence from genetic animal models suggests that the brain, particularly the hypothalamus, has a key role in the homeostatic regulation of energy and glucose metabolism. The brain integrates multiple metabolic inputs from the periphery through nutrients, gut-derived satiety signals and adiposity-related hormones. The brain modulates various aspects of metabolism, such as food intake, energy expenditure, insulin secretion, hepatic glucose production and glucose/fatty acid metabolism in adipose tissue and skeletal muscle. Highly coordinated interactions between the brain and peripheral metabolic organs are critical for the maintenance of energy and glucose homeostasis. Defective crosstalk between the brain and peripheral organs contributes to the development of obesity and type 2 diabetes. Here we comprehensively review the above topics, discussing the main findings related to the role of the brain in the homeostatic regulation of energy and glucose metabolism. PMID:26964832

  10. The dependence of neuronal encoding efficiency on Hebbian plasticity and homeostatic regulation of neurotransmitter release

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    Faramarz eFaghihi

    2015-04-01

    Full Text Available Synapses act as information filters by different molecular mechanisms including retrograde messenger that affect neuronal spiking activity. One of the well-known effects of retrograde messenger in presynaptic neurons is a change of the probability of neurotransmitter release. Hebbian learning describe a strengthening of a synapse between a presynaptic input onto a postsynaptic neuron when both pre- and postsynaptic neurons are coactive. In this work, a theory of homeostatic regulation of neurotransmitter release by retrograde messenger and Hebbian plasticity in neuronal encoding is presented. Encoding efficiency was measured for different synaptic conditions. In order to gain high encoding efficiency, the spiking pattern of a neuron should be dependent on the intensity of the input and show low levels of noise. In this work, we represent spiking trains as zeros and ones (corresponding to non-spike or spike in a time bin, respectively as words with length equal to three. Then the frequency of each word (here eight words is measured using spiking trains. These frequencies are used to measure neuronal efficiency in different conditions and for different parameter values. Results show that neurons that have synapses acting as band-pass filters show the highest efficiency to encode their input when both Hebbian mechanism and homeostatic regulation of neurotransmitter release exist in synapses. Specifically, the integration of homeostatic regulation of feedback inhibition with Hebbian mechanism and homeostatic regulation of neurotransmitter release in the synapses leads to even higher efficiency when high stimulus intensity is presented to the neurons. However, neurons with synapses acting as high-pass filters show no remarkable increase in encoding efficiency for all simulated synaptic plasticity mechanisms.

  11. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15.

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    Hsu, Jer-Yuan; Crawley, Suzanne; Chen, Michael; Ayupova, Dina A; Lindhout, Darrin A; Higbee, Jared; Kutach, Alan; Joo, William; Gao, Zhengyu; Fu, Diana; To, Carmen; Mondal, Kalyani; Li, Betty; Kekatpure, Avantika; Wang, Marilyn; Laird, Teresa; Horner, Geoffrey; Chan, Jackie; McEntee, Michele; Lopez, Manuel; Lakshminarasimhan, Damodharan; White, Andre; Wang, Sheng-Ping; Yao, Jun; Yie, Junming; Matern, Hugo; Solloway, Mark; Haldankar, Raj; Parsons, Thomas; Tang, Jie; Shen, Wenyan D; Alice Chen, Yu; Tian, Hui; Allan, Bernard B

    2017-10-12

    Under homeostatic conditions, animals use well-defined hypothalamic neural circuits to help maintain stable body weight, by integrating metabolic and hormonal signals from the periphery to balance food consumption and energy expenditure. In stressed or disease conditions, however, animals use alternative neuronal pathways to adapt to the metabolic challenges of altered energy demand. Recent studies have identified brain areas outside the hypothalamus that are activated under these 'non-homeostatic' conditions, but the molecular nature of the peripheral signals and brain-localized receptors that activate these circuits remains elusive. Here we identify glial cell-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) as a brainstem-restricted receptor for growth and differentiation factor 15 (GDF15). GDF15 regulates food intake, energy expenditure and body weight in response to metabolic and toxin-induced stresses; we show that Gfral knockout mice are hyperphagic under stressed conditions and are resistant to chemotherapy-induced anorexia and body weight loss. GDF15 activates GFRAL-expressing neurons localized exclusively in the area postrema and nucleus tractus solitarius of the mouse brainstem. It then triggers the activation of neurons localized within the parabrachial nucleus and central amygdala, which constitute part of the 'emergency circuit' that shapes feeding responses to stressful conditions. GDF15 levels increase in response to tissue stress and injury, and elevated levels are associated with body weight loss in numerous chronic human diseases. By isolating GFRAL as the receptor for GDF15-induced anorexia and weight loss, we identify a mechanistic basis for the non-homeostatic regulation of neural circuitry by a peripheral signal associated with tissue damage and stress. These findings provide opportunities to develop therapeutic agents for the treatment of disorders with altered energy demand.

  12. Control of Homeostatic Synaptic Plasticity by AKAP-Anchored Kinase and Phosphatase Regulation of Ca2+-Permeable AMPA Receptors.

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    Sanderson, Jennifer L; Scott, John D; Dell'Acqua, Mark L

    2018-02-13

    Neuronal information processing requires multiple forms of synaptic plasticity mediated by NMDA and AMPA-type glutamate receptors (NMDAR, AMPAR). These plasticity mechanisms include long-term potentiation (LTP) and depression (LTD), which are Hebbian, homosynaptic mechanisms locally regulating synaptic strength of specific inputs, and homeostatic synaptic scaling, which is a heterosynaptic mechanism globally regulating synaptic strength across all inputs. In many cases, LTP and homeostatic scaling regulate AMPAR subunit composition to increase synaptic strength via incorporation of Ca 2+ -permeable receptors (CP-AMPAR) containing GluA1, but lacking GluA2, subunits. Previous work by our group and others demonstrated that anchoring of the kinase PKA and the phosphatase calcineurin (CaN) to A-kinase anchoring protein (AKAP) 150 play opposing roles in regulation of GluA1 Ser845 phosphorylation and CP-AMPAR synaptic incorporation during hippocampal LTP and LTD. Here, using both male and female knock-in mice that are deficient in PKA or CaN anchoring, we show that AKAP150-anchored PKA and CaN also play novel roles in controlling CP-AMPAR synaptic incorporation during homeostatic plasticity in hippocampal neurons. We found that genetic disruption of AKAP-PKA anchoring prevented increases in Ser845 phosphorylation and CP-AMPAR synaptic recruitment during rapid homeostatic synaptic scaling-up induced by combined blockade of action potential firing and NMDAR activity. In contrast, genetic disruption of AKAP-CaN anchoring resulted in basal increases in Ser845 phosphorylation and CP-AMPAR synaptic activity that blocked subsequent scaling-up by preventing additional CP-AMPAR recruitment. Thus, the balanced, opposing phospho-regulation provided by AKAP-anchored PKA and CaN is essential for control of both Hebbian and homeostatic plasticity mechanisms that require CP-AMPARs. Significance statement: Neuronal circuit function is shaped by multiple forms of activity

  13. Homeostatic and Circadian Contribution to EEG and Molecular State Variables of Sleep Regulation

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    Curie, Thomas; Mongrain, Valérie; Dorsaz, Stéphane; Mang, Géraldine M.; Emmenegger, Yann; Franken, Paul

    2013-01-01

    Study Objectives: Besides their well-established role in circadian rhythms, our findings that the forebrain expression of the clock-genes Per2 and Dbp increases and decreases, respectively, in relation to time spent awake suggest they also play a role in the homeostatic aspect of sleep regulation. Here, we determined whether time of day modulates the effects of elevated sleep pressure on clock-gene expression. Time of day effects were assessed also for recognized electrophysiological (EEG delta power) and molecular (Homer1a) markers of sleep homeostasis. Design: EEG and qPCR data were obtained for baseline and recovery from 6-h sleep deprivation starting at ZT0, -6, -12, or -18. Setting: Mouse sleep laboratory. Participants: Male mice. Interventions: Sleep deprivation. Results: The sleep-deprivation induced changes in Per2 and Dbp expression importantly varied with time of day, such that Per2 could even decrease during sleep deprivations occurring at the decreasing phase in baseline. Dbp showed similar, albeit opposite dynamics. These unexpected results could be reliably predicted assuming that these transcripts behave according to a driven damped harmonic oscillator. As expected, the sleep-wake distribution accounted for a large degree of the changes in EEG delta power and Homer1a. Nevertheless, the sleep deprivation-induced increase in delta power varied also with time of day with higher than expected levels when recovery sleep started at dark onset. Conclusions: Per2 and delta power are widely used as exclusive state variables of the circadian and homeostatic process, respectively. Our findings demonstrate a considerable cross-talk between these two processes. As Per2 in the brain responds to both sleep loss and time of day, this molecule is well positioned to keep track of and to anticipate homeostatic sleep need. Citation: Curie T; Mongrain V; Dorsaz S; Mang GM; Emmenegger Y; Franken P. Homeostatic and circadian contribution to EEG and molecular state

  14. Diversity and noise effects in a model of homeostatic regulation of the sleep-wake cycle.

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    Marco Patriarca

    Full Text Available Recent advances in sleep neurobiology have allowed development of physiologically based mathematical models of sleep regulation that account for the neuronal dynamics responsible for the regulation of sleep-wake cycles and allow detailed examination of the underlying mechanisms. Neuronal systems in general, and those involved in sleep regulation in particular, are noisy and heterogeneous by their nature. It has been shown in various systems that certain levels of noise and diversity can significantly improve signal encoding. However, these phenomena, especially the effects of diversity, are rarely considered in the models of sleep regulation. The present paper is focused on a neuron-based physiologically motivated model of sleep-wake cycles that proposes a novel mechanism of the homeostatic regulation of sleep based on the dynamics of a wake-promoting neuropeptide orexin. Here this model is generalized by the introduction of intrinsic diversity and noise in the orexin-producing neurons, in order to study the effect of their presence on the sleep-wake cycle. A simple quantitative measure of the quality of a sleep-wake cycle is introduced and used to systematically study the generalized model for different levels of noise and diversity. The model is shown to exhibit a clear diversity-induced resonance: that is, the best wake-sleep cycle turns out to correspond to an intermediate level of diversity at the synapses of the orexin-producing neurons. On the other hand, only a mild evidence of stochastic resonance is found, when the level of noise is varied. These results show that disorder, especially in the form of quenched diversity, can be a key-element for an efficient or optimal functioning of the homeostatic regulation of the sleep-wake cycle. Furthermore, this study provides an example of a constructive role of diversity in a neuronal system that can be extended beyond the system studied here.

  15. Homeostatic regulation of sleep in the white-crowned sparrow (Zonotrichia leucophrys gambelii

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    Cirelli Chiara

    2008-05-01

    Full Text Available Abstract Background Sleep is regulated by both a circadian and a homeostatic process. The homeostatic process reflects the duration of prior wakefulness: the longer one stays awake, the longer and/or more intense is subsequent sleep. In mammals, the best marker of the homeostatic sleep drive is slow wave activity (SWA, the electroencephalographic (EEG power spectrum in the 0.5–4 Hz frequency range during non-rapid eye movement (NREM sleep. In mammals, NREM sleep SWA is high at sleep onset, when sleep pressure is high, and decreases progressively to reach low levels in late sleep. Moreover, SWA increases further with sleep deprivation, when sleep also becomes less fragmented (the duration of sleep episodes increases, and the number of brief awakenings decreases. Although avian and mammalian sleep share several features, the evidence of a clear homeostatic response to sleep loss has been conflicting in the few avian species studied so far. The aim of the current study was therefore to ascertain whether established markers of sleep homeostasis in mammals are also present in the white-crowned sparrow (Zonotrichia leucophrys gambelii, a migratory songbird of the order Passeriformes. To accomplish this goal, we investigated amount of sleep, sleep time course, and measures of sleep intensity in 6 birds during baseline sleep and during recovery sleep following 6 hours of sleep deprivation. Results Continuous (24 hours EEG and video recordings were used to measure baseline sleep and recovery sleep following short-term sleep deprivation. Sleep stages were scored visually based on 4-sec epochs. EEG power spectra (0.5–25 Hz were calculated on consecutive 4-sec epochs. Four vigilance states were reliably distinguished based on behavior, visual inspection of the EEG, and spectral EEG analysis: Wakefulness (W, Drowsiness (D, slow wave sleep (SWS and rapid-eye movement (REM sleep. During baseline, SWA during D, SWS, and NREM sleep (defined as D and SWS

  16. Regulation of kinetochore-microtubule attachments through homeostatic control during mitosis.

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    Godek, Kristina M; Kabeche, Lilian; Compton, Duane A

    2015-01-01

    Faithful chromosome segregation during mitosis is essential for genome integrity and is mediated by the bi-oriented attachment of replicated chromosomes to spindle microtubules through kinetochores. Errors in kinetochore-microtubule (k-MT) attachment that could cause chromosome mis-segregation are frequent and are corrected by the dynamic turnover of k-MT attachments. Thus, regulating the rate of spindle microtubule attachment and detachment to kinetochores is crucial for mitotic fidelity and is frequently disrupted in cancer cells displaying chromosomal instability. A model based on homeostatic principles involving receptors, a core control network, effectors and feedback control may explain the precise regulation of k-MT attachment stability during mitotic progression to ensure error-free mitosis.

  17. Low-Frequency Oscillations in Outer Hair Cells and Homeostatic Regulation of the Organ of Corti

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    Patuzzi, R. B.

    2003-02-01

    Microphonic potentials in the basal cochlear turn of guinea pigs evoked by 200-Hz tones can be analysed in terms of the Boltzmann parameters governing the mechanoelectrical transduction channels at the apex of outer hair cells (OHCs). Detailed analysis of the changes in these parameters with cochlear perturbations reveals slow damped oscillations with cycle times between 250s and 500s, interpretted as oscillations in the homeostatic feedback loops regulating cochlear transduction. We describe these oscillations, and present a model of cochlear homeostasis which includes known electrophysiological and mechanical properties of OHCs, and invokes a slow second-messenger system triggered by Ca2+ involving unknown intermediates (M2 and M3) which control OHC slow contractions and Ca2+ sequestration.

  18. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15

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    Hsu, Jer-Yuan; Crawley, Suzanne; Chen, Michael; Ayupova, Dina A.; Lindhout, Darrin A.; Higbee, Jared; Kutach, Alan; Joo, William; Gao, Zhengyu; Fu, Diana; To, Carmen; Mondal, Kalyani; Li, Betty; Kekatpure, Avantika; Wang, Marilyn; Laird, Teresa; Horner, Geoffrey; Chan, Jackie; McEntee, Michele; Lopez, Manuel; Lakshminarasimhan, Damodharan; White, Andre; Wang, Sheng-Ping; Yao, Jun; Yie, Junming; Matern, Hugo; Solloway, Mark; Haldankar, Raj; Parsons, Thomas; Tang, Jie; Shen, Wenyan D.; Alice Chen, Yu; Tian, Hui; Allan, Bernard B.

    2017-09-27

    Under homeostatic conditions, animals use well-defined hypothalamic neural circuits to help maintain stable body weight, by integrating metabolic and hormonal signals from the periphery to balance food consumption and energy expenditure1,2. In stressed or disease conditions, however, animals use alternative neuronal pathways to adapt to the metabolic challenges of altered energy demand3. Recent studies have identified brain areas outside the hypothalamus that are activated under these ‘non-homeostatic’ conditions4,5,6, but the molecular nature of the peripheral signals and brain-localized receptors that activate these circuits remains elusive. Here we identify glial cell-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) as a brainstem-restricted receptor for growth and differentiation factor 15 (GDF15). GDF15 regulates food intake, energy expenditure and body weight in response to metabolic and toxin-induced stresses; we show that Gfral knockout mice are hyperphagic under stressed conditions and are resistant to chemotherapy-induced anorexia and body weight loss. GDF15 activates GFRAL-expressing neurons localized exclusively in the area postrema and nucleus tractus solitarius of the mouse brainstem. It then triggers the activation of neurons localized within the parabrachial nucleus and central amygdala, which constitute part of the ‘emergency circuit’ that shapes feeding responses to stressful conditions7. GDF15 levels increase in response to tissue stress and injury, and elevated levels are associated with body weight loss in numerous chronic human diseases8,9. By isolating GFRAL as the receptor for GDF15-induced anorexia and weight loss, we identify a mechanistic basis for the non-homeostatic regulation of neural circuitry by a peripheral signal associated with tissue damage and stress. These findings provide opportunities to develop therapeutic agents for the treatment of disorders with altered energy demand.

  19. SynGAP regulates protein synthesis and homeostatic synaptic plasticity in developing cortical networks.

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    Chih-Chieh Wang

    Full Text Available Disrupting the balance between excitatory and inhibitory neurotransmission in the developing brain has been causally linked with intellectual disability (ID and autism spectrum disorders (ASD. Excitatory synapse strength is regulated in the central nervous system by controlling the number of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs. De novo genetic mutations of the synaptic GTPase-activating protein (SynGAP are associated with ID and ASD. SynGAP is enriched at excitatory synapses and genetic suppression of SynGAP increases excitatory synaptic strength. However, exactly how SynGAP acts to maintain synaptic AMPAR content is unclear. We show here that SynGAP limits excitatory synaptic strength, in part, by suppressing protein synthesis in cortical neurons. The data presented here from in vitro, rat and mouse cortical networks, demonstrate that regulation of translation by SynGAP involves ERK, mTOR, and the small GTP-binding protein Rheb. Furthermore, these data show that GluN2B-containing NMDARs and the cognitive kinase CaMKII act upstream of SynGAP and that this signaling cascade is required for proper translation-dependent homeostatic synaptic plasticity of excitatory synapses in developing cortical networks.

  20. Homeostatic response to hypoxia is regulated by the N-end rule pathway in plants.

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    Gibbs, Daniel J; Lee, Seung Cho; Isa, Nurulhikma Md; Gramuglia, Silvia; Fukao, Takeshi; Bassel, George W; Correia, Cristina Sousa; Corbineau, Françoise; Theodoulou, Frederica L; Bailey-Serres, Julia; Holdsworth, Michael J

    2011-10-23

    Plants and animals are obligate aerobes, requiring oxygen for mitochondrial respiration and energy production. In plants, an unanticipated decline in oxygen availability (hypoxia), as caused by roots becoming waterlogged or foliage submergence, triggers changes in gene transcription and messenger RNA translation that promote anaerobic metabolism and thus sustain substrate-level ATP production. In contrast to animals, oxygen sensing has not been ascribed to a mechanism of gene regulation in response to oxygen deprivation in plants. Here we show that the N-end rule pathway of targeted proteolysis acts as a homeostatic sensor of severe low oxygen levels in Arabidopsis, through its regulation of key hypoxia-response transcription factors. We found that plants lacking components of the N-end rule pathway constitutively express core hypoxia-response genes and are more tolerant of hypoxic stress. We identify the hypoxia-associated ethylene response factor group VII transcription factors of Arabidopsis as substrates of this pathway. Regulation of these proteins by the N-end rule pathway occurs through a characteristic conserved motif at the amino terminus initiating with Met-Cys. Enhanced stability of one of these proteins, HRE2, under low oxygen conditions improves hypoxia survival and reveals a molecular mechanism for oxygen sensing in plants via the evolutionarily conserved N-end rule pathway. SUB1A-1, a major determinant of submergence tolerance in rice, was shown not to be a substrate for the N-end rule pathway despite containing the N-terminal motif, indicating that it is uncoupled from N-end rule pathway regulation, and that enhanced stability may relate to the superior tolerance of Sub1 rice varieties to multiple abiotic stresses. © 2011 Macmillan Publishers Limited. All rights reserved

  1. Tonic and transient endocannabinoid regulation of AMPAergic mPSCs and homeostatic plasticity in embryonic motor networks

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    Gonzalez-Islas, Carlos; Garcia-Bereguiain, Miguel Angel

    2012-01-01

    Endocannabinoid signaling has been shown to mediate synaptic plasticity by retrogradely inhibiting presynaptic transmitter release in several systems. We found that endocannabinoids act tonically to regulate AMPA mPSC frequency in embryonic motor circuits of the chick spinal cord. Further, strong postsynaptic depolarizations also induced a short-lived endocannabinoid–mediated suppression of mEPSC frequency. Unlike many previous studies, endocannabinoid signaling was not found to influence evoked transmitter release. The results suggest a special role for spontaneous glutamatergic mPSCs, and their control by endocannabinoids in the developing spinal cord. We determined that blocking endocannabinoid signaling, which increases spontaneous glutamatergic release, increased spontaneous network activity in vitro and in vivo. Previous work in spinal motoneurons had shown that reducing SNA chronically in vivo led to homeostatic increases in AMPA and GABA mPSC amplitude (homeostatic synaptic plasticity). Blocking endocannabinoid signaling in vivo, and thus increasing SNA, triggered compensatory decreases of both AMPA and GABA mPSC amplitudes. These findings, combined with previous results, are consistent with the idea that this form of homeostatic synaptic plasticity is a bidirectional process in the living embryo. Together, our results suggest a role for tonic signaling of endocannabinoids as a potential mechanism to regulate the level of SNA, which is known to be critical for synaptic maturation in the embryonic spinal cord. PMID:23015449

  2. Homeostatic Presynaptic Plasticity Is Specifically Regulated by P/Q-type Ca2+ Channels at Mammalian Hippocampal Synapses

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    Alexander F. Jeans

    2017-10-01

    Full Text Available Voltage-dependent Ca2+ channels (VGCC represent the principal source of Ca2+ ions driving evoked neurotransmitter release at presynaptic boutons. In mammals, presynaptic Ca2+ influx is mediated mainly via P/Q-type and N-type VGCC, which differ in their properties. Changes in their relative contributions tune neurotransmission both during development and in Hebbian plasticity. However, whether this represents a functional motif also present in other forms of activity-dependent regulation is unknown. Here, we study the role of VGCC in homeostatic plasticity (HSP in mammalian hippocampal neurons using optical techniques. We find that changes in evoked Ca2+ currents specifically through P/Q-type, but not N-type, VGCC mediate bidirectional homeostatic regulation of both neurotransmitter release efficacy and the size of the major synaptic vesicle pools. Selective dependence of HSP on P/Q-type VGCC in mammalian terminals has important implications for phenotypes associated with P/Q-type channelopathies, including migraine and epilepsy.

  3. Activity-Dependent Bidirectional Regulation of GAD Expression in a Homeostatic Fashion Is Mediated by BDNF-Dependent and Independent Pathways

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    Hanno-Iijima, Yoko; Tanaka, Masami; Iijima, Takatoshi

    2015-01-01

    Homeostatic synaptic plasticity, or synaptic scaling, is a mechanism that tunes neuronal transmission to compensate for prolonged, excessive changes in neuronal activity. Both excitatory and inhibitory neurons undergo homeostatic changes based on synaptic transmission strength, which could effectively contribute to a fine-tuning of circuit activity. However, gene regulation that underlies homeostatic synaptic plasticity in GABAergic (GABA, gamma aminobutyric) neurons is still poorly understood. The present study demonstrated activity-dependent dynamic scaling in which NMDA-R (N-methyl-D-aspartic acid receptor) activity regulated the expression of GABA synthetic enzymes: glutamic acid decarboxylase 65 and 67 (GAD65 and GAD67). Results revealed that activity-regulated BDNF (brain-derived neurotrophic factor) release is necessary, but not sufficient, for activity-dependent up-scaling of these GAD isoforms. Bidirectional forms of activity-dependent GAD expression require both BDNF-dependent and BDNF-independent pathways, both triggered by NMDA-R activity. Additional results indicated that these two GAD genes differ in their responsiveness to chronic changes in neuronal activity, which could be partially caused by differential dependence on BDNF. In parallel to activity-dependent bidirectional scaling in GAD expression, the present study further observed that a chronic change in neuronal activity leads to an alteration in neurotransmitter release from GABAergic neurons in a homeostatic, bidirectional fashion. Therefore, the differential expression of GAD65 and 67 during prolonged changes in neuronal activity may be implicated in some aspects of bidirectional homeostatic plasticity within mature GABAergic presynapses. PMID:26241953

  4. Activity-Dependent Bidirectional Regulation of GAD Expression in a Homeostatic Fashion Is Mediated by BDNF-Dependent and Independent Pathways.

    Science.gov (United States)

    Hanno-Iijima, Yoko; Tanaka, Masami; Iijima, Takatoshi

    2015-01-01

    Homeostatic synaptic plasticity, or synaptic scaling, is a mechanism that tunes neuronal transmission to compensate for prolonged, excessive changes in neuronal activity. Both excitatory and inhibitory neurons undergo homeostatic changes based on synaptic transmission strength, which could effectively contribute to a fine-tuning of circuit activity. However, gene regulation that underlies homeostatic synaptic plasticity in GABAergic (GABA, gamma aminobutyric) neurons is still poorly understood. The present study demonstrated activity-dependent dynamic scaling in which NMDA-R (N-methyl-D-aspartic acid receptor) activity regulated the expression of GABA synthetic enzymes: glutamic acid decarboxylase 65 and 67 (GAD65 and GAD67). Results revealed that activity-regulated BDNF (brain-derived neurotrophic factor) release is necessary, but not sufficient, for activity-dependent up-scaling of these GAD isoforms. Bidirectional forms of activity-dependent GAD expression require both BDNF-dependent and BDNF-independent pathways, both triggered by NMDA-R activity. Additional results indicated that these two GAD genes differ in their responsiveness to chronic changes in neuronal activity, which could be partially caused by differential dependence on BDNF. In parallel to activity-dependent bidirectional scaling in GAD expression, the present study further observed that a chronic change in neuronal activity leads to an alteration in neurotransmitter release from GABAergic neurons in a homeostatic, bidirectional fashion. Therefore, the differential expression of GAD65 and 67 during prolonged changes in neuronal activity may be implicated in some aspects of bidirectional homeostatic plasticity within mature GABAergic presynapses.

  5. The Inappropriate Occurrence of REM Sleep in Narcolepsy is not due to a Defect in Homeostatic Regulation of REM Sleep.

    Science.gov (United States)

    Roman, Alexis; Meftah, Soraya; Arthaud, Sébastien; Luppi, Pierre-Hervé; Peyron, Christelle

    2018-03-07

    Narcolepsy type 1 is a disabling disorder with four primary symptoms: excessive-daytime-sleepiness, cataplexy, hypnagogic hallucinations and sleep paralysis. The three latter symptoms together with a short REM sleep latency have suggested impairment in REM sleep homeostatic regulation with an enhanced propensity for (i.e. tendency to enter) REM sleep. To test this hypothesis, we challenged REM sleep homeostatic regulation in a recognized model of narcolepsy, the orexin knock-out (Orex-KO) mice and their wild-type (WT) littermates. We first performed 48hrs of REM sleep deprivation using the classic small-platforms-over-water method. We found that narcoleptic mice are similarly REM sleep deprived to WT mice. Although they had shorter sleep latency, Orex-KO mice recovered similarly to WT during the following 10hrs of recovery. Interestingly, Orex-KO mice also had cataplexy episodes immediately after REM sleep deprivation, anticipating REM sleep rebound, at a time of day when cataplexy does not occur in baseline condition. We then evaluated REM sleep propensity using our new automated method of deprivation that performs a specific and efficient REM sleep deprivation. We showed that REM sleep propensity is similar during light phase in Orex-KO and WT mice. However, during the dark phase REM sleep propensity was not suppressed in Orex-KO mice when hypocretin/orexin neuropeptides are normally released. Altogether our data suggest that in addition to the well-known wake-promoting role of hypocretin/orexin, these neuropeptides would also suppress REM sleep. Therefore, hypocretin/orexin deficiency would facilitate the occurrence of REM sleep at any time of day in an opportunistic manner as seen in human narcolepsy.

  6. Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions.

    Science.gov (United States)

    Karigane, Daiki; Takubo, Keiyo

    2017-07-01

    Hematopoietic stem cells (HSCs) exhibit multilineage differentiation and self-renewal activities that maintain the entire hematopoietic system during an organism's lifetime. These abilities are sustained by intrinsic transcriptional programs and extrinsic cues from the microenvironment or niche. Recent studies using metabolomics technologies reveal that metabolic regulation plays an essential role in HSC maintenance. Metabolic pathways provide energy and building blocks for other factors functioning at steady state and in stress. Here we review recent advances in our understanding of metabolic regulation in HSCs relevant to cell cycle quiescence, symmetric/asymmetric division, and proliferation following stress and lineage commitment, and discuss the therapeutic potential of targeting metabolic factors or pathways to treat hematological malignancies.

  7. Homeostatic response to hypoxia is regulated by the N-end rule pathway in plants

    OpenAIRE

    Gibbs, Daniel J.; Lee, Seung Cho; Isa, Nurulhikma Md; Gramuglia, Silvia; Fukao, Takeshi; Bassel, George W.; Correia, Cristina Sousa; Corbineau, Françoise; Theodoulou, Frederica L.; Bailey-Serres, Julia; Holdsworth, Michael J.

    2011-01-01

    Plants and animals are obligate aerobes, requiring oxygen for mitochondrial respiration and energy production. In plants, an unanticipated decline in oxygen availability (hypoxia), as caused by roots becoming waterlogged or foliage submergence, triggers changes in gene transcription and messenger RNA translation that promote anaerobic metabolism and thus sustain substrate-level ATP production. In contrast to animals, oxygen sensing has not been ascribed to a mechanism of gene regulation in re...

  8. A new approach to homeostatic regulation: towards a unified view of physiological and ecological concepts.

    Directory of Open Access Journals (Sweden)

    Cédric L Meunier

    Full Text Available Stoichiometric homeostasis is the ability of an organism to keep its body chemical composition constant, despite varying inputs. Stoichiometric homeostasis therefore constrains the metabolic needs of consumers which in turn often feed on resources not matching these requirements. In a broader context, homeostasis also relates to the capacity of an organism to maintain other biological parameters (e.g. body temperature at a constant level over ambient environmental variations. Unfortunately, there are discrepancies in the literature and ecological and physiological definitions of homeostasis are disparate and partly contradictory. Here, we address this matter by reviewing the existing knowledge considering two distinct groups, regulators and conformers and, based on examples of thermo- and osmoregulation, we propose a new approach to stoichiometric homeostasis, unifying ecological and physiological concepts. We suggest a simple and precise graphical way to identify regulators and conformers: for any given biological parameter (e.g. nutrient stoichiometry, temperature, a sigmoidal relation between internal and external conditions can be observed for conformers while an inverse sigmoidal response is characteristic of regulators. This new definition and method, based on well-studied physiological mechanisms, unifies ecological and physiological approaches and is a useful tool for understanding how organisms are affected by and affect their environment.

  9. A new approach to homeostatic regulation: towards a unified view of physiological and ecological concepts.

    Science.gov (United States)

    Meunier, Cédric L; Malzahn, Arne M; Boersma, Maarten

    2014-01-01

    Stoichiometric homeostasis is the ability of an organism to keep its body chemical composition constant, despite varying inputs. Stoichiometric homeostasis therefore constrains the metabolic needs of consumers which in turn often feed on resources not matching these requirements. In a broader context, homeostasis also relates to the capacity of an organism to maintain other biological parameters (e.g. body temperature) at a constant level over ambient environmental variations. Unfortunately, there are discrepancies in the literature and ecological and physiological definitions of homeostasis are disparate and partly contradictory. Here, we address this matter by reviewing the existing knowledge considering two distinct groups, regulators and conformers and, based on examples of thermo- and osmoregulation, we propose a new approach to stoichiometric homeostasis, unifying ecological and physiological concepts. We suggest a simple and precise graphical way to identify regulators and conformers: for any given biological parameter (e.g. nutrient stoichiometry, temperature), a sigmoidal relation between internal and external conditions can be observed for conformers while an inverse sigmoidal response is characteristic of regulators. This new definition and method, based on well-studied physiological mechanisms, unifies ecological and physiological approaches and is a useful tool for understanding how organisms are affected by and affect their environment.

  10. B cell development in the bone marrow is regulated by homeostatic feedback exerted by mature B cells

    Directory of Open Access Journals (Sweden)

    Gitit eShahaf

    2016-03-01

    Full Text Available Cellular homeostasis in the B cell compartment is strictly imposed to balance cell production and cell loss. However, it is not clear whether B cell development in the bone marrow (BM is an autonomous process or subjected to regulation by the peripheral B cell compartment. To specifically address this question, we used mice transgenic for human CD20, where effective depletion of B lineage cells is obtained upon administration of mouse-anti-human CD20 antibodies, in the absence of any effect on other cell lineages and/or tissues. We followed the kinetics of B cell return to equilibrium by BrdU labeling and flow cytometry and analyzed the resulting data by mathematical modeling. Labeling was much faster in depleted mice. Compared to control mice, B cell-depleted mice exhibited a higher proliferation rate in the pro-/pre-B compartment, and higher cell death and lower differentiation in the immature B cell compartment. We validated the first result by analysis of the expression of Ki67, the nuclear protein expressed in proliferating cells, and the second using Annexin-V staining. Collectively, our results suggest that B lymphopoiesis is subjected to homeostatic feedback mechanisms imposed by mature B cells in the peripheral compartment.

  11. Ghrelin modulates the fMRI BOLD response of homeostatic and hedonic brain centers regulating energy balance in the rat.

    Directory of Open Access Journals (Sweden)

    Miklós Sárvári

    Full Text Available The orexigenic gut-brain peptide, ghrelin and its G-protein coupled receptor, the growth hormone secretagogue receptor 1a (GHS-R1A are pivotal regulators of hypothalamic feeding centers and reward processing neuronal circuits of the brain. These systems operate in a cooperative manner and receive a wide array of neuronal hormone/transmitter messages and metabolic signals. Functional magnetic resonance imaging was employed in the current study to map BOLD responses to ghrelin in different brain regions with special reference on homeostatic and hedonic regulatory centers of energy balance. Experimental groups involved male, ovariectomized female and ovariectomized estradiol-replaced rats. Putative modulation of ghrelin signaling by endocannabinoids was also studied. Ghrelin-evoked effects were calculated as mean of the BOLD responses 30 minutes after administration. In the male rat, ghrelin evoked a slowly decreasing BOLD response in all studied regions of interest (ROI within the limbic system. This effect was antagonized by pretreatment with GHS-R1A antagonist JMV2959. The comparison of ghrelin effects in the presence or absence of JMV2959 in individual ROIs revealed significant changes in the prefrontal cortex, nucleus accumbens of the telencephalon, and also within hypothalamic centers like the lateral hypothalamus, ventromedial nucleus, paraventricular nucleus and suprachiasmatic nucleus. In the female rat, the ghrelin effects were almost identical to those observed in males. Ovariectomy and chronic estradiol replacement had no effect on the BOLD response. Inhibition of the endocannabinoid signaling by rimonabant significantly attenuated the response of the nucleus accumbens and septum. In summary, ghrelin can modulate hypothalamic and mesolimbic structures controlling energy balance in both sexes. The endocannabinoid signaling system contributes to the manifestation of ghrelin's BOLD effect in a region specific manner. In females, the

  12. Homeostatic Regulation of the PI(4,5)P2-Ca2+ Signaling System at ER-PM Junctions

    Science.gov (United States)

    Chang, Chi-Lun; Liou, Jen

    2016-01-01

    The phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-Ca2+ signaling system is important for cell activation in response to various extracellular stimuli. This signaling system is initiated by receptor-induced hydrolysis of PI(4,5)P2 in the plasma membrane (PM) to generate the soluble second messenger inositol 1,4,5-trisphosphate (IP3). IP3 subsequently triggers the release of Ca2+ from the endoplasmic reticulum (ER) store to the cytosol to activate Ca2+-mediated responses, such as secretion and proliferation. The consumed PM PI(4,5)P2 and ER Ca2+ must be quickly restored to sustain signaling responses, and to maintain the homeostasis of PI(4,5)P2 and Ca2+. Since phosphatidylinositol (PI), the precursor lipid for PM PI(4,5)P2, is synthesized in the ER membrane, and a Ca2+ influx across the PM is required to refill the ER Ca2+ store, efficient communications between the ER and the PM are critical for the homeostatic regulation of the PI(4,5)P2-Ca2+ signaling system. This review describes the major findings that established the framework of the PI(4,5)P2-Ca2+ signaling system, and recent discoveries on feedback control mechanisms at ER-PM junctions that sustain the PI(4,5)P2-Ca2+ signaling system. Particular emphasis is placed on the characterization of ER-PM junctions where efficient communications between the ER and the PM occurs, and the activation mechanisms of proteins that dynamically localize to ER-PM junctions to provide the feedback control during PI(4,5)P2-Ca2+ signaling, including the ER Ca2+ sensor STIM1, the extended synaptotagmin E-Syt1, and the PI transfer protein Nir2. This review is part of a Special Issue entitled The Cellular Lipid Landscape. PMID:26924250

  13. Homeostatic theory of obesity

    Directory of Open Access Journals (Sweden)

    David F Marks

    2015-06-01

    Full Text Available Health is regulated by homeostasis, a property of all living things. Homeostasis maintains equilibrium at set-points using feedback loops for optimum functioning of the organism. Imbalances in homeostasis causing overweight and obesity are evident in more than 1 billion people. In a new theory, homeostatic obesity imbalance is attributed to a hypothesized ‘Circle of Discontent’, a system of feedback loops linking weight gain, body dissatisfaction, negative affect and over-consumption. The Circle of Discontent theory is consistent with an extensive evidence base. A four-armed strategy to halt the obesity epidemic consists of (1 putting a stop to victim-blaming, stigma and discrimination; (2 devalorizing the thin-ideal; (3 reducing consumption of energy-dense, low-nutrient foods and drinks; and (4 improving access to plant-based diets. If fully implemented, interventions designed to restore homeostasis have the potential to halt the obesity epidemic.

  14. Homeostatic theory of obesity.

    Science.gov (United States)

    Marks, David F

    2015-01-01

    Health is regulated by homeostasis, a property of all living things. Homeostasis maintains equilibrium at set-points using feedback loops for optimum functioning of the organism. Imbalances in homeostasis causing overweight and obesity are evident in more than 1 billion people. In a new theory, homeostatic obesity imbalance is attributed to a hypothesized 'Circle of Discontent', a system of feedback loops linking weight gain, body dissatisfaction, negative affect and over-consumption. The Circle of Discontent theory is consistent with an extensive evidence base. A four-armed strategy to halt the obesity epidemic consists of (1) putting a stop to victim-blaming, stigma and discrimination; (2) devalorizing the thin-ideal; (3) reducing consumption of energy-dense, low-nutrient foods and drinks; and (4) improving access to plant-based diets. If fully implemented, interventions designed to restore homeostasis have the potential to halt the obesity epidemic.

  15. Homeostatic theory of obesity

    Science.gov (United States)

    2015-01-01

    Health is regulated by homeostasis, a property of all living things. Homeostasis maintains equilibrium at set-points using feedback loops for optimum functioning of the organism. Imbalances in homeostasis causing overweight and obesity are evident in more than 1 billion people. In a new theory, homeostatic obesity imbalance is attributed to a hypothesized ‘Circle of Discontent’, a system of feedback loops linking weight gain, body dissatisfaction, negative affect and over-consumption. The Circle of Discontent theory is consistent with an extensive evidence base. A four-armed strategy to halt the obesity epidemic consists of (1) putting a stop to victim-blaming, stigma and discrimination; (2) devalorizing the thin-ideal; (3) reducing consumption of energy-dense, low-nutrient foods and drinks; and (4) improving access to plant-based diets. If fully implemented, interventions designed to restore homeostasis have the potential to halt the obesity epidemic. PMID:28070357

  16. Major vault protein, a candidate gene in 16p11.2 microdeletion syndrome, is required for the homeostatic regulation of visual cortical plasticity.

    Science.gov (United States)

    Ip, Jacque P K; Nagakura, Ikue; Petravicz, Jeremy; Li, Keji; Wiemer, Erik A C; Sur, Mriganka

    2018-03-14

    Microdeletion of a region in chromosome 16p11.2 increases susceptibility to autism. Although this region contains exons of 29 genes, disrupting only a small segment of the region, which spans 5 genes, is sufficient to cause autistic traits. One candidate gene in this critical segment is MVP , which encodes for the major vault protein (MVP) that has been implicated in regulation of cellular transport mechanisms. MVP expression levels in MVP +/- mice closely phenocopy those of 16p11.2 mutant mice, suggesting that MVP +/- mice may serve as a model of MVP function in 16p11.2 microdeletion. Here we show that MVP regulates the homeostatic component of ocular dominance (OD) plasticity in primary visual cortex (V1). MVP +/- mice of both sexes show impairment in strengthening of open-eye responses after several days of monocular deprivation (MD) while closed-eye responses are weakened as normal, resulting in reduced overall OD plasticity. The frequency of mEPSCs in pyramidal neurons is decreased in MVP +/- mice after extended MD, suggesting a reduction of functional synapses. Correspondingly, upregulation of surface GluA1 AMPA receptors is reduced in MVP +/- mice after extended MD, and is accompanied by altered expression of STAT1 and phosphorylated ERK, which have been previously implicated in OD plasticity. Normalization of STAT1 levels by introducing STAT1 shRNA rescues surface GluA1 and open-eye responses, implicating STAT1 as a downstream effector of MVP. These findings demonstrate a specific role for MVP as a key molecule influencing the homeostatic component of activity-dependent synaptic plasticity, and potentially the corresponding phenotypes of 16p11.2 microdeletion syndrome. Significance Statement Major vault protein (MVP), a candidate gene in 16p11.2 microdeletion syndrome, has been implicated in the regulation of several cellular processes including transport mechanisms and scaffold signaling. However, its role in brain function and plasticity remains unknown

  17. Computer Simulation of Noise Effects of the Neighborhood of Stimulus Threshold for a Mathematical Model of Homeostatic Regulation of Sleep-Wake Cycles

    Directory of Open Access Journals (Sweden)

    Wuyin Jin

    2017-01-01

    Full Text Available The noise effects on a homeostatic regulation of sleep-wake cycles’ neuronal mathematical model determined by the hypocretin/orexin and the local glutamate interneurons spatiotemporal behaviors are studied within the neighborhood of stimulus threshold in this work; the neuronal noise added to the stimulus, the conductance, and the activation variable of the modulation function are investigated, respectively, based on a circadian input skewed in sine function. The computer simulation results suggested that the increased amplitude of external current input will lead to the fact that awakening time is advanced but the sleepy time remains the same; for the bigger conductance and modulation noise, the regulatory mechanism of the model sometimes will be collapsed and the coupled two neurons of the model show very irregular activities; the falling asleep or wake transform appears at nondeterminate time.

  18. Macrophages in Homeostatic Immune Function

    Directory of Open Access Journals (Sweden)

    Jonathan eJantsch

    2014-05-01

    Full Text Available Macrophages are not only involved in inflammatory and anti-infective processes, but also play an important role in maintaining tissue homeostasis. In this review, we summarize recent evidence investigating the role of macrophages in controlling angiogenesis, metabolism and salt and water balance. Particularly, we summarize the importance of macrophage tonicity enhancer binding protein (TonEBP, also termed nuclear factor of activated T-cells 5 [NFAT5] expression in the regulation of salt and water homeostasis. Further understanding of homeostatic macrophage function may lead to new therapeutic approaches to treat ischemia, hypertension and metabolic disorders.

  19. Homeostatic Eosinophils: Characteristics and Functions

    Directory of Open Access Journals (Sweden)

    Thomas Marichal

    2017-07-01

    Full Text Available Eosinophils are typically considered to be specialized effector cells that are recruited to the tissues as a result of T helper type 2 (Th2 cell responses associated with helminth infections or allergic diseases such as asthma. Once at the site of injury, eosinophils release their cytotoxic granule proteins as well as preformed cytokines and lipid mediators, contributing to parasite destruction but also to exacerbation of inflammation and tissue damage. Accumulating evidence indicates that, besides their roles in Th2 responses, eosinophils also regulate homeostatic processes at steady state, thereby challenging the exclusive paradigm of the eosinophil as a destructive and inflammatory cell. Indeed, under baseline conditions, eosinophils rapidly leave the bloodstream to enter tissues, mainly the gastrointestinal tract, lungs, adipose tissue, thymus, uterus, and mammary glands, where they regulate a variety of important biological functions, such as immunoregulation, control of glucose homeostasis, protection against obesity, regulation of mammary gland development, and preparation of the uterus for pregnancy. This article provides an overview of the characteristics and functions of these homeostatic eosinophils.

  20. Homeostatic NF-κB Signaling in Steady-State Migratory Dendritic Cells Regulates Immune Homeostasis and Tolerance.

    Science.gov (United States)

    Baratin, Myriam; Foray, Chloe; Demaria, Olivier; Habbeddine, Mohamed; Pollet, Emeline; Maurizio, Julien; Verthuy, Christophe; Davanture, Suzel; Azukizawa, Hiroaki; Flores-Langarica, Adriana; Dalod, Marc; Lawrence, Toby

    2015-04-21

    Migratory non-lymphoid tissue dendritic cells (NLT-DCs) transport antigens to lymph nodes (LNs) and are required for protective immune responses in the context of inflammation and to promote tolerance to self-antigens in steady-state. However, the molecular mechanisms that elicit steady-state NLT-DC maturation and migration are unknown. By comparing the transcriptome of NLT-DCs in the skin with their migratory counterparts in draining LNs, we have identified a novel NF-κB-regulated gene network specific to migratory DCs. We show that targeted deletion of IKKβ in DCs, a major activator of NF-κB, prevents NLT-DC accumulation in LNs and compromises regulatory T cell conversion in vivo. This was associated with impaired tolerance and autoimmunity. NF-κB is generally considered the prototypical pro-inflammatory transcription factor, but this study describes a role for NF-κB signaling in DCs for immune homeostasis and tolerance that could have implications in autoimmune diseases and immunity. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Regulatory Coordination between Two Major Intracellular Homeostatic Systems

    DEFF Research Database (Denmark)

    Dokladny, Karol; Zuhl, Micah Nathaniel; Mandell, Michael

    2013-01-01

    whether there are interactions between these homeostatic systems, one universally operational in all prokaryotic and eukaryotic cells, and the other one (autophagy) is limited to eukaryotes. We found that heat shock response regulates autophagy. The interaction between the two systems was demonstrated......The eukaryotic cell depends on multitiered homeostatic systems ensuring maintenance of proteostasis, organellar integrity, function and turnover, and overall cellular viability. At the two opposite ends of the homeostatic system spectrum are heat shock response and autophagy. Here, we tested...... of the homeostatic systems in the eukaryotic cell....

  2. DNA supercoiling in Escherichia coli in under tight and subtle homeostatic control, involving gene-expression and metabolic regulation of both toposiomerase 1 and DNA gyrase.

    NARCIS (Netherlands)

    Snoep, J.L.; van der Weijden, C.C.; Andersen, H.W.; Westerhoff, H.V.; Jensen, P.R.

    2002-01-01

    DNA of prokaryotes is in a nonequilibrium structural state, characterized as 'active' DNA supercoiling. Alterations in this state affect many life processes and a homeostatic control of DNA supercoiling has been suggested [Menzel, R. & Gellert, M. (1983) Cell 34, 105-113]. We here report on a new

  3. DNA supercoiling in Escherichia coli is under tight and subtle homeostatic control, involving gene-expression and metabolic regulation of both topoisomerase I and DNA gyrase

    DEFF Research Database (Denmark)

    Snoep, J.L.; van der Weijden, C.C.; Andersen, H.W.

    2002-01-01

    DNA of prokaryotes is in a nonequilibrium. structural state, characterized as 'active' DNA supercoiling. Alterations in this state affect many life processes and a homeostatic control of DNA supercoiling has been suggested [Menzel, R. & Gellert. M. (1983) Cell 34, 105-113]. We here report on a ne...... of the nonequilibrium DNA structure in wild-type Escherichia coli is almost complete and subtle (i.e. involving at least three regulatory mechanisms)....

  4. The interaction of psychological and physiological homeostatic drives and role of general control principles in the regulation of physiological systems, exercise and the fatigue process - The Integrative Governor theory.

    Science.gov (United States)

    St Clair Gibson, A; Swart, J; Tucker, R

    2018-02-01

    Either central (brain) or peripheral (body physiological system) control mechanisms, or a combination of these, have been championed in the last few decades in the field of Exercise Sciences as how physiological activity and fatigue processes are regulated. In this review, we suggest that the concept of 'central' or 'peripheral' mechanisms are both artificial constructs that have 'straight-jacketed' research in the field, and rather that competition between psychological and physiological homeostatic drives is central to the regulation of both, and that governing principles, rather than distinct physical processes, underpin all physical system and exercise regulation. As part of the Integrative Governor theory we develop in this review, we suggest that both psychological and physiological drives and requirements are underpinned by homeostatic principles, and that regulation of the relative activity of each is by dynamic negative feedback activity, as the fundamental general operational controller. Because of this competitive, dynamic interplay, we propose that the activity in all systems will oscillate, that these oscillations create information, and comparison of this oscillatory information with either prior information, current activity, or activity templates create efferent responses that change the activity in the different systems in a similarly dynamic manner. Changes in a particular system are always the result of perturbations occurring outside the system itself, the behavioural causative 'history' of this external activity will be evident in the pattern of the oscillations, and awareness of change occurs as a result of unexpected rather than planned change in physiological activity or psychological state.

  5. Emerging Links between Homeostatic Synaptic Plasticity and Neurological Disease

    Directory of Open Access Journals (Sweden)

    Dion eDickman

    2013-11-01

    Full Text Available Homeostatic signaling systems are ubiquitous forms of biological regulation, having been studied for hundreds of years in the context of diverse physiological processes including body temperature and osmotic balance. However, only recently has this concept been brought to the study of excitatory and inhibitory electrical activity that the nervous system uses to establish and maintain stable communication. Synapses are a primary target of neuronal regulation with a variety of studies over the past 15 years demonstrating that these cellular junctions are under bidirectional homeostatic control. Recent work from an array of diverse systems and approaches has revealed exciting new links between homeostatic synaptic plasticity and a variety of seemingly disparate neurological and psychiatric diseases. These include autism spectrum disorders, intellectual disabilities, schizophrenia, and Fragile X Syndrome. Although the molecular mechanisms through which defective homeostatic signaling may lead to disease pathogenesis remain unclear, rapid progress is likely to be made in the coming years using a powerful combination of genetic, imaging, electrophysiological, and next generation sequencing approaches. Importantly, understanding homeostatic synaptic plasticity at a cellular and molecular level may lead to developments in new therapeutic innovations to treat these diseases. In this review we will examine recent studies that demonstrate homeostatic control of postsynaptic protein translation, retrograde signaling, and presynaptic function that may contribute to the etiology of complex neurological and psychiatric diseases.

  6. Ca2+-permeable AMPA receptors in homeostatic synaptic plasticity

    Directory of Open Access Journals (Sweden)

    Hey-Kyoung eLee

    2012-02-01

    Full Text Available Neurons possess diverse mechanisms of homeostatic adaptation to overall changes in neural and synaptic activity, which are critical for proper brain functions. Homeostatic regulation of excitatory synapses has been studied in the context of synaptic scaling, which allows neurons to adjust their excitatory synaptic gain to maintain their activity within a dynamic range. Recent evidence suggests that one of the main mechanisms underlying synaptic scaling is by altering the function of postsynaptic AMPA receptors (AMPARs, including synaptic expression of Ca2+-permeable (CP- AMPARs. CP-AMPARs endow synapses with unique properties, which may benefit adaptation of neurons to periods of inactivity as would occur when a major input is lost. This review will summarize how synaptic expression of CP-AMPARs is regulated during homeostatic synaptic plasticity in the context of synaptic scaling, and will address the potential functional consequences of altering synaptic CP-AMPAR content.

  7. Homeostatic role of heterosynaptic plasticity: Models and experiments

    Directory of Open Access Journals (Sweden)

    Marina eChistiakova

    2015-07-01

    Full Text Available Homosynaptic Hebbian-type plasticity provides a cellular mechanism of learning and refinement of connectivity during development in a variety of biological systems. In this review we argue that a complimentary form of plasticity - heterosynaptic plasticity - represents a necessary cellular component for homeostatic regulation of synaptic weights and neuronal activity. The required properties of a homeostatic mechanism which acutely constrains the runaway dynamics imposed by Hebbian associative plasticity have been well-articulated by theoretical and modeling studies. Such mechanism(s should robustly support the stability of operation of neuronal networks and synaptic competition, include changes at non-active synapses, and operate on a similar time scale to Hebbian-type plasticity. The experimentally observed properties of heterosynaptic plasticity have introduced it as a strong candidate to fulfill this homeostatic role. Subsequent modeling studies which incorporate heterosynaptic plasticity into model neurons with Hebbian synapses (utilizing an STDP learning rule have confirmed its ability to robustly provide stability and competition. In contrast, properties of homeostatic synaptic scaling, which is triggered by extreme and long lasting (hours and days changes of neuronal activity, do not fit two crucial requirements for a hypothetical homeostatic mechanism needed to provide stability of operation in the face of on-going synaptic changes driven by Hebbian-type learning rules. Both the trigger and the time scale of homeostatic synaptic scaling are fundamentally different from those of the Hebbian-type plasticity. We conclude that heterosynaptic plasticity, which is triggered by the same episodes of strong postsynaptic activity and operates on the same time scale as Hebbian-type associative plasticity, is ideally suited to serve homeostatic role during on-going synaptic plasticity.

  8. Homeostatic Agent for General Environment

    Science.gov (United States)

    Yoshida, Naoto

    2018-03-01

    One of the essential aspect in biological agents is dynamic stability. This aspect, called homeostasis, is widely discussed in ethology, neuroscience and during the early stages of artificial intelligence. Ashby's homeostats are general-purpose learning machines for stabilizing essential variables of the agent in the face of general environments. However, despite their generality, the original homeostats couldn't be scaled because they searched their parameters randomly. In this paper, first we re-define the objective of homeostats as the maximization of a multi-step survival probability from the view point of sequential decision theory and probabilistic theory. Then we show that this optimization problem can be treated by using reinforcement learning algorithms with special agent architectures and theoretically-derived intrinsic reward functions. Finally we empirically demonstrate that agents with our architecture automatically learn to survive in a given environment, including environments with visual stimuli. Our survival agents can learn to eat food, avoid poison and stabilize essential variables through theoretically-derived single intrinsic reward formulations.

  9. Interoception, homeostatic emotions and sympathovagal balance.

    Science.gov (United States)

    Strigo, Irina A; Craig, Arthur D Bud

    2016-11-19

    We briefly review the evidence for distinct neuroanatomical substrates that underlie interoception in humans, and we explain how they substantialize feelings from the body (in the insular cortex) that are conjoined with homeostatic motivations that guide adaptive behaviours (in the cingulate cortex). This hierarchical sensorimotor architecture coincides with the limbic cortical architecture that underlies emotions, and thus we regard interoceptive feelings and their conjoint motivations as homeostatic emotions We describe how bivalent feelings, emotions and sympathovagal balance can be organized and regulated efficiently in the bicameral forebrain as asymmetric positive/negative, approach/avoidance and parasympathetic/sympathetic components. We provide original evidence supporting this organization from studies of cardiorespiratory vagal activity in monkeys and functional imaging studies in healthy humans showing activation modulated by paced breathing and passively viewed emotional images. The neuroanatomical architecture of interoception provides deep insight into the functional organization of all emotional feelings and behaviours in humans.This article is part of the themed issue 'Interoception beyond homeostasis: affect, cognition and mental health'. © 2016 The Author(s).

  10. AMPA Receptor Trafficking in Homeostatic Synaptic Plasticity: Functional Molecules and Signaling Cascades

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    Guan Wang

    2012-01-01

    Full Text Available Homeostatic synaptic plasticity is a negative-feedback response employed to compensate for functional disturbances in the nervous system. Typically, synaptic activity is strengthened when neuronal firing is chronically suppressed or weakened when neuronal activity is chronically elevated. At both the whole cell and entire network levels, activity manipulation leads to a global up- or downscaling of the transmission efficacy of all synapses. However, the homeostatic response can also be induced locally at subcellular regions or individual synapses. Homeostatic synaptic scaling is expressed mainly via the regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR trafficking and synaptic expression. Here we review the recently identified functional molecules and signaling pathways that are involved in homeostatic plasticity, especially the homeostatic regulation of AMPAR localization at excitatory synapses.

  11. Homeostatic disturbances and human aggression.

    Science.gov (United States)

    Naisberg, Y

    1997-04-01

    A new model on the nature of human aggression is presented. It rests on the assumption that a pre-established organismic homeostatic modification, based on a decrease in neuronal membrane electric threshold, causes neural facilitation. In turn, this influences the cut-off phenomenon, in particular, neuronal network and therefore either inherited schemata representation, or acquired engram linkage programs run inadequately. These programs adjust the response to working loads of the eight normal serial stages in the body's operational regime activity. The effect of facilitation on these programs is: (1) loss of discrimination when approaching involuntary multi-stimuli; (2) the corruption of acquired engram linkage portions used in neural networks; (3) significant reduction of the voluntary degrees of freedom of response, thus narrowing the body's operational regime activity. This results in damage to certain cognitive links from some acquired engram linkages, enhancing impulse-like program mismatches and causing a unilateral 'fight' response of an aggressive nature.

  12. Homeostatic Immunity and the Microbiota.

    Science.gov (United States)

    Belkaid, Yasmine; Harrison, Oliver J

    2017-04-18

    The microbiota plays a fundamental role in the induction, education, and function of the host immune system. In return, the host immune system has evolved multiple means by which to maintain its symbiotic relationship with the microbiota. The maintenance of this dialogue allows the induction of protective responses to pathogens and the utilization of regulatory pathways involved in the sustained tolerance to innocuous antigens. The ability of microbes to set the immunological tone of tissues, both locally and systemically, requires tonic sensing of microbes and complex feedback loops between innate and adaptive components of the immune system. Here we review the dominant cellular mediators of these interactions and discuss emerging themes associated with our current understanding of the homeostatic immunological dialogue between the host and its microbiota. Published by Elsevier Inc.

  13. Stable Control of Firing Rate Mean and Variance by Dual Homeostatic Mechanisms.

    Science.gov (United States)

    Cannon, Jonathan; Miller, Paul

    2017-12-01

    Homeostatic processes that provide negative feedback to regulate neuronal firing rates are essential for normal brain function. Indeed, multiple parameters of individual neurons, including the scale of afferent synapse strengths and the densities of specific ion channels, have been observed to change on homeostatic time scales to oppose the effects of chronic changes in synaptic input. This raises the question of whether these processes are controlled by a single slow feedback variable or multiple slow variables. A single homeostatic process providing negative feedback to a neuron's firing rate naturally maintains a stable homeostatic equilibrium with a characteristic mean firing rate; but the conditions under which multiple slow feedbacks produce a stable homeostatic equilibrium have not yet been explored. Here we study a highly general model of homeostatic firing rate control in which two slow variables provide negative feedback to drive a firing rate toward two different target rates. Using dynamical systems techniques, we show that such a control system can be used to stably maintain a neuron's characteristic firing rate mean and variance in the face of perturbations, and we derive conditions under which this happens. We also derive expressions that clarify the relationship between the homeostatic firing rate targets and the resulting stable firing rate mean and variance. We provide specific examples of neuronal systems that can be effectively regulated by dual homeostasis. One of these examples is a recurrent excitatory network, which a dual feedback system can robustly tune to serve as an integrator.

  14. Homeostatic reinforcement learning for integrating reward collection and physiological stability.

    Science.gov (United States)

    Keramati, Mehdi; Gutkin, Boris

    2014-12-02

    Efficient regulation of internal homeostasis and defending it against perturbations requires adaptive behavioral strategies. However, the computational principles mediating the interaction between homeostatic and associative learning processes remain undefined. Here we use a definition of primary rewards, as outcomes fulfilling physiological needs, to build a normative theory showing how learning motivated behaviors may be modulated by internal states. Within this framework, we mathematically prove that seeking rewards is equivalent to the fundamental objective of physiological stability, defining the notion of physiological rationality of behavior. We further suggest a formal basis for temporal discounting of rewards by showing that discounting motivates animals to follow the shortest path in the space of physiological variables toward the desired setpoint. We also explain how animals learn to act predictively to preclude prospective homeostatic challenges, and several other behavioral patterns. Finally, we suggest a computational role for interaction between hypothalamus and the brain reward system.

  15. The homeostasis solution – Mechanical homeostasis in architecturally homeostatic buildings

    International Nuclear Information System (INIS)

    Wang, Lin-Shu; Ma, Peizheng

    2016-01-01

    Highlights: • Architectural homeostatic buildings (AHBs) make sense because of the laws of physics. • However, high efficiency can be obtained only with AHBs and equipment considered as systems. • Mechanical homeostasis facilitates AHB-equipment system synergy with heat extraction. • Entropically speaking a building needs neither energy nor a fixed amount of heat, but its homeostatic existence. • Homeostatic buildings can reduce building energy consumption from 80% to 90%. - Abstract: We already know, for energy-saving potential, the necessary architectural features in well-designed buildings: high performance building envelope, sufficient interior thermal mass, and hydronic-network activated radiant surfaces for cooling and heating. Buildings with these features may be referred to as architecturally homeostatic buildings (AHBs); such a building-system is thermally semi-autonomous in the sense that its temperature variation stays within a certain range even without conditioning equipment, and, with conditioning equipment in operation, its thermal regulation is handled by its hydronic heat-distribution-network for controlling the temperature level of the building. At the present time conventional HVAC equipment is used for maintaining the heat-distribution-network: this arrangement, however, has resulted in great energy saving only for AHBs with accessible natural water bodies. In operation of general AHBs, a case is made here for a new kind of mechanical equipment having the attribute of mechanical homeostasis (MH). MH is a new energy transformation concept in a triadic framework. Superlative energy efficiency is predicted as a result of combined improvements in higher triadCOPs and lower total (inducted + removed) heat rates—evincing existence of synergy in architectural and mechanical homeostasis, which together will be referred to as the homeostasis solution.

  16. Neural ECM molecules in axonal and synaptic homeostatic plasticity.

    Science.gov (United States)

    Frischknecht, Renato; Chang, Kae-Jiun; Rasband, Matthew N; Seidenbecher, Constanze I

    2014-01-01

    Neural circuits can express different forms of plasticity. So far, Hebbian synaptic plasticity was considered the most important plastic phenomenon, but over the last decade, homeostatic mechanisms gained more interest because they can explain how a neuronal network maintains stable baseline function despite multiple plastic challenges, like developmental plasticity, learning, or lesion. Such destabilizing influences can be counterbalanced by the mechanisms of homeostatic plasticity, which restore the stability of neuronal circuits. Synaptic scaling is a mechanism in which neurons can detect changes in their own firing rates through a set of molecular sensors that then regulate receptor trafficking to scale the accumulation of glutamate receptors at synaptic sites. Additional homeostatic mechanisms allow local changes in synaptic activation to generate local synaptic adaptations and network-wide changes in activity, which lead to adjustments in the balance between excitation and inhibition. The molecular pathways underlying these forms of homeostatic plasticity are currently under intense investigation, and it becomes clear that the extracellular matrix (ECM) of the brain, which surrounds individual neurons and integrates them into the tissue, is an important element in these processes. As a highly dynamic structure, which can be remodeled and degraded in an activity-dependent manner and in concerted action of neurons and glial cells, it can on one hand promote structural and functional plasticity and on the other hand stabilize neural microcircuits. This chapter highlights the composition of brain ECM with particular emphasis on perisynaptic and axonal matrix formations and its involvement in plastic and adaptive processes of the central nervous system.

  17. Sleep and energy balance: Interactive homeostatic systems.

    Science.gov (United States)

    Vanitallie, Theodore B

    2006-10-01

    For early humans, acquisition of food by hunting and/or gathering was a hunger-driven process requiring vigilance and (often) strenuous physical effort during daylight hours. To sustain such activities, hunter-gatherers also needed periodic rest and sleep-pursuits most effectively undertaken at night. In recent years, research has given us new insights into the physiologic underpinnings of these behaviors. Specifically, evidence has been uncovered indicating that the homeostatic regulation of food intake on the one hand and that of sleep on the other hand, are intertwined. Thus, carefully performed studies of eating behavior in rats indicate that duration of sleep after ingestion of a meal is closely correlated to the meal's energy content. In 1999, it was discovered that mice and dogs functionally deficient in the appetite-stimulating hormone, hypocretin-1, become narcoleptic, suggesting the existence of a "hard-wired" connection between regulation of hunger and satiety and regulation of sleep. Administered into the nucleus accumbens shell, hypocretin-1 induces feeding and locomotor activity in Sprague-Dawley rats. Hypocretin neurons in the hypothalamus are responsive to metabolic cues capable of signaling nutritional status. The suprachiasmatic nucleus, the body's principal circadian clock, exchanges information with the hypocretin system about the light/dark cycle and the body's metabolic condition. Circadian Clock mutant mice exhibit an attenuated diurnal feeding rhythm and become hyperphagic and obese. Both disruption of the circadian cycle and sleep deprivation can affect energy balance and, over time, may bring about substantial changes in body composition. Although there is growing evidence that interleukin-6 and several other proinflammatory cytokines are "sleep factors" that also affect energy balance, any possible role they might have in coordinating sleep/wakefulness with food-motivated behavior awaits clarification. Yet, the evidence is increasingly

  18. Social insect symbionts: evolution in homeostatic fortresses

    DEFF Research Database (Denmark)

    Hughes, David P; Pierce, Naomi E; Boomsma, Jacobus J

    2008-01-01

    The massive environmentally buffered nests of some social insects can contain millions of individuals and a wide variety of parasites, commensals and mutualists. We suggest that the ways in which these homeostatic fortress environments affect the evolution of social insect symbionts are relevant ...

  19. Adipose Tissue Remodeling as Homeostatic Inflammation

    Directory of Open Access Journals (Sweden)

    Michiko Itoh

    2011-01-01

    Full Text Available Evidence has accumulated indicating that obesity is associated with a state of chronic, low-grade inflammation. Obese adipose tissue is characterized by dynamic changes in cellular composition and function, which may be referred to as “adipose tissue remodeling”. Among stromal cells in the adipose tissue, infiltrated macrophages play an important role in adipose tissue inflammation and systemic insulin resistance. We have demonstrated that a paracrine loop involving saturated fatty acids and tumor necrosis factor-α derived from adipocytes and macrophages, respectively, aggravates obesity-induced adipose tissue inflammation. Notably, saturated fatty acids, which are released from hypertrophied adipocytes via the macrophage-induced lipolysis, serve as a naturally occurring ligand for Toll-like receptor 4 complex, thereby activating macrophages. Such a sustained interaction between endogenous ligands derived from parenchymal cells and pathogen sensors expressed in stromal immune cells should lead to chronic inflammatory responses ranging from the basal homeostatic state to diseased tissue remodeling, which may be referred to as “homeostatic inflammation”. We, therefore, postulate that adipose tissue remodeling may represent a prototypic example of homeostatic inflammation. Understanding the molecular mechanism underlying homeostatic inflammation may lead to the identification of novel therapeutic strategies to prevent or treat obesity-related complications.

  20. A Basic Set of Homeostatic Controller Motifs

    Science.gov (United States)

    Drengstig, T.; Jolma, I.W.; Ni, X.Y.; Thorsen, K.; Xu, X.M.; Ruoff, P.

    2012-01-01

    Adaptation and homeostasis are essential properties of all living systems. However, our knowledge about the reaction kinetic mechanisms leading to robust homeostatic behavior in the presence of environmental perturbations is still poor. Here, we describe, and provide physiological examples of, a set of two-component controller motifs that show robust homeostasis. This basic set of controller motifs, which can be considered as complete, divides into two operational work modes, termed as inflow and outflow control. We show how controller combinations within a cell can integrate uptake and metabolization of a homeostatic controlled species and how pathways can be activated and lead to the formation of alternative products, as observed, for example, in the change of fermentation products by microorganisms when the supply of the carbon source is altered. The antagonistic character of hormonal control systems can be understood by a combination of inflow and outflow controllers. PMID:23199928

  1. Integrating intervention targets offered by homeostatic theory.

    Science.gov (United States)

    Annunziato, Rachel A; Grossman, Stephanie L

    2016-01-01

    Marks presents "homeostatic theory" which proposes that weight gain is fostered by a "Circle of Discontent" consisting of body dissatisfaction, negative affect, and overconsumption. This innovative framework offers potential intervention approaches, including victim-blaming, stigma, and discrimination, as well as devalorizing the thin-ideal. Our article discusses possible ways that clinical health psychologists based in university settings may be uniquely positioned to consider and implement large-scale programs that have shown great promise for addressing these core issues.

  2. Human Homeostatic Control Matrix in Norm

    Directory of Open Access Journals (Sweden)

    Alexander G. Kruglov

    2016-09-01

    Full Text Available We undertook our research to study and systemize the relationship between hemodynamics and biochemical parameters of arterial and venous blood in healthy people. Hemodynamic and biochemical characteristics were obtained through a probe by using catheterization in various vascular areas (aorta, brain, heart, lungs, and liver. Correlation and factor analyses were conducted to study the relationship between the obtained characteristics of the regional and systemic blood flow. Due to the nature of the correlation analysis, the significant (p<0.05 relation signs (+, 0, - without regard to their power were considered. The obtained results suggested that there are sets of both intra-organ and system regulatory relationships between metabolic and hemodynamic characteristics. The complex of relationships among the studied parameters makes it possible to maintain the homeostatic equilibrium in the body. The psychophysiological control system includes the subsystems we described: 1 the cardiac-hepatic-pulmonary complex having properties of the metabolic and hemodynamic information field providing biological stability of the homeostasis; any significant imbalance of its elements triggers afferent information flows actualizing an afferent synthesis; 2 the mind forming gradient patterns of targeted behavior to eliminate metabolic imbalance, to achieve goals both as coded biological parameters and as the highest forms of behavior, to reach the ultimate goal: parametric, homeostatic equilibrium in the “biosphere” of the human body. By using the results of our research and the complex of dynamic relationships in human homeostasis, we built a homeostatic control matrix (HCM.

  3. Integrating intervention targets offered by homeostatic theory

    Directory of Open Access Journals (Sweden)

    Rachel A Annunziato

    2016-02-01

    Full Text Available Marks presents “homeostatic theory” which proposes that weight gain is fostered by a “Circle of Discontent” consisting of body dissatisfaction, negative affect, and overconsumption. This innovative framework offers potential intervention approaches, including victim-blaming, stigma, and discrimination, as well as devalorizing the thin-ideal. Our article discusses possible ways that clinical health psychologists based in university settings may be uniquely positioned to consider and implement large-scale programs that have shown great promise for addressing these core issues.

  4. Propagation of Homeostatic Sleep Signals by Segregated Synaptic Microcircuits of the Drosophila Mushroom Body.

    Science.gov (United States)

    Sitaraman, Divya; Aso, Yoshinori; Jin, Xin; Chen, Nan; Felix, Mario; Rubin, Gerald M; Nitabach, Michael N

    2015-11-16

    The Drosophila mushroom body (MB) is a key associative memory center that has also been implicated in the control of sleep. However, the identity of MB neurons underlying homeostatic sleep regulation, as well as the types of sleep signals generated by specific classes of MB neurons, has remained poorly understood. We recently identified two MB output neuron (MBON) classes whose axons convey sleep control signals from the MB to converge in the same downstream target region: a cholinergic sleep-promoting MBON class and a glutamatergic wake-promoting MBON class. Here, we deploy a combination of neurogenetic, behavioral, and physiological approaches to identify and mechanistically dissect sleep-controlling circuits of the MB. Our studies reveal the existence of two segregated excitatory synaptic microcircuits that propagate homeostatic sleep information from different populations of intrinsic MB "Kenyon cells" (KCs) to specific sleep-regulating MBONs: sleep-promoting KCs increase sleep by preferentially activating the cholinergic MBONs, while wake-promoting KCs decrease sleep by preferentially activating the glutamatergic MBONs. Importantly, activity of the sleep-promoting MB microcircuit is increased by sleep deprivation and is necessary for homeostatic rebound sleep (i.e., the increased sleep that occurs after, and in compensation for, sleep lost during deprivation). These studies reveal for the first time specific functional connections between subsets of KCs and particular MBONs and establish the identity of synaptic microcircuits underlying transmission of homeostatic sleep signals in the MB. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. A postsynaptic PI3K-cII dependent signaling controller for presynaptic homeostatic plasticity

    Science.gov (United States)

    Hauswirth, Anna G; Ford, Kevin J; Wang, Tingting; Fetter, Richard D; Tong, Amy

    2018-01-01

    Presynaptic homeostatic plasticity stabilizes information transfer at synaptic connections in organisms ranging from insect to human. By analogy with principles of engineering and control theory, the molecular implementation of PHP is thought to require postsynaptic signaling modules that encode homeostatic sensors, a set point, and a controller that regulates transsynaptic negative feedback. The molecular basis for these postsynaptic, homeostatic signaling elements remains unknown. Here, an electrophysiology-based screen of the Drosophila kinome and phosphatome defines a postsynaptic signaling platform that includes a required function for PI3K-cII, PI3K-cIII and the small GTPase Rab11 during the rapid and sustained expression of PHP. We present evidence that PI3K-cII localizes to Golgi-derived, clathrin-positive vesicles and is necessary to generate an endosomal pool of PI(3)P that recruits Rab11 to recycling endosomal membranes. A morphologically distinct subdivision of this platform concentrates postsynaptically where we propose it functions as a homeostatic controller for retrograde, trans-synaptic signaling. PMID:29303480

  6. BACE1 Is Necessary for Experience-Dependent Homeostatic Synaptic Plasticity in Visual Cortex

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    Emily Petrus

    2014-01-01

    Full Text Available Alzheimer’s disease (AD is the most common form of age-related dementia, which is thought to result from overproduction and/or reduced clearance of amyloid-beta (Aβ peptides. Studies over the past few decades suggest that Aβ is produced in an activity-dependent manner and has physiological relevance to normal brain functions. Similarly, physiological functions for β- and γ-secretases, the two key enzymes that produce Aβ by sequentially processing the amyloid precursor protein (APP, have been discovered over recent years. In particular, activity-dependent production of Aβ has been suggested to play a role in homeostatic regulation of excitatory synaptic function. There is accumulating evidence that activity-dependent immediate early gene Arc is an activity “sensor,” which acts upstream of Aβ production and triggers AMPA receptor endocytosis to homeostatically downregulate the strength of excitatory synaptic transmission. We previously reported that Arc is critical for sensory experience-dependent homeostatic reduction of excitatory synaptic transmission in the superficial layers of visual cortex. Here we demonstrate that mice lacking the major neuronal β-secretase, BACE1, exhibit a similar phenotype: stronger basal excitatory synaptic transmission and failure to adapt to changes in visual experience. Our results indicate that BACE1 plays an essential role in sensory experience-dependent homeostatic synaptic plasticity in the neocortex.

  7. Blaming the Brain for Obesity: Integration of Hedonic and Homeostatic Mechanisms.

    Science.gov (United States)

    Berthoud, Hans-Rudolf; Münzberg, Heike; Morrison, Christopher D

    2017-05-01

    The brain plays a key role in the controls of energy intake and expenditure, and many genes associated with obesity are expressed in the central nervous system. Technological and conceptual advances in both basic and clinical neurosciences have expanded the traditional view of homeostatic regulation of body weight by mainly the hypothalamus to include hedonic controls of appetite by cortical and subcortical brain areas processing external sensory information, reward, cognition, and executive functions. Hedonic controls interact with homeostatic controls to regulate body weight in a flexible and adaptive manner that takes environmental conditions into account. This new conceptual framework has several important implications for the treatment of obesity. Because much of this interactive neural processing is outside awareness, cognitive restraint in a world of plenty is made difficult and prevention and treatment of obesity should be more rationally directed to the complex and often redundant mechanisms underlying this interaction. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

  8. How voltage-gated calcium channels gate forms of homeostatic synaptic plasticity

    Directory of Open Access Journals (Sweden)

    C. Andrew eFrank

    2014-02-01

    Full Text Available Throughout life, animals face a variety of challenges such as developmental growth, the presence of toxins, or changes in temperature. Neuronal circuits and synapses respond to challenges by executing an array of neuroplasticity paradigms. Some paradigms allow neurons to up- or downregulate activity outputs, while countervailing ones ensure that outputs remain within appropriate physiological ranges. A growing body of evidence suggests that homeostatic synaptic plasticity (HSP is critical in the latter case. Voltage-gated calcium channels gate forms of HSP. Presynaptically, the aggregate data show that when synapse activity is weakened, homeostatic signaling systems can act to correct impairments, in part by increasing calcium influx through presynaptic CaV2-type channels. Increased calcium influx is often accompanied by parallel increases in the size of active zones and the size of the readily releasable pool of presynaptic vesicles. These changes coincide with homeostatic enhancements of neurotransmitter release. Postsynaptically, there is a great deal of evidence that reduced network activity and loss of calcium influx through CaV1-type calcium channels also results in adaptive homeostatic signaling. Some adaptations drive presynaptic enhancements of vesicle pool size and turnover rate via retrograde signaling, as well as de novo insertion of postsynaptic neurotransmitter receptors. Enhanced calcium influx through CaV1 after network activation or single cell stimulation can elicit the opposite response – homeostatic depression via removal of excitatory receptors.There exist intriguing links between HSP and calcium channelopathies – such as forms of epilepsy, migraine, ataxia, and myasthenia. The episodic nature of some of these disorders suggests alternating periods of stable and unstable function. Uncovering information about how calcium channels are regulated in the context of HSP could be relevant toward understanding these and other

  9. How voltage-gated calcium channels gate forms of homeostatic synaptic plasticity.

    Science.gov (United States)

    Frank, C Andrew

    2014-01-01

    Throughout life, animals face a variety of challenges such as developmental growth, the presence of toxins, or changes in temperature. Neuronal circuits and synapses respond to challenges by executing an array of neuroplasticity paradigms. Some paradigms allow neurons to up- or downregulate activity outputs, while countervailing ones ensure that outputs remain within appropriate physiological ranges. A growing body of evidence suggests that homeostatic synaptic plasticity (HSP) is critical in the latter case. Voltage-gated calcium channels gate forms of HSP. Presynaptically, the aggregate data show that when synapse activity is weakened, homeostatic signaling systems can act to correct impairments, in part by increasing calcium influx through presynaptic CaV2-type channels. Increased calcium influx is often accompanied by parallel increases in the size of active zones and the size of the readily releasable pool of presynaptic vesicles. These changes coincide with homeostatic enhancements of neurotransmitter release. Postsynaptically, there is a great deal of evidence that reduced network activity and loss of calcium influx through CaV1-type calcium channels also results in adaptive homeostatic signaling. Some adaptations drive presynaptic enhancements of vesicle pool size and turnover rate via retrograde signaling, as well as de novo insertion of postsynaptic neurotransmitter receptors. Enhanced calcium influx through CaV1 after network activation or single cell stimulation can elicit the opposite response-homeostatic depression via removal of excitatory receptors. There exist intriguing links between HSP and calcium channelopathies-such as forms of epilepsy, migraine, ataxia, and myasthenia. The episodic nature of some of these disorders suggests alternating periods of stable and unstable function. Uncovering information about how calcium channels are regulated in the context of HSP could be relevant toward understanding these and other disorders.

  10. Dynamic Networks of Human Homeostatic Control in Norm

    Directory of Open Access Journals (Sweden)

    Veronica A. Sherman

    2016-06-01

    Full Text Available The research has been undertaken to study the regional and common relationships between hemodynamic and metabolic parameters of human body functioning in individuals without clinical signs of pathology (in "norm". Indicators of hemodynamics and metabolism were obtained by catheterization in a variety of areas: LV, RV, RA, CS, Ao, fixed SS, IJV, SVC, right VH, renal vena, and PA. Correlation and factor analyses were conducted for the study of: 1 the relationship between biochemical parameters in the blood stream, 2 the relationship between hemodynamic parameters, 3 relationship between the hemodynamic and biochemical parameters. Due to the nature of the correlation analysis, the significant (p<0.05 relation signs (+, 0, - without regard to their power were considered. The obtained results in the study of brain blood flow, heart, liver, lungs, kidneys suggested the existence of the primary homeostatic control of the factors determining rheological and thrombogenic properties of blood; the regulation of brain gas exchange and intracranial venous pressure by the minimum level of pressure in the cerebral outflow pathway—the pressure in RA; the regulating relationships between blood flow in CS with blood flow in HV, RA, SS, and LV; and the existence of a synergistic complex of the relationships between the studied biochemical and hemodynamic characteristics that form the human homeostasis control matrix in norm.

  11. Operation of a homeostatic sleep switch.

    Science.gov (United States)

    Pimentel, Diogo; Donlea, Jeffrey M; Talbot, Clifford B; Song, Seoho M; Thurston, Alexander J F; Miesenböck, Gero

    2016-08-18

    Sleep disconnects animals from the external world, at considerable risks and costs that must be offset by a vital benefit. Insight into this mysterious benefit will come from understanding sleep homeostasis: to monitor sleep need, an internal bookkeeper must track physiological changes that are linked to the core function of sleep. In Drosophila, a crucial component of the machinery for sleep homeostasis is a cluster of neurons innervating the dorsal fan-shaped body (dFB) of the central complex. Artificial activation of these cells induces sleep, whereas reductions in excitability cause insomnia. dFB neurons in sleep-deprived flies tend to be electrically active, with high input resistances and long membrane time constants, while neurons in rested flies tend to be electrically silent. Correlative evidence thus supports the simple view that homeostatic sleep control works by switching sleep-promoting neurons between active and quiescent states. Here we demonstrate state switching by dFB neurons, identify dopamine as a neuromodulator that operates the switch, and delineate the switching mechanism. Arousing dopamine caused transient hyperpolarization of dFB neurons within tens of milliseconds and lasting excitability suppression within minutes. Both effects were transduced by Dop1R2 receptors and mediated by potassium conductances. The switch to electrical silence involved the downregulation of voltage-gated A-type currents carried by Shaker and Shab, and the upregulation of voltage-independent leak currents through a two-pore-domain potassium channel that we term Sandman. Sandman is encoded by the CG8713 gene and translocates to the plasma membrane in response to dopamine. dFB-restricted interference with the expression of Shaker or Sandman decreased or increased sleep, respectively, by slowing the repetitive discharge of dFB neurons in the ON state or blocking their entry into the OFF state. Biophysical changes in a small population of neurons are thus linked to the

  12. Homeostatic mechanisms in dopamine synthesis and release: a mathematical model

    Directory of Open Access Journals (Sweden)

    Nijhout H Frederik

    2009-09-01

    Full Text Available Abstract Background Dopamine is a catecholamine that is used as a neurotransmitter both in the periphery and in the central nervous system. Dysfunction in various dopaminergic systems is known to be associated with various disorders, including schizophrenia, Parkinson's disease, and Tourette's syndrome. Furthermore, microdialysis studies have shown that addictive drugs increase extracellular dopamine and brain imaging has shown a correlation between euphoria and psycho-stimulant-induced increases in extracellular dopamine 1. These consequences of dopamine dysfunction indicate the importance of maintaining dopamine functionality through homeostatic mechanisms that have been attributed to the delicate balance between synthesis, storage, release, metabolism, and reuptake. Methods We construct a mathematical model of dopamine synthesis, release, and reuptake and use it to study homeostasis in single dopaminergic neuron terminals. We investigate the substrate inhibition of tyrosine hydroxylase by tyrosine, the consequences of the rapid uptake of extracellular dopamine by the dopamine transporters, and the effects of the autoreceoptors on dopaminergic function. The main focus is to understand the regulation and control of synthesis and release and to explicate and interpret experimental findings. Results We show that the substrate inhibition of tyrosine hydroxylase by tyrosine stabilizes cytosolic and vesicular dopamine against changes in tyrosine availability due to meals. We find that the autoreceptors dampen the fluctuations in extracellular dopamine caused by changes in tyrosine hydroxylase expression and changes in the rate of firing. We show that short bursts of action potentials create significant dopamine signals against the background of tonic firing. We explain the observed time courses of extracellular dopamine responses to stimulation in wild type mice and mice that have genetically altered dopamine transporter densities and the observed

  13. Maternal Zinc Intakes and Homeostatic Adjustments during Pregnancy and Lactation

    OpenAIRE

    Donangelo, Carmen Marino; King, Janet C.

    2012-01-01

    Zinc plays critical roles during embryogenesis, fetal growth, and milk secretion, which increase the zinc need for pregnancy and lactation. Increased needs can be met by increasing the dietary zinc intake, along with making homeostatic adjustments in zinc utilization. Potential homeostatic adjustments include changes in circulating zinc, increased zinc absorption, decreased zinc losses, and changes in whole body zinc kinetics. Although severe zinc deficiency during pregnancy has devastating e...

  14. Phosphorylation of AMPA receptors is required for sensory deprivation-induced homeostatic synaptic plasticity.

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    Anubhuti Goel

    Full Text Available Sensory experience, and the lack thereof, can alter the function of excitatory synapses in the primary sensory cortices. Recent evidence suggests that changes in sensory experience can regulate the synaptic level of Ca(2+-permeable AMPA receptors (CP-AMPARs. However, the molecular mechanisms underlying such a process have not been determined. We found that binocular visual deprivation, which is a well-established in vivo model to produce multiplicative synaptic scaling in visual cortex of juvenile rodents, is accompanied by an increase in the phosphorylation of AMPAR GluR1 (or GluA1 subunit at the serine 845 (S845 site and the appearance of CP-AMPARs at synapses. To address the role of GluR1-S845 in visual deprivation-induced homeostatic synaptic plasticity, we used mice lacking key phosphorylation sites on the GluR1 subunit. We found that mice specifically lacking the GluR1-S845 site (GluR1-S845A mutants, which is a substrate of cAMP-dependent kinase (PKA, show abnormal basal excitatory synaptic transmission and lack visual deprivation-induced homeostatic synaptic plasticity. We also found evidence that increasing GluR1-S845 phosphorylation alone is not sufficient to produce normal multiplicative synaptic scaling. Our study provides concrete evidence that a GluR1 dependent mechanism, especially S845 phosphorylation, is a necessary pre-requisite step for in vivo homeostatic synaptic plasticity.

  15. Phosphorylation of AMPA receptors is required for sensory deprivation-induced homeostatic synaptic plasticity.

    Science.gov (United States)

    Goel, Anubhuti; Xu, Linda W; Snyder, Kevin P; Song, Lihua; Goenaga-Vazquez, Yamila; Megill, Andrea; Takamiya, Kogo; Huganir, Richard L; Lee, Hey-Kyoung

    2011-03-31

    Sensory experience, and the lack thereof, can alter the function of excitatory synapses in the primary sensory cortices. Recent evidence suggests that changes in sensory experience can regulate the synaptic level of Ca(2+)-permeable AMPA receptors (CP-AMPARs). However, the molecular mechanisms underlying such a process have not been determined. We found that binocular visual deprivation, which is a well-established in vivo model to produce multiplicative synaptic scaling in visual cortex of juvenile rodents, is accompanied by an increase in the phosphorylation of AMPAR GluR1 (or GluA1) subunit at the serine 845 (S845) site and the appearance of CP-AMPARs at synapses. To address the role of GluR1-S845 in visual deprivation-induced homeostatic synaptic plasticity, we used mice lacking key phosphorylation sites on the GluR1 subunit. We found that mice specifically lacking the GluR1-S845 site (GluR1-S845A mutants), which is a substrate of cAMP-dependent kinase (PKA), show abnormal basal excitatory synaptic transmission and lack visual deprivation-induced homeostatic synaptic plasticity. We also found evidence that increasing GluR1-S845 phosphorylation alone is not sufficient to produce normal multiplicative synaptic scaling. Our study provides concrete evidence that a GluR1 dependent mechanism, especially S845 phosphorylation, is a necessary pre-requisite step for in vivo homeostatic synaptic plasticity.

  16. EEA1 restores homeostatic synaptic plasticity in hippocampal neurons from Rett syndrome mice.

    Science.gov (United States)

    Xu, Xin; Pozzo-Miller, Lucas

    2017-08-15

    Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in MECP2, the gene encoding the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). Mecp2 deletion in mice results in an imbalance of excitation and inhibition in hippocampal neurons, which affects 'Hebbian' synaptic plasticity. We show that Mecp2-deficient neurons also lack homeostatic synaptic plasticity, likely due to reduced levels of EEA1, a protein involved in AMPA receptor endocytosis. Expression of EEA1 restored homeostatic synaptic plasticity in Mecp2-deficient neurons, providing novel targets of intervention in Rett syndrome. Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in MECP2, the gene encoding the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). Deletion of Mecp2 in mice results in an imbalance of synaptic excitation and inhibition in hippocampal pyramidal neurons, which affects 'Hebbian' long-term synaptic plasticity. Since the excitatory-inhibitory balance is maintained by homeostatic mechanisms, we examined the role of MeCP2 in homeostatic synaptic plasticity (HSP) at excitatory synapses. Negative feedback HSP, also known as synaptic scaling, maintains the global synaptic strength of individual neurons in response to sustained alterations in neuronal activity. Hippocampal neurons from Mecp2 knockout (KO) mice do not show the characteristic homeostatic scaling up of the amplitude of miniature excitatory postsynaptic currents (mEPSCs) and of synaptic levels of the GluA1 subunit of AMPA-type glutamate receptors after 48 h silencing with the Na + channel blocker tetrodotoxin. This deficit in HSP is bidirectional because Mecp2 KO neurons also failed to scale down mEPSC amplitudes and GluA1 synaptic levels after 48 h blockade of type A GABA receptor (GABA A R)-mediated inhibition with bicuculline. Consistent with the role of synaptic trafficking of AMPA-type of glutamate receptors in HSP, Mecp2 KO neurons

  17. Experience-dependent homeostatic synaptic plasticity in neocortex.

    Science.gov (United States)

    Whitt, Jessica L; Petrus, Emily; Lee, Hey-Kyoung

    2014-03-01

    The organism's ability to adapt to the changing sensory environment is due in part to the ability of the nervous system to change with experience. Input and synapse specific Hebbian plasticity, such as long-term potentiation (LTP) and long-term depression (LTD), are critical for sculpting the nervous system to wire its circuit in tune with the environment and for storing memories. However, these synaptic plasticity mechanisms are innately unstable and require another mode of plasticity that maintains homeostasis to allow neurons to function within a desired dynamic range. Several modes of homeostatic adaptation are known, some of which work at the synaptic level. This review will focus on the known mechanisms of experience-induced homeostatic synaptic plasticity in the neocortex and their potential function in sensory cortex plasticity. This article is part of the Special Issue entitled 'Homeostatic Synaptic Plasticity'. Copyright © 2013 Elsevier Ltd. All rights reserved.

  18. Maternal Zinc Intakes and Homeostatic Adjustments during Pregnancy and Lactation

    Directory of Open Access Journals (Sweden)

    Janet C. King

    2012-07-01

    Full Text Available Zinc plays critical roles during embryogenesis, fetal growth, and milk secretion, which increase the zinc need for pregnancy and lactation. Increased needs can be met by increasing the dietary zinc intake, along with making homeostatic adjustments in zinc utilization. Potential homeostatic adjustments include changes in circulating zinc, increased zinc absorption, decreased zinc losses, and changes in whole body zinc kinetics. Although severe zinc deficiency during pregnancy has devastating effects, systematic reviews and meta-analysis of the effect of maternal zinc supplementation on pregnancy outcomes have consistently shown a limited benefit. We hypothesize, therefore, that zinc homeostatic adjustments during pregnancy and lactation improve zinc utilization sufficiently to provide the increased zinc needs in these stages and, therefore, mitigate immediate detrimental effects due to a low zinc intake. The specific questions addressed are the following: How is zinc utilization altered during pregnancy and lactation? Are those homeostatic adjustments influenced by maternal zinc status, dietary zinc, or zinc supplementation? These questions are addressed by critically reviewing results from published human studies on zinc homeostasis during pregnancy and lactation carried out in different populations worldwide.

  19. Mitotic Diversity in Homeostatic Human Interfollicular Epidermis

    Directory of Open Access Journals (Sweden)

    Katharina Nöske

    2016-01-01

    Full Text Available Despite decades of skin research, regulation of proliferation and homeostasis in human epidermis is still insufficiently understood. To address the role of mitoses in tissue regulation, we utilized human long-term skin equivalents and systematically assessed mitoses during early epidermal development and long-term epidermal regeneration. We now demonstrate four different orientations: (1 horizontal, i.e., parallel to the basement membrane (BM and suggestive of symmetric divisions; (2 oblique with an angle of 45°–70°; or (3 perpendicular, suggestive of asymmetric division. In addition, we demonstrate a fourth substantial fraction of suprabasal mitoses, many of which are committed to differentiation (Keratin K10-positive. As verified also for normal human skin, this spatial mitotic organization is part of the regulatory program of human epidermal tissue homeostasis. As a potential marker for asymmetric division, we investigated for Numb and found that it was evenly spread in almost all undifferentiated keratinocytes, but indeed asymmetrically distributed in some mitoses and particularly frequent under differentiation-repressing low-calcium conditions. Numb deletion (stable knockdown by CRISPR/Cas9, however, did not affect proliferation, neither in a three-day follow up study by life cell imaging nor during a 14-day culture period, suggesting that Numb is not essential for the general control of keratinocyte division.

  20. Mitotic Diversity in Homeostatic Human Interfollicular Epidermis.

    Science.gov (United States)

    Nöske, Katharina; Stark, Hans-Jürgen; Nevaril, Leonard; Berning, Manuel; Langbein, Lutz; Goyal, Ashish; Diederichs, Sven; Boukamp, Petra

    2016-01-28

    Despite decades of skin research, regulation of proliferation and homeostasis in human epidermis is still insufficiently understood. To address the role of mitoses in tissue regulation, we utilized human long-term skin equivalents and systematically assessed mitoses during early epidermal development and long-term epidermal regeneration. We now demonstrate four different orientations: (1) horizontal, i.e., parallel to the basement membrane (BM) and suggestive of symmetric divisions; (2) oblique with an angle of 45°-70°; or (3) perpendicular, suggestive of asymmetric division. In addition, we demonstrate a fourth substantial fraction of suprabasal mitoses, many of which are committed to differentiation (Keratin K10-positive). As verified also for normal human skin, this spatial mitotic organization is part of the regulatory program of human epidermal tissue homeostasis. As a potential marker for asymmetric division, we investigated for Numb and found that it was evenly spread in almost all undifferentiated keratinocytes, but indeed asymmetrically distributed in some mitoses and particularly frequent under differentiation-repressing low-calcium conditions. Numb deletion (stable knockdown by CRISPR/Cas9), however, did not affect proliferation, neither in a three-day follow up study by life cell imaging nor during a 14-day culture period, suggesting that Numb is not essential for the general control of keratinocyte division.

  1. Homeostatic T Cell Expansion to Induce Anti-Tumor Autoimmunity in Breast Cancer

    National Research Council Canada - National Science Library

    Baccala, Roberto

    2007-01-01

    ... that (a) homeostatic T-cell proliferation consistently elicits anti-tumor responses; (b) irradiation is more effective than Tcell depletion by antibodies in inducing anti-tumor responses mediated by homeostatic T-cell proliferation...

  2. Cellular and Molecular Mechanisms of REM Sleep Homeostatic Drive: A Plausible Component for Behavioral Plasticity

    Directory of Open Access Journals (Sweden)

    Subimal Datta

    2017-09-01

    Full Text Available Homeostatic regulation of REM sleep drive, as measured by an increase in the number of REM sleep transitions, plays a key role in neuronal and behavioral plasticity (i.e., learning and memory. Deficits in REM sleep homeostatic drive (RSHD are implicated in the development of many neuropsychiatric disorders. Yet, the cellular and molecular mechanisms underlying this RSHD remain to be incomplete. To further our understanding of this mechanism, the current study was performed on freely moving rats to test a hypothesis that a positive interaction between extracellular-signal-regulated kinase 1 and 2 (ERK1/2 activity and brain-derived neurotrophic factor (BDNF signaling in the pedunculopontine tegmentum (PPT is a causal factor for the development of RSHD. Behavioral results of this study demonstrated that a short period (<90 min of selective REM sleep restriction (RSR exhibited a strong RSHD. Molecular analyses revealed that this increased RSHD increased phosphorylation and activation of ERK1/2 and BDNF expression in the PPT. Additionally, pharmacological results demonstrated that the application of the ERK1/2 activation inhibitor U0126 into the PPT prevented RSHD and suppressed BDNF expression in the PPT. These results, for the first time, suggest that the positive interaction between ERK1/2 and BDNF in the PPT is a casual factor for the development of RSHD. These findings provide a novel direction in understanding how RSHD-associated specific molecular changes can facilitate neuronal plasticity and memory processing.

  3. Synapse-specific and compartmentalized expression of presynaptic homeostatic potentiation.

    Science.gov (United States)

    Li, Xiling; Goel, Pragya; Chen, Catherine; Angajala, Varun; Chen, Xun; Dickman, Dion K

    2018-04-05

    Postsynaptic compartments can be specifically modulated during various forms of synaptic plasticity, but it is unclear whether this precision is shared at presynaptic terminals. Presynaptic Homeostatic Plasticity (PHP) stabilizes neurotransmission at the Drosophila neuromuscular junction, where a retrograde enhancement of presynaptic neurotransmitter release compensates for diminished postsynaptic receptor functionality. To test the specificity of PHP induction and expression, we have developed a genetic manipulation to reduce postsynaptic receptor expression at one of the two muscles innervated by a single motor neuron. We find that PHP can be induced and expressed at a subset of synapses, over both acute and chronic time scales, without influencing transmission at adjacent release sites. Further, homeostatic modulations to CaMKII, vesicle pools, and functional release sites are compartmentalized and do not spread to neighboring pre- or post-synaptic structures. Thus, both PHP induction and expression mechanisms are locally transmitted and restricted to specific synaptic compartments. © 2018, Li et al.

  4. Traditional Chinese medicine and the positive correlation with homeostatic evolution of human being: based on medical perspective.

    Science.gov (United States)

    Wang, Jie-Hua

    2012-08-01

    Adaptation is an eternal theme of biological evolution. The paper aims at exploring the conception of positive correlation between traditional Chinese medicine (TCM) and human homeostatic evolution based on medical perspective. Discussions mainly involve TCM conforming to natural laws and natural evolution of life, spontaneous harmonization of yin and yang and operating system of human self-healing, modern human immunology and human endogenous immune function in TCM, self-homeostasis of human micro-ecological state and balance mechanism on regulating base in TCM, as well as adaptation-eternal theme of biological evolution and safeguarding adaptability-value of TCM. In perspective of medicine, theory and practice of TCM are in positive correlation with human homeostatic evolution, and what TCM tries to maintain is human intrinsic adaptive capability to disease and nature. Therefore, it is the core value of TCM, which is to be further studied, explored, realized and known to the world.

  5. Homeostatic Control of the Thyroid Pituitary Axis: Perspectives for Diagnosis and Treatment

    Directory of Open Access Journals (Sweden)

    Rudolf eHoermann

    2015-11-01

    Full Text Available The long-held concept of a proportional negative feedback control between the thyroid and pituitary gland requires reconsideration in the light of more recent studies. Homeostatic equilibria depend on dynamic interrelationships between thyroid hormones and pituitary thyrotropin (TSH. They display a high degree of individuality, thyroid-state-related hierarchy and adaptive conditionality. Molecular mechanisms involve multiple feedback loops on several levels of organization, different time scales and varying conditions of their optimum operation, including a proposed feedforward motif. This supports the concept of a dampened response and multistep regulation, making the interactions between TSH, FT4 and FT3 situational and mathematically more complex. As a homeostatically integrated parameter, TSH becomes neither normatively fixed nor a precise marker of euthyroidism. This is exemplified by the therapeutic situation with L-thyroxine (L-T4 where TSH levels defined for optimum health may not apply equivalently during treatment. In particular, an FT3-FT4 dissociation, discernible FT3-TSH disjoint and conversion inefficiency have been recognised in L-T4-treated athyreotic patients. In addition to regulating T4 production, TSH appears to play an essential role in maintaining T3 homeostasis by directly controlling deiodinase activity. While still allowing for tissue-specific variation this questions the currently assumed independence of the local T3 supply. Rather it integrates peripheral and central elements into an overarching control system. On L-T4 treatment, altered equilibria have been shown to give rise to lower circulating FT3 concentrations in the presence of normal serum TSH. While data on T3 in tissues are largely lacking in humans, rodent models suggest that the disequilibria may reflect widespread T3 deficiencies at the tissue level in various organs.As a consequence, the use of TSH, valuable though it is in many situations, should be

  6. Long-Term Homeostatic Properties Complementary to Hebbian Rules in CuPc-Based Multifunctional Memristor

    Science.gov (United States)

    Wang, Laiyuan; Wang, Zhiyong; Lin, Jinyi; Yang, Jie; Xie, Linghai; Yi, Mingdong; Li, Wen; Ling, Haifeng; Ou, Changjin; Huang, Wei

    2016-10-01

    Most simulations of neuroplasticity in memristors, which are potentially used to develop artificial synapses, are confined to the basic biological Hebbian rules. However, the simplex rules potentially can induce excessive excitation/inhibition, even collapse of neural activities, because they neglect the properties of long-term homeostasis involved in the frameworks of realistic neural networks. Here, we develop organic CuPc-based memristors of which excitatory and inhibitory conductivities can implement both Hebbian rules and homeostatic plasticity, complementary to Hebbian patterns and conductive to the long-term homeostasis. In another adaptive situation for homeostasis, in thicker samples, the overall excitement under periodic moderate stimuli tends to decrease and be recovered under intense inputs. Interestingly, the prototypes can be equipped with bio-inspired habituation and sensitization functions outperforming the conventional simplified algorithms. They mutually regulate each other to obtain the homeostasis. Therefore, we develop a novel versatile memristor with advanced synaptic homeostasis for comprehensive neural functions.

  7. An Improved Test for Detecting Multiplicative Homeostatic Synaptic Scaling

    Science.gov (United States)

    Kim, Jimok; Tsien, Richard W.; Alger, Bradley E.

    2012-01-01

    Homeostatic scaling of synaptic strengths is essential for maintenance of network “gain”, but also poses a risk of losing the distinctions among relative synaptic weights, which are possibly cellular correlates of memory storage. Multiplicative scaling of all synapses has been proposed as a mechanism that would preserve the relative weights among them, because they would all be proportionately adjusted. It is crucial for this hypothesis that all synapses be affected identically, but whether or not this actually occurs is difficult to determine directly. Mathematical tests for multiplicative synaptic scaling are presently carried out on distributions of miniature synaptic current amplitudes, but the accuracy of the test procedure has not been fully validated. We now show that the existence of an amplitude threshold for empirical detection of miniature synaptic currents limits the use of the most common method for detecting multiplicative changes. Our new method circumvents the problem by discarding the potentially distorting subthreshold values after computational scaling. This new method should be useful in assessing the underlying neurophysiological nature of a homeostatic synaptic scaling transformation, and therefore in evaluating its functional significance. PMID:22615990

  8. The homeostatic and circadian sleep recovery responses after total sleep deprivation in mice.

    Science.gov (United States)

    Dispersyn, Garance; Sauvet, Fabien; Gomez-Merino, Danielle; Ciret, Sylvain; Drogou, Catherine; Leger, Damien; Gallopin, Thierry; Chennaoui, Mounir

    2017-10-01

    Many studies on sleep deprivation effects lack data regarding the recovery period. We investigated the 2-day homeostatic and circadian sleep recovery response to 24 h of total sleep deprivation (TSD) induced by brief rotation of an activity wheel. Eight mice were implanted with telemetry transmitters (DSI F40-EET) that recorded simultaneously their electroencephalography (EEG), locomotor activity and temperature during 24 h of baseline (BSL), TSD and 2 days of recovery (D1 and D2). In a second experiment, two groups of five non-implanted mice underwent TSD or ad libitum sleep, after which they were killed, adrenal glands were weighed and blood was collected for analysis of corticosterone concentration. During TSD mice were awake at least 97% of the time, with a consecutive sleep rebound during D1 that persisted during D2. This was characterized by increases of non-rapid eye movement (NREM) sleep (44.2 ± 6.9% for D1 and 43.0 ± 7.7% for D2 versus 33.8 ± 9.2% for BSL) and the relative delta band power (179.2 ± 34.4% for D1 and 81.9 ± 11.2% for D2). Greater NREM and REM sleep amounts were observed during the 'light' periods. Temperature and locomotor activity characteristics were unchanged during D1 and D2 versus BSL. In non-implanted mice, corticosterone levels as well as adrenal gland and overall body weights did not differ between TSD and ad libitum sleep groups. In conclusion, 24 h of TSD in an activity wheel without stress responses influence homeostatic sleep regulation with no effect on the circadian regulation over at least 2 days of recovery in mice. © 2017 European Sleep Research Society.

  9. β-Amyloid triggers aberrant over-scaling of homeostatic synaptic plasticity.

    Science.gov (United States)

    Gilbert, James; Shu, Shu; Yang, Xin; Lu, Youming; Zhu, Ling-Qiang; Man, Heng-Ye

    2016-12-13

    The over-production of β-amyloid (Aβ) has been strongly correlated to neuronal dysfunction and altered synaptic plasticity in Alzheimer's disease (AD). Accordingly, it has been proposed that disrupted synaptic transmission and neuronal network instability underlie memory failure that is evident in the early phases of AD. Homeostatic synaptic plasticity (HSP) serves to restrain neuronal activity within a physiological range. Therefore a disruption of this mechanism may lead to destabilization in synaptic and neural circuit function. Here, we report that during HSP by neuronal activity deprivation, application of Aβ results in an aberrant over-response of the up-regulation of AMPA receptor (AMPAR)-mediated synaptic currents and cell-surface AMPAR expression. In the visual cortex, in vivo HSP induced by visual deprivation shows a similar over-response following an Aβ local injection. Aβ increases the expression of GluA2-lacking, calcium permeable AMPARs (CP-AMPARs), which are required for the initiation, but not maintenance of HSP. Both GluA2-lacking and GluA2-containing AMPARs contribute to the Aβ-mediated over-scaling of HSP. We also find that Aβ induces the dissociation of HDAC1 from the miR124 transcription factor EVI1, leading to an up-regulation of miR124 expression and increased amount of CP-AMPARs. Thus, via aberrant stimulation of miR124 expression and biogenesis of CP-AMPARs, Aβ is able to induce an over response in HSP. This Aβ-mediated dysregulation in homeostatic plasticity may play an important role in the pathogenesis of altered neural function and memory deficits in the early stages of AD.

  10. Blockade of cholesterol absorption by ezetimibe reveals a complex homeostatic network in enterocytes[S

    Science.gov (United States)

    Engelking, Luke J.; McFarlane, Matthew R.; Li, Christina K.; Liang, Guosheng

    2012-01-01

    Enterocyte cholesterol homeostasis reflects aggregated rates of sterol synthesis, efflux, and uptake from plasma and gut lumen. Cholesterol synthesis and LDL uptake are coordinately regulated by sterol regulatory element-binding proteins (SREBP), whereas sterol efflux is regulated by liver X receptors (LXR). How these processes are coordinately regulated in enterocytes, the site of cholesterol absorption, is not well understood. Here, we treat mice with ezetimibe to investigate the effect of blocking cholesterol absorption on intestinal SREBPs, LXRs, and their effectors. Ezetimibe increased nuclear SREBP-2 8-fold. HMG-CoA reductase (HMGR) and LDL receptor (LDLR) mRNA levels increased less than 3-fold, whereas their protein levels increased 30- and 10-fold, respectively. Expression of inducible degrader of LDLR (IDOL), an LXR-regulated gene that degrades LDLRs, was reduced 50% by ezetimibe. Coadministration of ezetimibe with the LXR agonist T0901317 abolished the reduction in IDOL and prevented the increase in LDLR protein. Ezetimibe-stimulated LDLR expression was independent of proprotein convertase subtilisin/kexin type 9 (PSCK9), a protein that degrades LDLRs. To maintain cholesterol homeostasis in the face of ezetimibe, enterocytes boost LDL uptake by increasing LDLR number, and they boost sterol synthesis by increasing HMGR and other cholesterologenic genes. These studies reveal a hitherto undescribed homeostatic network in enterocytes triggered by blockade of cholesterol absorption. PMID:22523394

  11. Homeostatic scaling of excitability in recurrent neural networks.

    Directory of Open Access Journals (Sweden)

    Michiel W H Remme

    Full Text Available Neurons adjust their intrinsic excitability when experiencing a persistent change in synaptic drive. This process can prevent neural activity from moving into either a quiescent state or a saturated state in the face of ongoing plasticity, and is thought to promote stability of the network in which neurons reside. However, most neurons are embedded in recurrent networks, which require a delicate balance between excitation and inhibition to maintain network stability. This balance could be disrupted when neurons independently adjust their intrinsic excitability. Here, we study the functioning of activity-dependent homeostatic scaling of intrinsic excitability (HSE in a recurrent neural network. Using both simulations of a recurrent network consisting of excitatory and inhibitory neurons that implement HSE, and a mean-field description of adapting excitatory and inhibitory populations, we show that the stability of such adapting networks critically depends on the relationship between the adaptation time scales of both neuron populations. In a stable adapting network, HSE can keep all neurons functioning within their dynamic range, while the network is undergoing several (pathophysiologically relevant types of plasticity, such as persistent changes in external drive, changes in connection strengths, or the loss of inhibitory cells from the network. However, HSE cannot prevent the unstable network dynamics that result when, due to such plasticity, recurrent excitation in the network becomes too strong compared to feedback inhibition. This suggests that keeping a neural network in a stable and functional state requires the coordination of distinct homeostatic mechanisms that operate not only by adjusting neural excitability, but also by controlling network connectivity.

  12. Pro-oxidant induced DNA damage in human lymphoblastoid cells: homeostatic mechanisms of genotoxic tolerance.

    Science.gov (United States)

    Seager, Anna L; Shah, Ume-Kulsoom; Mikhail, Jane M; Nelson, Bryant C; Marquis, Bryce J; Doak, Shareen H; Johnson, George E; Griffiths, Sioned M; Carmichael, Paul L; Scott, Sharon J; Scott, Andrew D; Jenkins, Gareth J S

    2012-08-01

    Oxidative stress contributes to many disease etiologies including ageing, neurodegeneration, and cancer, partly through DNA damage induction (genotoxicity). Understanding the i nteractions of free radicals with DNA is fundamental to discern mutation risks. In genetic toxicology, regulatory authorities consider that most genotoxins exhibit a linear relationship between dose and mutagenic response. Yet, homeostatic mechanisms, including DNA repair, that allow cells to tolerate low levels of genotoxic exposure exist. Acceptance of thresholds for genotoxicity has widespread consequences in terms of understanding cancer risk and regulating human exposure to chemicals/drugs. Three pro-oxidant chemicals, hydrogen peroxide (H(2)O(2)), potassium bromate (KBrO(3)), and menadione, were examined for low dose-response curves in human lymphoblastoid cells. DNA repair and antioxidant capacity were assessed as possible threshold mechanisms. H(2)O(2) and KBrO(3), but not menadione, exhibited thresholded responses, containing a range of nongenotoxic low doses. Levels of the DNA glycosylase 8-oxoguanine glycosylase were unchanged in response to pro- oxidant stress. DNA repair-focused gene expression arrays reported changes in ATM and BRCA1, involved in double-strand break repair, in response to low-dose pro-oxidant exposure; however, these alterations were not substantiated at the protein level. Determination of oxidatively induced DNA damage in H(2)O(2)-treated AHH-1 cells reported accumulation of thymine glycol above the genotoxic threshold. Further, the H(2)O(2) dose-response curve was shifted by modulating the antioxidant glutathione. Hence, observed pro- oxidant thresholds were due to protective capacities of base excision repair enzymes and antioxidants against DNA damage, highlighting the importance of homeostatic mechanisms in "genotoxic tolerance."

  13. Corruption of homeostatic mechanisms in the guanylyl cyclase C signaling pathway underlying colorectal tumorigenesis

    Science.gov (United States)

    Waldman, Scott A

    2010-01-01

    Colon cancer, the second leading cause of cancer-related mortality worldwide, originates from the malignant transformation of intestinal epithelial cells. The intestinal epithelium undergoes a highly organized process of rapid regeneration along the crypt-villus axis, characterized by proliferation, migration, differentiation and apoptosis, whose coordination is essential to maintaining the mucosal barrier. Disruption of these homeostatic processes predisposes cells to mutations in tumor suppressors or oncogenes, whose dysfunction provides transformed cells an evolutionary growth advantage. While sequences of genetic mutations at different stages along the neoplastic continuum have been established, little is known of the events initiating tumorigenesis prior to adenomatous polyposis coli (APC) mutations. Here, we examine a role for the corruption of homeostasis induced by silencing novel tumor suppressors, including the intestine-specific transcription factor CDX2 and its gene target guanylyl cyclase C (GCC), as early events predisposing cells to mutations in APC and other sequential genes that initiate colorectal cancer. CDX2 and GCC maintain homeostatic regeneration in the intestine by restricting cell proliferation, promoting cell maturation and adhesion, regulating cell migration and defending the intestinal barrier and genomic integrity. Elimination of CDX2 or GCC promotes intestinal tumor initiation and growth in aged mice, mice carrying APC mutations or mice exposed to carcinogens. The roles of CDX2 and GCC in suppressing intestinal tumorigenesis, universal disruption in their signaling through silencing of hormones driving GCC, and the uniform overexpression of GCC by tumors underscore the potential value of oral replacement with GCC ligands as targeted prevention and therapy for colorectal cancer. PMID:20592492

  14. Repeated sleep restriction in rats leads to homeostatic and allostatic responses during recovery sleep.

    Science.gov (United States)

    Kim, Youngsoo; Laposky, Aaron D; Bergmann, Bernard M; Turek, Fred W

    2007-06-19

    Recent studies indicate that chronic sleep restriction can have negative consequences for brain function and peripheral physiology and can contribute to the allostatic load throughout the body. Interestingly, few studies have examined how the sleep-wake system itself responds to repeated sleep restriction. In this study, rats were subjected to a sleep-restriction protocol consisting of 20 h of sleep deprivation (SD) followed by a 4-h sleep opportunity each day for 5 consecutive days. In response to the first 20-h SD block on day 1, animals responded during the 4-h sleep opportunity with enhanced sleep intensity [i.e., nonrapid eye movement (NREM) delta power] and increased rapid eye movement sleep time compared with baseline. This sleep pattern is indicative of a homeostatic response to acute sleep loss. Remarkably, after the 20-h SD blocks on days 2-5, animals failed to exhibit a compensatory NREM delta power response during the 4-h sleep opportunities and failed to increase NREM and rapid eye movement sleep times, despite accumulating a sleep debt each consecutive day. After losing approximately 35 h of sleep over 5 days of sleep restriction, animals regained virtually none of their lost sleep, even during a full 3-day recovery period. These data demonstrate that the compensatory/homeostatic sleep response to acute SD does not generalize to conditions of chronic partial sleep loss. We propose that the change in sleep-wake regulation in the context of repeated sleep restriction reflects an allostatic process, and that the allostatic load produced by SD has direct effects on the sleep-wake regulatory system.

  15. Corruption of homeostatic mechanisms in the guanylyl cyclase C signaling pathway underlying colorectal tumorigenesis.

    Science.gov (United States)

    Li, Peng; Waldman, Scott A

    2010-08-01

    Colon cancer, the second leading cause of cancer-related mortality worldwide, originates from the malignant transformation of intestinal epithelial cells. The intestinal epithelium undergoes a highly organized process of rapid regeneration along the crypt-villus axis, characterized by proliferation, migration, differentiation and apoptosis, whose coordination is essential to maintaining the mucosal barrier. Disruption of these homeostatic processes predisposes cells to mutations in tumor suppressors or oncogenes, whose dysfunction provides transformed cells an evolutionary growth advantage. While sequences of genetic mutations at different stages along the neoplastic continuum have been established, little is known of the events initiating tumorigenesis prior to adenomatous polyposis coli (APC) mutations. Here, we examine a role for the corruption of homeostasis induced by silencing novel tumor suppressors, including the intestine-specific transcription factor CDX2 and its gene target guanylyl cyclase C (GCC), as early events predisposing cells to mutations in APC and other sequential genes that initiate colorectal cancer. CDX2 and GCC maintain homeostatic regeneration in the intestine by restricting cell proliferation, promoting cell maturation and adhesion, regulating cell migration and defending the intestinal barrier and genomic integrity. Elimination of CDX2 or GCC promotes intestinal tumor initiation and growth in aged mice, mice carrying APC mutations or mice exposed to carcinogens. The roles of CDX2 and GCC in suppressing intestinal tumorigenesis, universal disruption in their signaling through silencing of hormones driving GCC, and the uniform overexpression of GCC by tumors underscore the potential value of oral replacement with GCC ligands as targeted prevention and therapy for colorectal cancer.

  16. The suprachiasmatic nucleus regulates sleep timing and amount in mice

    NARCIS (Netherlands)

    Easton, Amy; Meerlo, Peter; Bergmann, Bernard; Turek, Fred W.

    2004-01-01

    Context: Sleep is regulated by circadian and homeostatic processes. The circadian pacemaker, located in the suprachiasmatic nuclei (SCN), regulates the timing and consolidation of the sleep-wake cycle, while a homeostatic mechanism governs the accumulation of sleep debt and sleep, recovery. Recent

  17. Distinctive effects of modafinil and d-amphetamine on the homeostatic and circadian modulation of the human waking EEG.

    Science.gov (United States)

    Chapotot, Florian; Pigeau, Ross; Canini, Frédéric; Bourdon, Lionel; Buguet, Alain

    2003-03-01

    Modafinil is a wake-promoting agent that affects hypothalamic structures involved in the homeostatic and circadian regulation of vigilance. Administered during sleep deprivation, it reduces the need for prolonged recovery sleep and decreases the rebound in EEG slow-wave activity. These diachronic effects suggest an action of modafinil on a homeostatic sleep regulatory process. The aim of this study was to determine whether modafinil, in comparison to the d-amphetamine reference psychostimulant and to placebo, interferes with the vigilance regulatory processes reflected in the EEG during waking. Thirty-three healthy subjects were investigated during 60 h of sustained wakefulness in a double-blind placebo-controlled parallel-design study. A 4-min maintenance-of-wakefulness test administered hourly allowed the concomitant assessment of alertness and waking EEG activity. The effects of equipotent psychostimulant dosages (modafinil 300 mg and d-amphetamine 20 mg) were evaluated at the beginning of the first sleep deprivation night, at the end of the second sleep deprivation night and in the afternoon preceding the first recovery night. One hour following ingestion, both psychostimulants increased alertness during 10-12 h, independently of the time of administration. At the level of the waking EEG, d-amphetamine attenuated the natural circadian rhythm of the different frequency bands and suppressed the sleep deprivation-related increase in low frequency (0.5-7 Hz) powers. In contrast, modafinil, which exhibited a transient amphetamine-like effect, had slight effect on circadian rhythms. Its selective action was characterized by maintenance of the alpha(1) (8.5-11.5 Hz) EEG power, which under placebo exhibited a homeostatic decrease paralleling that of alertness with a circadian trough at night. These findings demonstrate that the alertness-promoting effects of modafinil and d-amphetamine involve distinct EEG activities and do not reside on the same vigilance regulatory

  18. Retinoid Homeostatic Gene Expression in Liver, Lung and Kidney: Ontogeny and Response to Vitamin A-Retinoic Acid (VARA) Supplementation from Birth to Adult Age

    OpenAIRE

    Owusu, Sarah A.; Ross, A. Catharine

    2016-01-01

    Vitamin A (VA, retinol) metabolism is homeostatically controlled, but little is known of its regulation in the postnatal period. Here, we determined the postnatal trajectory of VA storage and metabolism in major compartments of VA metabolism-plasma, liver, lung, and kidney from postnatal (P) day 1 to adulthood. We also investigated the response to supplementation with VARA, a combination of VA and 10% all-trans-retinoic acid that previously was shown to synergistically increase retinol uptake...

  19. Sleep Patterns and Homeostatic Mechanisms in Adolescent Mice

    Directory of Open Access Journals (Sweden)

    Giulio Tononi

    2013-03-01

    Full Text Available Sleep changes were studied in mice (n = 59 from early adolescence to adulthood (postnatal days P19–111. REM sleep declined steeply in early adolescence, while total sleep remained constant and NREM sleep increased slightly. Four hours of sleep deprivation starting at light onset were performed from ages P26 through adulthood (>P60. Following this acute sleep deprivation all mice slept longer and with more consolidated sleep bouts, while NREM slow wave activity (SWA showed high interindividual variability in the younger groups, and increased consistently only after P42. Three parameters together explained up to 67% of the variance in SWA rebound in frontal cortex, including weight-adjusted age and increase in alpha power during sleep deprivation, both of which positively correlated with the SWA response. The third, and strongest predictor was the SWA decline during the light phase in baseline: mice with high peak SWA at light onset, resulting in a large SWA decline, were more likely to show no SWA rebound after sleep deprivation, a result that was also confirmed in parietal cortex. During baseline, however, SWA showed the same homeostatic changes in adolescents and adults, declining in the course of sleep and increasing across periods of spontaneous wake. Thus, we hypothesize that, in young adolescent mice, a ceiling effect and not the immaturity of the cellular mechanisms underlying sleep homeostasis may prevent the SWA rebound when wake is extended beyond its physiological duration.

  20. Dynamic Networks of Human Homeostatic Control in Norm (Part 2

    Directory of Open Access Journals (Sweden)

    Alexander G. Kruglov

    2016-09-01

    Full Text Available We undertook this research to study the relationships between elements of the vascular system in individuals without clinical signs of pathology (in "norm". Indicators of hemodynamics obtained by catheterization in various vascular areas (RA, RV, LV, PT, Ao, SS, RHV (FHVP and HVWP, CS were the pressure levels (mmHg. During the correlation analysis, the significant (p<0.05 relation signs (+, 0, - without regard to their power were considered. The obtained results allow us to draw following conclusions: -\tCapacitive venous vessels of the liver are a communication channel between the evolutionarily younger (lungs and older (SP organs functional systems of the human body. -\tHepatic venous circulation is a field of interference of the information and biochemical relationships between the body and the external environment through the venous outflow from GIT (the zone preceding the liver and arterial flow - CHA (an indicator of aortic hemodynamics and gas exchange in lungs. -\tThe result of marked interactions is an integrated BIF of venous outflow from the liver (whose “thesaurus” includes the information volumes of organs preceding the liver, which has uniform hemodynamic and biochemical parameters and interacts with the blood flow of RA and all phases of CC and hemodynamics in IVC/SVC pools and CS. -\tThe intersystem relationship in the cardio-hepato-pulmonary complex of the human body is the highest biology hierarchical level of the homeostatic relationships in the human–external-environment system.

  1. Emerging Link between Alzheimer's Disease and Homeostatic Synaptic Plasticity

    Science.gov (United States)

    Jang, Sung-Soo; Chung, Hee Jung

    2016-01-01

    Alzheimer's disease (AD) is an irreversible brain disorder characterized by progressive cognitive decline and neurodegeneration of brain regions that are crucial for learning and memory. Although intracellular neurofibrillary tangles and extracellular senile plaques, composed of insoluble amyloid-β (Aβ) peptides, have been the hallmarks of postmortem AD brains, memory impairment in early AD correlates better with pathological accumulation of soluble Aβ oligomers and persistent weakening of excitatory synaptic strength, which is demonstrated by inhibition of long-term potentiation, enhancement of long-term depression, and loss of synapses. However, current, approved interventions aiming to reduce Aβ levels have failed to retard disease progression; this has led to a pressing need to identify and target alternative pathogenic mechanisms of AD. Recently, it has been suggested that the disruption of Hebbian synaptic plasticity in AD is due to aberrant metaplasticity, which is a form of homeostatic plasticity that tunes the magnitude and direction of future synaptic plasticity based on previous neuronal or synaptic activity. This review examines emerging evidence for aberrant metaplasticity in AD. Putative mechanisms underlying aberrant metaplasticity in AD will also be discussed. We hope this review inspires future studies to test the extent to which these mechanisms contribute to the etiology of AD and offer therapeutic targets. PMID:27019755

  2. Hyper-homeostatic learning of anticipatory hunger in rats.

    Science.gov (United States)

    Jarvandi, Soghra; Booth, David A; Thibault, Louise

    2007-11-23

    Anticipatory hunger is a learnt increase in intake of food having a flavour or texture that predicts a long fast. This learning was studied in rats trained on a single food or a choice between protein-rich and carbohydrate-rich foods, presented for 1.5 h after 3 h without maintenance food at the start of the dark phase. Eight training cycles provided a pseudo-random sequence of 3 h and 10 h post-prandial fasts with a day on maintenance food between each training fast. The measure of anticipatory hunger is the difference over one 4-day cycle between the intake of test food having an odour predictive of the longer fast (TL) and intake of food with an odour cuing to the shorter fast (TS). Previous experiments showed that conditioning of preference for the odour before the shorter fast competes with learning to avoid hunger during the longer fast (anticipatory hunger), generating a cubic or quartic contrast. TL minus TS showed a strong cubic trend over 8 training cycles with both single and choice meals. There was a switch from preference for the short-fast odour at cycle 2 (TL-TS=-0.86 g) to a peak of anticipatory hunger at cycle 6 (TL-TS=1.57 g). We conclude that anticipatory hunger is learnt when a choice is given between protein-rich and carbohydrate-rich foods as well as on a single food. In addition, since anticipatory hunger extinguishes itself, such learning improves on negative-feedback homeostasis with a feed-forward "hyper-homeostatic" mechanism.

  3. Multiple shared mechanisms for homeostatic plasticity in rodent somatosensory and visual cortex.

    Science.gov (United States)

    Gainey, Melanie A; Feldman, Daniel E

    2017-03-05

    We compare the circuit and cellular mechanisms for homeostatic plasticity that have been discovered in rodent somatosensory (S1) and visual (V1) cortex. Both areas use similar mechanisms to restore mean firing rate after sensory deprivation. Two time scales of homeostasis are evident, with distinct mechanisms. Slow homeostasis occurs over several days, and is mediated by homeostatic synaptic scaling in excitatory networks and, in some cases, homeostatic adjustment of pyramidal cell intrinsic excitability. Fast homeostasis occurs within less than 1 day, and is mediated by rapid disinhibition, implemented by activity-dependent plasticity in parvalbumin interneuron circuits. These processes interact with Hebbian synaptic plasticity to maintain cortical firing rates during learned adjustments in sensory representations.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'. © 2017 The Author(s).

  4. Homeostasis balance, homeostasis imbalance or distinct motivational processes? Comments on Marks (2015) ?Homeostatic Theory of Obesity?

    OpenAIRE

    Pelletier, Luc G; Guertin, Camille; Pope, J Paige; Rocchi, Meredith

    2016-01-01

    In his article, ‘Homeostatic theory of obesity’, Marks suggested that imbalances in homeostatic processes could explain weight gain and obesity. He proposes that over-consumption of high-caloric, low-nutrient and low satiating foods, combined with a stressful environment, is the origin of weight gain. Once weight gain occurs, individuals may develop body dissatisfaction and negative affect, leading to continued over-consumption, which sets in motion a system of feedback loops that leads to a ...

  5. Upregulation of μ3A Drives Homeostatic Plasticity by Rerouting AMPAR into the Recycling Endosomal Pathway

    Directory of Open Access Journals (Sweden)

    Celine C. Steinmetz

    2016-09-01

    Full Text Available Synaptic scaling is a form of homeostatic plasticity driven by transcription-dependent changes in AMPA-type glutamate receptor (AMPAR trafficking. To uncover the pathways involved, we performed a cell-type-specific screen for transcripts persistently altered during scaling, which identified the μ subunit (μ3A of the adaptor protein complex AP-3A. Synaptic scaling increased μ3A (but not other AP-3 subunits in pyramidal neurons and redistributed dendritic μ3A and AMPAR to recycling endosomes (REs. Knockdown of μ3A prevented synaptic scaling and this redistribution, while overexpression (OE of full-length μ3A or a truncated μ3A that cannot interact with the AP-3A complex was sufficient to drive AMPAR to REs. Finally, OE of μ3A acted synergistically with GRIP1 to recruit AMPAR to the dendritic membrane. These data suggest that excess μ3A acts independently of the AP-3A complex to reroute AMPAR to RE, generating a reservoir of receptors essential for the regulated recruitment to the synaptic membrane during scaling up.

  6. Homeostatic properties and phenotypic maturation of murine CD4+ pre-thymic emigrants in the thymus.

    Directory of Open Access Journals (Sweden)

    Jie Dong

    Full Text Available After a tightly regulated developmental program in the thymus, "mature" single positive (SP thymocytes leave the thymus and enter the periphery. These newly arrived recent thymic emigrants (RTEs are phenotypically and functionally immature, and will complete a dynamic maturation in the peripheral lymphoid organs before being licensed to be resident naïve T cells. To study the early events occurring in the RTE maturation process, we identified the phenotype of CD4(+ pre-RTEs, a population of CD4(+ SP thymocytes that have acquired the thymus egress capability. Compared to peripheral naïve T cells, CD4(+ pre-RTEs displayed superior survival capability in lymphoreplete mice and faster proliferation under lymphopenic condition. The differences in Bcl2/Bim expression and/or heightened IL-7 signaling pathway may account for the pre-RTEs' better responsiveness to homeostatic signals. Qa2, the expression of which indicates the phenotypic maturation of SPs and RTEs, was found to be upregulated in CD4(+ pre-RTEs in thymic perivascular space. Migratory dendritic cells that surround this region contribute to Qa2 expression in pre-RTEs. The dendritic cell-driven Qa2 induction of CD4(+ pre-RTEs is independent of MHC class II and Aire molecules.

  7. MHC class I-positive dendritic cells (DC) control CD8 T cell homeostasis in vivo: T cell lymphopenia as a prerequisite for DC-mediated homeostatic proliferation of naive CD8 T cells.

    Science.gov (United States)

    Gruber, Anton; Brocker, Thomas

    2005-07-01

    The sizes of peripheral T cell pools are regulated by competition for environmental signals within a given ecological T cell niche. Cytokines and MHC molecules have been identified as resources for which naive T cells compete to proliferate homeostatically in lymphopenic hosts to fill up their respective compartments. However, it still remains unclear to what extent CD4 and CD8 T cells intercompete for these resources and which role dendritic cells (DC) play in this scenario. Using transgenic mice in which only DC express MHC class I, we demonstrate that this type of APC is sufficient to trigger complete homeostatic proliferation of CD8 T cells in vivo. However, normal numbers of endogenous naive CD4 T cells, but not CD25(+)CD4(+) T regulatory cells, efficiently suppress this expansion in vivo. These findings identify DC as a major resource and a possible target for homeostatic competition between naive CD4 and CD8 T cells.

  8. OX40 and IL-7 play synergistic roles in the homeostatic proliferation of effector memory CD4⁺ T cells.

    Science.gov (United States)

    Yamaki, Satoshi; Ine, Shouji; Kawabe, Takeshi; Okuyama, Yuko; Suzuki, Nobu; Soroosh, Pejman; Mousavi, Seyed Fazlollah; Nagashima, Hiroyuki; Sun, Shu-lan; So, Takanori; Sasaki, Takeshi; Harigae, Hideo; Sugamura, Kazuo; Kudo, Hironori; Wada, Motoshi; Nio, Masaki; Ishii, Naoto

    2014-10-01

    T-cell homeostasis preserves the numbers, the diversity and functional competence of different T-cell subsets that are required for adaptive immunity. Naïve CD4(+) T (TN ) cells are maintained in the periphery via the common γ-chain family cytokine IL-7 and weak antigenic signals. However, it is not clear how memory CD4(+) T-cell subsets are maintained in the periphery and which factors are responsible for the maintenance. To examine the homeostatic mechanisms, CFSE-labeled CD4(+) CD44(high) CD62L(low) effector memory T (TEM ) cells were transferred into sublethally-irradiated syngeneic C57BL/6 mice, and the systemic cell proliferative responses, which can be divided distinctively into fast and slow proliferations, were assessed by CFSE dye dilution. We found that the fast homeostatic proliferation of TEM cells was strictly regulated by both antigen and OX40 costimulatory signals and that the slow proliferation was dependent on IL-7. The simultaneous blockade of both OX40 and IL-7 signaling completely inhibited the both fast and slow proliferation. The antigen- and OX40-dependent fast proliferation preferentially expanded IL-17-producing helper T cells (Th17 cells). Thus, OX40 and IL-7 play synergistic, but distinct roles in the homeostatic proliferation of CD4(+) TEM cells. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Homeostatic proliferation fails to efficiently reactivate HIV-1 latently infected central memory CD4+ T cells.

    Directory of Open Access Journals (Sweden)

    Alberto Bosque

    2011-10-01

    Full Text Available Homeostatic proliferation ensures the longevity of central memory T-cells by inducing cell proliferation in the absence of cellular differentiation or activation. This process is governed mainly by IL-7. Central memory T-cells can also be stimulated via engagement of the T-cell receptor, leading to cell proliferation but also activation and differentiation. Using an in vitro model of HIV-1 latency, we have examined in detail the effects of homeostatic proliferation on latently infected central memory T cells. We have also used antigenic stimulation via anti-CD3/anti-CD28 antibodies and established a comparison with a homeostatic proliferation stimulus, to evaluate potential differences in how either treatment affects the dynamics of latent virus populations. First, we show that homeostatic proliferation, as induced by a combination of IL-2 plus IL-7, leads to partial reactivation of latent HIV-1 but is unable to reduce the size of the reservoir in vitro. Second, latently infected cells are able to homeostatically proliferate in the absence of viral reactivation or cell differentiation. These results indicate that IL-2 plus IL-7 may induce a detrimental effect by favoring the maintenance of the latent HIV-1 reservoir. On the other hand, antigenic stimulation efficiently reactivated latent HIV-1 in cultured central memory cells and led to depletion of the latently infected cells via virus-induced cell death.

  10. Cell volume homeostatic mechanisms: effectors and signalling pathways

    DEFF Research Database (Denmark)

    Hoffmann, E K; Pedersen, Stine Helene Falsig

    2011-01-01

    Cell volume homeostasis and its fine-tuning to the specific physiological context at any given moment are processes fundamental to normal cell function. The understanding of cell volume regulation owes much to August Krogh, yet has advanced greatly over the last decades. In this review, we outline...... the historical context of studies of cell volume regulation, focusing on the lineage started by Krogh, Bodil Schmidt-Nielsen, Hans-Henrik Ussing, and their students. The early work was focused on understanding the functional behaviour, kinetics and thermodynamics of the volume-regulatory ion transport mechanisms....... Later work addressed the mechanisms through which cellular signalling pathways regulate the volume regulatory effectors or flux pathways. These studies were facilitated by the molecular identification of most of the relevant channels and transporters, and more recently also by the increased...

  11. Legume Shrubs Are More Nitrogen-Homeostatic than Non-legume Shrubs

    Science.gov (United States)

    Guo, Yanpei; Yang, Xian; Schöb, Christian; Jiang, Youxu; Tang, Zhiyao

    2017-01-01

    Legumes are characterized as keeping stable nutrient supply under nutrient-limited conditions. However, few studies examined the legumes' stoichiometric advantages over other plants across various taxa in natural ecosystems. We explored differences in nitrogen (N) and phosphorus (P) stoichiometry of different tissue types (leaf, stem, and root) between N2-fixing legume shrubs and non-N2-fixing shrubs from 299 broadleaved deciduous shrubland sites in northern China. After excluding effects of taxonomy and environmental variables, these two functional groups differed considerably in nutrient regulation. N concentrations and N:P ratios were higher in legume shrubs than in non-N2-fixing shrubs. N concentrations were positively correlated between the plants and soil for non-N2-fixing shrubs, but not for legume shrubs, indicating a stronger stoichiometric homeostasis in legume shrubs than in non-N2-fixing shrubs. N concentrations were positively correlated among three tissue types for non-N2-fixing shrubs, but not between leaves and non-leaf tissues for legume shrubs, demonstrating that N concentrations were more dependent among tissues for non-N2-fixing shrubs than for legume shrubs. N and P concentrations were correlated within all tissues for both functional groups, but the regression slopes were flatter for legume shrubs than non-N2-fixing shrubs, implying that legume shrubs were more P limited than non-N2-fixing shrubs. These results address significant differences in stoichiometry between legume shrubs and non-N2-fixing shrubs, and indicate the influence of symbiotic nitrogen fixation (SNF) on plant stoichiometry. Overall, N2-fixing legume shrubs are higher and more stoichiometrically homeostatic in N concentrations. However, due to excess uptake of N, legumes may suffer from potential P limitation. With their N advantage, legume shrubs could be good nurse plants in restoration sites with degraded soil, but their P supply should be taken care of during management

  12. Legume Shrubs Are More Nitrogen-Homeostatic than Non-legume Shrubs

    Directory of Open Access Journals (Sweden)

    Yanpei Guo

    2017-09-01

    Full Text Available Legumes are characterized as keeping stable nutrient supply under nutrient-limited conditions. However, few studies examined the legumes' stoichiometric advantages over other plants across various taxa in natural ecosystems. We explored differences in nitrogen (N and phosphorus (P stoichiometry of different tissue types (leaf, stem, and root between N2-fixing legume shrubs and non-N2-fixing shrubs from 299 broadleaved deciduous shrubland sites in northern China. After excluding effects of taxonomy and environmental variables, these two functional groups differed considerably in nutrient regulation. N concentrations and N:P ratios were higher in legume shrubs than in non-N2-fixing shrubs. N concentrations were positively correlated between the plants and soil for non-N2-fixing shrubs, but not for legume shrubs, indicating a stronger stoichiometric homeostasis in legume shrubs than in non-N2-fixing shrubs. N concentrations were positively correlated among three tissue types for non-N2-fixing shrubs, but not between leaves and non-leaf tissues for legume shrubs, demonstrating that N concentrations were more dependent among tissues for non-N2-fixing shrubs than for legume shrubs. N and P concentrations were correlated within all tissues for both functional groups, but the regression slopes were flatter for legume shrubs than non-N2-fixing shrubs, implying that legume shrubs were more P limited than non-N2-fixing shrubs. These results address significant differences in stoichiometry between legume shrubs and non-N2-fixing shrubs, and indicate the influence of symbiotic nitrogen fixation (SNF on plant stoichiometry. Overall, N2-fixing legume shrubs are higher and more stoichiometrically homeostatic in N concentrations. However, due to excess uptake of N, legumes may suffer from potential P limitation. With their N advantage, legume shrubs could be good nurse plants in restoration sites with degraded soil, but their P supply should be taken care of

  13. Homeostasis balance, homeostasis imbalance or distinct motivational processes? Comments on Marks (2015) 'Homeostatic Theory of Obesity'.

    Science.gov (United States)

    Pelletier, Luc G; Guertin, Camille; Pope, J Paige; Rocchi, Meredith

    2016-01-01

    In his article, 'Homeostatic theory of obesity', Marks suggested that imbalances in homeostatic processes could explain weight gain and obesity. He proposes that over-consumption of high-caloric, low-nutrient and low satiating foods, combined with a stressful environment, is the origin of weight gain. Once weight gain occurs, individuals may develop body dissatisfaction and negative affect, leading to continued over-consumption, which sets in motion a system of feedback loops that leads to a Circle of Discontent and further weight gain. In this article, we attempt to clarify certain problematic aspects of Marks framework and identify specific directions that researchers should pursue to address these shortcomings.

  14. Extinction of aversive taste memory homeostatically prevents the maintenance of in vivo insular cortex LTP: Calcineurin participation.

    Science.gov (United States)

    Rivera-Olvera, Alejandro; Nelson-Mora, Janikua; Gonsebatt, María E; Escobar, Martha L

    2018-04-06

    Accumulating evidence indicates that homeostatic plasticity mechanisms dynamically adjust synaptic strength to promote stability that is crucial for memory storage. Our previous studies have shown that prior training in conditioned taste aversion (CTA) prevents the subsequent induction of long-term potentiation (LTP) in the projection from the basolateral nucleus of the amygdala (Bla) to the insular cortex (IC) in vivo. We have also reported that induction of LTP in the Bla-IC pathway modifies the CTA extinction. Memoryextinction involves the formation of a new associativememorythat inhibits a previously conditioned association. The aim of the present study was to analyze the effect of CTA extinction on the ability to induce subsequent LTP in the Bla-IC projection in vivo. Thus, 48 h after CTA extinction animals received high frequency stimulation in order to induce IC-LTP. Our results show that extinction training allows the induction but not the maintenance of IC-LTP. In addition, with the purpose of exploring part of the mechanisms involved in this process and since a body of evidence suggests that protein phosphatase calcineurin (CaN) is involved in the extinction of some behavioral tasks, we analyzed the participation of this phosphatase. The present results show that extinction training increases the CaN expression in the IC, as well as that the inhibition of this phosphatase reverts the effects of the CTA-extinction on the IC-LTP. These findings reveal that CTA extinction promotes a homeostatic regulation of subsequent IC synaptic plasticity maintenance through increases in CaN levels. Copyright © 2018 Elsevier Inc. All rights reserved.

  15. Temporal mapping of CEBPA and CEBPB binding during liver regeneration reveals dynamic occupancy and specific regulatory codes for homeostatic and cell cycle gene batteries

    DEFF Research Database (Denmark)

    Jakobsen, Janus Schou; Waage, Johannes; Rapin, Nicolas

    2013-01-01

    of homeostatic gene expression prior to S-phase entry. By analyzing the three classes of CEBP bound regions, we uncovered mutually exclusive sets of sequence motifs, suggesting temporal codes of CEBP recruitment by differential cobinding with other factors. These findings were validated by sequential ChIP...... experiments involving a panel of central transcription factors and/or by comparison to external ChIP-seq data. Our quantitative investigation not only provides in vivo evidence for the involvement of many new factors in liver regeneration but also points to similarities in the circuitries regulating self...

  16. Inflammasome-independent regulation of IL-1-family cytokines

    NARCIS (Netherlands)

    Netea, M.G.; Veerdonk, F.L. van de; Meer, J.W.M. van der; Dinarello, C.A.; Joosten, L.A.B.

    2015-01-01

    Induction, production, and release of proinflammatory cytokines are essential steps to establish an effective host defense. Cytokines of the interleukin-1 (IL-1) family induce inflammation and regulate T lymphocyte responses while also displaying homeostatic and metabolic activities. With the

  17. Endocannabinoids: Multi-scaled, Global Homeostatic Regulators of Cells and Society

    Science.gov (United States)

    Melamede, Robert

    Living systems are far from equilibrium open systems that exhibit many scales of emergent behavior. They may be abstractly viewed as a complex weave of dissipative structures that maintain organization by passing electrons from reduced hydrocarbons to oxygen. Free radicals are unavoidable byproducts of biological electron flow. Due to their highly reactive chemical properties, free radicals modify all classes of biological molecules (carbohydrates, lipids, nucleic acids, and proteins). As a result, free radicals are destructive. The generally disruptive nature of free radicals makes them the "friction of life." As such, they are believed to be the etiological agents behind age related illnesses such as cardiovascular, immunological, and neurological diseases, cancer, and ageing itself. Free radicals also play a critical constructive role in living systems. From a thermodynamic perspective, life can only exist if a living system takes in sufficient negative entropy from its environment to overcome the obligatory increase in entropy that would result if the system could not appropriately exchange mass, energy and information with its environment. Free radicals are generated in response to perturbations in the relationship between a living system and its environment. However, evolution has selected for biological response systems to free radicals so that the cellular biochemistry can adapt to environmental perturbations by modifying cellular gene expression and biochemistry. Endocannabinoids are marijuana-like compounds that have their origins hundreds of millions of years in the evolutionary past. They serve as fundamental modulators of energy homeostasis in all vertebrates. Their widespread biological activities may often be attributed to their ability to minimize the negative consequences of free radicals.

  18. Activity-dependent, homeostatic regulation of neurotransmitter release from auditory nerve fibers

    OpenAIRE

    Ngodup, Tenzin; Goetz, Jack A.; McGuire, Brian C.; Sun, Wei; Lauer, Amanda M.; Xu-Friedman, Matthew A.

    2015-01-01

    Synapses with high probability of neurotransmitter release (Pr) depress during prolonged activity, which reduces the faithful transfer of information. Auditory nerve synapses onto bushy cells show particularly strong depression at physiologically relevant rates of activity, which raises the question of how bushy cells transmit information when sound levels are high for a prolonged period. After rearing mice in constant, nondamaging noise, auditory nerve synapses changed from high to low Pr, w...

  19. A New Approach to Homeostatic Regulation: Towards a Unified View of Physiological and Ecological Concepts

    OpenAIRE

    Meunier, Cédric L.; Malzahn, Arne M.; Boersma, Maarten

    2014-01-01

    Stoichiometric homeostasis is the ability of an organism to keep its body chemical composition constant, despite varying inputs. Stoichiometric homeostasis therefore constrains the metabolic needs of consumers which in turn often feed on resources not matching these requirements. In a broader context, homeostasis also relates to the capacity of an organism to maintain other biological parameters (e.g. body temperature) at a constant level over ambient environmental variations. Unfortunately, ...

  20. A homeostatic sleep-stabilizing pathway in Drosophila composed of the sex peptide receptor and its ligand, the myoinhibitory peptide.

    Directory of Open Access Journals (Sweden)

    Yangkyun Oh

    2014-10-01

    Full Text Available Sleep, a reversible quiescent state found in both invertebrate and vertebrate animals, disconnects animals from their environment and is highly regulated for coordination with wakeful activities, such as reproduction. The fruit fly, Drosophila melanogaster, has proven to be a valuable model for studying the regulation of sleep by circadian clock and homeostatic mechanisms. Here, we demonstrate that the sex peptide receptor (SPR of Drosophila, known for its role in female reproduction, is also important in stabilizing sleep in both males and females. Mutants lacking either the SPR or its central ligand, myoinhibitory peptide (MIP, fall asleep normally, but have difficulty in maintaining a sleep-like state. Our analyses have mapped the SPR sleep function to pigment dispersing factor (pdf neurons, an arousal center in the insect brain. MIP downregulates intracellular cAMP levels in pdf neurons through the SPR. MIP is released centrally before and during night-time sleep, when the sleep drive is elevated. Sleep deprivation during the night facilitates MIP secretion from specific brain neurons innervating pdf neurons. Moreover, flies lacking either SPR or MIP cannot recover sleep after the night-time sleep deprivation. These results delineate a central neuropeptide circuit that stabilizes the sleep state by feeding a slow-acting inhibitory input into the arousal system and plays an important role in sleep homeostasis.

  1. Retinoid Homeostatic Gene Expression in Liver, Lung and Kidney: Ontogeny and Response to Vitamin A-Retinoic Acid (VARA) Supplementation from Birth to Adult Age.

    Science.gov (United States)

    Owusu, Sarah A; Ross, A Catharine

    2016-01-01

    Vitamin A (VA, retinol) metabolism is homeostatically controlled, but little is known of its regulation in the postnatal period. Here, we determined the postnatal trajectory of VA storage and metabolism in major compartments of VA metabolism-plasma, liver, lung, and kidney from postnatal (P) day 1 to adulthood. We also investigated the response to supplementation with VARA, a combination of VA and 10% all-trans-retinoic acid that previously was shown to synergistically increase retinol uptake and storage in lung. Nursling pups of dams fed a VA-marginal diet received an oral dose of oil (placebo) or VARA on each of four neonatal days: P1, P4, P7, and P10; and again as adults. Tissues were collected 6 h after the final dosing on P1, P4, P10, and at adult age. Gene transcripts for Lrat and Rbp4 in liver and Raldh-1 and Raldh-3 in lung, did not differ in the neonatal period but were higher, Psupplementation increased total retinol in plasma, liver and lung, with a dose-by-dose accumulation in neonatal liver and lung, while transcripts for Lrat in liver, megalin in kidney, Cyp26A1/B1 in liver and lung, respectively, and Stra6 in lung, were all increased, suggesting pathways of VA uptake, storage and RA oxidation were each augmented after VARA. VARA decreased hepatic expression of Rbp4, responsible for VA trafficking from liver to plasma, and, in lung, of Raldh-1 and Raldh-2, which function in RA production. Our results define retinoid homeostatic gene expression from neonatal and adult age and show that while supplementation with VARA acutely alters retinol content and retinoid homeostatic gene expression in neonatal and adult lung, liver and kidney, VARA supplementation of neonates increased adult-age VA content only in the liver.

  2. Evolutionary conservation of divergent pro-inflammatory and homeostatic responses in Lamprey phagocytes.

    Directory of Open Access Journals (Sweden)

    Jeffrey J Havixbeck

    Full Text Available In higher vertebrates, phagocytosis plays a critical role in development and immunity, based on the internalization and removal of apoptotic cells and invading pathogens, respectively. Previous studies describe the effective uptake of these particles by lower vertebrate and invertebrate phagocytes, and identify important molecular players that contribute to this internalization. However, it remains unclear if individual phagocytes mediate internalization processes in these ancient organisms, and how this impacts the balance of pro-inflammatory and homeostatic events within their infection sites. Herein we show that individual phagocytes of the jawless vertebrate Petromyzon marinus (sea lamprey, like those of teleost fish and mice, display the capacity for divergent pro-inflammatory and homeostatic responses following internalization of zymosan and apoptotic cells, respectively. Professional phagocytes (macrophages, monocytes, neutrophils were the primary contributors to the internalization of pro-inflammatory particles among goldfish (C. auratus and lamprey (P. marinus hematopoietic leukocytes. However, goldfish showed a greater ability for zymosan phagocytosis when compared to their jawless counterparts. Coupled to this increase was a significantly lower sensitivity of goldfish phagocytes to homeostatic signals derived from apoptotic cell internalization. Together, this translated into a significantly greater capacity for induction of antimicrobial respiratory burst responses compared to lamprey phagocytes, but also a decreased efficacy in apoptotic cell-driven leukocyte homeostatic mechanisms that attenuate this pro-inflammatory process. Overall, our results show the long-standing evolutionary contribution of intrinsic phagocyte mechanisms for the control of inflammation, and illustrate one effective evolutionary strategy for increased responsiveness against invading pathogens. In addition, they highlight the need for development of

  3. Homeostatic structural plasticity can account for topology changes following deafferentation and focal stroke.

    Science.gov (United States)

    Butz, Markus; Steenbuck, Ines D; van Ooyen, Arjen

    2014-01-01

    After brain lesions caused by tumors or stroke, or after lasting loss of input (deafferentation), inter- and intra-regional brain networks respond with complex changes in topology. Not only areas directly affected by the lesion but also regions remote from the lesion may alter their connectivity-a phenomenon known as diaschisis. Changes in network topology after brain lesions can lead to cognitive decline and increasing functional disability. However, the principles governing changes in network topology are poorly understood. Here, we investigated whether homeostatic structural plasticity can account for changes in network topology after deafferentation and brain lesions. Homeostatic structural plasticity postulates that neurons aim to maintain a desired level of electrical activity by deleting synapses when neuronal activity is too high and by providing new synaptic contacts when activity is too low. Using our Model of Structural Plasticity, we explored how local changes in connectivity induced by a focal loss of input affected global network topology. In accordance with experimental and clinical data, we found that after partial deafferentation, the network as a whole became more random, although it maintained its small-world topology, while deafferentated neurons increased their betweenness centrality as they rewired and returned to the homeostatic range of activity. Furthermore, deafferentated neurons increased their global but decreased their local efficiency and got longer tailed degree distributions, indicating the emergence of hub neurons. Together, our results suggest that homeostatic structural plasticity may be an important driving force for lesion-induced network reorganization and that the increase in betweenness centrality of deafferentated areas may hold as a biomarker for brain repair.

  4. Rivalry of homeostatic and sensory-evoked emotions: Dehydration attenuates olfactory disgust and its neural correlates.

    Science.gov (United States)

    Meier, Lea; Friedrich, Hergen; Federspiel, Andrea; Jann, Kay; Morishima, Yosuke; Landis, Basile Nicolas; Wiest, Roland; Strik, Werner; Dierks, Thomas

    2015-07-01

    Neural correlates have been described for emotions evoked by states of homeostatic imbalance (e.g. thirst, hunger, and breathlessness) and for emotions induced by external sensory stimulation (such as fear and disgust). However, the neurobiological mechanisms of their interaction, when they are experienced simultaneously, are still unknown. We investigated the interaction on the neurobiological and the perceptional level using subjective ratings, serum parameters, and functional magnetic resonance imaging (fMRI) in a situation of emotional rivalry, when both a homeostatic and a sensory-evoked emotion were experienced at the same time. Twenty highly dehydrated male subjects rated a disgusting odor as significantly less repulsive when they were thirsty. On the neurobiological level, we found that this reduction in subjective disgust during thirst was accompanied by a significantly reduced neural activity in the insular cortex, a brain area known to be considerably involved in processing of disgust. Furthermore, during the experience of disgust in the satiated condition, we observed a significant functional connectivity between brain areas responding to the disgusting odor, which was absent during the stimulation in the thirsty condition. These results suggest interference of conflicting emotions: an acute homeostatic imbalance can attenuate the experience of another emotion evoked by the sensory perception of a potentially harmful external agent. This finding offers novel insights with regard to the behavioral relevance of biologically different types of emotions, indicating that some types of emotions are more imperative for behavior than others. As a general principle, this modulatory effect during the conflict of homeostatic and sensory-evoked emotions may function to safeguard survival. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Sleep inertia, sleep homeostatic, and circadian influences on higher-order cognitive functions

    OpenAIRE

    Burke, Tina M.; Scheer, Frank A. J. L.; Ronda, Joseph M.; Czeisler, Charles A.; Wright, Kenneth P.

    2015-01-01

    Sleep inertia, sleep homeostatic, and circadian processes modulate cognition, including reaction time, memory, mood, and alertness. How these processes influence higher-order cognitive functions is not well known. Six participants completed a 73-daylong study that included two 14-daylong 28h forced desynchrony protocols, to examine separate and interacting influences of sleep inertia, sleep homeostasis, and circadian phase on higher-order cognitive functions of inhibitory control and selectiv...

  6. Tumor necrosis factor alpha maintains denervation-induced homeostatic synaptic plasticity of mouse dentate granule cells

    Directory of Open Access Journals (Sweden)

    Denise eBecker

    2013-12-01

    Full Text Available Neurons which lose part of their input respond with a compensatory increase in excitatory synaptic strength. This observation is of particular interest in the context of neurological diseases, which are accompanied by the loss of neurons and subsequent denervation of connected brain regions. However, while the cellular and molecular mechanisms of pharmacologically induced homeostatic synaptic plasticity have been identified to a certain degree, denervation-induced homeostatic synaptic plasticity remains not well understood. Here, we employed the entorhinal denervation in vitro model to study the role of tumor necrosis factor alpha (TNFα on changes in excitatory synaptic strength of mouse dentate granule cells following partial deafferentation. Our experiments disclose that TNFα is required for the maintenance of a compensatory increase in excitatory synaptic strength at 3/4 days postlesion (dpl, but not for the induction of synaptic scaling at 1 - 2 dpl. Furthermore, laser capture microdissection (LMD combined with quantitative PCR (qPCR demonstrates an increase in TNFα-mRNA levels in the denervated zone, which is consistent with our previous finding on a local, i.e., layer-specific increase in excitatory synaptic strength at 3 - 4 dpl. Immunostainings for the glial fibrillary acidic protein (GFAP and TNFα suggest that astrocytes are a source of TNFα in our experimental setting. We conclude that TNFα-signaling is a major regulatory system that aims at maintaining the homeostatic synaptic response of denervated neurons.

  7. Optimization of biomathematical model predictions for cognitive performance impairment in individuals: accounting for unknown traits and uncertain states in homeostatic and circadian processes.

    Science.gov (United States)

    Van Dongen, Hans P A; Mott, Christopher G; Huang, Jen-Kuang; Mollicone, Daniel J; McKenzie, Frederic D; Dinges, David F

    2007-09-01

    Current biomathematical models of fatigue and performance do not accurately predict cognitive performance for individuals with a priori unknown degrees of trait vulnerability to sleep loss, do not predict performance reliably when initial conditions are uncertain, and do not yield statistically valid estimates of prediction accuracy. These limitations diminish their usefulness for predicting the performance of individuals in operational environments. To overcome these 3 limitations, a novel modeling approach was developed, based on the expansion of a statistical technique called Bayesian forecasting. The expanded Bayesian forecasting procedure was implemented in the two-process model of sleep regulation, which has been used to predict performance on the basis of the combination of a sleep homeostatic process and a circadian process. Employing the two-process model with the Bayesian forecasting procedure to predict performance for individual subjects in the face of unknown traits and uncertain states entailed subject-specific optimization of 3 trait parameters (homeostatic build-up rate, circadian amplitude, and basal performance level) and 2 initial state parameters (initial homeostatic state and circadian phase angle). Prior information about the distribution of the trait parameters in the population at large was extracted from psychomotor vigilance test (PVT) performance measurements in 10 subjects who had participated in a laboratory experiment with 88 h of total sleep deprivation. The PVT performance data of 3 additional subjects in this experiment were set aside beforehand for use in prospective computer simulations. The simulations involved updating the subject-specific model parameters every time the next performance measurement became available, and then predicting performance 24 h ahead. Comparison of the predictions to the subjects' actual data revealed that as more data became available for the individuals at hand, the performance predictions became

  8. Challenging the sleep homeostat does not influence the thermoregulatory system in men: evidence from a nap vs. sleep-deprivation study.

    Science.gov (United States)

    Kräuchi, Kurt; Knoblauch, Vera; Wirz-Justice, Anna; Cajochen, Christian

    2006-04-01

    The purpose of our study was to understand the relationship between the components of the three-process model of sleepiness regulation (homeostatic, circadian, and sleep inertia) and the thermoregulatory system. This was achieved by comparing the impact of a 40-h sleep deprivation vs. a 40-h multiple nap paradigm (10 cycles with 150/75 min wakefulness/sleep episodes) on distal and proximal skin temperatures, core body temperature (CBT), melatonin secretion, subjective sleepiness, and nocturnal sleep EEG slow-wave activity in eight healthy young men in a "controlled posture" protocol. The main finding of the study was that accumulation of sleep pressure increased subjective sleepiness and slow-wave activity during the succeeding recovery night but did not influence the thermoregulatory system as measured by distal, proximal, and CBT. The circadian rhythm of sleepiness (and proximal temperature) was significantly correlated and phase locked with CBT, whereas distal temperature and melatonin secretion were phase advanced (by 113 +/- 28 and 130 +/- 30 min, respectively; both P sleep inertia. These effects showed minor and nonsignificant circadian modulation. In summary, the thermoregulatory system seems to be independent of the sleep homeostat, but the circadian modulation of sleepiness and sleep inertia is clearly associated with thermoregulatory changes.

  9. Activity-Dependent Arc Expression and Homeostatic Synaptic Plasticity Are Altered in Neurons from a Mouse Model of Angelman Syndrome

    Science.gov (United States)

    Pastuzyn, Elissa D.; Shepherd, Jason D.

    2017-01-01

    Angelman syndrome (AS) is a neurodevelopmental disorder that results from deletions or mutations in chromosome 15, which usually includes the UBE3A gene. Ube3A protein is an E3 ubiquitin ligase that ubiquitinates proteins and targets them for degradation. The immediate-early gene Arc, a master regulator of synaptic plasticity, was identified as a putative substrate of Ube3A, but there have been conflicting reports on whether Arc is a bona fide E3 ligase substrate. Using multiple approaches, we found no evidence for a physical interaction between Arc and Ube3A in vivo. Nonetheless, activity-induced subcellular distribution of Arc is altered in brains from Ube3am−/p+ mice, with abnormal concentration of Arc at synapses. Furthermore, although activation of Arc transcription is normal, the stability of Arc protein is enhanced in dendrites of hippocampal neurons cultured from Ube3am−/p+ mice. Finally, homeostatic synaptic scaling of surface AMPA receptors does not occur in Ube3am−/p+ hippocampal neurons, reminiscent of neurons that lack Arc protein. Although Ube3A does not seem to bind Arc in a canonical E3 ligase-substrate interaction, Arc-dependent synaptic plasticity is still altered in Ube3am−/p+ mice, which may underlie the cognitive deficits observed in AS. PMID:28804447

  10. Activity-Dependent Arc Expression and Homeostatic Synaptic Plasticity Are Altered in Neurons from a Mouse Model of Angelman Syndrome

    Directory of Open Access Journals (Sweden)

    Elissa D. Pastuzyn

    2017-07-01

    Full Text Available Angelman syndrome (AS is a neurodevelopmental disorder that results from deletions or mutations in chromosome 15, which usually includes the UBE3A gene. Ube3A protein is an E3 ubiquitin ligase that ubiquitinates proteins and targets them for degradation. The immediate-early gene Arc, a master regulator of synaptic plasticity, was identified as a putative substrate of Ube3A, but there have been conflicting reports on whether Arc is a bona fide E3 ligase substrate. Using multiple approaches, we found no evidence for a physical interaction between Arc and Ube3A in vivo. Nonetheless, activity-induced subcellular distribution of Arc is altered in brains from Ube3am−/p+ mice, with abnormal concentration of Arc at synapses. Furthermore, although activation of Arc transcription is normal, the stability of Arc protein is enhanced in dendrites of hippocampal neurons cultured from Ube3am−/p+ mice. Finally, homeostatic synaptic scaling of surface AMPA receptors does not occur in Ube3am−/p+ hippocampal neurons, reminiscent of neurons that lack Arc protein. Although Ube3A does not seem to bind Arc in a canonical E3 ligase-substrate interaction, Arc-dependent synaptic plasticity is still altered in Ube3am−/p+ mice, which may underlie the cognitive deficits observed in AS.

  11. Sleep Homeostatic and Waking Behavioral Phenotypes in Egr3-Deficient Mice Associated with Serotonin Receptor 5-HT2 Deficits.

    Science.gov (United States)

    Grønli, Janne; Clegern, William C; Schmidt, Michelle A; Nemri, Rahmi S; Rempe, Michael J; Gallitano, Amelia L; Wisor, Jonathan P

    2016-12-01

    The expression of the immediate early gene early growth response 3 ( Egr3 ) is a functional marker of brain activity including responses to novelty, sustained wakefulness, and sleep. We examined the role of this gene in regulating wakefulness and sleep. Electroencephalogram/electromyogram (EEG/EMG) were recorded in Egr3 -/- and wild-type (WT) mice during 24 h baseline, 6 h sleep disruption and 6 h recovery. Serotonergic signaling was assessed with 6 h EEG/EMG recordings after injections of nonselective 5-HT2 antagonist (clozapine), selective 5-HT2 antagonists (5-HT2A; MDL100907 and 5-HT2BC; SB206553) and a cocktail of both selective antagonists, administered in a randomized order to each animal. Egr3 -/- mice did not exhibit abnormalities in the timing of wakefulness and slow wave sleep (SWS); however, EEG dynamics in SWS (suppressed 1-3 Hz power) and in quiet wakefulness (elevated 3-8 Hz and 15-35 Hz power) differed in comparison to WT-mice. Egr3 -/- mice showed an exaggerated response to sleep disruption as measured by active wakefulness, but with a blunted increase in homeostatic sleep drive (elevated 1-4 Hz power) relative to WT-mice. Egr3 -/-mice exhibit greatly reduced sedative effects of clozapine at the electroencephalographic level. In addition, clozapine induced a previously undescribed dissociated state (low amplitude, low frequency EEG and a stable, low muscle tone) lasting up to 2 h in WT-mice. Egr3 -/- mice did not exhibit this phenomenon. Selective 5-HT2A antagonist, alone or in combination with selective 5-HT2BC antagonist, caused EEG slowing coincident with behavioral quiescence in WT-mice but not in Egr3 -/- mice. Egr3 has an essential role in regulating cortical arousal, wakefulness, and sleep, presumably by its regulation of 5-HT2 receptors. © 2016 Associated Professional Sleep Societies, LLC.

  12. Modeling of hydronic radiant cooling of a thermally homeostatic building using a parametric cooling tower

    International Nuclear Information System (INIS)

    Ma, Peizheng; Wang, Lin-Shu; Guo, Nianhua

    2014-01-01

    Highlights: • Investigated cooling of thermally homeostatic buildings in 7 U.S. cities by modeling. • Natural energy is harnessed by cooling tower to extract heat for building cooling. • Systematically studied possibility and conditions of using cooling tower in buildings. • Diurnal ambient temperature amplitude is taken into account in cooling tower cooling. • Homeostatic building cooling is possible in locations with large ambient T amplitude. - Abstract: A case is made that while it is important to mitigate dissipative losses associated with heat dissipation and mechanical/electrical resistance for engineering efficiency gain, the “architect” of energy efficiency is the conception of best heat extraction frameworks—which determine the realm of possible efficiency. This precept is applied to building energy efficiency here. Following a proposed process assumption-based design method, which was used for determining the required thermal qualities of building thermal autonomy, this paper continues this line of investigation and applies heat extraction approach investigating the extent of building partial homeostasis and the possibility of full homeostasis by using cooling tower in one summer in seven selected U.S. cities. Cooling tower heat extraction is applied parametrically to hydronically activated radiant-surfaces model-buildings. Instead of sizing equipment as a function of design peak hourly temperature as it is done in heat balance design-approach of selecting HVAC equipment, it is shown that the conditions of using cooling tower depend on both “design-peak” daily-mean temperature and the distribution of diurnal range in hourly temperature (i.e., diurnal temperature amplitude). Our study indicates that homeostatic building with natural cooling (by cooling tower alone) is possible only in locations of special meso-scale climatic condition such as Sacramento, CA. In other locations the use of cooling tower alone can only achieve homeostasis

  13. Homeostasis and change: A commentary on Homeostatic Theory of Obesity by David Marks.

    Science.gov (United States)

    DiClemente, Carlo C; Delahanty, Janine

    2016-01-01

    This commentary on David Marks' article on the Homeostatic Theory of Obesity and his Circle of Discontent mechanism for maintaining problematic eating behavior and obesity offers a perspective on the promise and potential of this theory. At the same time, we challenge the author to incorporate more of a process perspective into the theory. This would include greater exploration of how individuals enter and exit this hypothesized Circle of Discontent, how these mechanisms lead to obesity rather than other internalizing or externalizing disorders, and how the interactions among key variables differ for males and females and developmental stages.

  14. Advances in applied homeostatic modelling of the relationship between thyrotropin and free thyroxine.

    Directory of Open Access Journals (Sweden)

    Rudolf Hoermann

    Full Text Available The relationship between pituitary TSH and thyroid hormones is central to our understanding of thyroid physiology and thyroid function testing. Here, we generated distribution patterns by using validated tools of thyroid modelling.We simulated patterns of individual set points under various conditions, based on a homeostatic model of thyroid feedback control. These were compared with observed data points derived from clinical trials.A random mix of individual set points was reconstructed by simulative modelling with defined structural parameters. The pattern displayed by the cluster of hypothetical points resembled that observed in a natural control group. Moderate variation of the TSH-FT4 gradient over the functional range introduced further flexibility, implementing a scenario of adaptive set points. Such a scenario may be a realistic possibility for instance in treatment where relationships and equilibria between thyroid parameters are altered by various influences such as LT4 dose and conversion efficiency.We validated a physiologically based homeostatic model that permits simulative reconstruction of individual set points. This produced a pattern resembling the observed data under various conditions. Applied modelling, although still experimental at this stage, shows a potential to aid our physiological understanding of the interplay between TSH and thyroid hormones. It should eventually benefit personalised clinical decision making.

  15. Nonlinear feedback drives homeostatic plasticity in H2O2 stress response

    Science.gov (United States)

    Goulev, Youlian; Morlot, Sandrine; Matifas, Audrey; Huang, Bo; Molin, Mikael; Toledano, Michel B; Charvin, Gilles

    2017-01-01

    Homeostatic systems that rely on genetic regulatory networks are intrinsically limited by the transcriptional response time, which may restrict a cell’s ability to adapt to unanticipated environmental challenges. To bypass this limitation, cells have evolved mechanisms whereby exposure to mild stress increases their resistance to subsequent threats. However, the mechanisms responsible for such adaptive homeostasis remain largely unknown. Here, we used live-cell imaging and microfluidics to investigate the adaptive response of budding yeast to temporally controlled H2O2 stress patterns. We demonstrate that acquisition of tolerance is a systems-level property resulting from nonlinearity of H2O2 scavenging by peroxiredoxins and our study reveals that this regulatory scheme induces a striking hormetic effect of extracellular H2O2 stress on replicative longevity. Our study thus provides a novel quantitative framework bridging the molecular architecture of a cellular homeostatic system to the emergence of nonintuitive adaptive properties. DOI: http://dx.doi.org/10.7554/eLife.23971.001 PMID:28418333

  16. Loss of Homeostatic Gas Exchange in Eastern Hemlock in Response to Pollution and Rising CO2?

    Science.gov (United States)

    Rayback, S. A.; Gagen, M. H.; Lini, A.; Cogbill, C. V.

    2014-12-01

    In eastern North American, multiple environmental effects, natural and anthropogenic, may impinge upon tree-ring based stable carbon isotope ratios when examined over long time periods. Investigation of relationships between a Vermont (USA) eastern hemlock δ¹³C (1849-2010) chronology and local and regional climate variables, as well as a regional sulfur dioxide time series revealed the decoupling of δ¹³C from significant climate drivers such as May-August maximum temperature (r=0.50, pwater use efficiency (iWUE) showed homeostatic maintenance of ci levels against ca until 1965 and rising iWUE. Then, ci increased proportional (1965-2000) and later at the same rate as ca (2001-2010) and iWUE leveled off indicating a potential loss of sensitivity to increasing atmospheric carbon dioxide. This more recent passive response may be an indication of a loss of homeostatic maintenance of stomatal control and/or may be linked to changing climate in the region (e.g., wetter conditions).

  17. Homeostatic interplay between FoxO proteins and ER proteostasis in cancer and other diseases.

    Science.gov (United States)

    González-Quiroz, Matías; Urra, Hery; Limia, Celia María; Hetz, Claudio

    2018-01-31

    Cancer cells are exposed to adverse conditions within the tumor microenvironment that challenge cells to adapt and survive. Several of these homeostatic perturbations insults alter the normal function of the endoplasmic reticulum (ER), resulting in the accumulation of misfolded proteins. ER stress triggers a conserved signaling pathway known as the unfolded protein response (UPR) to cope with the stress or trigger apoptosis of damaged cells. The UPR has been described as a major driver in the acquisition of malignant characteristics that ultimately lead to cancer progression. Although, several reports describe the relevance of the UPR in tumor growth, the possible crosstalk with other cancer-related pathways is starting to be elucidated. The Forkhead Box O (FoxO) subfamily of proteins has a major role in cancer progression, where chromosomal translocations and deregulated signaling lead to loss-of-function of FoxO proteins, contributing to tumor progression. Here we discuss the homeostatic connection between the UPR and FoxO proteins and its possible implications to tumor progression and the acquisition of several hallmarks of cancer. In addition, studies linking a crosstalk between the UPR and FoxO proteins in other diseases, including neurodegeneration and metabolic disorders is provided. Copyright © 2018 Elsevier Ltd. All rights reserved.

  18. Melatonin is required for the circadian regulation of sleep.

    Science.gov (United States)

    Gandhi, Avni V; Mosser, Eric A; Oikonomou, Grigorios; Prober, David A

    2015-03-18

    Sleep is an evolutionarily conserved behavioral state whose regulation is poorly understood. A classical model posits that sleep is regulated by homeostatic and circadian mechanisms. Several factors have been implicated in mediating the homeostatic regulation of sleep, but molecules underlying the circadian mechanism are unknown. Here we use animals lacking melatonin due to mutation of arylalkylamine N-acetyltransferase 2 (aanat2) to show that melatonin is required for circadian regulation of sleep in zebrafish. Sleep is dramatically reduced at night in aanat2 mutants maintained in light/dark conditions, and the circadian regulation of sleep is abolished in free-running conditions. We find that melatonin promotes sleep downstream of the circadian clock as it is not required to initiate or maintain circadian rhythms. Additionally, we provide evidence that melatonin may induce sleep in part by promoting adenosine signaling, thus potentially linking circadian and homeostatic control of sleep. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Homeostatic balance as an indicator of prolonged technogenic exposure in low dose range

    International Nuclear Information System (INIS)

    Karpov, A.B.; Voronova, I.A.; Takhauov, R.M.; Semyonova, Yu.V.; Sherstoboev, E.Yu.; Udut, V.V.

    2008-01-01

    Full text: Indication of changes induced by ionizing radiation starting up a wide range of pathologic reactions in the disease developments still poses a significant problem in radiation medicine. It mainly concerns exposure to low dose-rate ionizing radiation, since its effects are still open to question, and today any researcher acknowledges that radiation induced pathological changes can accumulate at both subclinical and prenosological stages and develop not only in exposed persons, but also in their offspring. The subject of this study was workers of reactor and radiochemical productions of Siberian Group of Chemical Enterprises (SGCE) exposed to external and combined (external and internal) radiation respectively. Two comparative groups were formed: reactor and radiochemical production workers. In the reactor production group of workers the cumulative dose of external γ-radiation was up to 300 mSv, in the radiochemical production group - up to 150 mSv. Age ranged from 40 to 50 years. The two groups were compared between each other. Above all, there were formed 'insider control' groups (workers of the same productions with zero doses) to assess the impact of radiation factor on central homeostatic mechanisms. These groups were created using pair technique in order to level somatic disorders influence on the parameters under study. Numbers of full and biochemical blood examinations, energy metabolism between cells, hormones of homeostasis by the adaptive hormone level - insulin and cortisol, lipid peroxidation and antioxidant protection systems, immune and vegetative systems were all analyzed. Analyses of the systems performed, it was found out that in persons having been exposed to long term occupational radiation there were significant changes indicating lipid peroxidation system activation, antioxidant protection system depression, as well as lowered energy metabolism. The higher external γ-doses the bigger these changes are. Results from the two groups of

  20. Retinoid Homeostatic Gene Expression in Liver, Lung and Kidney: Ontogeny and Response to Vitamin A-Retinoic Acid (VARA Supplementation from Birth to Adult Age.

    Directory of Open Access Journals (Sweden)

    Sarah A Owusu

    Full Text Available Vitamin A (VA, retinol metabolism is homeostatically controlled, but little is known of its regulation in the postnatal period. Here, we determined the postnatal trajectory of VA storage and metabolism in major compartments of VA metabolism-plasma, liver, lung, and kidney from postnatal (P day 1 to adulthood. We also investigated the response to supplementation with VARA, a combination of VA and 10% all-trans-retinoic acid that previously was shown to synergistically increase retinol uptake and storage in lung. Nursling pups of dams fed a VA-marginal diet received an oral dose of oil (placebo or VARA on each of four neonatal days: P1, P4, P7, and P10; and again as adults. Tissues were collected 6 h after the final dosing on P1, P4, P10, and at adult age. Gene transcripts for Lrat and Rbp4 in liver and Raldh-1 and Raldh-3 in lung, did not differ in the neonatal period but were higher, P<0.05, in adults, while Cyp26B1, Stra6, megalin, and Raldh-2 in lung did not differ from perinatal to adult ages. VARA supplementation increased total retinol in plasma, liver and lung, with a dose-by-dose accumulation in neonatal liver and lung, while transcripts for Lrat in liver, megalin in kidney, Cyp26A1/B1 in liver and lung, respectively, and Stra6 in lung, were all increased, suggesting pathways of VA uptake, storage and RA oxidation were each augmented after VARA. VARA decreased hepatic expression of Rbp4, responsible for VA trafficking from liver to plasma, and, in lung, of Raldh-1 and Raldh-2, which function in RA production. Our results define retinoid homeostatic gene expression from neonatal and adult age and show that while supplementation with VARA acutely alters retinol content and retinoid homeostatic gene expression in neonatal and adult lung, liver and kidney, VARA supplementation of neonates increased adult-age VA content only in the liver.

  1. The habenula as a novel link between the homeostatic and hedonic pathways in cancer-associated weight loss: a pilot study.

    Science.gov (United States)

    Maldonado, Maria; Molfese, David L; Viswanath, Humsini; Curtis, Kaylah; Jones, Ashley; Hayes, Teresa G; Marcelli, Marco; Mediwala, Sanjay; Baldwin, Philip; Garcia, Jose M; Salas, Ramiro

    2018-03-25

    Little is known about the brain mechanisms underlying cancer-associated weight loss (C-WL) in humans despite this condition negatively affecting their quality of life and survival. We tested the hypothesis that patients with C-WL have abnormal connectivity in homeostatic and hedonic brain pathways together with altered brain activity during food reward. In 12 patients with cancer and 12 healthy controls, resting-state functional connectivity (RSFC, resting brain activity observed through changes in blood flow in the brain which creates a blood oxygen level-dependent signal that can be measured using functional magnetic resonance imaging) was used to compare three brain regions hypothesized to play a role in C-WL: the hypothalamus (homeostatic), the nucleus accumbens (hedonic), and the habenula (an important regulator of reward). In addition, the brain reward response to juice was studied. Participants included 12 patients with histological diagnosis of incurable cancer (solid tumours), a European Cooperative Oncology Group performance status of 0-2, and a ≥5% involuntary body weight loss from pre-illness over the previous 6 months and 12 non-cancer controls matched for age, sex, and race. RSFC between the hypothalamus, nucleus accumbens, and habenula and brain striatum activity as measured by functional MRI during juice reward delivery events were the main outcome measures. After adjusting for BMI and compared with matched controls, patients with C-WL were found to have reduced RSFC between the habenula and hypothalamus (P = 0.04) and between the habenula and nucleus accumbens (P = 0.014). Patients with C-WL also had reduced juice reward responses in the striatum compared with controls. In patients with C-WL, reduced connectivity between both homeostatic and hedonic brain regions and the habenula and reduced juice reward were observed. Further research is needed to establish the relevance of the habenula and striatum in C-WL. Published 2018. This article is

  2. Metabolic Interplay between Astrocytes and Neurons Regulates Endocannabinoid Action

    Directory of Open Access Journals (Sweden)

    Andreu Viader

    2015-08-01

    Full Text Available The endocannabinoid 2-arachidonoylglycerol (2-AG is a retrograde lipid messenger that modulates synaptic function, neurophysiology, and behavior. 2-AG signaling is terminated by enzymatic hydrolysis—a reaction that is principally performed by monoacylglycerol lipase (MAGL. MAGL is broadly expressed throughout the nervous system, and the contributions of different brain cell types to the regulation of 2-AG activity in vivo remain poorly understood. Here, we genetically dissect the cellular anatomy of MAGL-mediated 2-AG metabolism in the brain and show that neurons and astrocytes coordinately regulate 2-AG content and endocannabinoid-dependent forms of synaptic plasticity and behavior. We also find that astrocytic MAGL is mainly responsible for converting 2-AG to neuroinflammatory prostaglandins via a mechanism that may involve transcellular shuttling of lipid substrates. Astrocytic-neuronal interplay thus provides distributed oversight of 2-AG metabolism and function and, through doing so, protects the nervous system from excessive CB1 receptor activation and promotes endocannabinoid crosstalk with other lipid transmitter systems.

  3. Neutral dynamics and cell renewal of colonic crypts in homeostatic regime

    Science.gov (United States)

    Fendrik, A. J.; Romanelli, L.; Rotondo, E.

    2018-05-01

    The self renewal process in colonic crypts is the object of several studies. We present here a new compartment model with the following characteristics: (a) we distinguish different classes of cells: stem cells, six generations of transit amplifying cells and the differentiated cells; (b) in order to take into account the monoclonal character of crypts in homeostatic regimes we include symmetric divisions of the stem cells. We first consider the dynamic differential equations that describe the evolution of the mean values of the populations, but the small observed value of the total number of cells involved plus the huge dispersion of experimental data found in the literature leads us to study the stochastic discrete process. This analysis allows us to study fluctuations, the neutral drift that leads to monoclonality, and the effects of the fixation of mutant clones.

  4. Learning and retrieval behavior in recurrent neural networks with pre-synaptic dependent homeostatic plasticity

    Science.gov (United States)

    Mizusaki, Beatriz E. P.; Agnes, Everton J.; Erichsen, Rubem; Brunnet, Leonardo G.

    2017-08-01

    The plastic character of brain synapses is considered to be one of the foundations for the formation of memories. There are numerous kinds of such phenomenon currently described in the literature, but their role in the development of information pathways in neural networks with recurrent architectures is still not completely clear. In this paper we study the role of an activity-based process, called pre-synaptic dependent homeostatic scaling, in the organization of networks that yield precise-timed spiking patterns. It encodes spatio-temporal information in the synaptic weights as it associates a learned input with a specific response. We introduce a correlation measure to evaluate the precision of the spiking patterns and explore the effects of different inhibitory interactions and learning parameters. We find that large learning periods are important in order to improve the network learning capacity and discuss this ability in the presence of distinct inhibitory currents.

  5. Homeostatic study of the effects of sportswear color on the contest outcome

    Science.gov (United States)

    Yuan, Jian-Qin; Liu, Timon Cheng-Yi; Wu, Ren-Le; Ruan, Chang-Xiong; He, Li-Mei; Liu, Song-Hao

    2008-12-01

    There are effects of sportswear color on the contest outcome. It has been explained from the psychological and perceptual viewpoints, respectively. It was studied by integrating the homeostatic theory of exercise training and autonomic nervous model of color vision in this paper. It was found that the effects of sportswear color on the contest outcome depend on autonomic nervous homeostasis (ANH). Color can be classified into hot color such as red, orange and yellow and cold color such as green, blue and violet. If the athletes have been in ANH, there are no effects of sportswear color on the contest outcome. If the autonomic nervous system is far from ANH due to exercise induced fatigue, wearing cold color had no predominance for cold-hot matches, and wearing white had no predominance for white-color matches.

  6. Denervation-induced homeostatic dendritic plasticity in morphological granule cell models

    Directory of Open Access Journals (Sweden)

    Hermann Cuntz

    2014-03-01

    Full Text Available Neuronal death and subsequent denervation of target areas are major consequences of several neurological conditions such asischemia or neurodegeneration (Alzheimer's disease. The denervation-induced axonal loss results in reorganization of the dendritic tree of denervated neurons. The dendritic reorganization has been previously studied using entorhinal cortex lesion (ECL. ECL leads to shortening and loss of dendritic segments in the denervated outer molecular layer of the dentate gyrus. However, the functional importance of these long-term dendritic alterations is not yet understood and their impact on neuronal electrical properties remains unclear. Here we analyzed what happens to the electrotonic structure and excitability of dentate granule cells after lesion-induced alterations of their dendritic morphology, assuming all other parameters remain equal. We performed comparative electrotonic analysis in anatomically and biophysically realistic compartmental models of 3D-reconstructed healthy and denervated granule cells. Using the method of morphological modeling based on optimization principles minimizing the amount of wiring and maximizing synaptic democracy, we built artificial granule cells which replicate morphological features of their real counterparts. Our results show that somatofugal and somatopetal voltage attenuation in the passive cable model are strongly reduced in denervated granule cells. In line with these predictions, the attenuation both of simulated backpropagating action potentials and forward propagating EPSPs was significantly reduced in dendrites of denervated neurons. Intriguingly, the enhancement of action potential backpropagation occurred specifically in the denervated dendritic layers. Furthermore, simulations of synaptic f-I curves revealed a homeostatic increase of excitability in denervated granule cells. In summary, our morphological and compartmental modeling indicates that unless modified by changes of

  7. Circadian and ultradian components of hunger in human non-homeostatic meal-to-meal eating.

    Science.gov (United States)

    Wuorinen, Elizabeth C; Borer, Katarina T

    2013-10-02

    A unifying physiological explanation of the urge to initiate eating is still not available as human hunger in meal-to-meal eating may not be under homeostatic control. We hypothesized that a central circadian and a gastrointestinal ultradian timing mechanism coordinate non-deprivation meal-to-meal eating. We examined hunger as a function of time of day, inter-meal (IM) energy expenditure (EE), and concentrations of proposed hunger-controlling hormones ghrelin, leptin, and insulin. In two crossover studies, 10 postmenopausal women, BMI 23-26 kg/m(2) engaged in exercise (EX) and sedentary (SED) trials. Weight maintenance meals were provided at 6h intervals with an ad libitum meal at 13 h in study 1 and 21 h snack in study 2. EE during IM intervals was measured by indirect calorimetry and included EX EE of 801 kcal in study 1, and 766-1,051 kcal in study 2. Hunger was assessed with a visual analog scale and blood was collected for hormonal determination. Hunger displayed a circadian variation with acrophase at 13 and 19 h and was unrelated to preceding EE. Hunger was suppressed by EX between 10 and 16 h and bore no relationship to either EE during preceding IM intervals or changes in leptin, insulin, and ghrelin; however leptin reflected IM energy changes and ghrelin and insulin, prandial events. During non-deprivation meal-to-meal eating, hunger appears to be under non-homeostatic central circadian control as it is unrelated to EE preceding meals or concentrations of proposed appetite-controlling hormones. Gastrointestinal meal processing appears to intermittently suppress this control and entrain an ultradian hunger pattern. © 2013 Elsevier Inc. All rights reserved.

  8. of Caenorhabditis elegans: Adaptive and developmental regulation

    Indian Academy of Sciences (India)

    In this study, the expression pattern of rft-2 at different life stages of C. elegans was studied through real-time PCR, and found to be consistent from larval to adult stages that demonstrate its involvement in maintaining the body homeostatic riboflavin levels at whole animal level all through its life. A possible regulation of rft-2 ...

  9. Spontaneous T Cell Proliferation: A Physiologic Process to Create and Maintain Homeostatic Balance and Diversity of the Immune System

    Science.gov (United States)

    Min, Booki

    2018-01-01

    Naive T lymphocytes undergo heterogeneous proliferative responses when introduced into lymphopenic hosts, referred to as “homeostatic proliferation” and “spontaneous proliferation.” Spontaneous proliferation is a unique process through which the immune system generates memory phenotype cells with increasing T cell receptors repertoire complexity. Here, the mechanisms that initiate and control spontaneous proliferation are discussed. PMID:29616038

  10. Process of endogenous homeostatic characteristics decline in two suproopganismal biosystems from the standpoint of parametabolistic theory of senescence.

    Science.gov (United States)

    Makrushin, A V; Aladin, N V

    2016-01-01

    Endogenous decline in homeostatic characteristics of supraorganismal level systems is similar to individual senescence. Similarity is in the fact that this decline as individual senescence is called by negative consequences from specialization of elements the system consists. In systems of supraorganismal level these effects are analogues of parametabolic reactions of senescence individuals.

  11. Age-Related Changes in Gustatory, Homeostatic, Reward, and Memory Processing of Sweet Taste in the Metabolic Syndrome: An fMRI Study.

    Science.gov (United States)

    Jacobson, Aaron; Green, Erin; Haase, Lori; Szajer, Jacquelyn; Murphy, Claire

    2017-01-01

    Age affects the human taste system at peripheral and central levels. Metabolic syndrome is a constellation of risk factors (e.g., abdominal obesity and hypertension) that co-occur, increase with age, and heighten risk for cardiovascular disease, diabetes, and cognitive decline. Little is known about how age, metabolic syndrome, and hunger state interact to influence how the brain processes information about taste. We investigated brain activation during the hedonic evaluation of a pleasant, nutritive stimulus (sucrose) within regions critical for taste, homeostatic energy regulation, and reward, as a function of the interactions among age, metabolic syndrome, and hunger condition. We scanned young and elderly adults, half with risk factors associated with metabolic syndrome twice: Once fasted overnight and once after a preload. Functional magnetic resonance imaging data indicated significant effects of age as well as interactive effects with metabolic syndrome and hunger condition. Age-related differences in activation were dependent on the hunger state in regions critical for homoeostatic energy regulation and basic as well as higher order sensory processing and integration. The effects of age and metabolic syndrome on activation in the insula, orbital frontal cortex, caudate, and the hypothalamus may have particularly important implications for taste processing, energy regulation, and dietary choices.

  12. Renal renin secretion as regulator of body fluid homeostasis

    DEFF Research Database (Denmark)

    Damkjær, Mads; Isaksson, Gustaf L; Stubbe, Jane

    2013-01-01

    The renin-angiotensin system is essential for body fluid homeostasis and blood pressure regulation. This review focuses on the homeostatic regulation of the secretion of active renin in the kidney, primarily in humans. Under physiological conditions, renin secretion is determined mainly by sodium...

  13. PER3 polymorphism predicts cumulative sleep homeostatic but not neurobehavioral changes to chronic partial sleep deprivation.

    Directory of Open Access Journals (Sweden)

    Namni Goel

    2009-06-01

    Full Text Available The variable number tandem repeat (VNTR polymorphism 5-repeat allele of the circadian gene PERIOD3 (PER3(5/5 has been associated with cognitive decline at a specific circadian phase in response to a night of total sleep deprivation (TSD, relative to the 4-repeat allele (PER3(4/4. PER3(5/5 has also been related to higher sleep homeostasis, which is thought to underlie this cognitive vulnerability. To date, no study has used a candidate gene approach to investigate the response to chronic partial sleep deprivation (PSD, a condition distinct from TSD and one commonly experienced by millions of people on a daily and persistent basis. We evaluated whether the PER3 VNTR polymorphism contributed to cumulative neurobehavioral deficits and sleep homeostatic responses during PSD.PER3(5/5 (n = 14, PER3(4/5 (n = 63 and PER3(4/4 (n = 52 healthy adults (aged 22-45 y demonstrated large, but equivalent cumulative decreases in cognitive performance and physiological alertness, and cumulative increases in sleepiness across 5 nights of sleep restricted to 4 h per night. Such effects were accompanied by increasing daily inter-subject variability in all groups. The PER3 genotypes did not differ significantly at baseline in habitual sleep, physiological sleep structure, circadian phase, physiological sleepiness, cognitive performance, or subjective sleepiness, although during PSD, PER3(5/5 subjects had slightly but reliably elevated sleep homeostatic pressure as measured physiologically by EEG slow-wave energy in non-rapid eye movement sleep compared with PER3(4/4 subjects. PER3 genotypic and allelic frequencies did not differ significantly between Caucasians and African Americans.The PER3 VNTR polymorphism was not associated with individual differences in neurobehavioral responses to PSD, although it was related to one marker of sleep homoeostatic response during PSD. The comparability of PER3 genotypes at baseline and their equivalent inter-individual vulnerability

  14. Grape Seed Procyanidins and Cholestyramine Differentially Alter Bile Acid and Cholesterol Homeostatic Gene Expression in Mouse Intestine and Liver.

    Directory of Open Access Journals (Sweden)

    Rebecca M Heidker

    Full Text Available Bile acid (BA sequestrants, lipid-lowering agents, may be prescribed as a monotherapy or combination therapy to reduce the risk of coronary artery disease. Over 33% of adults in the United States use complementary and alternative medicine strategies, and we recently reported that grape seed procyanidin extract (GSPE reduces enterohepatic BA recirculation as a means to reduce serum triglyceride (TG levels. The current study was therefore designed to assess the effects on BA, cholesterol and TG homeostatic gene expression following co-administration with GSPE and the BA sequestrant, cholestyramine (CHY. Eight-week old male C57BL/6 mice were treated for 4 weeks with either a control or 2% CHY-supplemented diet, after which, they were administered vehicle or GSPE for 14 hours. Liver and intestines were harvested and gene expression was analyzed. BA, cholesterol, non-esterified fatty acid and TG levels were also analyzed in serum and feces. Results reveal that GSPE treatment alone, and co-administration with CHY, regulates BA, cholesterol and TG metabolism differently than CHY administration alone. Notably, GSPE decreased intestinal apical sodium-dependent bile acid transporter (Asbt gene expression, while CHY significantly induced expression. Administration with GSPE or CHY robustly induced hepatic BA biosynthetic gene expression, especially cholesterol 7α-hydroxylase (Cyp7a1, compared to control, while co-administration further enhanced expression. Treatment with CHY induced both intestinal and hepatic cholesterologenic gene expression, while co-administration with GSPE attenuated the CHY-induced increase in the liver but not intestine. CHY also induced hepatic lipogenic gene expression, which was attenuated by co-administration with GSPE. Consequently, a 25% decrease in serum TG levels was observed in the CHY+GSPE group, compared to the CHY group. Collectively, this study presents novel evidence demonstrating that GSPE provides additive and

  15. Emerging Link between Alzheimer’s Disease and Homeostatic Synaptic Plasticity

    Directory of Open Access Journals (Sweden)

    Sung-Soo Jang

    2016-01-01

    Full Text Available Alzheimer’s disease (AD is an irreversible brain disorder characterized by progressive cognitive decline and neurodegeneration of brain regions that are crucial for learning and memory. Although intracellular neurofibrillary tangles and extracellular senile plaques, composed of insoluble amyloid-β (Aβ peptides, have been the hallmarks of postmortem AD brains, memory impairment in early AD correlates better with pathological accumulation of soluble Aβ oligomers and persistent weakening of excitatory synaptic strength, which is demonstrated by inhibition of long-term potentiation, enhancement of long-term depression, and loss of synapses. However, current, approved interventions aiming to reduce Aβ levels have failed to retard disease progression; this has led to a pressing need to identify and target alternative pathogenic mechanisms of AD. Recently, it has been suggested that the disruption of Hebbian synaptic plasticity in AD is due to aberrant metaplasticity, which is a form of homeostatic plasticity that tunes the magnitude and direction of future synaptic plasticity based on previous neuronal or synaptic activity. This review examines emerging evidence for aberrant metaplasticity in AD. Putative mechanisms underlying aberrant metaplasticity in AD will also be discussed. We hope this review inspires future studies to test the extent to which these mechanisms contribute to the etiology of AD and offer therapeutic targets.

  16. Inducing homeostatic-like plasticity in human motor cortex through converging corticocortical inputs

    DEFF Research Database (Denmark)

    Pötter-Nerger, Monika; Fischer, Sarah; Mastroeni, Claudia

    2009-01-01

    Transcranial stimulation techniques have revealed homeostatic-like metaplasticity in the hand area of the human primary motor cortex (M1(HAND)) that controls stimulation-induced changes in corticospinal excitability. Here we combined two interventional protocols that induce long-term depression......TMS) of the left dorsal premotor cortex (PMD) was first applied to produce an LTP-like increase (5 Hz rTMS) or LTD-like decrease (1 Hz rTMS) in corticospinal excitability in left M1(HAND) via premotor-to-motor inputs. Following PMD rTMS, paired-associative stimulation (PAS) was applied to the right median nerve...... and left M1(HAND) to induce spike-time-dependent plasticity in sensory-to-motor inputs to left M1(HAND). We adjusted the interstimulus interval to the N20 latency of the median nerve somatosensory-evoked cortical potential to produce an LTP-like increase (PAS(N20+2ms)) or an LTD-like decrease (PAS(N20-5ms...

  17. Intracellular Position of Centrioles and the Direction of Homeostatic Epithelial Cell Movements in the Mouse Cornea.

    Science.gov (United States)

    Silverman, Erika; Zhao, Jin; Merriam, John C; Nagasaki, Takayuki

    2017-02-01

    Corneal epithelial cells exhibit continuous centripetal movements at a rate of about 30 µm per day, but neither the driving force nor the mechanism that determines the direction of movements is known. To facilitate the investigation of homeostatic cell movement, we examined if the intracellular position of a centriole can be used as a directional marker of epithelial cell movements in the mouse cornea. A direction of cell movements was estimated in fixed specimens from a pattern of underlying subepithelial nerve fibers. Intracellular position of centrioles was determined by gamma-tubulin immunohistology and plotted in a narrow strip along the entire diameter of a cornea from limbus to limbus. When we determined the position of centrioles in the peripheral cornea where cell movements proceed generally along a radial path, about 55% of basal epithelial cells contained a centriole in the front half of a cell. However, in the central cornea where cells exhibit a spiral pattern of movements, centrioles were distributed randomly. These results suggest that centrioles tend to be positioned toward the direction of movement in corneal basal epithelial cells when they are moving centripetally at a steady rate.

  18. Turing mechanism for homeostatic control of synaptic density during C. elegans growth

    Science.gov (United States)

    Brooks, Heather A.; Bressloff, Paul C.

    2017-07-01

    We propose a mechanism for the homeostatic control of synapses along the ventral cord of Caenorhabditis elegans during development, based on a form of Turing pattern formation on a growing domain. C. elegans is an important animal model for understanding cellular mechanisms underlying learning and memory. Our mathematical model consists of two interacting chemical species, where one is passively diffusing and the other is actively trafficked by molecular motors, which switch between forward and backward moving states (bidirectional transport). This differs significantly from the standard mechanism for Turing pattern formation based on the interaction between fast and slow diffusing species. We derive evolution equations for the chemical concentrations on a slowly growing one-dimensional domain, and use numerical simulations to demonstrate the insertion of new concentration peaks as the length increases. Taking the passive component to be the protein kinase CaMKII and the active component to be the glutamate receptor GLR-1, we interpret the concentration peaks as sites of new synapses along the length of C. elegans, and thus show how the density of synaptic sites can be maintained.

  19. Creatine supplementation reduces sleep need and homeostatic sleep pressure in rats.

    Science.gov (United States)

    Dworak, Markus; Kim, Tae; Mccarley, Robert W; Basheer, Radhika

    2017-06-01

    Sleep has been postulated to promote brain energy restoration. It is as yet unknown if increasing the energy availability within the brain reduces sleep need. The guanidine amino acid creatine (Cr) is a well-known energy booster in cellular energy homeostasis. Oral Cr-monohydrate supplementation (CS) increases exercise performance and has been shown to have substantial effects on cognitive performance, neuroprotection and circadian rhythms. The effect of CS on cellular high-energy molecules and sleep-wake behaviour is unclear. Here, we examined the sleep-wake behaviour and brain energy metabolism before and after 4-week-long oral administration of CS in the rat. CS decreased total sleep time and non-rapid eye movement (NREM) sleep significantly during the light (inactive) but not during the dark (active) period. NREM sleep and NREM delta activity were decreased significantly in CS rats after 6 h of sleep deprivation. Biochemical analysis of brain energy metabolites showed a tendency to increase in phosphocreatine after CS, while cellular adenosine triphosphate (ATP) level decreased. Microdialysis analysis showed that the sleep deprivation-induced increase in extracellular adenosine was attenuated after CS. These results suggest that CS reduces sleep need and homeostatic sleep pressure in rats, thereby indicating its potential in the treatment of sleep-related disorders. © 2017 European Sleep Research Society.

  20. Identification of cutoff points for Homeostatic Model Assessment for Insulin Resistance index in adolescents: systematic review

    Science.gov (United States)

    de Andrade, Maria Izabel Siqueira; Oliveira, Juliana Souza; Leal, Vanessa Sá; da Lima, Niedja Maria Silva; Costa, Emília Chagas; de Aquino, Nathalia Barbosa; de Lira, Pedro Israel Cabral

    2016-01-01

    Abstract Objective: To identify cutoff points of the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) index established for adolescents and discuss their applicability for the diagnosis of insulin resistance in Brazilian adolescents. Data source: A systematic review was performed in the PubMed, Lilacs and SciELO databases, using the following descriptors: "adolescents", "insulin resistance" and "Receiver Operating Characteristics Curve". Original articles carried out with adolescents published between 2005 and 2015 in Portuguese, English or Spanish languages, which included the statistical analysis using Receiver Operating Characteristics Curve to determine the index cutoff (HOMA-IR) were included. Data synthesis: A total of 184 articles were identified and after the study phases were applied, seven articles were selected for the review. All selected studies established their cutoffs using a Receiver Operating Characteristics Curve, with the lowest observed cutoff of 1.65 for girls and 1.95 for boys and the highest of 3.82 for girls and 5.22 for boys. Of the studies analyzed, one proposed external validity, recommending the use of the HOMA-IR cutoff>2.5 for both genders. Conclusions: The HOMA-IR index constitutes a reliable method for the detection of insulin resistance in adolescents, as long as it uses cutoffs that are more adequate for the reality of the study population, allowing early diagnosis of insulin resistance and enabling multidisciplinary interventions aiming at health promotion of this population. PMID:26559605

  1. 1Protein Energy Malnutrition Impairs Homeostatic Proliferation of Memory CD8 T cells

    Science.gov (United States)

    Iyer, Smita S.; Chatraw, Janel Hart; Tan, Wendy G.; Wherry, E. John; Becker, Todd C.; Ahmed, Rafi; Kapasi, Zoher F.

    2011-01-01

    Nutrition is a critical but poorly understood determinant of immunity. There is abundant epidemiological evidence linking protein malnutrition to impaired vaccine efficacy and increased susceptibility to infections; yet, the role of dietary protein in immune memory homeostasis remains poorly understood. Here we show that protein energy malnutrition (PEM) induced in mice by low-protein (LP) feeding has a detrimental impact on CD8 memory. Relative to adequate-protein (AP) fed controls, LP feeding in lymphocytic choriomeningitis virus (LCMV) immune mice resulted in a 2-fold decrease in LCMV-specific CD8 memory T cells. Adoptive transfer of memory cells, labeled with a division tracking dye, from AP mice into naive LP or AP mice demonstrated that PEM caused profound defects in homeostatic proliferation. Remarkably, this defect occurred despite the lymphopenic environment in LP hosts. While antigen-specific memory cells in LP and AP hosts were phenotypically similar, memory cells in LP hosts were markedly less-responsive to poly(I:C)-induced acute proliferative signals. Furthermore, upon recall, memory cells in LP hosts displayed reduced proliferation and protection from challenge with LCMV-clone 13 resulting in impaired viral clearance in the liver. The findings show a metabolic requirement of dietary protein in sustaining functional CD8 memory and suggest that interventions to optimize dietary protein intake may improve vaccine efficacy in malnourished individuals. PMID:22116826

  2. Protein energy malnutrition impairs homeostatic proliferation of memory CD8 T cells.

    Science.gov (United States)

    Iyer, Smita S; Chatraw, Janel Hart; Tan, Wendy G; Wherry, E John; Becker, Todd C; Ahmed, Rafi; Kapasi, Zoher F

    2012-01-01

    Nutrition is a critical but poorly understood determinant of immunity. There is abundant epidemiological evidence linking protein malnutrition to impaired vaccine efficacy and increased susceptibility to infections; yet, the role of dietary protein in immune memory homeostasis remains poorly understood. In this study, we show that protein-energy malnutrition induced in mice by low-protein (LP) feeding has a detrimental impact on CD8 memory. Relative to adequate protein (AP)-fed controls, LP feeding in lymphocytic choriomeningitis virus (LCMV)-immune mice resulted in a 2-fold decrease in LCMV-specific CD8 memory T cells. Adoptive transfer of memory cells, labeled with a division tracking dye, from AP mice into naive LP or AP mice demonstrated that protein-energy malnutrition caused profound defects in homeostatic proliferation. Remarkably, this defect occurred despite the lymphopenic environment in LP hosts. Whereas Ag-specific memory cells in LP and AP hosts were phenotypically similar, memory cells in LP hosts were markedly less responsive to polyinosinic-polycytidylic acid-induced acute proliferative signals. Furthermore, upon recall, memory cells in LP hosts displayed reduced proliferation and protection from challenge with LCMV-clone 13, resulting in impaired viral clearance in the liver. The findings show a metabolic requirement of dietary protein in sustaining functional CD8 memory and suggest that interventions to optimize dietary protein intake may improve vaccine efficacy in malnourished individuals.

  3. Homeostatic imbalance between apoptosis and cell renewal in the liver of premature aging Xpd mice.

    Directory of Open Access Journals (Sweden)

    Jung Yoon Park

    2008-06-01

    Full Text Available Unrepaired or misrepaired DNA damage has been implicated as a causal factor in cancer and aging. Xpd(TTD mice, harboring defects in nucleotide excision repair and transcription due to a mutation in the Xpd gene (R722W, display severe symptoms of premature aging but have a reduced incidence of cancer. To gain further insight into the molecular basis of the mutant-specific manifestation of age-related phenotypes, we used comparative microarray analysis of young and old female livers to discover gene expression signatures distinguishing Xpd(TTD mice from their age-matched wild type controls. We found a transcription signature of increased apoptosis in the Xpd(TTD mice, which was confirmed by in situ immunohistochemical analysis and found to be accompanied by increased proliferation. However, apoptosis rate exceeded the rate of proliferation, resulting in homeostatic imbalance. Interestingly, a metabolic response signature was observed involving decreased energy metabolism and reduced IGF-1 signaling, a major modulator of life span. We conclude that while the increased apoptotic response to endogenous DNA damage contributes to the accelerated aging phenotypes and the reduced cancer incidence observed in the Xpd(TTD mice, the signature of reduced energy metabolism is likely to reflect a compensatory adjustment to limit the increased genotoxic stress in these mutants. These results support a general model for premature aging in DNA repair deficient mice based on cellular responses to DNA damage that impair normal tissue homeostasis.

  4. The interaction of meal-related, rhythmic and homeostatic mechanisms and the generation of thirst and drinking

    Directory of Open Access Journals (Sweden)

    R.F. Johnson

    1997-04-01

    Full Text Available One of the primary goals of the study of thirst is to understand why drinking occurs under ad libitum or natural conditions. An appreciation of the experimental strategies applied by physiologists studying thirst from different perspectives can facilitate progress toward understanding the natural history of drinking behavior. Drinking research carried out using three separate perspectives - homeostatic, circadian rhythms, and food-associated - generates types of information about the mechanisms underlying drinking behavior. By combining research strategies and methods derived from each of these approaches, it has been possible to gain new information that increases our appreciation of the interactions between homeostatic mechanisms and circadian rhythms in the modulation of water intake and how these might be related to drinking associated with food intake under near natural conditions

  5. Associative, Bidirectional Changes in Neural Signaling Utilizing NMDA Receptor- and Endocannabinoid-Dependent Mechanisms

    Science.gov (United States)

    Li, Qin; Burrell, Brian D.

    2011-01-01

    Persistent, bidirectional changes in synaptic signaling (that is, potentiation and depression of the synapse) can be induced by the precise timing of individual pre- and postsynaptic action potentials. However, far less attention has been paid to the ability of paired trains of action potentials to elicit persistent potentiation or depression. We…

  6. Sleep homeostatic pressure and PER3 VNTR gene polymorphism influence antidepressant response to sleep deprivation in bipolar depression.

    Science.gov (United States)

    Dallaspezia, Sara; Locatelli, Clara; Lorenzi, Cristina; Pirovano, Adele; Colombo, Cristina; Benedetti, Francesco

    2016-03-01

    Combined Total sleep deprivation (TSD) and light therapy (LT) cause a rapid improvement in bipolar depression which has been hypothesized to be paralleled by changes in sleep homeostasis. Recent studies showed that bipolar patients had lower changes of EEG theta power after sleep and responders to antidepressant TSD+LT slept less and showed a lower increase of EEG theta power then non-responders. A polymorphism in PER3 gene has been associated with diurnal preference, sleep structure and homeostatic response to sleep deprivation in healthy subjects. We hypothesized that the individual variability in the homeostatic response to TSD could be a correlate of antidepressant response and be influenced by genetic factors. We administered three TSD+LT cycles to bipolar depressed patients. Severity of depression was rated on Hamilton Depression Rating Scale. Actigraphic recordings were performed in a group of patients. PER3 polymorphism influenced changes in total sleep time (F=2.24; p=0.024): while PER3(4/4) and PER3(4/5) patients showed a reduction in it after treatment, PER3(5/5) subjects showed an increase of about 40min, suggesting a higher homeostatic pressure. The same polymorphism influenced the change of depressive symptomatology during treatment (F=3.72; p=0.028). Sleep information was recorded till the day after the end of treatment: a longer period of observation could give more information about the possible maintenance of allostatic adaptation. A higher sleep homeostatic pressure reduced the antidepressant response to TSD+LT, while an allostatic adaptation to sleep loss was associated with better response. This process seems to be under genetic control. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Exercise‐induced homeostatic perturbations provoked by singles tennis match play with reference to development of fatigue

    OpenAIRE

    Mendez‐Villanueva, Alberto; Fernandez‐Fernandez, Jaime; Bishop, David

    2007-01-01

    This review addresses metabolic, neural, mechanical and thermal alterations during tennis match play with special focus on associations with fatigue. Several studies have provided a link between fatigue and the impairment of tennis skills proficiency. A tennis player's ability to maintain skilled on‐court performance and/or optimal muscle function during a demanding match can be compromised as a result of several homeostatic perturbations, for example hypoglycaemia, muscle damage and hyperthe...

  8. The associations between increasing degrees of homeostatic model assessment for insulin resistance and muscular strengthening activities among euglycaemic US adults.

    Science.gov (United States)

    Boyer, William R; Johnson, Tammie M; Fitzhugh, Eugene C; Richardson, Michael R; Churilla, James R

    2015-11-01

    To examine the associations between the homeostatic model assessment for insulin resistance and self-reported muscular strengthening activity in a nationally representative sample of euglycaemic US adults. Sample included euglycaemic adults (⩾20 years of age (n = 2009)) from the 1999 to 2004 National Health and Nutrition Examination Survey. Homeostatic model assessment for insulin resistance was categorized into quartiles and was the primary independent variable of interest. No reported muscular strengthening activity was the dependent variable. Following adjustment for covariates, those with homeostatic model assessment for insulin resistance values in fourth (odds ratio: 2.04, 95% confidence interval: 1.35-3.06, p activity. Following further adjustment for non-muscular strengthening activity specific aerobic leisure-time physical activity, results remained significant for the fourth (odds ratio: 2.30, 95% confidence interval: 1.50-3.52, p insulin resistance for increasing prevalence of no muscular strengthening activity (p insulin resistance value is associated with greater odds of reporting no muscular strengthening activity among euglycaemic US adults. This implies that subjects with an increasing degree of insulin resistance are more likely to not engage in muscular strengthening activity, an exercise modality that has been shown to reduce the risk of several cardiometabolic diseases and improve glycaemic status. © The Author(s) 2015.

  9. Homeostatically maintained resting naïve CD4+ T cells resist latent HIV reactivation

    Directory of Open Access Journals (Sweden)

    Yasuko Tsunetsugu-Yokota

    2016-12-01

    Full Text Available Homeostatic proliferation (HSP is a major mechanism by which long-lived naïve and memory CD4+ T cells are maintained in vivo and suggested to contribute to the persistence of the latent HIV-1 reservoir. However, while many in vitro latency models rely on CD4+ T cells that were initially differentiated via T-cell receptor stimulation (TCR into memory/effector cells, latent infection of naïve resting CD4+ T cells maintained under HSP conditions has not been fully addressed. Here we describe an in vitro HSP culture system utilizing the cytokines IL-7 and IL-15 that allows studying latency in naïve resting CD4+ T cells. CD4+ T cells isolated from several healthy donors were infected with HIV pseudotypes expressing GFP and cultured under HSP conditions or TCR conditions as control. Cell proliferation, phenotype and GFP expression were analyzed by flow cytometry. RNA expression was quantified by qRT-PCR. Under HSP culture conditions, latently HIV-1 infected naïve cells are in part maintained in the non-dividing (= resting state. Although a few HIV-1 provirus+ cells were present in these resting GFP negative cells, the estimated level of GFP transcripts per infected cell seems to indicate a block at the post-transcriptional level. Interestingly, neither TCR nor the prototypic HDAC inhibitor SAHA were able to reactivate HIV-1 provirus from these cells. This lack of reactivation was not due to methylation of the HIV LTR. These results point to a mechanism of HIV control in HSP-cultured resting naïve CD4+ T cells that may be distinct from that in TCR-stimulated memory/effector T cells.

  10. Homeostatically Maintained Resting Naive CD4+T Cells Resist Latent HIV Reactivation.

    Science.gov (United States)

    Tsunetsugu-Yokota, Yasuko; Kobayahi-Ishihara, Mie; Wada, Yamato; Terahara, Kazutaka; Takeyama, Haruko; Kawana-Tachikawa, Ai; Tokunaga, Kenzo; Yamagishi, Makoto; Martinez, Javier P; Meyerhans, Andreas

    2016-01-01

    Homeostatic proliferation (HSP) is a major mechanism by which long-lived naïve and memory CD4 + T cells are maintained in vivo and suggested to contribute to the persistence of the latent HIV-1 reservoir. However, while many in vitro latency models rely on CD4 + T cells that were initially differentiated via T-cell receptor (TCR) stimulation into memory/effector cells, latent infection of naïve resting CD4 + T cells maintained under HSP conditions has not been fully addressed. Here, we describe an in vitro HSP culture system utilizing the cytokines IL-7 and IL-15 that allows studying latency in naïve resting CD4 + T cells. CD4 + T cells isolated from several healthy donors were infected with HIV pseudotypes expressing GFP and cultured under HSP conditions or TCR conditions as control. Cell proliferation, phenotype, and GFP expression were analyzed by flow cytometry. RNA expression was quantified by qRT-PCR. Under HSP culture conditions, latently HIV-1 infected naïve cells are in part maintained in the non-dividing (= resting) state. Although a few HIV-1 provirus + cells were present in these resting GFP negative cells, the estimated level of GFP transcripts per infected cell seems to indicate a block at the post-transcriptional level. Interestingly, neither TCR nor the prototypic HDAC inhibitor SAHA were able to reactivate HIV-1 provirus from these cells. This lack of reactivation was not due to methylation of the HIV LTR. These results point to a mechanism of HIV control in HSP-cultured resting naïve CD4 + T cells that may be distinct from that in TCR-stimulated memory/effector T cells.

  11. Selective insulin resistance in homeostatic and cognitive control brain areas in overweight and obese adults.

    Science.gov (United States)

    Kullmann, Stephanie; Heni, Martin; Veit, Ralf; Scheffler, Klaus; Machann, Jürgen; Häring, Hans-Ulrich; Fritsche, Andreas; Preissl, Hubert

    2015-06-01

    Impaired brain insulin action has been linked to obesity, type 2 diabetes, and neurodegenerative diseases. To date, the central nervous effects of insulin in obese humans still remain ill defined, and no study thus far has evaluated the specific brain areas affected by insulin resistance. In 25 healthy lean and 23 overweight/obese participants, we performed magnetic resonance imaging to measure cerebral blood flow (CBF) before and 15 and 30 min after application of intranasal insulin or placebo. Additionally, participants explicitly rated pictures of high-caloric savory and sweet food 60 min after the spray for wanting and liking. In response to insulin compared with placebo, we found a significant CBF decrease in the hypothalamus in both lean and overweight/obese participants. The magnitude of this response correlated with visceral adipose tissue independent of other fat compartments. Furthermore, we observed a differential response in the lean compared with the overweight/obese group in the prefrontal cortex, resulting in an insulin-induced CBF reduction in lean participants only. This prefrontal cortex response significantly correlated with peripheral insulin sensitivity and eating behavior measures such as disinhibition and food craving. Behaviorally, we were able to observe a significant reduction for the wanting of sweet foods after insulin application in lean men only. Brain insulin action was selectively impaired in the prefrontal cortex in overweight and obese adults and in the hypothalamus in participants with high visceral adipose tissue, potentially promoting an altered homeostatic set point and reduced inhibitory control contributing to overeating behavior. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  12. Peculiarities of homeostatic system in highland conditions using llizarov distraction transosseous osteosynthesis method

    Directory of Open Access Journals (Sweden)

    Jumabekov S.A.

    2012-06-01

    Full Text Available Purpose. The purpose is to study the reaction of homeostasis system in stable and in distraction llizarov transosseous ostesysnthesis of the limbs bones at experimental animals (dogs in highland conditions. Material and Methods. 63 adult mongrels aged from 1 to 3 years with 10-20 kg body weight and 15 cm minimal length of tibia were included in the experiment. Open osteosotmy of tibial mid-shaft followed by Kirschner wires insertion through tibial bone and llizarov frame assembly comprising 3 or 4 rings was performed under IV anaesthesia at 3200 m altitude above sea level. In experimental group including 33 mongrels the distraction was performed on the 5th day after osteotomy by 1 mm rate divided into 4 times within 10 days but in control group comprising 30 dogs the distraction was not provided. Every 10 days after distraction blood samples were taken in both groups to examine coagulation; the samples were taken from subcutaneous lateral tibial vein, ex tempora mixing with 3,8% solution of sodium citrate at 9:1 ratio. Then the plasma was separated and examined biochemically according to the accepted standards. Results. We obtained the data witnessing activation of coagulation component of homeostatic system in stable osteosynthesis of the limb bones using llizarov fixator with simultaneous inhibition of fibrinolytic component. In distraction osteosynthesis hyper-coagulation trend in homeostasis system with simultaneous suppression of fibrinolytic blood activity is vividly defined within the entire experiment period. Conclusion. Transosseous distraction osteosynthesis in highland condition causes considerable shifts in the system of homeostasis with definite domination of coagulation component which promotes formation of pre-thrombotic condition. Limb segment lengthening on the background of pre-thrombotic condition increases the risk of thromboembolic complications in highland conditions and requires appropriate measures of prophylaxis

  13. Sleep inertia, sleep homeostatic and circadian influences on higher-order cognitive functions.

    Science.gov (United States)

    Burke, Tina M; Scheer, Frank A J L; Ronda, Joseph M; Czeisler, Charles A; Wright, Kenneth P

    2015-08-01

    Sleep inertia, sleep homeostatic and circadian processes modulate cognition, including reaction time, memory, mood and alertness. How these processes influence higher-order cognitive functions is not well known. Six participants completed a 73-day-long study that included two 14-day-long 28-h forced desynchrony protocols to examine separate and interacting influences of sleep inertia, sleep homeostasis and circadian phase on higher-order cognitive functions of inhibitory control and selective visual attention. Cognitive performance for most measures was impaired immediately after scheduled awakening and improved during the first ~2-4 h of wakefulness (decreasing sleep inertia); worsened thereafter until scheduled bedtime (increasing sleep homeostasis); and was worst at ~60° and best at ~240° (circadian modulation, with worst and best phases corresponding to ~09:00 and ~21:00 hours, respectively, in individuals with a habitual wake time of 07:00 hours). The relative influences of sleep inertia, sleep homeostasis and circadian phase depended on the specific higher-order cognitive function task examined. Inhibitory control appeared to be modulated most strongly by circadian phase, whereas selective visual attention for a spatial-configuration search task was modulated most strongly by sleep inertia. These findings demonstrate that some higher-order cognitive processes are differentially sensitive to different sleep-wake regulatory processes. Differential modulation of cognitive functions by different sleep-wake regulatory processes has important implications for understanding mechanisms contributing to performance impairments during adverse circadian phases, sleep deprivation and/or upon awakening from sleep. © 2015 European Sleep Research Society.

  14. Homeostatic & Circadian Regulation of Wakefulness During Jet Lag and Sleep. Sleep Deprivation: Effect of Wake-Promoting Countermeasures

    National Research Council Canada - National Science Library

    Dinges, David

    2000-01-01

    .... Major human research projects on the effects of induced jet lag and sleep deprivation and their mitigation by sustained low-dose caffeine and naps were undertaken at the University of Pennsylvania...

  15. Constructive effects of diversity in a multi-neuron model of the homeostatic regulation of the sleep–wake cycle

    International Nuclear Information System (INIS)

    Patriarca, Marco; Hernández-García, Emilio; Toral, Raúl

    2015-01-01

    As an instance of diversity-induced resonance and of the constructive role of heterogeneity in complex systems, here we study a generalized version of a physiologically-motivated sleep–wake cycle model taking into account the role of orexin [Patriarca et al. (2012) [16]; Postnova et al. (2009) [9

  16. Inactivity Is Nycthemeral, Endogenously Generated, Homeostatically Regulated, and Melatonin Modulated in a Free-Living Platyhelminth Flatworm.

    Science.gov (United States)

    Omond, Shauni; Ly, Linh M T; Beaton, Russell; Storm, Jonathan J; Hale, Matthew W; Lesku, John A

    2017-10-01

    Sleep either appeared once early in the evolution of animals, or at multiple instances over evolutionary time. Understanding whether sleep is a diagnostic trait for members of the kingdom Animalia has important implications for our understanding of the evolution of sleep and sleep functions. Unfortunately, knowledge on the phylogenetic breadth of sleep is restricted to vertebrates, a few arthropods and molluscs, and one species of nematode. There is a dearth of information on the other 30 or so animal phyla. Here, we provide original data on a previously unstudied group of animals with respect to sleep: platyhelminth flatworms. These free-living animals are relatively simple, with a rudimentary central nervous system and absence of many other specialized physiological systems. Despite this simplicity, inactive flatworms appeared to be sleeping. Specifically, quiescence was organized in a circadian manner, occurring largely during the daytime. This basic rhythm persisted under constant darkness, suggesting that it was endogenously generated. Active flatworms responded more readily to stimulation, and flatworms recovered lost sleep by sleeping longer after a 3-hour period of inactivity deprivation. We were also able to increase inactivity in a dose-dependent manner with exposure to melatonin, a hormone that increases sleep in diurnal animals. Taken together, these data expand our understanding of the phylogenetic extent of sleep and reinforce the idea that sleep evolved early in the evolutionary history of animals. However, additional studies on other types of animals are required for a comprehensive understanding of the origin(s) and evolution of sleep. © Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

  17. AFOSR PRET: Homeostatic & Circadian Regulation of Wakefulness During Jet Lag and Sleep Deprivation: Effect of Wake-Promoting Countermeasures

    Science.gov (United States)

    2005-05-31

    found for circulating cortisol levels; melatonin levels; physical activity mean or variability; or any nap polysomnographic outcome. Table 3. Experiment...temperaturet 12 4.32 0.060 3, 37 0.70 0.557 Plasma cortisol 18 1.29 0.271 3, 57 2.01 0.122 Plasma melatonin 18 1.83 0.193 3, 57 1.75 0.166 Plasma...of subjective scales. PENN-Experiment 1: 200ma modafinil/24h (1200h) vs . placebo during 88 hours of partial sleep deprivation (2-hr nap oer day) In

  18. Lysine trimethylation regulates 78-kDa glucose-regulated protein proteostasis during endoplasmic reticulum stress.

    Science.gov (United States)

    Sieber, Jonas; Wieder, Nicolas; Ostrosky-Frid, Mauricio; Dvela-Levitt, Moran; Aygün, Ozan; Udeshi, Namrata D; Carr, Steven A; Greka, Anna

    2017-11-17

    The up-regulation of chaperones such as the 78-kDa glucose-regulated protein (GRP78, also referred to as BiP or HSPA5) is part of the adaptive cellular response to endoplasmic reticulum (ER) stress. GRP78 is widely used as a marker of the unfolded protein response, associated with sustained ER stress. Here we report the discovery of a proteostatic mechanism involving GRP78 trimethylation in the context of ER stress. Using mass spectrometry-based proteomics, we identified two GRP78 fractions, one homeostatic and one induced by ER stress. ER stress leads to de novo biosynthesis of non-trimethylated GRP78, whereas homeostatic, METTL21A-dependent lysine 585-trimethylated GRP78 is reduced. This proteostatic mechanism, dependent on the posttranslational modification of GRP78, allows cells to differentially regulate specific protein abundance during cellular stress. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  19. Data integration reveals key homeostatic mechanisms following low dose radiation exposure

    Energy Technology Data Exchange (ETDEWEB)

    Tilton, Susan C.; Matzke, Melissa M. [Computational Biology and Bioinformatics, Pacific Northwest National Laboratory, Richland, WA 99338 (United States); Sowa, Marianne B.; Stenoien, David L.; Weber, Thomas J. [Health Impacts and Exposure Science, Pacific Northwest National Laboratory, Richland, WA 99338 (United States); Morgan, William F. [Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99338 (United States); Waters, Katrina M., E-mail: katrina.waters@pnnl.gov [Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99338 (United States)

    2015-05-15

    The goal of this study was to define pathways regulated by low dose radiation to understand how biological systems respond to subtle perturbations in their environment and prioritize pathways for human health assessment. Using an in vitro 3-D human full thickness skin model, we have examined the temporal response of dermal and epidermal layers to 10 cGy X-ray using transcriptomic, proteomic, phosphoproteomic and metabolomic platforms. Bioinformatics analysis of each dataset independently revealed potential signaling mechanisms affected by low dose radiation, and integrating data shed additional insight into the mechanisms regulating low dose responses in human tissue. We examined direct interactions among datasets (top down approach) and defined several hubs as significant regulators, including transcription factors (YY1, MYC and CREB1), kinases (CDK2, PLK1) and a protease (MMP2). These data indicate a shift in response across time — with an increase in DNA repair, tissue remodeling and repression of cell proliferation acutely (24–72 h). Pathway-based integration (bottom up approach) identified common molecular and pathway responses to low dose radiation, including oxidative stress, nitric oxide signaling and transcriptional regulation through the SP1 factor that would not have been identified by the individual data sets. Significant regulation of key downstream metabolites of nitrative stress was measured within these pathways. Among the features identified in our study, the regulation of MMP2 and SP1 was experimentally validated. Our results demonstrate the advantage of data integration to broadly define the pathways and networks that represent the mechanisms by which complex biological systems respond to perturbation. - Highlights: • Low dose ionizing radiation altered homeostasis in 3D skin tissue model. • Global gene/protein/metabolite data integrated using complementary statistical approaches • Time and location-specific change in matrix regulation

  20. Corticotropin-Releasing Hormone As the Homeostatic Rheostat of Feto-Maternal Symbiosis and Developmental Programming In Utero and Neonatal Life

    Directory of Open Access Journals (Sweden)

    Viridiana Alcántara-Alonso

    2017-07-01

    Full Text Available A balanced interaction between the homeostatic mechanisms of mother and the developing organism during pregnancy and in early neonatal life is essential in order to ensure optimal fetal development, ability to respond to various external and internal challenges, protection from adverse programming, and safeguard maternal care availability after parturition. In the majority of pregnancies, this relationship is highly effective resulting in successful outcomes. However, in a number of pathological settings, perturbations of the maternal homeostasis disrupt this symbiosis and initiate adaptive responses with unpredictable outcomes for the fetus or even the neonate. This may lead to development of pathological phenotypes arising from developmental reprogramming involving interaction of genetic, epigenetic, and environmental-driven pathways, sometimes with acute consequences (e.g., growth impairment and sometimes delayed (e.g., enhanced susceptibility to disease that last well into adulthood. Most of these adaptive mechanisms are activated and controlled by hormones of the hypothalamo-pituitary adrenal axis under the influence of placental steroid and peptide hormones. In particular, the hypothalamic peptide corticotropin-releasing hormone (CRH plays a key role in feto-maternal communication by orchestrating and integrating a series of neuroendocrine, immune, metabolic, and behavioral responses. CRH also regulates neural networks involved in maternal behavior and this determines efficiency of maternal care and neonate interactions. This review will summarize our current understanding of CRH actions during the perinatal period, focusing on the physiological roles for both mother and offspring and also how external challenges can alter CRH actions and potentially impact on fetus/neonate health.

  1. Data Integration Reveals Key Homeostatic Mechanisms Following Low Dose Radiation Exposure

    Energy Technology Data Exchange (ETDEWEB)

    Tilton, Susan C.; Matzke, Melissa M.; Sowa, Marianne B.; Stenoien, David L.; Weber, Thomas J.; Morgan, William F.; Waters, Katrina M.

    2015-05-01

    The goal of this study was to define pathways regulated by low dose radiation to understand how biological systems respond to subtle perturbations in their environment and prioritize pathways for human health assessment. Using an in vitro 3-D human full thickness skin model, we have examined the temporal response of dermal and epidermal layers to 10 cGy X-ray using transcriptomic, proteomic, phosphoproteomic and metabolomic platforms. Bioinformatics analysis of each dataset independently revealed potential signaling mechanisms affected by low dose radiation, and integrating data shed additional insight into the mechanisms regulating low dose responses in human tissue. We examined direct interactions among datasets (top down approach) and defined several hubs as significant regulators, including transcription factors (YY1, MYC and CREB1), kinases (CDK2, PLK1) and a protease (MMP2). These data indicate a shift in response across time - with an increase in DNA repair, tissue remodeling and repression of cell proliferation acutely (24 – 72 hr). Pathway-based integration (bottom up approach) identified common molecular and pathway responses to low dose radiation, including oxidative stress, nitric oxide signaling and transcriptional regulation through the SP1 factor that would not have been identified by the individual data sets. Significant regulation of key downstream metabolites of nitrative stress were measured within these pathways. Among the features identified in our study, the regulation of MMP2 and SP1 were experimentally validated. Our results demonstrate the advantage of data integration to broadly define the pathways and networks that represent the mechanisms by which complex biological systems respond to perturbation.

  2. Effects of tilting on central hemodynamics and homeostatic mechanisms in cirrhosis

    DEFF Research Database (Denmark)

    Møller, Søren; Nørgaard, Annette; Henriksen, Jens H

    2004-01-01

    Patients with cirrhosis have a hyperdynamic circulation and an abnormal blood volume distribution with central hypovolemia, an activated sympathetic nervous system (SNS) as well as the renin-angiotensin-aldosterone system (RAAS). As the hyperdynamic circulation in cirrhosis may be present only in...... the CBV less in patients with cirrhosis, and the results suggest a differential regulation of central hemodynamics in patients with cirrhosis....

  3. Homeostatic scaling of neuronal excitability by synaptic modulation of somatic hyperpolarization-activated Ih channels.

    NARCIS (Netherlands)

    van Welie, I.; van Hooft, J.A.; Wadman, W.J.

    2004-01-01

    The hyperpolarization-activated cation current (Ih) plays an important role in determining membrane potential and firing characteristics of neurons and therefore is a potential target for regulation of intrinsic excitability. Here we show that an increase in AMPA-receptor-dependent synaptic activity

  4. Neural pathways controlling homeostatic and hedonic feeding in rats on free-choice diets

    NARCIS (Netherlands)

    van den Heuvel, J.K.

    2014-01-01

    The incidence of obesity is closely associated with the increased intake of saturated fat and sugar-sweetened beverages, however the mechanisms that regulate the consumption of dietary fat and sugared beverages remain to be determined. We used a novel animal model of obesity that closely resembles

  5. Central lipid detection and the regulation of feeding behavior

    Directory of Open Access Journals (Sweden)

    Cansell Céline

    2013-03-01

    Full Text Available The modern abundance of energy-rich foods combined with a shift to more sedentary lifestyles has led to a thermodynamic imbalance in which excessive caloric intake and reduced energy expenditure account for the prevalence of obesity. In particular, exposure to lipid-rich diet is thought to promote metabolic alteration in peripheral tissue associated with obesity-related diseases. The regulation of energy balance depends on the ability of the brain to provide an adaptive response to change in circulating factors of hunger and satiety. The hypothalamus is particularly regarded as key integrative structure but, aside from hypothalamic-mediated homeostatic control, feeding behavior is also modulated by sensory inputs, such as tastes and odors, as well as by affective or emotional states. The reinforcing and motivational aspects of food are closely tied to the release of the neurotransmitter dopamine by the mesolimbic system, which is stimulated by calorie-dense foods as well as by most other objects of desire. Therefore feeding behavior is regulated by homeostatic as well as non-homeostatic inputs from the hypothalamus and the mesolimbic region. Interestingly, these structures expresses several enzymes involved in the processing of triglyceride and fatty acid and the recent literature provide growing evidence that fatty acid metabolism within discrete brain regions can function as sensor of nutrient availability directly control the hedonic and the homeostatic aspect of feeding.

  6. Association Between the Visceral Adiposity Index and Homeostatic Model Assessment of Insulin Resistance in Participants With Normal Waist Circumference.

    Science.gov (United States)

    Ji, Baolan; Qu, Hua; Wang, Hang; Wei, Huili; Deng, Huacong

    2017-09-01

    We assessed the correlation between the visceral adiposity index (VAI; a useful indicator of adipose distribution and function) and homeostatic model assessment of insulin resistance (HOMA-IR) in participants with normal waist circumference. A cross-sectional study was conducted, which included 1834 Chinese adults. The blood pressure, anthropometric measurements, fasting and postprandial blood glucose, fasting insulin, and lipid profiles were measured. The VAI and HOMA-IR were calculated. Participants were divided into 4 groups according to the HOMA-IR level, and the correlation between the VAI and HOMA-IR was analyzed. The VAI gradually increased across the HOMA-IR quartiles ( P HOMA-IR ( P HOMA-IR. A logistic regression analysis indicated that VAI elevation was the main risk factor for the increased HOMA-IR in both genders. Overall, the VAI was closely correlated with the HOMA-IR in a population without central obesity.

  7. Expression and Function of the Homeostatic Molecule Del-1 in Endothelial Cells and the Periodontal Tissue

    Directory of Open Access Journals (Sweden)

    Jieun Shin

    2013-01-01

    Full Text Available Developmental endothelial locus-1 (Del-1 is an endothelial cell-secreted protein that limits the recruitment of neutrophils by antagonizing the interaction between the LFA-1 integrin on neutrophils and the intercellular adhesion molecule (ICAM-1 on endothelial cells. Mice with genetic or age-associated Del-1 deficiency exhibit increased neutrophil infiltration in the periodontium resulting in inflammatory bone loss. Here we investigated additional novel mechanisms whereby Del-1 could interfere with neutrophil recruitment and inflammation. Treatment of human endothelial cells with Del-1 did not affect the expression of endothelial molecules involved in the leukocyte adhesion cascade (ICAM-1, VCAM-1, and E-selectin. Moreover, genetic or age-associated Del-1 deficiency did not significantly alter the expression of these adhesion molecules in the murine periodontium, further ruling out altered adhesion molecule expression as a mechanism whereby Del-1 regulates leukocyte recruitment. Strikingly, Del-1 inhibited ICAM-1-dependent chemokine release (CXCL2, CCL3 by neutrophils. Therefore, Del-1 could potentially suppress the amplification of inflammatory cell recruitment mediated through chemokine release by infiltrating neutrophils. Interestingly, Del-1 was itself regulated by inflammatory stimuli, which generally exerted opposite effects on adhesion molecule expression. The reciprocal regulation between Del-1 and inflammation may contribute to optimally balance the protective and the potentially harmful effects of inflammatory cell recruitment.

  8. Intraindividual Increase of Homeostatic Sleep Pressure Across Acute and Chronic Sleep Loss: A High-Density EEG Study.

    Science.gov (United States)

    Maric, Angelina; Lustenberger, Caroline; Werth, Esther; Baumann, Christian R; Poryazova, Rositsa; Huber, Reto

    2017-09-01

    To compare intraindividually the effects of acute sleep deprivation (ASD) and chronic sleep restriction (CSR) on the homeostatic increase in slow wave activity (SWA) and to relate it to impairments in basic cognitive functioning, that is, vigilance. The increase in SWA after ASD (40 hours of wakefulness) and after CSR (seven nights with time in bed restricted to 5 hours per night) relative to baseline sleep was assessed in nine healthy, male participants (age = 18-26 years) by high-density electroencephalography. The SWA increase during the initial part of sleep was compared between the two conditions of sleep loss. The increase in SWA was related to the increase in lapses of vigilance in the psychomotor vigilance task (PVT) during the preceding days. While ASD induced a stronger increase in initial SWA than CSR, the increase was globally correlated across the two conditions in most electrodes. The increase in initial SWA was positively associated with the increase in PVT lapses. The individual homeostatic response in SWA is globally preserved across acute and chronic sleep loss, that is, individuals showing a larger increase after ASD also do so after CSR and vice versa. Furthermore, the increase in SWA is globally correlated to vigilance impairments after sleep loss over both conditions. Thus, the increase in SWA might therefore provide a physiological marker for individual differences in performance impairments after sleep loss. © Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

  9. Homeostatic tissue responses in skin biopsies from NOMID patients with constitutive overproduction of IL-1β.

    Directory of Open Access Journals (Sweden)

    Pamela Aubert

    Full Text Available The autoinflammatory disorder, Neonatal-onset Multisystem Inflammatory Disease (NOMID is the most severe phenotype of disorders caused by mutations in CIAS1 that result in increased production and secretion of active IL-1β. NOMID patients present with systemic and organ-specific inflammation of the skin, central nervous system and bone, and respond dramatically to treatment with IL-1 blocking agents. We compared the cellular infiltrates and transcriptome of skin biopsies from patients with NOMID (n = 14 before treatment (lesional (LS and non-lesional (pre-NL skin and after treatment (post-NL with the IL-1 blocker anakinra (recombinant IL-1 receptor antagonist, Kineret®, Swedish Orphan Biovitrum AB, SOBI, to normal skin (n = 5 to assess tissue responses in the context of untreated and treated disease. Abundant neutrophils distinguish LS skin from pre-NL and post-NL skin. CD11c(+ dermal dendritic cells and CD163(+ macrophages expressed activated caspase-1 and are a likely source of cutaneous IL-1 production. Treatment with anakinra led to the disappearance of neutrophils, but CD3(+ T cells and HLA-DR(+ cells remained elevated. Among the upregulated genes IL-6, IL-8, TNF, IL-17A, CCL20, and the neutrophil defensins DEFA1 and DEFA3 were differentially regulated in LS tissues (compared to normal skin. Important significantly downregulated pathways in LS skin included IL-1R/TLR signaling, type I and II cytokine receptor signaling, mitochondrial dysfunction, and antigen presentation. The differential expression and regulation of microRNAs and pathways involved in post-transcriptional modification were suggestive of epigenetic modification in the chronically inflamed tissue. Overall, the dysregulated genes and pathways suggest extensive "adaptive" mechanisms to control inflammation and maintain tissue homeostasis, likely triggered by chronic IL-1 release in the skin of patients with NOMID.

  10. Pituitary Adenylate-Cyclase Activating Polypeptide Regulates Hunger- and Palatability-Induced Binge Eating

    Directory of Open Access Journals (Sweden)

    Matthew M. Hurley

    2016-08-01

    Full Text Available While pituitary adenylate cyclase activating polypeptide (PACAP signaling in the hypothalamic ventromedial nuclei (VMN has been shown to regulate feeding, a challenge in unmasking a role for this peptide in obesity is that excess feeding can involve numerous mechanisms including homeostatic (hunger and hedonic-related (palatability drives. In these studies, we first isolated distinct feeding drives by developing a novel model of binge behavior in which homeostatic-driven feeding was temporally separated from feeding driven by food palatability. We found that stimulation of the VMN, achieved by local microinjections of AMPA, decreased standard chow consumption in food-restricted rats (e.g., homeostatic feeding; surprisingly, this manipulation failed to alter palatable food consumption in satiated rats (e.g., hedonic feeding. In contrast, inhibition of the nucleus accumbens (NAc, through local microinjections of GABA receptor agonists baclofen and muscimol, decreased hedonic feeding without altering homeostatic feeding. PACAP microinjections produced the site-specific changes in synaptic transmission needed to decrease feeding via VMN or NAc circuitry. PACAP into the NAc mimicked the actions of GABA agonists by reducing hedonic feeding without altering homeostatic feeding. In contrast, PACAP into the VMN mimicked the actions of AMPA by decreasing homeostatic feeding without affecting hedonic feeding. Slice electrophysiology recordings verified PACAP excitation of VMN neurons and inhibition of NAc neurons. These data suggest that the VMN and NAc regulate distinct circuits giving rise to unique feeding drives, but that both can be regulated by the neuropeptide PACAP to potentially curb excessive eating stemming from either drive.

  11. Homeostatic nuclear RAGE–ATM interaction is essential for efficient DNA repair

    Science.gov (United States)

    Kumar, Varun; Fleming, Thomas; Terjung, Stefan; Gorzelanny, Christian; Gebhardt, Christoffer; Agrawal, Raman; Mall, Marcus A.; Ranzinger, Julia; Zeier, Martin; Madhusudhan, Thati; Ranjan, Satish; Isermann, Berend; Liesz, Arthur; Deshpande, Divija; Häring, Hans-Ulrich; Biswas, Subrata K; Reynolds, Paul R.; Hammes, Hans-Peter; Peperkok, Rainer; Angel, Peter; Herzig, Stephan

    2017-01-01

    Abstract The integrity of genome is a prerequisite for healthy life. Indeed, defects in DNA repair have been associated with several human diseases, including tissue-fibrosis, neurodegeneration and cancer. Despite decades of extensive research, the spatio-mechanical processes of double-strand break (DSB)-repair, especially the auxiliary factor(s) that can stimulate accurate and timely repair, have remained elusive. Here, we report an ATM-kinase dependent, unforeseen function of the nuclear isoform of the Receptor for Advanced Glycation End-products (nRAGE) in DSB-repair. RAGE is phosphorylated at Serine376 and Serine389 by the ATM kinase and is recruited to the site of DNA-DSBs via an early DNA damage response. nRAGE preferentially co-localized with the MRE11 nuclease subunit of the MRN complex and orchestrates its nucleolytic activity to the ATR kinase signaling. This promotes efficient RPA2S4-S8 and CHK1S345 phosphorylation and thereby prevents cellular senescence, IPF and carcinoma formation. Accordingly, loss of RAGE causatively linked to perpetual DSBs signaling, cellular senescence and fibrosis. Importantly, in a mouse model of idiopathic pulmonary fibrosis (RAGE−/−), reconstitution of RAGE efficiently restored DSB-repair and reversed pathological anomalies. Collectively, this study identifies nRAGE as a master regulator of DSB-repair, the absence of which orchestrates persistent DSB signaling to senescence, tissue-fibrosis and oncogenesis. PMID:28977635

  12. Effects of nicotine on homeostatic and hedonic components of food intake.

    Science.gov (United States)

    Stojakovic, Andrea; Espinosa, Enma P; Farhad, Osman T; Lutfy, Kabirullah

    2017-10-01

    Chronic tobacco use leads to nicotine addiction that is characterized by exaggerated urges to use the drug despite the accompanying negative health and socioeconomic burdens. Interestingly, nicotine users are found to be leaner than the general population. Review of the existing literature revealed that nicotine affects energy homeostasis and food consumption via altering the activity of neurons containing orexigenic and anorexigenic peptides in the brain. Hypothalamus is one of the critical brain areas that regulates energy balance via the action of these neuropeptides. The equilibrium between these two groups of peptides can be shifted by nicotine leading to decreased food intake and weight loss. The aim of this article is to review the existing literature on the effect of nicotine on food intake and energy homeostasis and report on the changes that nicotine brings about in the level of these peptides and their receptors that may explain changes in food intake and body weight induced by nicotine. Furthermore, we review the effect of nicotine on the hedonic aspect of food intake. Finally, we discuss the involvement of different subtypes of nicotinic acetylcholine receptors in the regulatory action of nicotine on food intake and energy homeostasis. © 2017 Society for Endocrinology.

  13. Regulation of the mesolimbic dopamine circuit by feeding peptides.

    Science.gov (United States)

    Liu, S; Borgland, S L

    2015-03-19

    Polypeptides produced in the gastrointestinal tract, stomach, adipocytes, pancreas and brain that influence food intake are referred to as 'feeding-related' peptides. Most peptides that influence feeding exert an inhibitory effect (anorexigenic peptides). In contrast, only a few exert a stimulating effect (orexigenic peptides), such as ghrelin. Homeostatic feeding refers to when food consumed matches energy deficits. However, in western society where access to palatable energy-dense food is nearly unlimited, food is mostly consumed for non-homeostatic reasons. Emerging evidence implicates the mesocorticolimbic circuitry, including dopamine neurons of the ventral tegmental area (VTA), as a key substrate for non-homeostatic feeding. VTA dopamine neurons encode cues that predict rewards and phasic release of dopamine in the ventral striatum motivates animals to forage for food. To elucidate how feeding-related peptides regulate reward pathways is of importance to reveal the mechanisms underlying non-homeostatic or hedonic feeding. Here, we review the current knowledge of how anorexigenic peptides and orexigenic peptides act within the VTA. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  14. Differential regulation of human IL-7 receptor alpha expression by IL-7 and TCR signaling

    NARCIS (Netherlands)

    Alves, Nuno L.; van Leeuwen, Ester M. M.; Derks, Ingrid A. M.; van Lier, René A. W.

    2008-01-01

    IL-7Ralpha is essential for the development and homeostatic maintenance of mature T cells. Studies in humans and mice have shown that IL-7Ralpha expression is reduced by its cognate cytokine, IL-7, and Ag, suggesting that active regulation of IL-7 responsiveness is necessary to balance T cell

  15. Swelling-activated ion channels: functional regulation in cell-swelling, proliferation and apoptosis

    DEFF Research Database (Denmark)

    Stutzin, A; Hoffmann, E K

    2006-01-01

    Cell volume regulation is one of the most fundamental homeostatic mechanisms and essential for normal cellular function. At the same time, however, many physiological mechanisms are associated with regulatory changes in cell size meaning that the set point for cell volume regulation is under phys...... as key players in the maintenance of normal steady-state cell volume, with particular emphasis on the intracellular signalling pathways responsible for their regulation during hypotonic stress, cell proliferation and apoptosis....

  16. Impaired rRNA synthesis triggers homeostatic responses in hippocampal neurons

    Directory of Open Access Journals (Sweden)

    Anna eKiryk

    2013-11-01

    Full Text Available Decreased rRNA synthesis and nucleolar disruption, known as nucleolar stress, are primary signs of cellular stress associated with aging and neurodegenerative disorders. Silencing of rDNA occurs during early stages of Alzheimer´s disease (AD and may play a role in dementia. Moreover aberrant regulation of the protein synthesis machinery is present in the brain of suicide victims and implicates the epigenetic modulation of rRNA. Recently, we developed unique mouse models characterized by nucleolar stress in neurons. We inhibited RNA polymerase I by genetic ablation of the basal transcription factor TIF-IA in adult hippocampal neurons. Nucleolar stress resulted in progressive neurodegeneration, although with a differential vulnerability within the CA1, CA3 and dentate gyrus. Here, we investigate the consequences of nucleolar stress on learning and memory. The mutant mice show normal performance in the Morris water maze and in other behavioral tests, suggesting the activation of adaptive mechanisms. In fact, we observe a significantly enhanced learning and re-learning corresponding to the initial inhibition of rRNA transcription. This phenomenon is accompanied by aberrant synaptic plasticity. By the analysis of nucleolar function and integrity, we find that the synthesis of rRNA is later restored. Gene expression profiling shows that thirty-six transcripts are differentially expressed in comparison to the control group in absence of neurodegeneration. Additionally, we observe a significant enrichment of the putative serum response factor (SRF binding sites in the promoters of the genes with changed expression, indicating potential adaptive mechanisms mediated by the mitogen-activated protein kinase pathway. In the dentate gyrus a neurogenetic response might compensate the initial molecular deficits. These results underscore the role of nucleolar stress in neuronal homeostasis and open a new ground for therapeutic strategies aiming at preserving

  17. IL-4 directly signals tissue-resident macrophages to proliferate beyond homeostatic levels controlled by CSF-1

    Science.gov (United States)

    Ruckerl, Dominik; Thomas, Graham D.; Hewitson, James P.; Duncan, Sheelagh; Brombacher, Frank; Maizels, Rick M.; Hume, David A.; Allen, Judith E.

    2013-01-01

    Macrophages (MΦs) colonize tissues during inflammation in two distinct ways: recruitment of monocyte precursors and proliferation of resident cells. We recently revealed a major role for IL-4 in the proliferative expansion of resident MΦs during a Th2-biased tissue nematode infection. We now show that proliferation of MΦs during intestinal as well as tissue nematode infection is restricted to sites of IL-4 production and requires MΦ-intrinsic IL-4R signaling. However, both IL-4Rα–dependent and –independent mechanisms contributed to MΦ proliferation during nematode infections. IL-4R–independent proliferation was controlled by a rise in local CSF-1 levels, but IL-4Rα expression conferred a competitive advantage with higher and more sustained proliferation and increased accumulation of IL-4Rα+ compared with IL-4Rα− cells. Mechanistically, this occurred by conversion of IL-4Rα+ MΦs from a CSF-1–dependent to –independent program of proliferation. Thus, IL-4 increases the relative density of tissue MΦs by overcoming the constraints mediated by the availability of CSF-1. Finally, although both elevated CSF1R and IL-4Rα signaling triggered proliferation above homeostatic levels, only CSF-1 led to the recruitment of monocytes and neutrophils. Thus, the IL-4 pathway of proliferation may have developed as an alternative to CSF-1 to increase resident MΦ numbers without coincident monocyte recruitment. PMID:24101381

  18. Brain-derived neurotrophic factor--a major player in stimulation-induced homeostatic metaplasticity of human motor cortex?

    DEFF Research Database (Denmark)

    Mastroeni, Claudia; Bergmann, Til Ole; Rizzo, Vincenzo

    2013-01-01

    , at the same time priming the after effects caused by the second TBS intervention in a homeostatic fashion. Critically, val(66)met carriers and val(66)val carriers showed very similar response patterns to cTBS and iTBS regardless of the order of TBS interventions. Since none of the observed TBS effects......Repetitive transcranial magnetic stimulation (rTMS) of the human motor hand area (M1HAND) can induce lasting changes in corticospinal excitability as indexed by a change in amplitude of the motor-evoked potential. The plasticity-inducing effects of rTMS in M1HAND show substantial inter......TBS followed by cTBS (n = 27), cTBS followed by iTBS (n = 29), and iTBS followed by iTBS (n = 28). Participants and examiner were blinded to the genotype at the time of examination. As expected, the first TBS intervention induced a decrease (cTBS) and increase (iTBS) in corticospinal excitability, respectively...

  19. Role of homeostatic dis balance in formation of the late consequences for radiation exposure in Kazakhstan population

    International Nuclear Information System (INIS)

    Galich, B.V.; Belikhina, T.I.; Moldagaliev, T.Zh.; Tretyakova, E.B.

    2008-01-01

    The purpose of research is to study localizations and level of homeostatic disturbances in the key organism systems forming the social important illness for the realization of State and regional rehabilitation programs in the Kazakhstan population exposed to radiation and non-radiation risk factors. The object of research was the data of medical examinations in the exposed population living in Abaisky, Beskaragaisky, Zhanasemejsky districts of East-Kazakhstan area for the period from 1962 to 2006 in three time intervals: 1962-1966; 1968-1987; 2002-2006. The control data was the results of medical examination of the population of Shadrinskoe village of Pavlodar area and Kokpekty village of East-Kazakhstan area for the same time period. We have studied two dose groups: 1 group of exposed population (dose 0,5 > Sv); II group of exposed population (dose 0,2-0,25 Sv). Study of dynamics for prevalence of cardiovascular and gastrointestinal diseases connected with damage in haemopoietic, immune and vegetative homeostasis was carried out in 987 exposed persons and persons included to control group.

  20. The AMPK enzyme-complex: From the regulation of cellular energy homeostasis to a possible new molecular target in the management of chronic inflammatory disorders

    NARCIS (Netherlands)

    Antonioli, Luca; Colucci, Rocchina; Pellegrini, Carolina; Giustarini, Giulio; Sacco, Deborah; Tirotta, Erika; Caputi, Valentina; Marsilio, Ilaria; Giron, Maria Cecilia; Németh, Zoltán H; Blandizzi, Corrado; Fornai, Matteo

    2016-01-01

    Introduction: Adenosine monophosphate-activated protein kinase (AMPK), known as an enzymatic complex that regulates the energetic metabolism, is emerging as a pivotal enzyme and enzymatic pathway involved in the regulation of immune homeostatic networks. It is also involved in the molecular

  1. Dietary glucose regulates yeast consumption in adult Drosophila males

    OpenAIRE

    Lebreton, S?bastien; Witzgall, Peter; Olsson, Marie; Becher, Paul G.

    2014-01-01

    The adjustment of feeding behavior in response to hunger and satiety contributes to homeostatic regulation in animals. The fruit fly Drosophila melanogaster feeds on yeasts growing on overripe fruit, providing nutrients required for adult survival, reproduction and larval growth. Here, we present data on how the nutritional value of food affects subsequent yeast consumption in Drosophila adult males. After a period of starvation, flies showed intensive yeast consumption. In comparison, flies ...

  2. Cigarette smoking and brain regulation of energy homeostasis

    OpenAIRE

    Hui eChen; Hui eChen; Sonia eSaad; Shaun eSandow; Paul eBertrand

    2012-01-01

    Cigarette smoking is an addictive behaviour, and is the primary cause of cardiovascular and pulmonary disease, and cancer (among other diseases). Cigarette smoke contains thousands of components that may affect caloric intake and energy expenditure, although nicotine is the major addictive substance present, and has the best described actions. Nicotine exposure from cigarette smoke can change brain feeding regulation to reduce appetite via both energy homeostatic and reward mechanisms, causin...

  3. Cigarette Smoking and Brain Regulation of Energy Homeostasis

    OpenAIRE

    Chen, Hui; Saad, Sonia; Sandow, Shaun L.; Bertrand, Paul P.

    2012-01-01

    Cigarette smoking is an addictive behavior, and is the primary cause of cardiovascular and pulmonary disease, and cancer (among other diseases). Cigarette smoke contains thousands of components that may affect caloric intake and energy expenditure, although nicotine is the major addictive substance present, and has the best described actions. Nicotine exposure from cigarette smoke can change brain feeding regulation to reduce appetite via both energy homeostatic and reward mechanisms, causing...

  4. NMDA-receptor inhibition restores Protease-Activated Receptor 1 (PAR1) mediated alterations in homeostatic synaptic plasticity of denervated mouse dentate granule cells.

    Science.gov (United States)

    Becker, Denise; Ikenberg, Benno; Schiener, Sabine; Maggio, Nicola; Vlachos, Andreas

    2014-11-01

    A common feature of neurological diseases is the loss of central neurons, which leads to deafferentation of connected brain regions. In turn, the remodeling of denervated neuronal networks is considered to play an important role for the postlesional recovery, but has also been linked to maladaptive plasticity resulting in disease-related complications such as memory dysfunction or epilepsy. Recent work has indicated that Protease-Activated Receptor 1 (PAR1), which can be activated by thrombin that enters the brain under pathological conditions, alters synaptic plasticity and neuronal excitability. However, the role of PAR1 in lesion-induced synaptic plasticity remains incompletely understood. Here, we used entorhinal denervation of organotypic hippocampal slice cultures to study the effects of PAR1 on denervation-induced homeostatic synaptic plasticity. Our results disclose that PAR1 activation counters the ability of denervated dentate granule cells to increase their excitatory synaptic strength in a compensatory, i.e., homeostatic manner. Furthermore, we demonstrate that this PAR1 effect is rescued by pharmacological inhibition of N-methyl-d-aspartate receptors (NMDA-R). Thus, NMDA-R inhibitors may restore the ability of denervated neurons to express homeostatic synaptic plasticity under conditions of increased PAR1-activity, which may contribute to their beneficial effects seen in the context of neurological diseases. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Failure of Homeostatic Model Assessment of Insulin Resistance to Detect Marked Diet-Induced Insulin Resistance in Dogs

    Science.gov (United States)

    Ader, Marilyn; Stefanovski, Darko; Richey, Joyce M.; Kim, Stella P.; Kolka, Cathryn M.; Ionut, Viorica; Kabir, Morvarid; Bergman, Richard N.

    2014-01-01

    Accurate quantification of insulin resistance is essential for determining efficacy of treatments to reduce diabetes risk. Gold-standard methods to assess resistance are available (e.g., hyperinsulinemic clamp or minimal model), but surrogate indices based solely on fasting values have attractive simplicity. One such surrogate, the homeostatic model assessment of insulin resistance (HOMA-IR), is widely applied despite known inaccuracies in characterizing resistance across groups. Of greater significance is whether HOMA-IR can detect changes in insulin sensitivity induced by an intervention. We tested the ability of HOMA-IR to detect high-fat diet–induced insulin resistance in 36 healthy canines using clamp and minimal model analysis of the intravenous glucose tolerance test (IVGTT) to document progression of resistance. The influence of pancreatic function on HOMA-IR accuracy was assessed using the acute insulin response during the IVGTT (AIRG). Diet-induced resistance was confirmed by both clamp and minimal model (P HOMA-IR ([fasting insulin (μU/mL) × fasting glucose (mmol)]/22.5) did not detect reduced sensitivity induced by fat feeding (P = 0.22). In fact, 13 of 36 animals showed an artifactual decrease in HOMA-IR (i.e., increased sensitivity). The ability of HOMA-IR to detect diet-induced resistance was particularly limited under conditions when insulin secretory function (AIRG) is less than robust. In conclusion, HOMA-IR is of limited utility for detecting diet-induced deterioration of insulin sensitivity quantified by glucose clamp or minimal model. Caution should be exercised when using HOMA-IR to detect insulin resistance when pancreatic function is compromised. It is necessary to use other accurate indices to detect longitudinal changes in insulin resistance with any confidence. PMID:24353184

  6. Telomere shortening impairs regeneration of the olfactory epithelium in response to injury but not under homeostatic conditions.

    Directory of Open Access Journals (Sweden)

    Masami Watabe-Rudolph

    Full Text Available Atrophy of the olfactory epithelium (OE associated with impaired olfaction and dry nose represents one of the most common phenotypes of human aging. Impairment in regeneration of a functional olfactory epithelium can also occur in response to injury due to infection or nasal surgery. These complications occur more frequently in aged patients. Although age is the most unifying risk factor for atrophic changes and functional decline of the olfactory epithelium, little is known about molecular mechanisms that could influence maintenance and repair of the olfactory epithelium. Here, we analyzed the influence of telomere shortening (a basic mechanism of cellular aging on homeostasis and regenerative reserve in response to chemical induced injury of the OE in late generation telomere knockout mice (G3 mTerc(-/- with short telomeres compared to wild type mice (mTerc(+/+ with long telomeres. The study revealed no significant influence of telomere shortening on homeostatic maintenance of the OE during mouse aging. In contrast, the regenerative response to chemical induced injury of the OE was significantly impaired in G3 mTerc(-/- mice compared to mTerc(+/+ mice. Seven days after chemical induced damage, G3 mTerc(-/- mice exhibited significantly enlarged areas of persisting atrophy compared to mTerc(+/+ mice (p = 0.031. Telomere dysfunction was associated with impairments in cell proliferation in the regenerating epithelium. Deletion of the cell cycle inhibitor, Cdkn1a (p21 rescued defects in OE regeneration in telomere dysfunctional mice. Together, these data indicate that telomere shortening impairs the regenerative capacity of the OE by impairing cell cycle progression in a p21-dependent manner. These findings could be relevant for the impairment in OE function in elderly people.

  7. Influence of age, circadian and homeostatic processes on inhibitory motor control: a Go/Nogo task study.

    Directory of Open Access Journals (Sweden)

    Patricia Sagaspe

    Full Text Available INTRODUCTION: The contribution of circadian system and sleep pressure influences on executive performance as a function of age has never been studied. The aim of our study was to determine the age-related evolution of inhibitory motor control (i.e., ability to suppress a prepotent motor response and sustained attention under controlled high or low sleep pressure conditions. METHODS: 14 healthy young males (mean age = 23 ± 2.7; 20-29 years and 11 healthy older males (mean age = 68 ± 1.4; 66-70 years were recruited. The volunteers were placed for 40 hours in "constant routine". In the "Sleep Deprivation SD" condition, the volunteer was kept awake for 40 hours to obtain a high sleep pressure condition interacting with the circadian process. In the "NAP" condition, the volunteer adopted a short wake/sleep cycle (150/75 min resulting in a low sleep pressure condition to counteract the homeostatic pressure and investigate the circadian process. Performances were evaluated by a simple reaction time task and a Go/Nogo task repeated every 3H45. RESULTS: In the SD condition, inhibitory motor control (i.e., ability to inhibit an inappropriate response was impaired by extended wakefulness equally in both age groups (P<.01. Sustained attention (i.e. ability to respond accurately to appropriate stimuli on the executive task decreased under sleep deprivation in both groups, and even more in young participants (P<.05. In the NAP condition, age did not influence the time course of inhibitory motor control or sustained attention. In the SD and NAP conditions, older participants had a less fluctuating reaction time performance across time of day than young participants (P<.001. CONCLUSION: Aging could be a protective factor against the effects of extended wakefulness especially on sustained attention failures due to an attenuation of sleep pressure with duration of time awake.

  8. Influence of age, circadian and homeostatic processes on inhibitory motor control: a Go/Nogo task study.

    Science.gov (United States)

    Sagaspe, Patricia; Taillard, Jacques; Amiéva, Hélène; Beck, Arnaud; Rascol, Olivier; Dartigues, Jean-François; Capelli, Aurore; Philip, Pierre

    2012-01-01

    The contribution of circadian system and sleep pressure influences on executive performance as a function of age has never been studied. The aim of our study was to determine the age-related evolution of inhibitory motor control (i.e., ability to suppress a prepotent motor response) and sustained attention under controlled high or low sleep pressure conditions. 14 healthy young males (mean age = 23 ± 2.7; 20-29 years) and 11 healthy older males (mean age = 68 ± 1.4; 66-70 years) were recruited. The volunteers were placed for 40 hours in "constant routine". In the "Sleep Deprivation SD" condition, the volunteer was kept awake for 40 hours to obtain a high sleep pressure condition interacting with the circadian process. In the "NAP" condition, the volunteer adopted a short wake/sleep cycle (150/75 min) resulting in a low sleep pressure condition to counteract the homeostatic pressure and investigate the circadian process. Performances were evaluated by a simple reaction time task and a Go/Nogo task repeated every 3H45. In the SD condition, inhibitory motor control (i.e., ability to inhibit an inappropriate response) was impaired by extended wakefulness equally in both age groups (Page did not influence the time course of inhibitory motor control or sustained attention. In the SD and NAP conditions, older participants had a less fluctuating reaction time performance across time of day than young participants (PAging could be a protective factor against the effects of extended wakefulness especially on sustained attention failures due to an attenuation of sleep pressure with duration of time awake.

  9. Hoxb4 overexpression in CD4 memory phenotype T cells increases the central memory population upon homeostatic proliferation.

    Directory of Open Access Journals (Sweden)

    Héloïse Frison

    Full Text Available Memory T cell populations allow a rapid immune response to pathogens that have been previously encountered and thus form the basis of success in vaccinations. However, the molecular pathways underlying the development and maintenance of these cells are only starting to be unveiled. Memory T cells have the capacity to self renew as do hematopoietic stem cells, and overlapping gene expression profiles suggested that these cells might use the same self-renewal pathways. The transcription factor Hoxb4 has been shown to promote self-renewal divisions of hematopoietic stem cells resulting in an expansion of these cells. In this study we investigated whether overexpression of Hoxb4 could provide an advantage to CD4 memory phenotype T cells in engrafting the niche of T cell deficient mice following adoptive transfer. Competitive transplantation experiments demonstrated that CD4 memory phenotype T cells derived from mice transgenic for Hoxb4 contributed overall less to the repopulation of the lymphoid organs than wild type CD4 memory phenotype T cells after two months. These proportions were relatively maintained following serial transplantation in secondary and tertiary mice. Interestingly, a significantly higher percentage of the Hoxb4 CD4 memory phenotype T cell population expressed the CD62L and Ly6C surface markers, characteristic for central memory T cells, after homeostatic proliferation. Thus Hoxb4 favours the maintenance and increase of the CD4 central memory phenotype T cell population. These cells are more stem cell like and might eventually lead to an advantage of Hoxb4 T cells after subjecting the cells to additional rounds of proliferation.

  10. Homeostatic proliferation and IL-7R alpha expression do not correlate with enhanced T cell proliferation and protection in chronic mouse malaria.

    Directory of Open Access Journals (Sweden)

    Robin Stephens

    Full Text Available While chronic infection has been shown to enhance protection from disease caused by several pathogens, the mechanisms are not known. The gamma-c family of cytokines IL-7, IL-2, and IL-15 are implicated in homeostatic proliferation, which is thought to maintain T cell memory. However in chronic infection, prolonged antigen exposure itself may contribute to lymphocyte survival. We have previously observed that chronic malaria infection enhances protection to re-infection, as well as enhancing B cell responses. Here, we show that chronic Plasmodium chabaudi malaria infection in mice enhances the expansion of CD4(+ T cells in a second infection, and that this correlates with increased expression of the IL-2/15 Receptor beta (CD122 on memory T cells, as well as increasing IL-2 producers on re-infection. IL-2 has been recently linked to improved secondary proliferation, while the role of IL-7 in maintenance of CD4(+ memory cells has been demonstrated in homeostatic proliferation, but its role in protective memory populations in infectious disease protective has not been fully investigated. Increased IL-7Rα (CD127 expression correlated, as previously reported with increased turnover of CD4 memory cells, however, this was not linked to protection or enhanced response to rechallenge, These data support the idea that antigen or IL-2 production resulting from chronic stimulation may play a role in an enhanced secondary T cell response.

  11. Regulation of effector T cells by antigen-presenting cells via interaction of the C-type lectin MGL with CD45

    NARCIS (Netherlands)

    van Vliet, Sandra J.; Gringhuis, Sonja I.; Geijtenbeek, Teunis B. H.; van Kooyk, Yvette

    2006-01-01

    Homeostatic control of T cells involves tight regulation of effector T cells to prevent excessive activation that can cause tissue damage and autoimmunity. Little is known, however, about whether antigen-presenting cells (APCs) are also involved in maintaining immune system homeostasis once effector

  12. The perilipin homologue, lipid storage droplet 2, regulates sleep homeostasis and prevents learning impairments following sleep loss.

    Directory of Open Access Journals (Sweden)

    Matthew S Thimgan

    2010-08-01

    Full Text Available Extended periods of waking result in physiological impairments in humans, rats, and flies. Sleep homeostasis, the increase in sleep observed following sleep loss, is believed to counter the negative effects of prolonged waking by restoring vital biological processes that are degraded during sleep deprivation. Sleep homeostasis, as with other behaviors, is influenced by both genes and environment. We report here that during periods of starvation, flies remain spontaneously awake but, in contrast to sleep deprivation, do not accrue any of the negative consequences of prolonged waking. Specifically, the homeostatic response and learning impairments that are a characteristic of sleep loss are not observed following prolonged waking induced by starvation. Recently, two genes, brummer (bmm and Lipid storage droplet 2 (Lsd2, have been shown to modulate the response to starvation. bmm mutants have excess fat and are resistant to starvation, whereas Lsd2 mutants are lean and sensitive to starvation. Thus, we hypothesized that bmm and Lsd2 may play a role in sleep regulation. Indeed, bmm mutant flies display a large homeostatic response following sleep deprivation. In contrast, Lsd2 mutant flies, which phenocopy aspects of starvation as measured by low triglyceride stores, do not exhibit a homeostatic response following sleep loss. Importantly, Lsd2 mutant flies are not learning impaired after sleep deprivation. These results provide the first genetic evidence, to our knowledge, that lipid metabolism plays an important role in regulating the homeostatic response and can protect against neuronal impairments induced by prolonged waking.

  13. The Arc of cognition: Signaling cascades regulating Arc and implications for cognitive function and disease.

    Science.gov (United States)

    Epstein, Irina; Finkbeiner, Steven

    2018-05-01

    The activity-regulated cytoskeletal (Arc) gene is implicated in numerous synaptic plasticity paradigms, including long-term potentiation and depression and homeostatic plasticity, and is critical for consolidating memory. How Arc facilitates these forms of plasticity is not fully understood. Unlike other neuronal immediate-early genes, Arc encodes a protein that shuttles between the somatodendritic and nuclear compartments to regulate synaptic plasticity. Little attention has been paid to Arc's role in the nucleus. Here, we highlight the regulatory elements and signaling cascades required to induce Arc transcription and discuss the significance of Arc nuclear localization for synaptic plasticity and scaling. We integrate these findings into the context of cognitive function and disease and propose a model in which Arc mediates an effect on memory as a "chaser" of synaptic activity through homeostatic scaling. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Nasal insulin changes peripheral insulin sensitivity simultaneously with altered activity in homeostatic and reward-related human brain regions.

    Science.gov (United States)

    Heni, M; Kullmann, S; Ketterer, C; Guthoff, M; Linder, K; Wagner, R; Stingl, K T; Veit, R; Staiger, H; Häring, H-U; Preissl, H; Fritsche, A

    2012-06-01

    Impaired insulin sensitivity is a major factor leading to type 2 diabetes. Animal studies suggest that the brain is involved in the regulation of insulin sensitivity. We investigated whether insulin action in the human brain regulates peripheral insulin sensitivity and examined which brain areas are involved. Insulin and placebo were given intranasally. Plasma glucose, insulin and C-peptide were measured in 103 participants at 0, 30 and 60 min. A subgroup (n = 12) was also studied with functional MRI, and blood sampling at 0, 30 and 120 min. For each time-point, the HOMA of insulin resistance (HOMA-IR) was calculated as an inverse estimate of peripheral insulin sensitivity. Plasma insulin increased and subsequently decreased. This excursion was accompanied by slightly decreased plasma glucose, resulting in an initially increased HOMA-IR. At 1 h after insulin spray, the HOMA-IR subsequently decreased and remained lower up to 120 min. An increase in hypothalamic activity was observed, which correlated with the increased HOMA-IR at 30 min post-spray. Activity in the putamen, right insula and orbitofrontal cortex correlated with the decreased HOMA-IR at 120 min post-spray. Central insulin action in specific brain areas, including the hypothalamus, may time-dependently regulate peripheral insulin sensitivity. This introduces a potential novel mechanism for the regulation of peripheral insulin sensitivity and underlines the importance of cerebral insulin action for the whole organism.

  15. Role of Central Glucagon-like Peptide-1 in Stress Regulation

    OpenAIRE

    Ghosal, Sriparna; Myers, Brent; Herman, James P.

    2013-01-01

    Glucagon-like peptide 1 (GLP-1) is best known as an incretin hormone, secreted from L cells in the intestine in response to nutrient ingestion to stimulate glucose-dependent insulin secretion. However, GLP-1 is also expressed in neurons, and plays a major role in regulation of homeostatic function within the central nervous system (CNS). This review summarizes our current state of knowledge on the role GLP-1 plays in neural coordination of the organismal stress response. In brain, the primary...

  16. Homeostatic response to sleep/rest deprivation by constant water flow in larval zebrafish in both dark and light conditions.

    Science.gov (United States)

    Aho, Vilma; Vainikka, Maija; Puttonen, Henri A J; Ikonen, Heidi M K; Salminen, Tiia; Panula, Pertti; Porkka-Heiskanen, Tarja; Wigren, Henna-Kaisa

    2017-06-01

    Sleep-or sleep-like states-have been reported in adult and larval zebrafish using behavioural criteria. These reversible quiescent periods, displaying circadian rhythmicity, have been used in pharmacological, genetic and neuroanatomical studies of sleep-wake regulation. However, one of the important criteria for sleep, namely sleep homeostasis, has not been demonstrated unequivocally. To study rest homeostasis in zebrafish larvae, we rest-deprived 1-week-old larvae with a novel, ecologically relevant method: flow of water. Stereotyped startle responses to sensory stimuli were recorded after the rest deprivation to study arousal threshold using a high-speed camera, providing an appropriate time resolution to detect species-specific behavioural responses occurring in a millisecond time-scale. Rest-deprived larvae exhibited fewer startle responses than control larvae during the remaining dark phase and the beginning of the light phase, which can be interpreted as a sign of rest homeostasis-often used as equivalent of sleep homeostasis. To address sleep homeostasis further, we probed the adenosinergic system, which in mammals regulates sleep homeostasis. The adenosine A1 receptor agonist, cyclohexyladenosine, administered during the light period, decreased startle responses and increased immobility bouts, while the adenosine antagonist, caffeine, administered during the dark period, decreased immobility bouts. These results suggest that the regulation of sleep homeostasis in zebrafish larvae consists of the same elements as that of other species. © 2017 European Sleep Research Society.

  17. Endocannabinoid Regulation of Neuroendocrine Systems.

    Science.gov (United States)

    Tasker, Jeffrey G; Chen, Chun; Fisher, Marc O; Fu, Xin; Rainville, Jennifer R; Weiss, Grant L

    2015-01-01

    The hypothalamus is a part of the brain that is critical for sustaining life through its homeostatic control and integrative regulation of the autonomic nervous system and neuroendocrine systems. Neuroendocrine function in mammals is mediated mainly through the control of pituitary hormone secretion by diverse neuroendocrine cell groups in the hypothalamus. Cannabinoid receptors are expressed throughout the hypothalamus, and endocannabinoids have been found to exert pronounced regulatory effects on neuroendocrine function via modulation of the outputs of several neuroendocrine systems. Here, we review the physiological regulation of neuroendocrine function by endocannabinoids, focusing on the role of endocannabinoids in the neuroendocrine regulation of the stress response, food intake, fluid homeostasis, and reproductive function. Cannabis sativa (marijuana) has a long history of recreational and/or medicinal use dating back to ancient times. It was used as an analgesic, anesthetic, and antianxiety herb as early as 2600 B.C. The hedonic, anxiolytic, and mood-elevating properties of cannabis have also been cited in ancient records from different cultures. However, it was not until 1964 that the psychoactive constituent of cannabis, Δ(9)-tetrahydrocannabinol, was isolated and its chemical structure determined (Gaoni & Mechoulam, 1964). © 2015 Elsevier Inc. All rights reserved.

  18. Epigenetic regulation of neuroblastoma development.

    Science.gov (United States)

    Durinck, Kaat; Speleman, Frank

    2018-01-19

    In recent years, technological advances have enabled a detailed landscaping of the epigenome and the mechanisms of epigenetic regulation that drive normal cell function, development and cancer. Rather than merely a structural entity to support genome compaction, we now look at chromatin as a very dynamic and essential constellation that is actively participating in the tight orchestration of transcriptional regulation as well as DNA replication and repair. The unique feature of chromatin flexibility enabling fast switches towards more or less restricted epigenetic cellular states is, not surprisingly, intimately connected to cancer development and treatment resistance, and the central role of epigenetic alterations in cancer is illustrated by the finding that up to 50% of all mutations across cancer entities affect proteins controlling the chromatin status. We summarize recent insights into epigenetic rewiring underlying neuroblastoma (NB) tumor formation ranging from changes in DNA methylation patterns and mutations in epigenetic regulators to global effects on transcriptional regulatory circuits that involve key players in NB oncogenesis. Insights into the disruption of the homeostatic epigenetic balance contributing to developmental arrest of sympathetic progenitor cells and subsequent NB oncogenesis are rapidly growing and will be exploited towards the development of novel therapeutic strategies to increase current survival rates of patients with high-risk NB.

  19. Impairment of interrelated iron- and copper homeostatic mechanisms in brain contributes to the pathogenesis of neurodegenerative disorders

    DEFF Research Database (Denmark)

    Skjørringe, Tina; Møller, Lisbeth Birk; Moos, Torben

    2012-01-01

    is strictly regulated, and concordantly protective barriers, i.e., the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (BCB) have evolved to separate the brain environment from the circulation. The uptake mechanisms of the two metals interact. Both iron deficiency and overload lead...... involved in iron transport. Iron and copper are mainly taken up at the BBB, but the BCB also plays a vital role in the homeostasis of the two metals, in terms of sequestering, uptake, and efflux of iron and copper from the brain. Inside the brain, iron and copper are taken up by neurons and glia cells...

  20. The Complex Relationship between Liver Cancer and the Cell Cycle: A Story of Multiple Regulations

    Energy Technology Data Exchange (ETDEWEB)

    Bisteau, Xavier [Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, Proteos#3-09, Singapore 138673 (Singapore); Caldez, Matias J.; Kaldis, Philipp, E-mail: kaldis@imcb.a-star.edu.sg [Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, Proteos#3-09, Singapore 138673 (Singapore); National University of Singapore (NUS), Department of Biochemistry, Singapore 117597 (Singapore)

    2014-01-13

    The liver acts as a hub for metabolic reactions to keep a homeostatic balance during development and growth. The process of liver cancer development, although poorly understood, is related to different etiologic factors like toxins, alcohol, or viral infection. At the molecular level, liver cancer is characterized by a disruption of cell cycle regulation through many molecular mechanisms. In this review, we focus on the mechanisms underlying the lack of regulation of the cell cycle during liver cancer, focusing mainly on hepatocellular carcinoma (HCC). We also provide a brief summary of novel therapies connected to cell cycle regulation.

  1. Regulation of adolescent sleep: implications for behavior.

    Science.gov (United States)

    Carskadon, Mary A; Acebo, Christine; Jenni, Oskar G

    2004-06-01

    Adolescent development is accompanied by profound changes in the timing and amounts of sleep and wakefulness. Many aspects of these changes result from altered psychosocial and life-style circumstances that accompany adolescence. The maturation of biological processes regulating sleep/wake systems, however, may be strongly related to the sleep timing and amount during adolescence-either as "compelling" or "permissive" factors. The two-process model of sleep regulation posits a fundamental sleep-wake homeostatic process (process S) working in concert with the circadian biological timing system (process C) as the primary intrinsic regulatory factors. How do these systems change during adolescence? We present data from adolescent participants examining EEG markers of sleep homeostasis to evaluate whether process S shows maturational changes permissive of altered sleep patterns across puberty. Our data indicate that certain aspects of the homeostatic system are unchanged from late childhood to young adulthood, while other features change in a manner that is permissive of later bedtimes in older adolescents. We also show alterations of the circadian timing system indicating a possible circadian substrate for later adolescent sleep timing. The circadian parameters we have assessed include phase, period, melatonin secretory pattern, light sensitivity, and phase relationships, all of which show evidence of changes during pubertal development with potential to alter sleep patterns substantially. However the changes are mediated-whether through process S, process C, or by a combination-many adolescents have too little sleep at the wrong circadian phase. This pattern is associated with increased risks for excessive sleepiness, difficulty with mood regulation, impaired academic performance, learning difficulties, school tardiness and absenteeism, and accidents and injuries.

  2. Impairment of interrelated iron- and copper homeostatic mechanisms in brain contributes to the pathogenesis of neurodegenerative disorders

    Directory of Open Access Journals (Sweden)

    Tina eSkjørringe

    2012-09-01

    Full Text Available Iron and copper are important co-factors for a number of enzymes in the brain, including enzymes involved in neurotransmitter synthesis and myelin formation. Both shortage and an excess of iron or copper will affect the brain. The transport of iron and copper into the brain from the circulation is strictly regulated, and concordantly protective barriers i.e. the blood-brain barrier (BBB and the blood-cerebrospinal fluid (CSF barrier (BCB have evolved to separate the brain environment from the circulation. The uptake mechanisms of the two metals interact. Both iron deficiency and overload lead to altered copper homeostasis in the brain. Similarly, changes in dietary copper affect the brain-iron homeostasis. Moreover, the uptake routes of iron and copper overlap each other which affect the interplay between the concentrations of the two metals in the brain. The divalent metal transporter-1 (DMT1 is involved in the uptake of both iron and copper. Furthermore, copper is an essential co-factor in numerous proteins that are vital for iron homeostasis and affects the binding of iron-response proteins to iron-response elements in the mRNA of the transferrin receptor, DMT1 and ferroportin, all highly involved in iron transport. Iron and copper are mainly taken up at the BBB, but the BCB also plays a vital role in the homeostasis of the two metals, in terms of sequestering, uptake and efflux of iron and copper from the brain. Inside the brain, iron and copper are taken up by neurons and glia cells that express various transporters

  3. Cell-cycle-dependent Xenopus TRF1 recruitment to telomere chromatin regulated by Polo-like kinase

    OpenAIRE

    Nishiyama, Atsuya; Muraki, Keiko; Saito, Motoki; Ohsumi, Keita; Kishimoto, Takeo; Ishikawa, Fuyuki

    2006-01-01

    Telomeres are regulated by a homeostatic mechanism that includes telomerase and telomeric repeat binding proteins, TRF1 and TRF2. Recently, it has been hypothesized that telomeres assume distinct configurations in a cell-cycle-dependent manner, although direct biochemical evidence is lacking. Here we demonstrated that Xenopus TRF1 (xTRF1) associates with telomere chromatin specifically in mitotic Xenopus egg extracts, and dissociates from it upon mitotic exit. Both the N-terminal TRF-homology...

  4. The Usefulness of Homeostatic Measurement Assessment-Insulin Resistance (HOMA-IR) for Detection of Glucose Intolerance in Thai Women of Reproductive Age with Polycystic Ovary Syndrome.

    Science.gov (United States)

    Wongwananuruk, Thanyarat; Rattanachaiyanont, Manee; Leerasiri, Pichai; Indhavivadhana, Suchada; Techatraisak, Kitirat; Angsuwathana, Surasak; Tanmahasamut, Prasong; Dangrat, Chongdee

    2012-01-01

    Objectives. To study the cut-off point of Homeostatic Measurement Assessment-Insulin Resistance (HOMA-IR) as a screening test for detection of glucose intolerance in Thai women with polycystic ovary syndrome (PCOS). Study Design. Cross-sectional study. Setting. Department of Obstetrics and Gynecology, Faculty of Medicine Siriraj Hospital. Subject. Two hundred and fifty Thai PCOS women who attended the Gynecologic Endocrinology Unit, during May 2007 to January 2009. Materials and Methods. The paitents were interviewed and examined for weight, height, waist circumference, and blood pressure. Venous blood samples were drawn twice, one at 12-hour fasting and the other at 2 hours after glucose loading. Results. The prevalence of glucose intolerance in Thai PCOS women was 20.0%. The mean of HOMA-IR was 3.53  ±  7.7. Area under an ROC curve for HOMA-IR for detecting glucose intolerance was 0.82. Using the cut-off value of HOMA-IR >2.0, there was sensitivity at 84.0%, specificity at 61.0%, positive predictive value at 35.0%, negative predictive value at 93.8%, and accuracy at 65.6%. Conclusion. HOMA-IR >2.0 was used for screening test for glucose intolerance in Thai PCOS women. If the result was positive, a specific test should be done to prove the diagnosis.

  5. Mechanical homeostasis regulating adipose tissue volume

    Directory of Open Access Journals (Sweden)

    Svedman Paul

    2007-09-01

    Full Text Available Abstract Background The total body adipose tissue volume is regulated by hormonal, nutritional, paracrine, neuronal and genetic control signals, as well as components of cell-cell or cell-matrix interactions. There are no known locally acting homeostatic mechanisms by which growing adipose tissue might adapt its volume. Presentation of the hypothesis Mechanosensitivity has been demonstrated by mesenchymal cells in tissue culture. Adipocyte differentiation has been shown to be inhibited by stretching in vitro, and a pathway for the response has been elucidated. In humans, intermittent stretching of skin for reconstructional purposes leads to thinning of adipose tissue and thickening of epidermis – findings matching those observed in vitro in response to mechanical stimuli. Furthermore, protracted suspension of one leg increases the intermuscular adipose tissue volume of the limb. These findings may indicate a local homeostatic adipose tissue volume-regulating mechanism based on movement-induced reduction of adipocyte differentiation. This function might, during evolution, have been of importance in confined spaces, where overgrowth of adipose tissue could lead to functional disturbance, as for instance in the turtle. In humans, adipose tissue near muscle might in particular be affected, for instance intermuscularly, extraperitoneally and epicardially. Mechanical homeostasis might also contribute to protracted maintainment of soft tissue shape in the face and neck region. Testing of the hypothesis Assessment of messenger RNA-expression of human adipocytes following activity in adjacent muscle is planned, and study of biochemical and volumetric adipose tissue changes in man are proposed. Implications of the hypothesis The interpretation of metabolic disturbances by means of adipose tissue might be influenced. Possible applications in the head and neck were discussed.

  6. Exploitation of Apoptotic Regulation in Cancer

    Directory of Open Access Journals (Sweden)

    David S. Ucker

    2018-02-01

    Full Text Available Within an organism, environmental stresses can trigger cell death, particularly apoptotic cell death. Apoptotic cells, themselves, are potent regulators of their cellular environment, involved primarily in effecting homeostatic control. Tumors, especially, exist in a dynamic balance of cell proliferation and cell death. This special feature of the tumorous microenvironment—namely, the prominence and persistence of cell death—necessarily entails a magnification of the extrinsic, postmortem effects of dead cells. In both normal and malignant tissues, apoptotic regulation is exerted through immune as well as non-immune mechanisms. Apoptotic cells suppress the repertoire of immune reactivities, both by attenuating innate (especially inflammatory responses and by abrogating adaptive responses. In addition, apoptotic cells modulate multiple vital cell activities, including survival, proliferation (cell number, and growth (cell size. While the microenvironment of the tumor may contribute to apoptosis, the postmortem effects of apoptotic cells feature prominently in the reciprocal acclimatization between the tumor and its environment. In much the same way that pathogens evade the host’s defenses through exploitation of key aspects of innate and adaptive immunity, cancer cells subvert several normal homeostatic processes, in particular wound healing and organ regeneration, to transform and overtake their environment. In understanding this subversion, it is crucial to view a tumor not simply as a clone of malignant cells, but rather as a complex and highly organized structure in which there exists a multidirectional flow of information between the cancer cells themselves and the multiple other cell types and extracellular matrix components of which the tumor is comprised. Apoptotic cells, therefore, have the unfortunate consequence of facilitating tumorigenesis and tumor survival.

  7. Regulation of Glucose Metabolism - A Perspective From Cell Bioprocessing.

    Science.gov (United States)

    Mulukutla, Bhanu Chandra; Yongky, Andrew; Le, Tung; Mashek, Douglas G; Hu, Wei-Shou

    2016-08-01

    Cultured mammalian cells are the main workhorses for producing biologics. The performance of these cell culture processes, in terms of both productivity and product quality attributes, is significantly influenced by cellular metabolism. Glucose is the major carbon source for cellular biosynthesis and energy generation. We summarize here recent advances in our understanding of the regulation of glucose metabolism in cultured cells. The versatility of cells to sustain homeostatic states under widely varying environments is made possible by allosteric regulation of the metabolic network, interplay between the signaling pathways, and transcription factors. Understanding the regulation of metabolism holds the key to altering the metabolic regulatory circuit and implementing direct metabolic control over cell culture processes. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Homeostatic γδ T Cell Contents Are Preserved by Granulocyte Colony-Stimulating Factor Priming and Correlate with the Early Recovery of γδ T Cell Subsets after Haploidentical Hematopoietic Stem Cell Transplantation.

    Science.gov (United States)

    Bian, Zhilei; Xu, Lan-Ping; Fu, Qiang; Huo, Mingrui; Liu, Long; Zhao, Xiaosu; Huang, Xiao-Jun; Liu, Jiangying

    2018-02-01

    Emerging evidence from graft manipulations and immunotherapeutic treatments has highlighted a favorable effect of γδ T cells in the setting of allogeneic hematopoietic stem cell transplantation (alloHSCT). However, γδ T cell subsets and their distinct features in the allograft have not been characterized. Additionally, whether homeostatic γδ T cell fractions are influenced by treatment with granulocyte colony-stimulating factor (G-CSF) remains elusive. We initially compared the phenotypes of γδ T cell subsets, including CD27 + , CD27 - , Vδ1 + , Vδ2 + , Vδ1 + CD27 + , Vδ1 + CD27 - , Vδ2 + CD27 + , and Vδ2 + CD27 - cells, in the peripheral blood of 20 healthy donors before and after G-CSF mobilization. The effects of G-CSF on the cytokine production capacities of γδ T cell subsets were also detected. Moreover, the correlation between donor homeostatic γδ T cell content and the early recoveries of γδ T cell subgroups after haploidentical HSCT was investigated in 40 pairs of donors and recipients. We found that both the proportions and IFN-γ secretion capacities of peripheral γδ T cell subsets were preserved in G-CSF-primed grafts. Homeostatic Vδ1 and Vδ2 proportions of donors significantly correlated with the early recoveries of Vδ1 and Vδ2 cells after haploidentical HSCT. Interestingly, a higher day 30 Vδ1 concentration was associated with a lower incidence of cytomegalovirus reactivation in recipients. These results not only clarify the preservation of γδ T cell phenotypes and functional features by G-CSF mobilization but also suggest the importance of homeostatic γδ T cell content for immune recovery after alloHSCT. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  9. The incidence of metabolic syndrome in obese Czech children: the importance of early detection of insulin resistance using homeostatic indexes HOMA-IR and QUICKI.

    Science.gov (United States)

    Pastucha, D; Filipčíková, R; Horáková, D; Radová, L; Marinov, Z; Malinčíková, J; Kocvrlich, M; Horák, S; Bezdičková, M; Dobiáš, M

    2013-01-01

    Common alimentary obesity frequently occurs on a polygenic basis as a typical lifestyle disorder in the developed countries. It is associated with characteristic complex metabolic changes, which are the cornerstones for future metabolic syndrome development. The aims of our study were 1) to determine the incidence of metabolic syndrome (based on the diagnostic criteria defined by the International Diabetes Federation for children and adolescents) in Czech obese children, 2) to evaluate the incidence of insulin resistance according to HOMA-IR and QUICKI homeostatic indexes in obese children with and without metabolic syndrome, and 3) to consider the diagnostic value of these indexes for the early detection of metabolic syndrome in obese children. We therefore performed anthropometric and laboratory examinations to determine the incidence of metabolic syndrome and insulin resistance in the group of 274 children with obesity (128 boys and 146 girls) aged 9-17 years. Metabolic syndrome was found in 102 subjects (37 %). On the other hand, the presence of insulin resistance according to QUICKI HOMA-IR >3.16 in 53 % of obese subjects. This HOMA-IR limit was exceeded by 70 % children in the MS(+) group, but only by 43 % children in the MS(-) group (p<0.0001). However, a relatively high incidence of insulin resistance in obese children without metabolic syndrome raises a question whether the existing diagnostic criteria do not falsely exclude some cases of metabolic syndrome. On the basis of our results we suggest to pay a preventive attention also to obese children with insulin resistance even if they do not fulfill the actual diagnostic criteria for metabolic syndrome.

  10. The effects of a 2 week modified high intensity interval training program on the homeostatic model of insulin resistance (HOMA-IR) in adults with type 2 diabetes.

    Science.gov (United States)

    Shaban, N; Kenno, K A; Milne, K J

    2014-04-01

    High intensity interval training (HIIT) induces similar metabolic adaptations to traditional steady state aerobic exercise training. Until recently, most HIIT studies have examined maximum efforts in healthy populations. The current study aimed to examine the effects of a 2 week modified HIIT program on the homeostatic model of insulin resistance (HOMA-IR) in individuals with type 2 diabetes (T2D). It was hypothesized that HIIT would improve HOMA-IR. Nine individuals with T2D (age=40.2±9.7 y; BMI=33.9±5.3; fasting plasma glucose [FPG]=8.7±2.9 mmol/L; HbA1C=7.3±1.2%; [mean±SD]) performed 6 individualized training sessions of HIIT (4x30 seconds at 100% of estimated maximum workload followed by 4 minutes of active rest) over 2 weeks. HOMA-IR was calculated from FPG and serum insulin and compared against a prior 2 week baseline period. Blood glucose was reduced immediately after each HIIT session (PHOMA-IR were unchanged after training. However, 6 of the 9 individuals exhibited reduced HOMA-IR values after the training period and there was a significant negative correlation between HOMA-IR value prior to training and change in HOMA-IR after HIIT. These observations tend to support the positive health benefits of HITT for individuals with T2D reported in recently published data using a modified HIIT protocol. However, they suggest that the magnitude of the disease should be assessed when examining the effects of exercise interventions in individuals with T2D.

  11. Homeostatic Mass Control in Gastric Non-Neoplastic Epithelia under Infection of Helicobacter pylori: An Immunohistochemical Analysis of Cell Growth, Stem Cells and Programmed Cell Death

    International Nuclear Information System (INIS)

    Kato, Kenji; Hasui, Kazuhisa; Wang, Jia; Kawano, Yoshifumi; Aikou, Takashi; Murata, Fusayoshi

    2008-01-01

    We evaluated homeostatic mass control in non-neoplastic gastric epithelia under Helicobacter pylori (HP) infection in the macroscopically normal-appearing mucosa resected from the stomach with gastric cancer, immunohistochemically analyzing the proliferation, kinetics of stem cells and programmed cell death occurring in them. Ki67 antigen-positive proliferating cells were found dominantly in the elongated neck portion, sparsely in the fundic areas and sporadically in the stroma with chronic infiltrates. CD117 could monitor the kinetics of gastric stem cells and showed its expression in two stages of gastric epithelial differentiation, namely, in transient cells from the gastric epithelial stem cells to the foveolar and glandular cells in the neck portion and in what are apparently progenitor cells from the gastric stem cells in the stroma among the infiltrates. Most of the nuclei were positive for ssDNA in the almost normal mucosa, suggesting DNA damage. Cleaved caspase-3-positive foveolar cells were noted under the surface, suggesting the suppression of apoptosis in the surface foveolar cells. Besides such apoptosis of the foveolar cells, in the severely inflamed mucosa apoptotic cells were found in the neck portion where most of the cells were Ki67 antigen-positive proliferating cells. Beclin-1 was recognized in the cytoplasm and in a few nuclei of the fundic glandular cells, suggesting their autophagic cell death and mutated beclin-1 in the nuclei. Taken together, the direct and indirect effects of HP infection on the gastric epithelial proliferation, differentiation and programmed cell death suggested the in-situ occurrence of gastric cancer under HP infection

  12. Homeostatic effect of p-chloro-diphenyl diselenide on glucose metabolism and mitochondrial function alterations induced by monosodium glutamate administration to rats.

    Science.gov (United States)

    Quines, Caroline B; Rosa, Suzan G; Chagas, Pietro M; da Rocha, Juliana T; Dobrachinski, Fernando; Carvalho, Nélson R; Soares, Félix A; da Luz, Sônia C Almeida; Nogueira, Cristina W

    2016-01-01

    The metabolic syndrome is a group of metabolic alterations considered a worldwide public health problem. Organic selenium compounds have been reported to have many different pharmacological actions, such as anti-hypercholesterolemic and anti-hyperglycemic. The aim of this study was to evaluate the effect of p-chloro-diphenyl diselenide (p-ClPhSe)2, an organic selenium compound, in a model of obesity induced by monosodium glutamate (MSG) administration in rats. The rats were treated during the first ten postnatal days with MSG and received (p-ClPhSe)2 (10 mg/kg, intragastrically) from 45th to 51 th postnatal day. Glucose, lipid and lactate levels were determined in plasma of rats. Glycogen levels and activities of tyrosine aminotransferase, hexokinase, citrate synthase and glucose-6-phosphatase (G-6-Pase) were determined in livers of rats. Renal G-6-Pase activity was also determined. The purine content [Adenosine triphosphate (ATP), adenosine diphosphate (ADP) and adenosine monophosphate] and mitochondrial functionality in the liver were also investigated. p-(ClPhSe)2 did not alter the reduction in growth performance and in the body weight caused by MSG but reduced epididymal fat deposition of rats. p-(ClPhSe)2 restored glycemia, triglycerides, cholesterol and lactate levels as well as the glucose metabolism altered in rats treated with MSG. p-(ClPhSe)2 restored hepatic mitochondrial dysfunction and the decrease in citrate synthase activity and ATP and ADP levels caused by MSG in rats. In summary, (p-ClPhSe)2 had homeostatic effects on glucose metabolism and mitochondrial function alterations induced by MSG administration to rats.

  13. Market, Regulation, Market, Regulation

    DEFF Research Database (Denmark)

    Frankel, Christian; Galland, Jean-Pierre

    2015-01-01

    This paper focuses on the European Regulatory system which was settled both for opening the Single Market for products and ensuring the consumers' safety. It claims that the New Approach and Standardization, and the Global Approach to conformity assessment, which suppressed the last technical...... barriers to trade in Europe, realized the free movement of products by organizing progressively several orders of markets and regulation. Based on historical and institutional documents, on technical publications, and on interviews, this article relates how the European Commission and the Member States had...... alternatively recourse to markets and to regulations, at the three main levels of the New Approach Directives implementation. The article focuses also more specifically on the Medical Devices sector, not only because this New Approach sector has long been controversial in Europe, and has recently been concerned...

  14. MicroRNAs and the regulation of aldosterone signaling in the kidney.

    Science.gov (United States)

    Butterworth, Michael B

    2015-04-01

    The role of small noncoding RNAs, termed microRNAs (miRs), in development and disease has been recognized for many years. The number of miRs and regulated targets that reinforce a role for miRs in human disease and disease progression is ever-increasing. However, less is known about the involvement of miRs in steady-state, nondisease homeostatic pathways. In the kidney, much of the regulated ion transport is under the control of hormonal signaling. Evidence is emerging that miRs are involved in the hormonal regulation of kidney function and, particularly, in ion transport. In this short review, the production and intra- and extracellular signaling of miRs and the involvement of miRs in kidney disease are discussed. The discussion also focuses on the role of these small biological molecules in the homeostatic control of ion transport in the kidney. MiR regulation of and by corticosteroid hormones, in particular the mineralocorticoid hormone aldosterone, is considered. While information about the role of aldosterone-regulated miRs in the kidney is limited, an increase in the research in this area will undoubtedly highlight the involvement of miRs as central mediators of hormonal signaling in normal physiology. Copyright © 2015 the American Physiological Society.

  15. The effect of consumption temperature on the homeostatic and hedonic responses to glucose ingestion in the hypothalamus and the reward system.

    Science.gov (United States)

    van Opstal, Anna M; van den Berg-Huysmans, Annette A; Hoeksma, Marco; Blonk, Cor; Pijl, Hanno; Rombouts, Serge A R B; van der Grond, Jeroen

    2018-01-01

    Excessive consumption of sugar-sweetened beverages (SSBs) has been associated with obesity and related diseases. SSBs are often consumed cold, and both the energy content and temperature might influence the consumption behavior for SSBs. The main aim of this study was to elucidate whether consumption temperature and energy (i.e., glucose) content modulate homeostatic (hypothalamus) and reward [ventral tegmental area (VTA)] responses. Sixteen healthy men participated in our study [aged 18-25 y; body mass index (kg/m2): 20-23]. High-resolution functional magnetic resonance imaging data were collected after ingestion of 4 different study stimuli: plain tap water at room temperature (22°C), plain tap water at 0°C, a glucose-containing beverage (75 g glucose dissolved in 300 mL water) at 22°C, and a similar glucose drink at 0°C. Blood oxygen level-dependent (BOLD) changes from baseline (7 min preingestion) were analyzed over time in the hypothalamus and VTA for individual stimulus effects and for effects between stimuli. In the hypothalamus, water at 22°C led to a significantly increased BOLD response; all other stimuli resulted in a direct, significant decrease in BOLD response compared with baseline. In the VTA, a significantly decreased BOLD response compared with baseline was found after the ingestion of stimuli containing glucose at 0°C and 22°C. These responses were not significantly modulated by consumption temperature. The consumption of plain water did not have a significant VTA BOLD effect. Our data show that glucose at 22°C, glucose at 0°C, and water at 0°C lowered hypothalamic activity, which is associated with increased satiation. On the contrary, the consumption of water at room temperature increased activity. All stimuli led to a similar VTA response, which suggests that all drinks elicited a similar hedonic response. Our results indicate that, in addition to glucose, the low temperature at which SSBs are often consumed also leads to a response

  16. Enhancement of Endocannabinoid-dependent Depolarization-induced Suppression of Excitation in Glycinergic Neurons by Prolonged Exposure to High Doses of Salicylate.

    Science.gov (United States)

    Zugaib, João; Leão, Ricardo M

    2018-02-17

    The Dorsal Cochlear Nucleus (DCN) is a region which has been traditionally linked to the genesis of tinnitus, the constant perception of a phantom sound. Sodium salicylate, a COX-2 inhibitor, can induce tinnitus in high doses. Hyperactivity of DCN neurons is observed in several animal models of tinnitus, including salicylate-induced tinnitus. The DCN presents several forms of endocannabinoid (EC)-dependent synaptic plasticity and COX-2 can also participate in the oxidative degradation of ECs. We recently demonstrated that short-term perfusion of sodium salicylate and other inhibitors of both oxidative and hydrolytic EC degradation did not affect depolarization-induced suppression of excitation (DSE), a form of EC-dependent short-term synaptic plasticity. Here, we show that prolonged incubation with high doses of sodium salicylate (1.4 mM) enhances DSE of synapses onto glycinergic DCN interneurons but not those innervating glutamatergic DCN fusiform neurons. This effect was not reproduced with lower doses of salicylate (140 µM) or with ibuprofen, another inhibitor of COX-2. This effect was not observed in the presence of AM251, an antagonist/inverse agonist of cannabinoid CB1 receptors, showing that it was dependent on EC release. Finally we demonstrated that incubation with salicylate potentiated the increase in intracellular calcium during the depolarization. Our results point to an increased inhibition of DCN inhibitory CW neuron during depolarizations, probably by an enhanced EC release during the depolarizations, which is potentially significant for DCN hyperactivity and tinnitus generation. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

  17. The Mammalian Cortex as a Self-Organizing Complex System: Multi-Scale Homeostatic Approaches to Criticality via Dynamical Balance of Inhibition against Excitation

    Science.gov (United States)

    Ng, Tony T.

    The mammalian cortex is a highly structured network of densely packed neurons that interact strongly with each other in very specific ways. Loosely speaking, neurons are cells that fire clicks at each other as a means of communication. Common sites of communication, known as synapses, are enabled by transmitter molecules released from presynaptic sender cells, which bind to receptors on postsynaptic receiver cells. There are two major classes of neurons - excitatory ones that prompt their downstream neighbors to fire spikes through depolarization, and inhibitory ones that suppress spike activity of their postsynaptic partners via hyperpolarization. Depolarization and hyperpolarization make membrane potential of a cell more positive and more negative, respectively. A sufficiently depolarized neuron fires a spike, which technically is called an action potential. In this thesis, we focus on the interplay between three of the cortex's most ubiquitous features and examine some of the consequences that their interactions have on cortical dynamics. One of the features, widespread projections between clusters of excitatory neurons, is topological. The two remaining features, homeostasis and balance between the amount of excitatory and inhibitory activity are dynamical. Here, homeostasis refers to the regulatory mechanism of individual cells or collections of cells that maintains constant levels of spike activity over time. Simply by varying the average homeostatic firing rate in clusters of excitatory neurons or by tuning the common homoeostatic rate of individual inhibitory neurons, we show via simulation that cluster-based activity bursts can exhibit critical dynamics and display power-law distributions with exponents that are consistent with those found in in vivo experiments of awake animals. Criticality is an idea that originated in statistical physics. At the critical point, activity levels of sites across an entire system, such as those of different cortical regions

  18. Developmental Regulation of Indole-3-Acetic Acid Turnover in Scots Pine Seedlings1

    Science.gov (United States)

    Ljung, Karin; Östin, Anders; Lioussanne, Laetitia; Sandberg, Göran

    2001-01-01

    Indole-3-acetic acid (IAA) homeostasis was investigated during seed germination and early seedling growth in Scots pine (Pinus sylvestris). IAA-ester conjugates were initially hydrolyzed in the seed to yield a peak of free IAA prior to initiation of root elongation. Developmental regulation of IAA synthesis was observed, with tryptophan-dependent synthesis being initiated around 4 d and tryptophan-independent synthesis occurring around 7 d after imbibition. Induction of catabolism to yield 2-oxindole-3-acetic acid and irreversible conjugation to indole-3-acetyl-N-aspartic acid was noticed at the same time as de novo synthesis was first detected. As a part of the homeostatic regulation IAA was further metabolized to two new conjugates: glucopyranosyl-1-N-indole-3-acetyl-N-aspartic acid and glucopyranosyl-1-N-indole-3-acetic acid. The initial supply of IAA thus originates from stored pools of IAA-ester conjugates, mainly localized in the embryo itself rather than in the general nutrient storage tissue, the megagametophyte. We have found that de novo synthesis is first induced when the stored pool of conjugated IAA is used up and additional hormone is needed for elongation growth. It is interesting that when de novo synthesis is induced, a distinct induction of catabolic events occurs, indicating that the seedling needs mechanisms to balance synthesis rates for the homeostatic regulation of the IAA pool. PMID:11154354

  19. Thermophysiologic aspects of the three-process-model of sleepiness regulation.

    Science.gov (United States)

    Kräuchi, Kurt; Cajochen, Christian; Wirz-Justice, Anna

    2005-04-01

    The following overview reconsiders the three-process model of sleepiness regulation (homeostatic, circadian, and sleep inertia) from a thermophysiologic point of view. Our results gathered over the last decade indicate that the homeostatic aspect of sleepiness regulation (ie, buildup of sleepiness during wakefulness and its decay during sleep) is not related to the thermoregulatory system, whereas the two other processes of sleepiness regulation (ie, circadian and sleep inertia process) are clearly related to thermoregulation in humans. Distal skin temperature of hands and feet seems to be the crucial variable for the association between thermophysiology, sleepiness, and sleep. Increased distal skin temperature before a nocturnal sleep episode is a good predictor for short sleep-onset latency. The disappearance of sleep inertia after sleep or a nap episode shows very similar kinetics as distal vasoconstriction. Furthermore, relaxation-induced sleepiness (eg, after lying down, at lights-off, with thermal biofeedback training) also evokes an increase in distal skin temperatures. The reverse effect occurs at lights-on or a posture change from supine to standing, Therefore, in terms of thermophysiology, sleep inertia can be explained as the reverse of a relaxation process (ie, decrease in distal skin temperatures). Our results reinterpret the so-called "sleep-evoked" reduction of core body temperature as a consequence of relaxation-induced vasodilatation after lights-off. Sleep per se has no further thermoregulatory effect. Taken together, a thermophysiologic approach may provide a successful strategy to treat sleep-onset insomnia and alleviate sleep inertia.

  20. Late onset deficits in synaptic plasticity in the valproic acid rat model of autism

    Directory of Open Access Journals (Sweden)

    Henry Giles Stratten Martin

    2014-01-01

    Full Text Available Valproic acid (VPA is a frequently used drug in the treatment of epilepsy, bipolar disorders and migraines; however it is also a potent teratogen. Prenatal exposure increases the risk of childhood malformations and can result in cognitive deficits. In rodents in utero exposure to VPA also causes neurodevelopmental abnormalities and is an important model of autism. In early postnatal life VPA exposed rat pups show changes in medial prefrontal cortex (mPFC physiology and synaptic connectivity. Specifically, principal neurons show decreased excitability but increased local connectivity, coupled with an increase in long-term potentiation (LTP due to an up-regulation of NMDA receptor (NMDAR expression. However recent evidence suggests compensatory homeostatic mechanisms lead to normalization of synaptic NMDA receptors during later postnatal development. Here we have extended study of mPFC synaptic physiology into adulthood to better understand the longitudinal consequences of early developmental abnormalities in VPA exposed rats. Surprisingly in contrast to early postnatal life and adolescence, we find that adult VPA exposed rats show reduced synaptic function. Both NMDAR mediated currents and LTP are lower in adult VPA rats, although spontaneous activity and endocannabinoid dependent long-term depression are normal. We conclude that rather than correcting, synaptic abnormalities persist into adulthood in VPA exposed rats, although a quite different synaptic phenotype is present. This switch from hyper to hypo function in mPFC may be linked to some of the neurodevelopmental defects found in prenatal VPA exposure and autism spectrum disorders in general.

  1. Stem cell aging: mechanisms, regulators and therapeutic opportunities

    Science.gov (United States)

    Oh, Juhyun; Lee, Yang David; Wagers, Amy J

    2014-01-01

    Aging tissues experience a progressive decline in homeostatic and regenerative capacities, which has been attributed to degenerative changes in tissue-specific stem cells, stem cell niches and systemic cues that regulate stem cell activity. Understanding the molecular pathways involved in this age-dependent deterioration of stem cell function will be critical for developing new therapies for diseases of aging that target the specific causes of age-related functional decline. Here we explore key molecular pathways that are commonly perturbed as tissues and stem cells age and degenerate. We further consider experimental evidence both supporting and refuting the notion that modulation of these pathways per se can reverse aging phenotypes. Finally, we ask whether stem cell aging establishes an epigenetic ‘memory’ that is indelibly written or one that can be reset. PMID:25100532

  2. Regulation of Angiogenesis by Aminoacyl-tRNA Synthetases

    Directory of Open Access Journals (Sweden)

    Adam C. Mirando

    2014-12-01

    Full Text Available In addition to their canonical roles in translation the aminoacyl-tRNA synthetases (ARSs have developed secondary functions over the course of evolution. Many of these activities are associated with cellular survival and nutritional stress responses essential for homeostatic processes in higher eukaryotes. In particular, six ARSs and one associated factor have documented functions in angiogenesis. However, despite their connection to this process, the ARSs are mechanistically distinct and exhibit a range of positive or negative effects on aspects of endothelial cell migration, proliferation, and survival. This variability is achieved through the appearance of appended domains and interplay with inflammatory pathways not found in prokaryotic systems. Complete knowledge of the non-canonical functions of ARSs is necessary to understand the mechanisms underlying the physiological regulation of angiogenesis.

  3. Regulation of host metabolism and immunity by the gut microbiome

    DEFF Research Database (Denmark)

    Laursen, Janne Marie

    During recent years, central roles of the gut microbiome in metabolic and immunological diseases have been uncovered, and multiple studies have shown that bacterial-derived components shape host physiology and immune responses via direct cellular interactions. The intestinal immune system...... is crucial for the induction of effective immune responses against invading pathogens while simultaneously being vital for maintenance of homeostatic conditions. This balancing act requires a tightly regulated system that might be influenced by bacterial metabolites such as butyrate, since reduced...... frequencies of butyrate-producing species associate with various lifestyle-associated disorders. In the present work, we used systems biology approaches to understand how bacterial components may associate with metabolic disease and mediate phenotypic shifts in pro-inflammatory immune cells. First, we...

  4. The SOCS2 Ubiquitin Ligase Complex Regulates Growth Hormone Receptor Levels

    DEFF Research Database (Denmark)

    Vesterlund, Mattias; Zadjali, Fahad; Persson, Torbjörn

    2011-01-01

    Growth Hormone is essential for the regulation of growth and the homeostatic control of intermediary metabolism. GH actions are mediated by the Growth Hormone Receptor; a member of the cytokine receptor super family that signals chiefly through the JAK2/STAT5 pathway. Target tissue responsiveness......, a phenotype that is dependent on endogenous GH secretion. SOCS2 is a GH-stimulated, STAT5b-regulated gene that acts in a negative feedback loop to downregulate GHR signalling. Since the biochemical basis for these actions is poorly understood, we studied the molecular function of SOCS2. We demonstrated...... of SOCS2 in in vitro experiments. We showed that SOCS2 regulates cellular GHR levels through direct ubiquitination and in a proteasomally dependent manner. We also confirmed the importance of the SOCS-box for the proper function of SOCS2. Finally, we identified two phosphotyrosine residues in the GHR...

  5. Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche.

    Science.gov (United States)

    Mitroulis, Ioannis; Chen, Lan-Sun; Singh, Rashim Pal; Kourtzelis, Ioannis; Economopoulou, Matina; Kajikawa, Tetsuhiro; Troullinaki, Maria; Ziogas, Athanasios; Ruppova, Klara; Hosur, Kavita; Maekawa, Tomoki; Wang, Baomei; Subramanian, Pallavi; Tonn, Torsten; Verginis, Panayotis; von Bonin, Malte; Wobus, Manja; Bornhäuser, Martin; Grinenko, Tatyana; Di Scala, Marianna; Hidalgo, Andres; Wielockx, Ben; Hajishengallis, George; Chavakis, Triantafyllos

    2017-10-02

    Hematopoietic stem cells (HSCs) remain mostly quiescent under steady-state conditions but switch to a proliferative state following hematopoietic stress, e.g., bone marrow (BM) injury, transplantation, or systemic infection and inflammation. The homeostatic balance between quiescence, self-renewal, and differentiation of HSCs is strongly dependent on their interactions with cells that constitute a specialized microanatomical environment in the BM known as the HSC niche. Here, we identified the secreted extracellular matrix protein Del-1 as a component and regulator of the HSC niche. Specifically, we found that Del-1 was expressed by several cellular components of the HSC niche, including arteriolar endothelial cells, CXCL12-abundant reticular (CAR) cells, and cells of the osteoblastic lineage. Del-1 promoted critical functions of the HSC niche, as it regulated long-term HSC (LT-HSC) proliferation and differentiation toward the myeloid lineage. Del-1 deficiency in mice resulted in reduced LT-HSC proliferation and infringed preferentially upon myelopoiesis under both steady-state and stressful conditions, such as hematopoietic cell transplantation and G-CSF- or inflammation-induced stress myelopoiesis. Del-1-induced HSC proliferation and myeloid lineage commitment were mediated by β3 integrin on hematopoietic progenitors. This hitherto unknown Del-1 function in the HSC niche represents a juxtacrine homeostatic adaptation of the hematopoietic system in stress myelopoiesis.

  6. Regulation of leucocyte homeostasis in the circulation.

    Science.gov (United States)

    Scheiermann, Christoph; Frenette, Paul S; Hidalgo, Andrés

    2015-08-01

    The functions of blood cells extend well beyond the immune functions of leucocytes or the respiratory and hemostatic functions of erythrocytes and platelets. Seen as a whole, the bloodstream is in charge of nurturing and protecting all organs by carrying a mixture of cell populations in transit from one organ to another. To optimize these functions, evolution has provided blood and the vascular system that carries it with various mechanisms that ensure the appropriate influx and egress of cells into and from the circulation where and when needed. How this homeostatic control of blood is achieved has been the object of study for over a century, and although the major mechanisms that govern it are now fairly well understood, several new concepts and mediators have recently emerged that emphasize the dynamism of this liquid tissue. Here we review old and new concepts that relate to the maintenance and regulation of leucocyte homeostasis in blood and briefly discuss the mechanisms for platelets and red blood cells. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

  7. A role for cryptochromes in sleep regulation

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    Sancar Aziz

    2002-12-01

    Full Text Available Abstract Background The cryptochrome 1 and 2 genes (cry1 and cry2 are necessary for the generation of circadian rhythms, as mice lacking both of these genes (cry1,2-/- lack circadian rhythms. We studied sleep in cry1,2-/- mice under baseline conditions as well as under conditions of constant darkness and enforced wakefulness to determine whether cryptochromes influence sleep regulatory processes. Results Under all three conditions, cry1,2-/- mice exhibit the hallmarks of high non-REM sleep (NREMS drive (i.e., increases in NREMS time, NREMS consolidation, and EEG delta power during NREMS. This unexpected phenotype was associated with elevated brain mRNA levels of period 1 and 2 (per1,2, and albumin d-binding protein (dbp, which are known to be transcriptionally inhibited by CRY1,2. To further examine the relationship between circadian genes and sleep homeostasis, we examined wild type mice and rats following sleep deprivation and found increased levels of per1,2 mRNA and decreased levels of dbp mRNA specifically in the cerebral cortex; these changes subsided with recovery sleep. The expression of per3, cry1,2, clock, npas2, bmal1, and casein-kinase-1ε did not change with sleep deprivation. Conclusions These results indicate that mice lacking cryptochromes are not simply a genetic model of circadian arrhythmicity in rodents and functionally implicate cryptochromes in the homeostatic regulation of sleep.

  8. Transcriptional regulation of mononuclear phagocyte development

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    Roxane eTussiwand

    2015-10-01

    Full Text Available IntroductionThe mononuclear-phagocyte system (MPS, which comprises dendritic cells (DCs, macrophages and monocytes, is a heterogeneous group of myeloid cells. The complexity of the MPS is equally reflected by the plasticity in function and phenotype that characterizes each subset depending on their location and activation state. Specialized subsets of Mononuclear Phagocytes (MP reside in defined anatomical locations, are critical for the homeostatic maintenance of tissues, and provide the link between innate and adaptive immune responses during infections. The ability of MP to maintain or to induce the correct tolerogenic or inflammatory milieu also resides in their complex subset specialization. Such subset heterogeneity is obtained through lineage diversification and specification, which is controlled by defined transcriptional networks and programs. Understanding the MP biology means to define their transcriptional signature, which is required during lineage commitment, and which characterizes each subset’s features. This review will focus on the transcriptional regulation of the MPS; in particular what determines lineage commitment and functional identity; we will emphasizes recent advances in the field of single cell analysis and highlight unresolved questions in the field.

  9. Gene Regulation System of Vasopressin and Corticotoropin-Releasing Hormone

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    Masanori Yoshida

    2008-01-01

    Full Text Available The neurohypophyseal hormones, arginine vasopressin and corticotropin-releasing hormone (CRH, play a crucial role in the physiological and behavioral response to various kinds of stresses. Both neuropeptides activate the hypophysialpituitary-adrenal (HPA axis, which is a central mediator of the stress response in the body. Conversely, they receive the negative regulation by glucocorticoid, which is an end product of the HPA axis. Vasopressin and CRH are closely linked to immune response; they also interact with pro-inflammatory cytokines. Moreover, as for vasopressin, it has another important role, which is the regulation of water balance through its potent antidiuretic effect. Hence, it is conceivable that vasopressin and CRH mediate the homeostatic responses for survival and protect organisms from the external world. A tight and elaborate regulation system of the vasopressin and CRH gene is required for the rapid and flexible response to the alteration of the surrounding environments. Several important regulatory elements have been identified in the proximal promoter region in the vasopressin and CRH gene. Many transcription factors and intracellular signaling cascades are involved in the complicated gene regulation system. This review focuses on the current status of the basic research of vasopressin and CRH. In addition to the numerous known facts about their divergent physiological roles, the recent topics of promoter analyses will be discussed.

  10. Homeostatic regulatory role of Pokemon in NF-κB signaling: stimulating both p65 and IκBα expression in human hepatocellular carcinoma cells.

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    Zhang, Nan-Nan; Sun, Qin-Sheng; Chen, Zhe; Liu, Feng; Jiang, Yu-Yang

    2013-01-01

    NF-κB consists of p50, p65 (RelA), p52, c-Rel, and RelB, and among them p65 is a representative protein to investigate the regulation and function of this signaling. NF-κB integrates inflammation and carcinogenesis and regulates the expression of a variety of genes in response to immunity, inflammation, and apoptosis. IκBα acts as an inhibitor of NF-κB through forming an inactive NF-κB/IκBα complex. Pokemon is a ubiquitous transcription factor involved in different signaling pathways, playing a pivotal role in cell proliferation, anti-apoptosis, embryonic development, and maintenance. In this study, we found that p65 and IκBα are both novel regulatory targets of Pokemon. Ectopic expression of Pokemon in immortalized liver cells HL7702 enhanced p65 and IκBα expression, whereas silencing of Pokemon in hepatocellular carcinoma cells QGY7703 reduced cellular p65 levels. ChIP assay and targeted mutagenesis revealed that Pokemon directly binds to the element of -434 to -430 bp in p65 promoter and of -453 to -448 bp in IκBα promoter and stimulates luciferase reporter gene expression. Co-transfection of Pokemon with p65 or IκBα promoter-reporter notably enhanced their promoter activity. These data suggest that Pokemon activates the expression of both p65 and IκBα by sequence-specific binding to their promoters and plays a dual role in regulating NF-κB signaling.

  11. microRNA Regulation of Skeletal Development.

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    Sera, Steven R; Zur Nieden, Nicole I

    2017-08-01

    Osteogenesis is a complex process involving the specification of multiple progenitor cells and their maturation and differentiation into matrix-secreting osteoblasts. Osteogenesis occurs not only during embryogenesis but also during growth, after an injury, and in normal homeostatic maintenance. While much is known about osteogenesis-associated regulatory genes, the role of microRNAs (miRNAs), which are epigenetic regulators of protein expression, is just beginning to be explored. While miRNAs do not abrogate all protein expression, their purpose is to finely tune it, allowing for a timely and temporary protein down-regulation. The last decade has unveiled a multitude of miRNAs that regulate key proteins within the osteogenic lineage, thus qualifying them as "ostemiRs." These miRNAs may endogenously target an activator or inhibitor of differentiation, and depending on the target, may either lead to the prolongation of a progenitor maintenance state or to early differentiation. Interestingly, cellular identity seems intimately coupled to the expression of miRNAs, which participate in the suppression of previous and subsequent differentiation steps. In such cases where key osteogenic proteins were identified as direct targets of miRNAs in non-bone cell types, or through bioinformatic prediction, future research illuminating the activity of these miRNAs during osteogenesis will be extremely valuable. Many bone-related diseases involve the dysregulation of transcription factors or other proteins found within osteoblasts and their progenitors, and the dysregulation of miRNAs, which target such factors, may play a pivotal role in disease etiology, or even as a possible therapy.

  12. Regulation of Cation Balance in Saccharomyces cerevisiae

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    Cyert, Martha S.; Philpott, Caroline C.

    2013-01-01

    All living organisms require nutrient minerals for growth and have developed mechanisms to acquire, utilize, and store nutrient minerals effectively. In the aqueous cellular environment, these elements exist as charged ions that, together with protons and hydroxide ions, facilitate biochemical reactions and establish the electrochemical gradients across membranes that drive cellular processes such as transport and ATP synthesis. Metal ions serve as essential enzyme cofactors and perform both structural and signaling roles within cells. However, because these ions can also be toxic, cells have developed sophisticated homeostatic mechanisms to regulate their levels and avoid toxicity. Studies in Saccharomyces cerevisiae have characterized many of the gene products and processes responsible for acquiring, utilizing, storing, and regulating levels of these ions. Findings in this model organism have often allowed the corresponding machinery in humans to be identified and have provided insights into diseases that result from defects in ion homeostasis. This review summarizes our current understanding of how cation balance is achieved and modulated in baker’s yeast. Control of intracellular pH is discussed, as well as uptake, storage, and efflux mechanisms for the alkali metal cations, Na+ and K+, the divalent cations, Ca2+ and Mg2+, and the trace metal ions, Fe2+, Zn2+, Cu2+, and Mn2+. Signal transduction pathways that are regulated by pH and Ca2+ are reviewed, as well as the mechanisms that allow cells to maintain appropriate intracellular cation concentrations when challenged by extreme conditions, i.e., either limited availability or toxic levels in the environment. PMID:23463800

  13. Strong negative self regulation of Prokaryotic transcription factors increases the intrinsic noise of protein expression

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    Jenkins Dafyd J

    2008-01-01

    Full Text Available Abstract Background Many prokaryotic transcription factors repress their own transcription. It is often asserted that such regulation enables a cell to homeostatically maintain protein abundance. We explore the role of negative self regulation of transcription in regulating the variability of protein abundance using a variety of stochastic modeling techniques. Results We undertake a novel analysis of a classic model for negative self regulation. We demonstrate that, with standard approximations, protein variance relative to its mean should be independent of repressor strength in a physiological range. Consequently, in that range, the coefficient of variation would increase with repressor strength. However, stochastic computer simulations demonstrate that there is a greater increase in noise associated with strong repressors than predicted by theory. The discrepancies between the mathematical analysis and computer simulations arise because with strong repressors the approximation that leads to Michaelis-Menten-like hyperbolic repression terms ceases to be valid. Because we observe that strong negative feedback increases variability and so is unlikely to be a mechanism for noise control, we suggest instead that negative feedback is evolutionarily favoured because it allows the cell to minimize mRNA usage. To test this, we used in silico evolution to demonstrate that while negative feedback can achieve only a modest improvement in protein noise reduction compared with the unregulated system, it can achieve good improvement in protein response times and very substantial improvement in reducing mRNA levels. Conclusion Strong negative self regulation of transcription may not always be a mechanism for homeostatic control of protein abundance, but instead might be evolutionarily favoured as a mechanism to limit the use of mRNA. The use of hyperbolic terms derived from quasi-steady-state approximation should also be avoided in the analysis of stochastic

  14. Role of the melanin-concentrating hormone neuropeptide in sleep regulation.

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    Peyron, Christelle; Sapin, Emilie; Leger, Lucienne; Luppi, Pierre-Hervé; Fort, Patrice

    2009-11-01

    Melanin-concentrating hormone (MCH), a neuropeptide secreted by a limited number of neurons within the tuberal hypothalamus, has been drawn in the field of sleep only fairly recently in 2003. Since then, growing experimental evidence indicates that MCH may play a crucial role in the homeostatic regulation of paradoxical sleep (PS). MCH-expressing neurons fire specifically during PS. When injected icv MCH induces a 200% increase in PS quantities in rats and the lack of MCH induces a decrease in sleep quantities in transgenic mice. Here, we review recent studies suggesting a role for MCH in the regulation of the sleep-wake cycle, in particular PS, including insights on (1) the specific activity of MCH neurons during PS; (2) how they might be controlled across the sleep-wake cycle; (3) how they might modulate PS; (4) and finally whether MCH might take part in the expression of some symptoms observed in primary sleep disorders.

  15. The Regulation of Immunological Processes by Peripheral Neurons in Homeostasis and Disease.

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    Ordovas-Montanes, Jose; Rakoff-Nahoum, Seth; Huang, Siyi; Riol-Blanco, Lorena; Barreiro, Olga; von Andrian, Ulrich H

    2015-10-01

    The nervous system and the immune system are the principal sensory interfaces between the internal and external environment. They are responsible for recognizing, integrating, and responding to varied stimuli, and have the capacity to form memories of these encounters leading to learned or 'adaptive' future responses. We review current understanding of the cross-regulation between these systems. The autonomic and somatosensory nervous systems regulate both the development and deployment of immune cells, with broad functions that impact on hematopoiesis as well as on priming, migration, and cytokine production. In turn, specific immune cell subsets contribute to homeostatic neural circuits such as those controlling metabolism, hypertension, and the inflammatory reflex. We examine the contribution of the somatosensory system to autoimmune, autoinflammatory, allergic, and infectious processes in barrier tissues and, in this context, discuss opportunities for therapeutic manipulation of neuro-immune interactions. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. The Haematopoietic Stem Cell Niche: New Insights into the Mechanisms Regulating Haematopoietic Stem Cell Behaviour

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    Andrew J. Lilly

    2011-01-01

    Full Text Available The concept of the haematopoietic stem cell (HSC niche was formulated by Schofield in the 1970s, as a region within the bone marrow containing functional cell types that can maintain HSC potency throughout life. Since then, ongoing research has identified numerous cell types and a plethora of signals that not only maintain HSCs, but also dictate their behaviour with respect to homeostatic requirements and exogenous stresses. It has been proposed that there are endosteal and vascular niches within the bone marrow, which are thought to regulate different HSC populations. However, recent data depicts a more complicated picture, with functional crosstalk between cells in these two regions. In this review, recent research into the endosteal/vascular cell types and signals regulating HSC behaviour are considered, together with the possibility of a single subcompartmentalised niche.

  17. BAFF activation of the ERK5 MAP kinase pathway regulates B cell survival.

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    Jacque, Emilie; Schweighoffer, Edina; Tybulewicz, Victor L J; Ley, Steven C

    2015-06-01

    B cell activating factor (BAFF) stimulation of the BAFF receptor (BAFF-R) is essential for the homeostatic survival of mature B cells. Earlier in vitro experiments with inhibitors that block MEK 1 and 2 suggested that activation of ERK 1 and 2 MAP kinases is required for BAFF-R to promote B cell survival. However, these inhibitors are now known to also inhibit MEK5, which activates the related MAP kinase ERK5. In the present study, we demonstrated that BAFF-induced B cell survival was actually independent of ERK1/2 activation but required ERK5 activation. Consistent with this, we showed that conditional deletion of ERK5 in B cells led to a pronounced global reduction in mature B2 B cell numbers, which correlated with impaired survival of ERK5-deficient B cells after BAFF stimulation. ERK5 was required for optimal BAFF up-regulation of Mcl1 and Bcl2a1, which are prosurvival members of the Bcl-2 family. However, ERK5 deficiency did not alter BAFF activation of the PI3-kinase-Akt or NF-κB signaling pathways, which are also important for BAFF to promote mature B cell survival. Our study reveals a critical role for the MEK5-ERK5 MAP kinase signaling pathway in BAFF-induced mature B cell survival and homeostatic maintenance of B2 cell numbers. © 2015 Jacque et al.

  18. From The Cover: Genome-wide RNA interference screen identifies previously undescribed regulators of polyglutamine aggregation

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    Nollen, Ellen A. A.; Garcia, Susana M.; van Haaften, Gijs; Kim, Soojin; Chavez, Alejandro; Morimoto, Richard I.; Plasterk, Ronald H. A.

    2004-04-01

    Protein misfolding and the formation of aggregates are increasingly recognized components of the pathology of human genetic disease and hallmarks of many neurodegenerative disorders. As exemplified by polyglutamine diseases, the propensity for protein misfolding is associated with the length of polyglutamine expansions and age-dependent changes in protein-folding homeostasis, suggesting a critical role for a protein homeostatic buffer. To identify the complement of protein factors that protects cells against the formation of protein aggregates, we tested transgenic Caenorhabditis elegans strains expressing polyglutamine expansion yellow fluorescent protein fusion proteins at the threshold length associated with the age-dependent appearance of protein aggregation. We used genome-wide RNA interference to identify genes that, when suppressed, resulted in the premature appearance of protein aggregates. Our screen identified 186 genes corresponding to five principal classes of polyglutamine regulators: genes involved in RNA metabolism, protein synthesis, protein folding, and protein degradation; and those involved in protein trafficking. We propose that each of these classes represents a molecular machine collectively comprising the protein homeostatic buffer that responds to the expression of damaged proteins to prevent their misfolding and aggregation. protein misfolding | neurodegenerative diseases

  19. Distinguishing Emotional Co-Regulation From Co-Dysregulation: An Investigation of Emotional Dynamics and Body-Weight in Romantic Couples

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    Reed, Rebecca G.; Barnard, Kobus; Butler, Emily A.

    2015-01-01

    Well-regulated emotions, both within people and between relationship partners, play a key role in facilitating health and well-being. The present study examined 39 heterosexual couples’ joint weight status (both partners are healthy-weight, both overweight, one healthy-weight and one overweight) as a predictor of two interpersonal emotional patterns during a discussion of their shared lifestyle choices. The first pattern, co-regulation, is one in which partners’ coupled emotions show a dampening pattern over time and ultimately return to homeostatic levels. The second, co-dysregulation, is one in which partners’ coupled emotions are amplified away from homeostatic balance. We demonstrate how a coupled linear oscillator (CLO) model (Butner, Amazeen, & Mulvey, 2005) can be used to distinguish co-regulation from co-dysregulation. As predicted, healthy-weight couples and mixed-weight couples in which the man was heavier than the woman displayed co-regulation, but overweight couples and mixed-weight couples in which the woman was heavier showed co-dysregulation. These results suggest that heterosexual couples in which the woman is overweight may face formidable co-regulatory challenges that could undermine both partners’ well-being. The results also demonstrate the importance of distinguishing between various interpersonal emotional dynamics for understanding connections between interpersonal emotions and health. PMID:25664951

  20. Basal forebrain thermoregulatory mechanism modulates auto-regulated sleep

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    Hruda N Mallick

    2012-06-01

    Full Text Available Regulation of body temperature and sleep are two physiological mechanisms that are vital for our survival. Interestingly neural structures implicated in both these functions are common. These areas include the medial preoptic area, the lateral preoptic area, the ventrolateral preoptic area, the median preoptic nucleus and the medial septum, which form part of the basal forebrain.When given a choice, rats prefer to stay at an ambient temperature of 270C, though the maximum sleep was observed when they were placed at 300C. Ambient temperature around 270C should be considered as the thermoneutral temperature for rats in all sleep studies. At this temperature the diurnal oscillations of sleep and body temperature are properly expressed. The warm sensitive neurons of the preoptic area mediate the increase in sleep at 300C. Promotion of sleep during the rise in ambient temperature from 270C to 300C, serve a thermoregulatory function. Autonomous thermoregulatory changes in core body temperature and skin temperature could act as an input signal to modulate neuronal activity in sleep-promoting brain areas. The studies presented here show that the neurons of the basal forebrain play a key role in regulating sleep. Basal forebrain thermoregulatory system is a part of the global homeostatic sleep regulatory mechanism, which is auto-regulated.

  1. Carbonic anhydrase 5 regulates acid-base homeostasis in zebrafish.

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    Ruben Postel

    Full Text Available The regulation of the acid-base balance in cells is essential for proper cellular homeostasis. Disturbed acid-base balance directly affects cellular physiology, which often results in various pathological conditions. In every living organism, the protein family of carbonic anhydrases regulate a broad variety of homeostatic processes. Here we describe the identification, mapping and cloning of a zebrafish carbonic anhydrase 5 (ca5 mutation, collapse of fins (cof, which causes initially a collapse of the medial fins followed by necrosis and rapid degeneration of the embryo. These phenotypical characteristics can be mimicked in wild-type embryos by acetazolamide treatment, suggesting that CA5 activity in zebrafish is essential for a proper development. In addition we show that CA5 regulates acid-base balance during embryonic development, since lowering the pH can compensate for the loss of CA5 activity. Identification of selective modulators of CA5 activity could have a major impact on the development of new therapeutics involved in the treatment of a variety of disorders.

  2. Dietary glucose regulates yeast consumption in adult Drosophila males

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    Sebastien eLebreton

    2014-12-01

    Full Text Available The adjustment of feeding behavior in response to hunger and satiety contributes to homeostatic regulation in animals. The fruit fly Drosophila melanogaster feeds on yeasts growing on overripe fruit, providing nutrients required for adult survival, reproduction and larval growth. Here, we present data on how the nutritional value of food affects subsequent yeast consumption in Drosophila adult males. After a period of starvation, flies showed intensive yeast consumption. In comparison, flies stopped feeding after having access to a nutritive cornmeal diet. Interestingly, dietary glucose was equally efficient as the complex cornmeal diet. In contrast, flies fed with sucralose, a non-metabolizable sweetener, behaved as if they were starved. The adipokinetic hormone and insulin-like peptides regulate metabolic processes in insects. We did not find any effect of the adipokinetic hormone pathway on this modulation. Instead, the insulin pathway was involved in these changes. Flies lacking the insulin receptor did not respond to nutrient deprivation by increasing yeast consumption. Together these results show the importance of insulin in the regulation of yeast consumption in response to starvation in adult D. melanogaster males.

  3. CC2D1A Regulates Human Intellectual and Social Function as well as NF-κB Signaling Homeostasis

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    Manzini, M. Chiara; Xiong, Lan; Shaheen, Ranad; Tambunan, Dimira E.; Di Costanzo, Stefania; Mitisalis, Vanessa; Tischfield, David J.; Cinquino, Antonella; Ghaziuddin, Mohammed; Christian, Mehtab; Jiang, Qin; Laurent, Sandra; Nanjiani, Zohair A.; Rasheed, Saima; Hill, R. Sean; Lizarraga, Sofia B.; Gleason, Danielle; Sabbagh, Diya; Salih, Mustafa A.; Alkuraya, Fowzan S.; Walsh, Christopher A.

    2015-01-01

    SUMMARY Autism spectrum disorder (ASD) and intellectual disability (ID) are often comorbid, but the extent to which they share common genetic causes remains controversial. Here, we present two autosomal-recessive “founder” mutations in the CC2D1A gene causing fully penetrant cognitive phenotypes, including mild-to-severe ID, ASD, as well as seizures, suggesting shared developmental mechanisms. CC2D1A regulates multiple intracellular signaling pathways, and we found its strongest effect to be on the transcription factor nuclear factor κB (NF-κB). Cc2d1a gain and loss of function both increase activation of NF-κB, revealing a critical role of Cc2d1a in homeostatic control of intra-cellular signaling. Cc2d1a knockdown in neurons reduces dendritic complexity and increases NF-κB activity, and the effects of Cc2d1a depletion can be rescued by inhibiting NF-κB activity. Homeostatic regulation of neuronal signaling pathways provides a mechanism whereby common founder mutations could manifest diverse symptoms in different patients. PMID:25066123

  4. CC2D1A Regulates Human Intellectual and Social Function as well as NF-κB Signaling Homeostasis

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    M. Chiara Manzini

    2014-08-01

    Full Text Available Autism spectrum disorder (ASD and intellectual disability (ID are often comorbid, but the extent to which they share common genetic causes remains controversial. Here, we present two autosomal-recessive “founder” mutations in the CC2D1A gene causing fully penetrant cognitive phenotypes, including mild-to-severe ID, ASD, as well as seizures, suggesting shared developmental mechanisms. CC2D1A regulates multiple intracellular signaling pathways, and we found its strongest effect to be on the transcription factor nuclear factor κB (NF-κB. Cc2d1a gain and loss of function both increase activation of NF-κB, revealing a critical role of Cc2d1a in homeostatic control of intracellular signaling. Cc2d1a knockdown in neurons reduces dendritic complexity and increases NF-κB activity, and the effects of Cc2d1a depletion can be rescued by inhibiting NF-κB activity. Homeostatic regulation of neuronal signaling pathways provides a mechanism whereby common founder mutations could manifest diverse symptoms in different patients.

  5. [Regulation of behavior in the period between the world wars: Robert Musil and Kurt Lewin].

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    Innerhofer, Roland; Rothe, Katja

    2010-12-01

    The paper attempts to reconstruct the proto-cybernetic concept of regulation which emerged in early 20th century both in biology and psychology, and was critically reflected in literature. The basic premise is that Kurt Lewin's field-theoretical psychology played a crucial role in the development of behavioral self-regulation concepts. The goal is to show (1) that Lewin's early experiments and theories were based on the idea of a dynamic process of self-regulation determined by the actors and their personal motivation and interaction, (2) that this concept of self-regulation functioned as a camouflage for power-strategies that aimed to regulate and optimize the economic production and social reproduction processes, (3) that in Robert Musil's fragmentary, 'fringing' novel The Man without Qualities the attempt to optimize the social and economic behavior and to establish a homeostatic state proved to be a complete failure. As a notable result, this 'literary test' of behavioral self-regulation revealed the violence and imbalance of power inherent in this concept of self-regulation and its practical implementation.

  6. The neuron-specific interleukin-1 receptor accessory protein is required for homeostatic sleep and sleep responses to influenza viral challenge in mice.

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    Davis, Christopher J; Dunbrasky, Danielle; Oonk, Marcella; Taishi, Ping; Opp, Mark R; Krueger, James M

    2015-07-01

    Interleukin-1β (IL1) is involved in sleep regulation and sleep responses induced by influenza virus. The IL1 receptor accessory protein (AcP) and an alternatively spliced isoform of AcP found primarily in neurons, AcPb, form part of the IL1 signaling complex. IL1-induced sleep responses depend on injection time. In rat cortex, both IL1 mRNA and AcPb mRNA peak at Zeitgeber Time (ZT) 0 then decline over the daylight hours. Sleep deprivation enhances cortical IL1 mRNA and AcPb mRNA levels, but not AcP mRNA. We used wild type (WT) and AcPb knockout (KO) mice and performed sleep deprivation between ZT10 and 20 or between ZT22 and 8 based on the time of day expression profiles of AcPb and IL1. We hypothesized that the magnitude of the responses to sleep loss would be strain- and time of day-dependent. In WT mice, NREMS and REMS rebounds occurred regardless of when they were deprived of sleep. In contrast, when AcPbKO mice were sleep deprived from ZT10 to 20 NREMS and REMS rebounds were absent. The AcPbKO mice expressed sleep rebound if sleep loss occurred from ZT22 to 8 although the NREMS responses were not as robust as those that occurred in WT mice. We also challenged mice with intranasal H1N1 influenza virus. WT mice exhibited the expected enhanced sleep responses. In contrast, the AcPbKO mice had less sleep after influenza challenge compared to their own baseline values and compared to WT mice. Body temperature and locomotor activity responses after viral challenge were lower and mortality was higher in AcPbKO than in WT mice. We conclude that neuron-specific AcPb plays a critical role in host defenses and sleep homeostasis. Published by Elsevier Inc.

  7. Dopaminergic role in regulating neurophysiological markers of sleep homeostasis in humans.

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    Holst, Sebastian C; Bersagliere, Alessia; Bachmann, Valérie; Berger, Wolfgang; Achermann, Peter; Landolt, Hans-Peter

    2014-01-08

    While dopamine affects fundamental brain processes such as movement control, emotional responses, addiction, and pain, the roles for this neurotransmitter in regulating wakefulness and sleep are incompletely understood. Genetically modified animal models with reduced dopamine clearance exhibit hypersensitivity to caffeine, reduced-responsiveness to modafinil, and increased homeostatic response to prolonged wakefulness when compared with wild-type animals. Here we studied sleep-wake regulation in humans and combined pharmacogenetic and neurophysiologic methods to analyze the effects of the 3'-UTR variable-number-tandem-repeat polymorphism of the gene (DAT1, SLC6A3) encoding dopamine transporter (DAT). Previous research demonstrated that healthy homozygous 10-repeat (10R/10R) allele carriers of this genetic variant have reduced striatal DAT protein expression when compared with 9-repeat (9R) allele carriers. Objective and subjective estimates of caffeine sensitivity were higher in 10R allele homozygotes than in carriers of the 9R allele. Moreover, caffeine and modafinil affected wakefulness-induced changes in functional bands (delta, sigma, beta) of rhythmic brain activity in wakefulness and sleep in a DAT1 genotype-dependent manner. Finally, the sleep deprivation-induced increase in well established neurophysiologic markers of sleep homeostasis, including slow-wave sleep, electroencephalographic slow-wave activity (0.5-4.5 Hz), and number of low-frequency (0.5-2.0 Hz) oscillations in non-rapid-eye-movement sleep, was significantly larger in the 10R/10R genotype than in the 9R allele carriers of DAT1. Together, the data suggest that the dopamine transporter contributes to homeostatic sleep-wake regulation in humans.

  8. A Quick-responsive DNA Nanotechnology Device for Bio-molecular Homeostasis Regulation.

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    Wu, Songlin; Wang, Pei; Xiao, Chen; Li, Zheng; Yang, Bing; Fu, Jieyang; Chen, Jing; Wan, Neng; Ma, Cong; Li, Maoteng; Yang, Xiangliang; Zhan, Yi

    2016-08-10

    Physiological processes such as metabolism, cell apoptosis and immune responses, must be strictly regulated to maintain their homeostasis and achieve their normal physiological functions. The speed with which bio-molecular homeostatic regulation occurs directly determines the ability of an organism to adapt to conditional changes. To produce a quick-responsive regulatory system that can be easily utilized for various types of homeostasis, a device called nano-fingers that facilitates the regulation of physiological processes was constructed using DNA origami nanotechnology. This nano-fingers device functioned in linked open and closed phases using two types of DNA tweezers, which were covalently coupled with aptamers that captured specific molecules when the tweezer arms were sufficiently close. Via this specific interaction mechanism, certain physiological processes could be simultaneously regulated from two directions by capturing one biofactor and releasing the other to enhance the regulatory capacity of the device. To validate the universal application of this device, regulation of the homeostasis of the blood coagulant thrombin was attempted using the nano-fingers device. It was successfully demonstrated that this nano-fingers device achieved coagulation buffering upon the input of fuel DNA. This nano-device could also be utilized to regulate the homeostasis of other types of bio-molecules.

  9. Modulation of SF1 Neuron Activity Coordinately Regulates Both Feeding Behavior and Associated Emotional States

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    Paulius Viskaitis

    2017-12-01

    Full Text Available Feeding requires the integration of homeostatic drives with emotional states relevant to food procurement in potentially hostile environments. The ventromedial hypothalamus (VMH regulates feeding and anxiety, but how these are controlled in a concerted manner remains unclear. Using pharmacogenetic, optogenetic, and calcium imaging approaches with a battery of behavioral assays, we demonstrate that VMH steroidogenic factor 1 (SF1 neurons constitute a nutritionally sensitive switch, modulating the competing motivations of feeding and avoidance of potentially dangerous environments. Acute alteration of SF1 neuronal activity alters food intake via changes in appetite and feeding-related behaviors, including locomotion, exploration, anxiety, and valence. In turn, intrinsic SF1 neuron activity is low during feeding and increases with both feeding termination and stress. Our findings identify SF1 neurons as a key part of the neurocircuitry that controls both feeding and related affective states, giving potential insights into the relationship between disordered eating and stress-associated psychological disorders in humans.

  10. Eye Absence Does Not Regulate Planarian Stem Cells during Eye Regeneration.

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    LoCascio, Samuel A; Lapan, Sylvain W; Reddien, Peter W

    2017-02-27

    Dividing cells called neoblasts contain pluripotent stem cells and drive planarian flatworm regeneration from diverse injuries. A long-standing question is whether neoblasts directly sense and respond to the identity of missing tissues during regeneration. We used the eye to investigate this question. Surprisingly, eye removal was neither sufficient nor necessary for neoblasts to increase eye progenitor production. Neoblasts normally increase eye progenitor production following decapitation, facilitating regeneration. Eye removal alone, however, did not induce this response. Eye regeneration following eye-specific resection resulted from homeostatic rates of eye progenitor production and less cell death in the regenerating eye. Conversely, large head injuries that left eyes intact increased eye progenitor production. Large injuries also non-specifically increased progenitor production for multiple uninjured tissues. We propose a model for eye regeneration in which eye tissue production by planarian stem cells is not directly regulated by the absence of the eye itself. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Adjustment of the Arabidopsis circadian oscillator by sugar signalling dictates the regulation of starch metabolism.

    Science.gov (United States)

    Seki, Motohide; Ohara, Takayuki; Hearn, Timothy J; Frank, Alexander; da Silva, Viviane C H; Caldana, Camila; Webb, Alex A R; Satake, Akiko

    2017-08-16

    Arabidopsis plants store part of the carbon fixed by photosynthesis as starch to sustain growth at night. Two competing hypotheses have been proposed to explain this diel starch turnover based on either the measurement of starch abundance with respect to circadian time, or the sensing of sugars to feedback to the circadian oscillator to dynamically adjust the timing of starch turnover. We report a phase oscillator model that permitted derivation of the ideal responses of the circadian regulation of starch breakdown to maintain sucrose homeostasis. Testing the model predictions using a sugar-unresponsive mutant of Arabidopsis demonstrated that the dynamics of starch turnover arise from the circadian clock measuring and responding to the rate of change of cellular sucrose. Our theory and experiments suggest that starch turnover is controlled by the circadian clock acting as a dynamic homeostat responding to sucrose signals to maintain carbon homeostasis.

  12. Metals on the move: zinc ions in cellular regulation and in the coordination dynamics of zinc proteins.

    Science.gov (United States)

    Maret, Wolfgang

    2011-06-01

    Homeostatic control maintains essential transition metal ions at characteristic cellular concentrations to support their physiological functions and to avoid adverse effects. Zinc is especially widely used as a catalytic or structural cofactor in about 3000 human zinc proteins. In addition, the homeostatic control of zinc in eukaryotic cells permits functions of zinc(II) ions in regulation and in paracrine and intracrine signaling. Zinc ions are released from proteins through ligand-centered reactions in zinc/thiolate coordination environments, and from stores in cellular organelles, where zinc transporters participate in zinc loading and release. Muffling reactions allow zinc ions to serve as signaling ions (second messengers) in the cytosol that is buffered to picomolar zinc ion concentrations at steady-state. Muffling includes zinc ion binding to metallothioneins, cellular translocations of metallothioneins, delivery of zinc ions to transporter proteins, and zinc ion fluxes through cellular membranes with the result of removing the additional zinc ions from the cytosol and restoring the steady-state. Targets of regulatory zinc ions are proteins with sites for transient zinc binding, such as membrane receptors, enzymes, protein-protein interactions, and sensor proteins that control gene expression. The generation, transmission, targets, and termination of zinc ion signals involve proteins that use coordination dynamics in the inner and outer ligand spheres to control metal ion association and dissociation. These new findings establish critically important functions of zinc ions and zinc metalloproteins in cellular control.

  13. Regulation of Food Intake, Energy Balance, and Body Fat Mass: Implications for the Pathogenesis and Treatment of Obesity

    Science.gov (United States)

    Guyenet, Stephan J.

    2012-01-01

    Context: Obesity has emerged as one of the leading medical challenges of the 21st century. The resistance of this disorder to effective, long-term treatment can be traced to the fact that body fat stores are subject to homeostatic regulation in obese individuals, just as in lean individuals. Because the growing obesity epidemic is linked to a substantial increase in daily energy intake, a key priority is to delineate how mechanisms governing food intake and body fat content are altered in an obesogenic environment. Evidence Acquisition: We considered all relevant published research and cited references that represented the highest quality evidence available. Where space permitted, primary references were cited. Evidence Synthesis: The increase of energy intake that has fueled the U.S. obesity epidemic is linked to greater availability of highly rewarding/palatable and energy-dense food. Obesity occurs in genetically susceptible individuals and involves the biological defense of an elevated body fat mass, which may result in part from interactions between brain reward and homeostatic circuits. Inflammatory signaling, accumulation of lipid metabolites, or other mechanisms that impair hypothalamic neurons may also contribute to the development of obesity and offer a plausible mechanism to explain the biological defense of elevated body fat mass. Conclusions: Despite steady research progress, mechanisms underlying the resistance to fat loss once obesity is established remain incompletely understood. Breakthroughs in this area may be required for the development of effective new obesity prevention and treatment strategies. PMID:22238401

  14. Laser homeostatics on delayed onset muscle soreness

    International Nuclear Information System (INIS)

    Liu, T C Y; Fu, D R; Liu, X G; Tian, Z X

    2011-01-01

    Delayed onset muscle soreness (DOMS) and its photobiomodulation were reviewed from the viewpoint of function-specific homeostasis (FSH) in this paper. FSH is a negative-feedback response of a biosystem to maintain the function-specific fluctuations inside the biosystem so that the function is perfectly performed. A stressor may destroy a FSH. A stress is a response of a biosystem to a stressor and may also be in stress-specific homeostasis (StSH). A low level light (LLL) is so defined that it has no effects on a function in its FSH or a stress in its StSH, but it modulate a function far from its FSH or a stress far from its StSH. For DOMS recovery, protein metabolism in the Z-line streaming muscular cell is the essential process, but the inflammation, pain and soreness are non-essential processes. For many DOMS phenomena, protein metabolism in the Z-line streaming muscular cell is in protein metabolism-specific homeostasis (PmSH) so that there are no effects of LLL although the inflammation can be inhibited and the pain can be relieved. An athlete or animal in the dysfunctional conditions such as blood flow restriction and exercise exhaustion is far from PmSH and the protein metabolism can be improved with LLL.

  15. Hydrostatic homeostatic effects during changing force environments.

    Science.gov (United States)

    Wood, E H

    1990-04-01

    The G tolerance of internal organs depends on how closely force environments in body cavities mimic an aqueous system. Hydrostatic gradients in peritoneal and pericardial cavities sustain venous return and uniform transmyocardial pressures so that normotensive arterial pressures at heart level persist during initial (about 7 s) sudden sustained exposures to Gz acceleration followed by a compensatory baroreceptor-mediated hypertension. Further, cerebrospinal fluid hydrostatics-mediated negative intracranial pressures sustain cerebral perfusion and cognition in spite of Gz-produced zero or near zero systolic pressures at head level. Differences in the approximately 0 and 1.0 specific gravities of intra-alveolar gases and surrounding blood and tissues, respectively, render lung anatomy and functions highly susceptible to the force environment. Hydrostatic gradients in dependent regions, simultaneously with small gradients in superior regions, appear to be nature's method for decreasing force environment-mediated regional ventilation and perfusion inequalities within the thorax.

  16. Resilience of honeybee colonies via common stomach: A model of self-regulation of foraging.

    Directory of Open Access Journals (Sweden)

    Thomas Schmickl

    Full Text Available We propose a new regulation mechanism based on the idea of the "common stomach" to explain several aspects of the resilience and homeostatic regulation of honeybee colonies. This mechanism exploits shared pools of substances (pollen, nectar, workers, brood that modulate recruitment, abandonment and allocation patterns at the colony-level and enable bees to perform several survival strategies to cope with difficult circumstances: Lack of proteins leads to reduced feeding of young brood, to early capping of old brood and to regaining of already spent proteins through brood cannibalism. We modeled this system by linear interaction terms and mass-action law. To test the predictive power of the model of this regulatory mechanism we compared our model predictions to experimental data of several studies. These comparisons show that the proposed regulation mechanism can explain a variety of colony level behaviors. Detailed analysis of the model revealed that these mechanisms could explain the resilience, stability and self-regulation observed in honeybee colonies. We found that manipulation of material flow and applying sudden perturbations to colony stocks are quickly compensated by a resulting counter-acting shift in task selection. Selective analysis of feedback loops allowed us to discriminate the importance of different feedback loops in self-regulation of honeybee colonies. We stress that a network of simple proximate mechanisms can explain significant colony-level abilities that can also be seen as ultimate reasoning of the evolutionary trajectory of honeybees.

  17. An optimized method for measuring hypocretin-1 peptide in the mouse brain reveals differential circadian regulation of hypocretin-1 levels rostral and caudal to the hypothalamus

    DEFF Research Database (Denmark)

    Justinussen, Jessica; Holm, A; Kornum, B R

    2015-01-01

    The hypocretin/orexin system regulates, among other things, sleep and energy homeostasis. The system is likely regulated by both homeostatic and circadian mechanisms. Little is known about local differences in the regulation of hypocretin activity. The aim of this study was to establish...... an optimized peptide quantification method for hypocretin-1 extracted from different mouse brain areas and use this method for investigating circadian fluctuations of hypocretin-1 levels in these areas. The results show that hypocretin-1 peptide can be extracted from small pieces of intact tissue......, with sufficient yield for measurements in a standard radioimmunoassay. Utilizing the optimized method, it was found that prepro-hypocretin mRNA and peptide show circadian fluctuations in the mouse brain. This study further demonstrates that the hypocretin-1 peptide level in the frontal brain peaks during dark...

  18. Future trends in regulation

    International Nuclear Information System (INIS)

    Remick, F.J.

    1993-01-01

    This report presents a discussion on the future of nuclear regulations and what regulators should strive for. The following 6 trends are described: the regulatory presence around the world will grow; there is a trend towards giving the regulator greater independence; there is a trend toward greater self-regulation by the industry; less prescriptive regulation; regulators may be converging no a quantitative risk goal; increasing recognition of the importance of stability in the regulator

  19. Metabolic regulation of macrophages in tissues

    NARCIS (Netherlands)

    van den Bossche, Jan; Saraber, Doina L.

    2018-01-01

    Macrophages are innate immune cells that provide host defense and have tissue-specific roles in the maintenance of organ homeostasis and integrity. In most cases macrophages keep us healthy but when their balanced response to damage or homeostatic signals is perturbed, they can drive chronic

  20. Inflammasome-independent regulation of IL-1-family cytokines.

    Science.gov (United States)

    Netea, Mihai G; van de Veerdonk, Frank L; van der Meer, Jos W M; Dinarello, Charles A; Joosten, Leo A B

    2015-01-01

    Induction, production, and release of proinflammatory cytokines are essential steps to establish an effective host defense. Cytokines of the interleukin-1 (IL-1) family induce inflammation and regulate T lymphocyte responses while also displaying homeostatic and metabolic activities. With the exception of the IL-1 receptor antagonist, all IL-1 family cytokines lack a signal peptide and require proteolytic processing into an active molecule. One such unique protease is caspase-1, which is activated by protein platforms called the inflammasomes. However, increasing evidence suggests that inflammasomes and caspase-1 are not the only mechanism for processing IL-1 cytokines. IL-1 cytokines are often released as precursors and require extracellular processing for activity. Here we review the inflammasome-independent enzymatic processes that are able to activate IL-1 cytokines, paying special attention to neutrophil-derived serine proteases, which subsequently induce inflammation and modulate host defense. The inflammasome-independent processing of IL-1 cytokines has important consequences for understanding inflammatory diseases, and it impacts the design of IL-1-based modulatory therapies.

  1. Retino-hypothalamic regulation of light-induced murine sleep

    Directory of Open Access Journals (Sweden)

    Fanuel eMuindi

    2014-08-01

    Full Text Available The temporal organization of sleep is regulated by an interaction between the circadian clock and homeostatic processes. Light indirectly modulates sleep through its ability to phase shift and entrain the circadian clock. Light can also exert a direct, circadian-independent effect on sleep. For example, acute exposure to light promotes sleep in nocturnal animals and wake in diurnal animals. The mechanisms whereby light directly influences sleep and arousal are not well understood. In this review, we discuss the direct effect of light on sleep at the level of the retina and hypothalamus in rodents. We review murine data from recent publications showing the roles of rod-, cone- and melanopsin-based photoreception on the initiation and maintenance of light-induced sleep. We also present hypotheses about hypothalamic mechanisms that have been advanced to explain the acute control of sleep by light. Specifically, we review recent studies assessing the roles of the ventrolateral preoptic area and the suprachiasmatic nucleus. We also discuss how light might differentially promote sleep and arousal in nocturnal and diurnal animals respectively. Lastly, we suggest new avenues for research on this topic which is still in its early stages.

  2. Regulation of NKT Cell Localization in Homeostasis and Infection

    Science.gov (United States)

    Slauenwhite, Drew; Johnston, Brent

    2015-01-01

    Natural killer T (NKT) cells are a specialized subset of T lymphocytes that regulate immune responses in the context of autoimmunity, cancer, and microbial infection. Lipid antigens derived from bacteria, parasites, and fungi can be presented by CD1d molecules and recognized by the canonical T cell receptors on NKT cells. Alternatively, NKT cells can be activated through recognition of self-lipids and/or pro-inflammatory cytokines generated during infection. Unlike conventional T cells, only a small subset of NKT cells traffic through the lymph nodes under homeostatic conditions, with the largest NKT cell populations localizing to the liver, lungs, spleen, and bone marrow. This is thought to be mediated by differences in chemokine receptor expression profiles. However, the impact of infection on the tissue localization and function of NKT remains largely unstudied. This review focuses on the mechanisms mediating the establishment of peripheral NKT cell populations during homeostasis and how tissue localization of NKT cells is affected during infection. PMID:26074921

  3. Regulation of NKT Cell Localization in Homeostasis and Infection.

    Science.gov (United States)

    Slauenwhite, Drew; Johnston, Brent

    2015-01-01

    Natural killer T (NKT) cells are a specialized subset of T lymphocytes that regulate immune responses in the context of autoimmunity, cancer, and microbial infection. Lipid antigens derived from bacteria, parasites, and fungi can be presented by CD1d molecules and recognized by the canonical T cell receptors on NKT cells. Alternatively, NKT cells can be activated through recognition of self-lipids and/or pro-inflammatory cytokines generated during infection. Unlike conventional T cells, only a small subset of NKT cells traffic through the lymph nodes under homeostatic conditions, with the largest NKT cell populations localizing to the liver, lungs, spleen, and bone marrow. This is thought to be mediated by differences in chemokine receptor expression profiles. However, the impact of infection on the tissue localization and function of NKT remains largely unstudied. This review focuses on the mechanisms mediating the establishment of peripheral NKT cell populations during homeostasis and how tissue localization of NKT cells is affected during infection.

  4. The E2F-DP1 Transcription Factor Complex Regulates Centriole Duplication in Caenorhabditis elegans

    Directory of Open Access Journals (Sweden)

    Jacqueline G. Miller

    2016-03-01

    Full Text Available Centrioles play critical roles in the organization of microtubule-based structures, from the mitotic spindle to cilia and flagella. In order to properly execute their various functions, centrioles are subjected to stringent copy number control. Central to this control mechanism is a precise duplication event that takes place during S phase of the cell cycle and involves the assembly of a single daughter centriole in association with each mother centriole . Recent studies have revealed that posttranslational control of the master regulator Plk4/ZYG-1 kinase and its downstream effector SAS-6 is key to ensuring production of a single daughter centriole. In contrast, relatively little is known about how centriole duplication is regulated at a transcriptional level. Here we show that the transcription factor complex EFL-1-DPL-1 both positively and negatively controls centriole duplication in the Caenorhabditis elegans embryo. Specifically, we find that down regulation of EFL-1-DPL-1 can restore centriole duplication in a zyg-1 hypomorphic mutant and that suppression of the zyg-1 mutant phenotype is accompanied by an increase in SAS-6 protein levels. Further, we find evidence that EFL-1-DPL-1 promotes the transcription of zyg-1 and other centriole duplication genes. Our results provide evidence that in a single tissue type, EFL-1-DPL-1 sets the balance between positive and negative regulators of centriole assembly and thus may be part of a homeostatic mechanism that governs centriole assembly.

  5. HES1 Is a Master Regulator of Glucocorticoid Receptor-Dependent Gene Expression

    Science.gov (United States)

    Revollo, Javier R.; Oakley, Robert H.; Lu, Nick Z.; Kadmiel, Mahita; Gandhavadi, Maheer; Cidlowski, John A.

    2014-01-01

    Hairy and enhancer of split-1 (HES1) is a basic helix-loop-helix transcription factor that is a key regulator of development and organogenesis. However, little is known about the role of HES1 after birth. Glucocorticoids, primary stress hormones that are essential for life, regulate numerous homeostatic processes that permit vertebrates to cope with physiological challenges. The molecular actions of glucocorticoids are mediated by glucocorticoid receptor-dependent regulation of nearly 25% of the genome. We now establish a genome wide molecular link between HES1 and glucocorticoid receptors that controls the ability of cells and animals to respond to stress. Glucocorticoid signaling rapidly and robustly silenced HES1 expression. This glucocorticoid-dependent repression of HES1 was necessary for the glucocorticoid receptor to regulate many of its target genes. Mice with conditional knockout of HES1 in the liver exhibited an expanded glucocorticoid receptor signaling profile and aberrant metabolic phenotype. Our results indicate that HES1 acts as a master repressor, the silencing of which is required for proper glucocorticoid signaling. PMID:24300895

  6. Diet-dependent, microbiota-independent regulation of IL-10-producing lamina propria macrophages in the small intestine.

    Science.gov (United States)

    Ochi, Takanori; Feng, Yongjia; Kitamoto, Sho; Nagao-Kitamoto, Hiroko; Kuffa, Peter; Atarashi, Koji; Honda, Kenya; Teitelbaum, Daniel H; Kamada, Nobuhiko

    2016-06-15

    Intestinal resident macrophages (Mϕs) regulate gastrointestinal homeostasis via production of an anti-inflammatory cytokine interleukin (IL)-10. Although a constant replenishment by circulating monocytes is required to maintain the pool of resident Mϕs in the colonic mucosa, the homeostatic regulation of Mϕ in the small intestine (SI) remains unclear. Here, we demonstrate that direct stimulation by dietary amino acids regulates the homeostasis of intestinal Mϕs in the SI. Mice that received total parenteral nutrition (TPN), which deprives the animals of enteral nutrients, displayed a significant decrease of IL-10-producing Mϕs in the SI, whereas the IL-10-producing CD4(+) T cells remained intact. Likewise, enteral nutrient deprivation selectively affected the monocyte-derived F4/80(+) Mϕ population, but not non-monocytic precursor-derived CD103(+) dendritic cells. Notably, in contrast to colonic Mϕs, the replenishment of SI Mϕs and their IL-10 production were not regulated by the gut microbiota. Rather, SI Mϕs were directly regulated by dietary amino acids. Collectively, our study highlights the diet-dependent, microbiota-independent regulation of IL-10-producing resident Mϕs in the SI.

  7. Two research paths for probing the roles of oxygen in metabolic regulation

    Directory of Open Access Journals (Sweden)

    Hochachka P.W.

    1999-01-01

    Full Text Available Tissues such as skeletal and cardiac muscles must sustain very large-scale changes in ATP turnover rate during equally large changes in work. In many skeletal muscles these changes can exceed 100-fold. Examination of a number of cell and whole-organism level systems identifies ATP concentration as a key parameter of the interior milieu that is nearly universally 'homeostatic'; it is common to observe no change in ATP concentration even while change in its turnover rate can increase or decrease by two orders of magnitude or more. A large number of other intermediates of cellular metabolism are also regulated within narrow concentration ranges, but none seemingly as precisely as is [ATP]. In fact, the only other metabolite in aerobic energy metabolism that is seemingly as 'homeostatic' is oxygen - at least in working muscles where myoglobin serves to buffer oxygen concentrations at stable and constant values at work rates up to the aerobic maximum. In contrast to intracellular oxygen concentration, a 1:1 relationship between oxygen delivery and metabolic rate is observed over biologically realistic and large-magnitude changes in work. The central regulatory question is how the oxygen delivery signal is transmitted to the intracellular metabolic machinery. Traditional explanations assume diffusion as the dominant mechanism, while proponents of an ultrastructurally dominated view of the cell assume an intracellular perfusion system to account for the data which have been most perplexing to metabolic biochemistry so far: the striking lack of correlation between changes in pathway reaction rates and changes in concentrations of pathway substrates, including oxygen and pathway intermediates.

  8. Excitatory transmission onto AgRP neurons is regulated by cJun NH2-terminal kinase 3 in response to metabolic stress.

    Science.gov (United States)

    Vernia, Santiago; Morel, Caroline; Madara, Joseph C; Cavanagh-Kyros, Julie; Barrett, Tamera; Chase, Kathryn; Kennedy, Norman J; Jung, Dae Young; Kim, Jason K; Aronin, Neil; Flavell, Richard A; Lowell, Bradford B; Davis, Roger J

    2016-02-24

    The cJun NH2-terminal kinase (JNK) signaling pathway is implicated in the response to metabolic stress. Indeed, it is established that the ubiquitously expressed JNK1 and JNK2 isoforms regulate energy expenditure and insulin resistance. However, the role of the neuron-specific isoform JNK3 is unclear. Here we demonstrate that JNK3 deficiency causes hyperphagia selectively in high fat diet (HFD)-fed mice. JNK3 deficiency in neurons that express the leptin receptor LEPRb was sufficient to cause HFD-dependent hyperphagia. Studies of sub-groups of leptin-responsive neurons demonstrated that JNK3 deficiency in AgRP neurons, but not POMC neurons, was sufficient to cause the hyperphagic response. These effects of JNK3 deficiency were associated with enhanced excitatory signaling by AgRP neurons in HFD-fed mice. JNK3 therefore provides a mechanism that contributes to homeostatic regulation of energy balance in response to metabolic stress.

  9. The frequency of double-positive thymocytes expressing an αβ TCR clonotype regulates peripheral CD4 T cell compartment homeostasis

    Science.gov (United States)

    Reed, Amy J; Zarrabi, Yasaman; Perate, Alison L; Jeganathan, Arjun; Naji, Ali; Noorchashm, Hooman

    2005-01-01

    The present study aimed to determine whether the frequency of double positive (DP) thymocytes expressing αβ T-cell receptor (TCR) clonotypes at the time of selection regulates peripheral CD4 T-cell compartment size. Scid recipients were inoculated with various ratios of TCR Cα0/0 and wild-type bone marrow (BM) stem cells. Increasing the frequency of TCR Cα0/0 thymocytes at steady-state introduced a graded decrease in the maturation probability of the total DP thymocyte pool. At 12–14 weeks following BM inoculation, the frequency of TCR Cα0/0 DP thymocytes was inversely correlated with that of CD4 single positive (SP) thymocytes. Notwithstanding, a decreased frequency of wild-type DP thymocytes led to a marked increase in their transit efficiency from the DP to SP compartments. The frequency-dependent increase in thymocyte transit efficiency was associated with a CD4 SP cell surface phenotype indicative of increased antigenic experience. Importantly, the frequency of DP thymocytes capable of expressing TCR clonotypes dictated the steady-state size of the peripheral CD4 T cell compartment and its potential for homeostatic proliferation. Collectively, these results indicate that the efficiency of DP to CD4 SP transit is a frequency dependent process, which determines (1) the steady-state size of the peripheral T cell compartment and (2) the threshold for homeostatic expansion of peripheral CD4 T cells. PMID:16236130

  10. Behavior control in the sensorimotor loop with short-term synaptic dynamics induced by self-regulating neurons

    Directory of Open Access Journals (Sweden)

    Hazem eToutounji

    2014-05-01

    Full Text Available The behavior and skills of living systems depend on the distributed control provided by specialized and highly recurrent neural networks. Learning and memory in these systems is mediated by a set of adaptation mechanisms, known collectively as neuronal plasticity. Translating principles of recurrent neural control and plasticity to artificial agents has seen major strides, but is usually hampered by the complex interactions between the agent's body and its environment. One of the important standing issues is for the agent to support multiple stable states of behavior, so that its behavioral repertoire matches the requirements imposed by these interactions. The agent also must have the capacity to switch between these states in time scales that are comparable to those by which sensory stimulation varies. Achieving this requires a mechanism of short-term memory that allows the neurocontroller to keep track of the recent history of its input, which finds its biological counterpart in short-term synaptic plasticity. This issue is approached here by deriving synaptic dynamics in recurrent neural networks. Neurons are introduced as self-regulating units with a rich repertoire of dynamics. They exhibit homeostatic properties for certain parameter domains, which result in a set of stable states and the required short-term memory. They can also operate as oscillators, which allow them to surpass the level of activity imposed by their homeostatic operation conditions. Neural systems endowed with the derived synaptic dynamics can be utilized for the neural behavior control of autonomous mobile agents. The resulting behavior depends also on the underlying network structure, which is either engineered, or developed by evolutionary techniques. The effectiveness of these self-regulating units is demonstrated by controlling locomotion of a hexapod with eighteen degrees of freedom, and obstacle-avoidance of a wheel-driven robot.

  11. Primed T cell responses to chemokines are regulated by the immunoglobulin-like molecule CD31.

    Directory of Open Access Journals (Sweden)

    Madhav Kishore

    Full Text Available CD31, an immunoglobulin-like molecule expressed by leukocytes and endothelial cells, is thought to contribute to the physiological regulation T cell homeostasis due to the presence of two immunotyrosine-based inhibitory motifs in its cytoplasmic tail. Indeed, loss of CD31 expression leads to uncontrolled T cell-mediated inflammation in a variety of experimental models of disease and certain CD31 polymorphisms correlate with increased disease severity in human graft-versus-host disease and atherosclerosis. The molecular mechanisms underlying CD31-mediated regulation of T cell responses have not yet been clarified. We here show that CD31-mediated signals attenuate T cell chemokinesis both in vitro and in vivo. This effect selectively affects activated/memory T lymphocytes, in which CD31 is clustered on the cell membrane where it segregates to the leading edge. We provide evidence that this molecular segregation, which does not occur in naïve T lymphocytes, might lead to cis-CD31 engagement on the same membrane and subsequent interference with the chemokine-induced PI3K/Akt signalling pathway. We propose that CD31-mediated modulation of memory T cell chemokinesis is a key mechanism by which this molecule contributes to the homeostatic regulation of effector T cell immunity.

  12. Transient receptor potential melastatin 8 (TRPM8) channels are involved in body temperature regulation.

    Science.gov (United States)

    Gavva, Narender R; Davis, Carl; Lehto, Sonya G; Rao, Sara; Wang, Weiya; Zhu, Dawn X D

    2012-05-09

    Transient receptor potential cation channel subfamily M member 8 (TRPM8) is activated by cold temperature in vitro and has been demonstrated to act as a 'cold temperature sensor' in vivo. Although it is known that agonists of this 'cold temperature sensor', such as menthol and icilin, cause a transient increase in body temperature (Tb), it is not known if TRPM8 plays a role in Tb regulation. Since TRPM8 has been considered as a potential target for chronic pain therapeutics, we have investigated the role of TRPM8 in Tb regulation. We characterized five chemically distinct compounds (AMG0635, AMG2850, AMG8788, AMG9678, and Compound 496) as potent and selective antagonists of TRPM8 and tested their effects on Tb in rats and mice implanted with radiotelemetry probes. All five antagonists used in the study caused a transient decrease in Tb (maximum decrease of 0.98°C). Since thermoregulation is a homeostatic process that maintains Tb about 37°C, we further evaluated whether repeated administration of an antagonist attenuated the decrease in Tb. Indeed, repeated daily administration of AMG9678 for four consecutive days showed a reduction in the magnitude of the Tb decrease Day 2 onwards. The data reported here demonstrate that TRPM8 channels play a role in Tb regulation. Further, a reduction of magnitude in Tb decrease after repeated dosing of an antagonist suggests that TRPM8's role in Tb maintenance may not pose an issue for developing TRPM8 antagonists as therapeutics.

  13. Bi-directional astrocytic regulation of neuronal activity within a network

    Directory of Open Access Journals (Sweden)

    Susan Yu Gordleeva

    2012-11-01

    Full Text Available The concept of a tripartite synapse holds that astrocytes can affect both the pre- and postsynaptic compartments through the Ca2+-dependent release of gliotransmitters. Because astrocytic Ca2+ transients usually last for a few seconds, we assumed that astrocytic regulation of synaptic transmission may also occur on the scale of seconds. Here, we considered the basic physiological functions of tripartite synapses and investigated astrocytic regulation at the level of neural network activity. The firing dynamics of individual neurons in a spontaneous firing network was described by the Hodgkin-Huxley model. The neurons received excitatory synaptic input driven by the Poisson spike train with variable frequency. The mean field concentration of the released neurotransmitter was used to describe the presynaptic dynamics. The amplitudes of the excitatory postsynaptic currents (PSCs obeyed the gamma distribution law. In our model, astrocytes depressed the presynaptic release and enhanced the postsynaptic currents. As a result, low frequency synaptic input was suppressed while high frequency input was amplified. The analysis of the neuron spiking frequency as an indicator of network activity revealed that tripartite synaptic transmission dramatically changed the local network operation compared to bipartite synapses. Specifically, the astrocytes supported homeostatic regulation of the network activity by increasing or decreasing firing of the neurons. Thus, the astrocyte activation may modulate a transition of neural network into bistable regime of activity with two stable firing levels and spontaneous transitions between them.

  14. Bi-directional astrocytic regulation of neuronal activity within a network.

    Science.gov (United States)

    Gordleeva, S Yu; Stasenko, S V; Semyanov, A V; Dityatev, A E; Kazantsev, V B

    2012-01-01

    The concept of a tripartite synapse holds that astrocytes can affect both the pre- and post-synaptic compartments through the Ca(2+)-dependent release of gliotransmitters. Because astrocytic Ca(2+) transients usually last for a few seconds, we assumed that astrocytic regulation of synaptic transmission may also occur on the scale of seconds. Here, we considered the basic physiological functions of tripartite synapses and investigated astrocytic regulation at the level of neural network activity. The firing dynamics of individual neurons in a spontaneous firing network was described by the Hodgkin-Huxley model. The neurons received excitatory synaptic input driven by the Poisson spike train with variable frequency. The mean field concentration of the released neurotransmitter was used to describe the presynaptic dynamics. The amplitudes of the excitatory postsynaptic currents (PSCs) obeyed the gamma distribution law. In our model, astrocytes depressed the presynaptic release and enhanced the PSCs. As a result, low frequency synaptic input was suppressed while high frequency input was amplified. The analysis of the neuron spiking frequency as an indicator of network activity revealed that tripartite synaptic transmission dramatically changed the local network operation compared to bipartite synapses. Specifically, the astrocytes supported homeostatic regulation of the network activity by increasing or decreasing firing of the neurons. Thus, the astrocyte activation may modulate a transition of neural network into bistable regime of activity with two stable firing levels and spontaneous transitions between them.

  15. Cigarette smoking and brain regulation of energy homeostasis.

    Science.gov (United States)

    Chen, Hui; Saad, Sonia; Sandow, Shaun L; Bertrand, Paul P

    2012-01-01

    Cigarette smoking is an addictive behavior, and is the primary cause of cardiovascular and pulmonary disease, and cancer (among other diseases). Cigarette smoke contains thousands of components that may affect caloric intake and energy expenditure, although nicotine is the major addictive substance present, and has the best described actions. Nicotine exposure from cigarette smoke can change brain feeding regulation to reduce appetite via both energy homeostatic and reward mechanisms, causing a negative energy state which is characterized by reduced energy intake and increased energy expenditure that are linked to low body weight. These findings have led to the public perception that smoking is associated with weight loss. However, its effects at reducing abdominal fat mass (a predisposing factor for glucose intolerance and insulin resistance) are marginal, and its promotion of lean body mass loss in animal studies suggests a limited potential for treatment in obesity. Smoking during pregnancy puts pressure on the mother's metabolic system and is a significant contributor to adverse pregnancy outcomes. Smoking is a predictor of future risk for respiratory dysfunction, social behavioral problems, cardiovascular disease, obesity, and type-2 diabetes. Catch-up growth is normally observed in children exposed to intrauterine smoke, which has been linked to subsequent childhood obesity. Nicotine can have a profound impact on the developing fetal brain, via its ability to rapidly and fully pass the placenta. In animal studies this has been linked with abnormal hypothalamic gene expression of appetite regulators such as downregulation of NPY and POMC in the arcuate nucleus of the hypothalamus. Maternal smoking or nicotine replacement leads to unhealthy eating habits (such as junk food addiction) and other behavioral disorders in the offspring.

  16. Cigarette smoking and brain regulation of energy homeostasis

    Directory of Open Access Journals (Sweden)

    Hui eChen

    2012-07-01

    Full Text Available Cigarette smoking is an addictive behaviour, and is the primary cause of cardiovascular and pulmonary disease, and cancer (among other diseases. Cigarette smoke contains thousands of components that may affect caloric intake and energy expenditure, although nicotine is the major addictive substance present, and has the best described actions. Nicotine exposure from cigarette smoke can change brain feeding regulation to reduce appetite via both energy homeostatic and reward mechanisms, causing a negative energy state which is characterized by reduced energy intake and increased energy expenditure that are linked to low body weight. These findings have led to the public perception that smoking is associated with weight loss. However, its effects at reducing abdominal fat mass (a predisposing factor for glucose intolerance and insulin resistance are marginal, and its promotion of lean body mass loss in animal studies suggests a limited potential for treatment in obesity. Smoking during pregnancy puts pressure on the mother’s metabolic system and is a significant contributor to adverse pregnancy outcomes. Smoking is a predictor of future risk for respiratory dysfunction, social behavioral problems, cardiovascular disease, obesity and type-2 diabetes. Catch-up growth is normally observed in children exposed to intrauterine smoke, which has been linked to subsequent childhood obesity. Nicotine can have a profound impact on the developing fetal brain, via its ability to rapidly and fully pass the placenta. In animal studies this has been linked with abnormal hypothalamic gene expression of appetite regulators such as downregulation of NPY and POMC in the arcuate nucleus of the hypothalamus. Maternal smoking or nicotine replacement leads to unhealthy eating habits (such as junk food addiction and other behavioral disorders in the offspring.

  17. Regulating through leverage: Civil regulation in China

    NARCIS (Netherlands)

    Fürst, K.

    2016-01-01

    The overarching goal of this study is to examine the efforts of Chinese NGOs to prevent and/or control industrial pollution risks and then use the findings of this research to study the nature of civil regulation in, and beyond, China’s authoritarian setting. It first argues that 'regulation through

  18. Regulating fisheries under uncertainty

    DEFF Research Database (Denmark)

    Hansen, Lars Gårn; Jensen, Frank

    2017-01-01

    the effects of these uncertainties into a single welfare measure for comparing tax and quota regulation. It is shown that quotas are always preferred to fees when structural economic uncertainty dominates. Since most regulators are subject to this kind of uncertainty, this result is a potentially important......Regulator uncertainty is decisive for whether price or quantity regulation maximizes welfare in fisheries. In this paper, we develop a model of fisheries regulation that includes ecological uncertainly, variable economic uncertainty as well as structural economic uncertainty. We aggregate...... qualification of the pro-price regulation message dominating the fisheries economics literature. We also believe that the model of a fishery developed in this paper could be applied to the regulation of other renewable resources where regulators are subject to uncertainty either directly or with some...

  19. Ocean Dumping Control Regulations

    International Nuclear Information System (INIS)

    1978-01-01

    These Regulations were made further to the Ocean Dumping Control Act which provides for restrictions in dumping operations. The Regulations contain model applications for permits to dump or load a series of materials. (NEA)

  20. Trout Stream Special Regulations

    Data.gov (United States)

    Minnesota Department of Natural Resources — This layer shows Minnesota trout streams that have a special regulation as described in the 2006 Minnesota Fishing Regulations. Road crossings were determined using...

  1. Role of the bicarbonate-responsive soluble adenylyl cyclase in pH sensing and metabolic regulation

    Directory of Open Access Journals (Sweden)

    Jung-Chin eChang

    2014-02-01

    Full Text Available The evolutionarily conserved soluble adenylyl cyclase (sAC, adcy10 was recently identified as a unique source of cAMP in the cytoplasm and the nucleus. Its activity is regulated by bicarbonate and fine-tuned by calcium. As such, and in conjunction with carbonic anhydrase (CA, sAC constitutes an HCO3-/CO¬2/pH sensor. In both alpha-intercalated cells of the collecting duct and the clear cells of the epididymis, sAC is expressed at significant level and involved in pH homeostasis via apical recruitment of vacuolar H+-ATPase (VHA in a PKA-dependent manner. In addition to maintenance of pH homeostasis, sAC is also involved in metabolic regulation such as coupling of Krebs cycle to oxidative phosphorylation via bicarbonate/CO2 sensing. Additionally, sAC also regulates CFTR channel and plays an important role in regulation of barrier function and apoptosis. These observations suggest that sAC, via bicarbonate-sensing, plays an important role in maintaining homeostatic status of cells against fluctuations in their microenvironment.

  2. Radiation Control Regulation 1993

    International Nuclear Information System (INIS)

    1993-01-01

    This Regulation (No. 434-1993) was made in pursuance of the Radiation Control Act 1990 and replaces the Active Substances Regulations 1959 repealed by the Act. It entered into force on 1 September 1993. The Regulation specifies that the technical radiation protection definitions have the same meaning as in the 1990 recommendations. The Regulation provides for the licensing of persons to use radioactive substances and radiation apparatus. It prescribes activities which may only be carried out by an accredited radiation expert and regulates the use of radiation apparatus and radioactive substances as well as the disposal and transport of radiation apparatus and radioactive substances. (NEA)

  3. Load regulating expansion fixture

    International Nuclear Information System (INIS)

    Wagner, L.M.; Strum, M.J.

    1998-01-01

    A free standing self contained device for bonding ultra thin metallic films, such as 0.001 inch beryllium foils is disclosed. The device will regulate to a predetermined load for solid state bonding when heated to a bonding temperature. The device includes a load regulating feature, whereby the expansion stresses generated for bonding are regulated and self adjusting. The load regulator comprises a pair of friction isolators with a plurality of annealed copper members located there between. The device, with the load regulator, will adjust to and maintain a stress level needed to successfully and economically complete a leak tight bond without damaging thin foils or other delicate components. 1 fig

  4. Microglial Phagocytosis and Its Regulation: A Therapeutic Target in Parkinson’s Disease?

    Directory of Open Access Journals (Sweden)

    Elzbieta Janda

    2018-04-01

    Full Text Available The role of phagocytosis in the neuroprotective function of microglia has been appreciated for a long time, but only more recently a dysregulation of this process has been recognized in Parkinson’s disease (PD. Indeed, microglia play several critical roles in central nervous system (CNS, such as clearance of dying neurons and pathogens as well as immunomodulation, and to fulfill these complex tasks they engage distinct phenotypes. Regulation of phenotypic plasticity and phagocytosis in microglia can be impaired by defects in molecular machinery regulating critical homeostatic mechanisms, including autophagy. Here, we briefly summarize current knowledge on molecular mechanisms of microglia phagocytosis, and the neuro-pathological role of microglia in PD. Then we focus more in detail on the possible functional role of microglial phagocytosis in the pathogenesis and progression of PD. Evidence in support of either a beneficial or deleterious role of phagocytosis in dopaminergic degeneration is reported. Altered expression of target-recognizing receptors and lysosomal receptor CD68, as well as the emerging determinant role of α-synuclein (α-SYN in phagocytic function is discussed. We finally discuss the rationale to consider phagocytic processes as a therapeutic target to prevent or slow down dopaminergic degeneration.

  5. Elevated serum levels of interferon-regulated chemokines are biomarkers for active human systemic lupus erythematosus.

    Directory of Open Access Journals (Sweden)

    Jason W Bauer

    2006-12-01

    Full Text Available Systemic lupus erythematosus (SLE is a serious systemic autoimmune disorder that affects multiple organ systems and is characterized by unpredictable flares of disease. Recent evidence indicates a role for type I interferon (IFN in SLE pathogenesis; however, the downstream effects of IFN pathway activation are not well understood. Here we test the hypothesis that type I IFN-regulated proteins are present in the serum of SLE patients and correlate with disease activity.We performed a comprehensive survey of the serologic proteome in human SLE and identified dysregulated levels of 30 cytokines, chemokines, growth factors, and soluble receptors. Particularly striking was the highly coordinated up-regulation of 12 inflammatory and/or homeostatic chemokines, molecules that direct the movement of leukocytes in the body. Most of the identified chemokines were inducible by type I IFN, and their levels correlated strongly with clinical and laboratory measures of disease activity.These data suggest that severely disrupted chemokine gradients may contribute to the systemic autoimmunity observed in human SLE. Furthermore, the levels of serum chemokines may serve as convenient biomarkers for disease activity in lupus.

  6. Activity-dependent regulation of the cytochrome c promoter in individual hippocampal neurons

    Directory of Open Access Journals (Sweden)

    Jary Y Delgado

    2012-03-01

    Full Text Available The proximal enhancer of the cytochrome c gene (Cycs contains binding sites for both cAMP response element binding proteins (CREB and Nuclear Respiratory Factor 1 (NRF1. To investigate how neuronal activity regulates this enhancer region, a lentivirus was constructed in which a short-lived green fluorescent protein (GFP was placed under the transcriptional control of the Cycs proximal enhancer. Primary hippocampal neurons were infected, and the synaptic strengths of individual neurons were measured by whole cell patch clamping. On average the amplitude of miniature postsynaptic currents (mEPSCs was higher in brighter GFP+ neurons, while mEPSC frequencies were not significantly different. Inhibiting neural activity by applying a GABAA receptor agonist increased GFP expression in most neurons, which persisted after homeostatic synaptic scaling as evidenced by a decrease in the amplitude and frequency of mEPSCs. Removing the CREB binding sites revealed that calcium influx through L-type channels and NMDA receptors, and ERK1/2 activation played a role in NRF1-mediated transcription. CREB and NRF1 therefore combine to regulate transcription of Cycs in response to changing neural activity.

  7. Cell-Autonomous Regulation of Mu-Opioid Receptor Recycling by Substance P

    Directory of Open Access Journals (Sweden)

    Shanna L. Bowman

    2015-03-01

    Full Text Available How neurons coordinate and reprogram multiple neurotransmitter signals is an area of broad interest. Here, we show that substance P (SP, a neuropeptide associated with inflammatory pain, reprograms opioid receptor recycling and signaling. SP, through activation of the neurokinin 1 (NK1R receptor, increases the post-endocytic recycling of the mu-opioid receptor (MOR in trigeminal ganglion (TG neurons in an agonist-selective manner. SP-mediated protein kinase C (PKC activation is both required and sufficient for increasing recycling of exogenous and endogenous MOR in TG neurons. The target of this cross-regulation is MOR itself, given that mutation of either of two PKC phosphorylation sites on MOR abolishes the SP-induced increase in recycling and resensitization. Furthermore, SP enhances the resensitization of fentanyl-induced, but not morphine-induced, antinociception in mice. Our results define a physiological pathway that cross-regulates opioid receptor recycling via direct modification of MOR and suggest a mode of homeostatic interaction between the pain and analgesic systems.

  8. Cell-Autonomous Regulation of Mu-Opioid Receptor Recycling by Substance P

    Science.gov (United States)

    Bowman, Shanna L.; Soohoo, Amanda L.; Shiwarski, Daniel J.; Schulz, Stefan; Pradhan, Amynah A.; Puthenveedu, Manojkumar A.

    2015-01-01

    SUMMARY How neurons coordinate and reprogram multiple neurotransmitter signals is an area of broad interest. Here, we show that substance P (SP), a neuropep-tide associated with inflammatory pain, reprograms opioid receptor recycling and signaling. SP, through activation of the neurokinin 1 (NK1R) receptor, increases the post-endocytic recycling of the muopioid receptor (MOR) in trigeminal ganglion (TG) neurons in an agonist-selective manner. SP-mediated protein kinase C (PKC) activation is both required and sufficient for increasing recycling of exogenous and endogenous MOR in TG neurons. The target of this cross-regulation is MOR itself, given that mutation of either of two PKC phosphorylation sites on MOR abolishes the SP-induced increase in recycling and resensitization. Furthermore, SP enhances the resensitization of fentanyl-induced, but not morphine-induced, antinociception in mice. Our results define a physiological pathway that cross-regulates opioid receptor recycling via direct modification of MOR and suggest a mode of homeo-static interaction between the pain and analgesic systems. PMID:25801029

  9. Regulation of energy balance by a gut-brain axis and involvement of the gut microbiota.

    Science.gov (United States)

    Bauer, Paige V; Hamr, Sophie C; Duca, Frank A

    2016-02-01

    Despite significant progress in understanding the homeostatic regulation of energy balance, successful therapeutic options for curbing obesity remain elusive. One potential target for the treatment of obesity is via manipulation of the gut-brain axis, a complex bidirectional communication system that is crucial in maintaining energy homeostasis. Indeed, ingested nutrients induce secretion of gut peptides that act either via paracrine signaling through vagal and non-vagal neuronal relays, or in an endocrine fashion via entry into circulation, to ultimately signal to the central nervous system where appropriate responses are generated. We review here the current hypotheses of nutrient sensing mechanisms of enteroendocrine cells, including the release of gut peptides, mainly cholecystokinin, glucagon-like peptide-1, and peptide YY, and subsequent gut-to-brain signaling pathways promoting a reduction of food intake and an increase in energy expenditure. Furthermore, this review highlights recent research suggesting this energy regulating gut-brain axis can be influenced by gut microbiota, potentially contributing to the development of obesity.

  10. [Neurochemical mechanisms of sleep regulation].

    Science.gov (United States)

    2009-01-01

    Sleep is a complex, global and reversible behavioral state of all mammals, that is homeostatically regulated. Generally it is also defined as a rapidly reversible state of immobility and reduced sensory responsiveness. Still, there is no definition that has succeded in satisfying all aspects of sleep. The failure to define sleep as a single behavior lies in several facts: (1) sleep is not a homogenous state, but continuum of number of mixed states; (2) the control mechanisms of sleep are manifested at all levels of biological organization--from genes and intracellular mechanisms to the networks of neuronal populations within the central nervous system that control movement, arousal, autonomic functions, behavior and cognition; (3) the activity and interactions of these neurochemically greatly heterogenous neuronal populations are dependent of two biological rhythms--the circadian rhythm of wake/sleep and periodic cycles of NREM/REM sleep as two main sleep states. There are several levels of sleep control. The brain forebrain areas serve to control neuropsychology of dreaming; thalamo-cortical system controls NREM sleep rhythms, EEG activation and deactivation; hippocampo-cortical system controls memory consolidation; hypothalamic nuclei are the sources of circadian rhythm and sleep onset control; the control of periodic NREM/REM cycling is within the pons. The wake promoting neuronal populations are within the brainstem, midbrain, hypothalamus and basal forebrain. The main pontine wake-promoting centers are the noradrenergic neurons of locus coeruleus, the serotonergic neurons of dorsal raphe nucleus and the cholinerigic neurons of pedunculopontine tegmental nucleus and laterodorsal tegmental nucleus. The reciprocal connections and interactions of these neurons, and their opposite discharge pattern activity from wake to NREM and REM sleep have been the background of reciprocal interaction hypothesis of REM sleep generation. The wake-promoting neurons at the

  11. Temporal disorganization of circadian rhythmicity and sleep-wake regulation in mechanically ventilated patients receiving continuous intravenous sedation.

    Science.gov (United States)

    Gehlbach, Brian K; Chapotot, Florian; Leproult, Rachel; Whitmore, Harry; Poston, Jason; Pohlman, Mark; Miller, Annette; Pohlman, Anne S; Nedeltcheva, Arlet; Jacobsen, John H; Hall, Jesse B; Van Cauter, Eve

    2012-08-01

    Sleep is regulated by circadian and homeostatic processes and is highly organized temporally. Our study was designed to determine whether this organization is preserved in patients receiving mechanical ventilation (MV) and intravenous sedation. Observational study. Academic medical intensive care unit. Critically ill patients receiving MV and intravenous sedation. Continuous polysomnography (PSG) was initiated an average of 2.0 (1.0, 3.0) days after ICU admission and continued ≥ 36 h or until the patient was extubated. Sleep staging and power spectral analysis were performed using standard approaches. We also calculated the electroencephalography spectral edge frequency 95% SEF₉₅, a parameter that is normally higher during wakefulness than during sleep. Circadian rhythmicity was assessed in 16 subjects through the measurement of aMT6s in urine samples collected hourly for 24-48 hours. Light intensity at the head of the bed was measured continuously. We analyzed 819.7 h of PSG recordings from 21 subjects. REM sleep was identified in only 2/21 subjects. Slow wave activity lacked the normal diurnal and ultradian periodicity and homeostatic decline found in healthy adults. In nearly all patients, SEF₉₅ was consistently low without evidence of diurnal rhythmicity (median 6.3 [5.3, 7.8] Hz, n = 18). A circadian rhythm of aMT6s excretion was present in most (13/16, 81.3%) patients, but only 4 subjects had normal timing. Comparison of the SEF₉₅ during the melatonin-based biological night and day revealed no difference between the 2 periods (P = 0.64). The circadian rhythms and PSG of patients receiving mechanical ventilation and intravenous sedation exhibit pronounced temporal disorganization. The finding that most subjects exhibited preserved, but phase delayed, excretion of aMT6s suggests that the circadian pacemaker of such patients may be free-running.

  12. LAG-3 Regulates Plasmacytoid Dendritic Cell Homeostasis1

    Science.gov (United States)

    Workman, Creg J.; Wang, Yao; El Kasmi, Karim C.; Pardoll, Drew M.; Murray, Peter J.; Drake, Charles G.; Vignali, Dario A.A.

    2009-01-01

    LAG-3 is a CD4-related, activation-induced cell surface molecule expressed by various lymphoid cell types and binds to MHC class II with high affinity. We have previously shown that LAG-3 negatively regulates the expansion of activated T cells and T cell homeostasis, and is required for maximal regulatory T cell (Treg) function. Here we demonstrate for the first time that LAG-3 is also expressed on CD11clo/B220+/PDCA-1+ plasmacytoid dendritic cells (pDCs). Lag3 expression, as determined by real time PCR, was ∼10-fold greater in pDCs than in either Tregs or activated T effector cells. Activated pDCs also generate ∼5 times more sLAG-3 than activated T cells. LAG-3-deficient pDCs proliferate and expand more than wild-type pDCs in vivo in response to the TLR9 ligand, CpG. However, the effect of LAG-3 appears to be selective as there was no effect of LAG-3 on the expression of MHC class II, TLR9 and chemokine receptors, or on cytokine production. Lastly, adoptive transfer of either Lag3+/+ or Lag3−/− T cells plus or minus Lag3+/+ or Lag3−/− pDCs defined a role for LAG-3 in controlling pDC homeostasis as well as highlighting the consequences of deregulated Lag3−/− pDCs on T cell homeostasis. This raised the possibility of homeostatic reciprocity between T cells and pDCs. Collectively, our data suggests that LAG-3 plays an important but selective cell intrinsic and cell extrinsic role in pDC biology, and may serve as a key functional marker for their study. PMID:19201841

  13. Stress & the gut-brain axis: Regulation by the microbiome

    Directory of Open Access Journals (Sweden)

    Jane A. Foster

    2017-12-01

    Full Text Available The importance of the gut–brain axis in regulating stress-related responses has long been appreciated. More recently, the microbiota has emerged as a key player in the control of this axis, especially during conditions of stress provoked by real or perceived homeostatic challenge. Diet is one of the most important modifying factors of the microbiota-gut-brain axis. The routes of communication between the microbiota and brain are slowly being unravelled, and include the vagus nerve, gut hormone signaling, the immune system, tryptophan metabolism, and microbial metabolites such as short chain fatty acids. The importance of the early life gut microbiota in shaping later health outcomes also is emerging. Results from preclinical studies indicate that alterations of the early microbial composition by way of antibiotic exposure, lack of breastfeeding, birth by Caesarean section, infection, stress exposure, and other environmental influences - coupled with the influence of host genetics - can result in long-term modulation of stress-related physiology and behaviour. The gut microbiota has been implicated in a variety of stress-related conditions including anxiety, depression and irritable bowel syndrome, although this is largely based on animal studies or correlative analysis in patient populations. Additional research in humans is sorely needed to reveal the relative impact and causal contribution of the microbiome to stress-related disorders. In this regard, the concept of psychobiotics is being developed and refined to encompass methods of targeting the microbiota in order to positively impact mental health outcomes. At the 2016 Neurobiology of Stress Workshop in Newport Beach, CA, a group of experts presented the symposium “The Microbiome: Development, Stress, and Disease”. This report summarizes and builds upon some of the key concepts in that symposium within the context of how microbiota might influence the neurobiology of stress.

  14. TOWARD MORE EFFECTIVE REGULATION

    Energy Technology Data Exchange (ETDEWEB)

    J. GRAF

    2000-06-01

    This paper proposes a model relationship between the operator engaged in a hazardous activity, the regulator of that activity, and the general public. The roles and responsibilities of each entity are described in a way that allows effective communication flow. The role of the regulator is developed using the steam boiler as an example of a hazard subject to regulation; however, the model applies to any regulated activity. In this model the safety analyst has the extremely important role of communicating sometimes difficult technical information to the regulator in a way that the regulator can provide credible assurance to the general public as to the adequacy of the control of the hazardous activity. The conclusion asserts that acceptance of the model, understanding of the roles and responsibilities and definition of who communicates what information to whom will mitigate frustration on the part of each of the three entities.

  15. The development of regulations

    International Nuclear Information System (INIS)

    Slokan Dusic, D.; Levstek, M.F.; Stritar, A.

    2003-01-01

    In October 2002, The Act on Protection Against Ionising Radiation and Nuclear Safety which regulates all aspects of protection against ionising radiation and nuclear safety entered into force in Slovenia. The Slovenian government and its responsible ministries shall issue several governmental and ministerial regulations to support the above - mentioned act. The Slovenian Nuclear Safety Administration (SNSA) which acts within the Ministry of the Environment, Spatial Planing and Energy takes an active part in drafting the regulations which are defined in the act. Due to a very comprehensive and pretentious task, that is to be completed in a relatively short period of time, taking into consideration the involvement of stakeholders and all competent ministries, the SNSA within the Quality Management System developed a special procedure that insures the systematic approach to the preparation of regulations. The article will briefly represent the process that: defines the preparation, development, harmonisation, review, approval and issue of regulations and uniforms the format of developed regulations. (author)

  16. Regulating household financial advice

    Directory of Open Access Journals (Sweden)

    Benjamin F. Cummings

    2012-08-01

    Full Text Available This paper reviews economic theory related to investment advice. This theory explains 1 why financial advisors need to be carefully regulated for the benefit of both the investment advice industry and for consumers, 2 why principles-based regulation (e.g., a fiduciary standard is more efficient than rules-based regulation, 3 why dual regulation of financial professionals providing investment or insurance advice is inefficient and inequitable policy, and 4 why the application of a universal and uniform fiduciary standard will be difficult to implement.

  17. A genome-wide siRNA screen reveals multiple mTORC1 independent signaling pathways regulating autophagy under normal nutritional conditions.

    Science.gov (United States)

    Lipinski, Marta M; Hoffman, Greg; Ng, Aylwin; Zhou, Wen; Py, Bénédicte F; Hsu, Emily; Liu, Xuxin; Eisenberg, Jason; Liu, Jun; Blenis, John; Xavier, Ramnik J; Yuan, Junying

    2010-06-15

    Autophagy is a cellular catabolic mechanism that plays an essential function in protecting multicellular eukaryotes from neurodegeneration, cancer, and other diseases. However, we still know very little about mechanisms regulating autophagy under normal homeostatic conditions when nutrients are not limiting. In a genome-wide human siRNA screen, we demonstrate that under normal nutrient conditions upregulation of autophagy requires the type III PI3 kinase, but not inhibition of mTORC1, the essential negative regulator of starvation-induced autophagy. We show that a group of growth factors and cytokines inhibit the type III PI3 kinase through multiple pathways, including the MAPK-ERK1/2, Stat3, Akt/Foxo3, and CXCR4/GPCR, which are all known to positively regulate cell growth and proliferation. Our study suggests that the type III PI3 kinase integrates diverse signals to regulate cellular levels of autophagy, and that autophagy and cell proliferation may represent two alternative cell fates that are regulated in a mutually exclusive manner. Copyright 2010 Elsevier Inc. All rights reserved.

  18. Regulation of sleep by neuropeptide Y-like system in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Chunxia He

    Full Text Available Sleep is important for maintenance of normal physiology in animals. In mammals, neuropeptide Y (NPY, a homolog of Drosophila neuropeptide F (NPF, is involved in sleep regulation, with different effects in human and rat. However, the function of NPF on sleep in Drosophila melanogaster has not yet been described. In this study, we investigated the effects of NPF and its receptor-neuropeptide F receptor (NPFR1 on Drosophila sleep. Male flies over-expressing NPF or NPFR1 exhibited increased sleep during the nighttime. Further analysis demonstrated that sleep episode duration during nighttime was greatly increased and sleep latency was significantly reduced, indicating that NPF and NPFR1 promote sleep quality, and their action on sleep is not because of an impact of the NPF signal system on development. Moreover, the homeostatic regulation of flies after sleep deprivation was disrupted by altered NPF signaling, since sleep deprivation decreased transcription of NPF in control flies, and there were less sleep loss during sleep deprivation and less sleep gain after sleep deprivation in flies overexpressing NPF and NPFR1 than in control flies, suggesting that NPF system auto-regulation plays an important role in sleep homeostasis. However, these effects did not occur in females, suggesting a sex-dependent regulatory function in sleep for NPF and NPFR1. NPF in D1 brain neurons showed male-specific expression, providing the cellular locus for male-specific regulation of sleep by NPF and NPFR1. This study brings a new understanding into sleep studies of a sexually dimorphic regulatory mode in female and male flies.

  19. The SOCS2 ubiquitin ligase complex regulates growth hormone receptor levels.

    Directory of Open Access Journals (Sweden)

    Mattias Vesterlund

    Full Text Available Growth Hormone is essential for the regulation of growth and the homeostatic control of intermediary metabolism. GH actions are mediated by the Growth Hormone Receptor; a member of the cytokine receptor super family that signals chiefly through the JAK2/STAT5 pathway. Target tissue responsiveness to GH is under regulatory control to avoid excessive and off-target effects upon GHR activation. The suppressor of cytokine signalling 2 (SOCS is a key regulator of GHR sensitivity. This is clearly shown in mice where the SOCS2 gene has been inactivated, which show 30-40% increase in body length, a phenotype that is dependent on endogenous GH secretion. SOCS2 is a GH-stimulated, STAT5b-regulated gene that acts in a negative feedback loop to downregulate GHR signalling. Since the biochemical basis for these actions is poorly understood, we studied the molecular function of SOCS2. We demonstrated that SOCS2 is part of a multimeric complex with intrinsic ubiquitin ligase activity. Mutational analysis shows that the interaction with Elongin B/C controls SOCS2 protein turnover and affects its molecular activity. Increased GHR levels were observed in livers from SOCS2⁻/⁻ mice and in the absence of SOCS2 in in vitro experiments. We showed that SOCS2 regulates cellular GHR levels through direct ubiquitination and in a proteasomally dependent manner. We also confirmed the importance of the SOCS-box for the proper function of SOCS2. Finally, we identified two phosphotyrosine residues in the GHR to be responsible for the interaction with SOCS2, but only Y487 to account for the effects of SOCS2. The demonstration that SOCS2 is an ubiquitin ligase for the GHR unveils the molecular basis for its physiological actions.

  20. Soft Regulators, though judges

    NARCIS (Netherlands)

    de Geest, G.G.A.; Dari Mattiacci, G.

    Judges have a tendency to be more demanding than regulators. In the United States, a majority of the courts has adopted the rule that the unexcused violation of a statutory standard is negligence per se. However, the converse does not hold: compliance with regulation does not relieve the injurer of

  1. Peak regulation right

    International Nuclear Information System (INIS)

    Gao, Z. |; Ren, Z.; Li, Z.; Zhu, R.

    2005-01-01

    A peak regulation right concept and corresponding transaction mechanism for an electricity market was presented. The market was based on a power pool and independent system operator (ISO) model. Peak regulation right (PRR) was defined as a downward regulation capacity purchase option which allowed PRR owners to buy certain quantities of peak regulation capacity (PRC) at a specific price during a specified period from suppliers. The PRR owner also had the right to decide whether or not they would buy PRC from suppliers. It was the power pool's responsibility to provide competitive and fair peak regulation trading markets to participants. The introduction of PRR allowed for unit capacity regulation. The PRR and PRC were rated by the supplier, and transactions proceeded through a bidding process. PRR suppliers obtained profits by selling PRR and PRC, and obtained downward regulation fees regardless of whether purchases are made. It was concluded that the peak regulation mechanism reduced the total cost of the generating system and increased the social surplus. 6 refs., 1 tab., 3 figs

  2. Regulating Digital Power Supply.

    Science.gov (United States)

    The patent relates to a digital power supply regulator using pulse counts and a feedback servo loop. Analog MOS circuitry is extremely sensitive to...radiation and there are undesirable results when not placed in a suitable radiation-free environment. The present invention is a regulated power supply but

  3. Emotion-regulation choice

    NARCIS (Netherlands)

    Sheppes, Gal; Scheibe, Susanne; Suri, Gaurav; Gross, James J.

    2011-01-01

    Despite centuries of speculation about how to manage negative emotions, little is actually known about which emotion-regulation strategies people choose to use when confronted with negative situations of varying intensity. On the basis of a new process conception of emotion regulation, we

  4. Regulation as Rhetoric

    DEFF Research Database (Denmark)

    Boll, Karen; Györy, Csaba

    engage reflectively in image promotion which serves two purposes: establishing and maintaining legitimacy in a particular social and political environment and producing compliance. Further, we argue that this regulation is a form of ‘post-bureaucratic’ regulation in which compliance is achieved...

  5. Reconceptualizing Civil Regulation

    DEFF Research Database (Denmark)

    Galang, Roberto Martin; Castello, Itziar

    2011-01-01

    This article re-conceptualizes the notion of civil regulation, through an analysis of 775 projects by firms located in 21 Asian countries, wherein we map the state of civil regulation initiatives in the region. We challenge two established assumptions in the Corporate Social Responsibility....... Finally, we argue that, in Asia, governments act as a structuration mechanism which challenges the current understanding of CSR....

  6. Mortgage market regulation: Europe

    NARCIS (Netherlands)

    Aalbers, M.B.; Smith, S.J.

    2012-01-01

    Despite several European Union (EU) initiatives, there is only limited pan-European mortgage market regulation. The EU strategy can be characterised as one of parallel liberalisation and consolidation. This article highlights the key differences in regulation among European mortgage markets.

  7. Electrical installations and regulations

    CERN Document Server

    Whitfield, J F

    1966-01-01

    Electrical Installations and Regulations focuses on the regulations that apply to electrical installations and the reasons for them. Topics covered range from electrical science to alternating and direct current supplies, as well as equipment for providing protection against excess current. Cables, wiring systems, and final subcircuits are also considered, along with earthing, discharge lighting, and testing and inspection.Comprised of 12 chapters, this book begins with an overview of electrical installation work, traits of a good electrician, and the regulations governing installations. The r

  8. The regulation of hunting

    DEFF Research Database (Denmark)

    Abildtrup, Jens; Jensen, Frank

    Within hunting, wildlife populations are estimated to be too high in many countries which is assumed to be due to the market failure, that each hunter harvests too little compared to what the regulator wants. This may be due to the existing regulation which, among other things, requires knowledge...... by an individual, variable tax rate. The variable tax rate is, among other things, based on the difference in marginal value of the population between the hunter and the regulator. The paper shows that the population tax/subsidy secures a first-best optimum. Thus, the population tax is a good alternative...

  9. Collaborative Tax Regulation

    DEFF Research Database (Denmark)

    Boll, Karen

    2016-01-01

    This article shows a new form of regulation within a tax administration where tax administrators abate tax evasion by nudging and motivating consumers to only purchase services from tax compliant businesses. This indirectly closes or forces tax evading businesses to change their practices, because...... their customer bases decline to commercially non-viable levels. The analysis is framed by public governance literature and argues that the regulation is an example of collaborative or interactive governance, because the tax administrators do not regulate non-compliance directly, but activate external...... stakeholders, i.e. the consumers, in the regulatory craft. The study is based on a qualitative methodology and draws on a unique case of regulation in the cleaning sector. This sector is at high risk of tax evasion and human exploitation of vulnerable workers operating in the informal economy. The article has...

  10. Focus on PTEN regulation

    Directory of Open Access Journals (Sweden)

    Miriam eBermudez-Brito

    2015-07-01

    Full Text Available The role of PTEN as a tumour suppressor has been for a long time attributed to its lipid phosphatase activity against PI(3,4,5P3, the phospholipid product of the class I PI3Ks. Besides its traditional role as a lipid phosphatase at the plasma membrane, a wealth of data has shown that PTEN can function independently of its phosphatase activity and that PTEN also exists and plays a role in the nucleus, in cytoplasmic organelles and extracellularly. Accumulating evidence has shed light on diverse physiological functions of PTEN which are accompanied by a complex regulation of its expression and activity. PTEN levels and function are regulated transcriptionally, post-transcriptionally and post-translationally. PTEN is also sensitive to regulation by its interacting proteins and its localization. Herein, we summarize the current knowledge on mechanisms that regulate the expression and enzymatic activity of PTEN and its role in human diseases.

  11. Corruption, institutions and regulation

    OpenAIRE

    Breen, Michael; Gillanders, Robert

    2011-01-01

    We analyze the effects of corruption and institutional quality on the quality of business regulation. Our key findings indicate that corruption negatively aspects the quality of regulation and that general institutional quality is insignificant once corruption is controlled for. These findings hold over a number of specifications which include additional exogenous historical and geographic controls. The findings imply that policy-makers should focus on curbing corruption to improve regulat...

  12. Regulating deregulated energy markets

    International Nuclear Information System (INIS)

    Jackson, M.

    2002-01-01

    The North American gas and electricity markets are fast evolving, and regulators are currently faced with a host of issues such as market-based rates, unbundling, stranded costs, open access, and incentive regulation are surfacing as a result of deregulation. The regulatory environment in Ontario was reviewed by the author. Deregulated markets rule, from commodities to gas and electricity. Additionally, there is an evolution of traditional utility regulation. A look at deregulated markets revealed that there are regulations on boundary conditions on the deregulated market. Under the Ontario Energy Board (OEB), all generators, transmitters, distributors, and retailers of electricity must be licensed. The standard supply service (SSS) offered by electricity distributors and system gas which is still being sold by natural gas distributors continues to be regulated by OEB. One issue that was addressed was separation for revenues and costs of the utility's purchase and sale of gas business, at least for accounting purposes. The next issue discussed was cost of system gas and SSS, followed by timely signals and prudent incurred costs. Historical benefits were reviewed, such as historical commitments to low-cost electricity. Pooling transportation costs, transmission pricing continued, market-based rates, unbundling, stranded costs, open access, incentive regulation/ performance based regulation (PBR) were all discussed. Price cap on PBR, both partial and comprehensive were looked at. A requirement to review guidelines on cost of capital and an application to extend blanket approval provisions for gas storage were discussed, as they are amongst some of the challenges of the future. Other challenges include revised rules and practice and procedure; practice directions for cost awards, appeals, and other functions; confidentiality guidelines; and refinements to the role of and approaches to alternative dispute resolution. The future role of regulators was examined in light

  13. Delegation of Regulation

    OpenAIRE

    Kundu, Tapas; Nilssen, Tore

    2017-01-01

    We develop a model to discuss a government’s incentives to delegate to bureaucrats the regulation of an industry. The industry consists of a polluting firm with private information about its production technology. Implementing a transfer-based regulation policy requires the government to make use of a bureaucracy; this has a bureaucratic cost, as the bureaucracy diverts a fraction of the transfer. The government faces a trade-off in its delegation decision: bureaucrats have knowledge of the f...

  14. Turning regulation into value

    OpenAIRE

    Laamanen, Tomi; Reuter, Emmanuelle; Steiger, Fabio

    2015-01-01

    As an export-based industry, the survival of Swiss private banking depends on its access to an international client base in relevant markets. Adoption of transnational regulation is especially critical as the foreign onshore business gains importance while the offshore business declines. Transnational regulation should therefore not be seen as an option. Rather, it is central to a sustainable and successful Swiss private banking model.

  15. Neuroendocrine Regulation of Metabolism

    OpenAIRE

    Cornejo, Maria P.; Hentges, Shane T.; Maliqueo, Manuel; Coirini, Hector; Becu-Villalobos, Damasia; Elias, Carol F.

    2016-01-01

    Given the current environment in most developed countries, it is a challenge to maintain a good balance between calories consumed and calories burned, although maintenance of metabolic balance is key to good health. Therefore, understanding how metabolic regulation is achieved and how the dysregulation of metabolism affects health is an area of intense research. Most studies are focused on the hypothalamus, which is a brain area that acts as a key regulator of metabolism. Among the nuclei tha...

  16. In regulation we trust.

    Science.gov (United States)

    Wiig, Siri; Tharaldsen, Jorunn Elise

    2012-01-01

    The role of trust has been argued to play an increasingly important role in modern, complex, and ambivalent risk societies. Trust within organizational research is anticipated to have a general strategic impact on aspects such as organizational performance, communication and knowledge exchange, and learning from accidents. Trust is also an important aspect related to regulation of risk. Diverse regulatory regimes, their contexts and risks influence regulators use of trust and distrust in regulatory practice. The aim of this paper is to discuss the relationship between risk regulation and trust across diverse risk regulation regimes. By drawing from studies of risk regulation, risk perception, and trust the purpose is to discuss how regulation and trust are linked and used in practice to control risk across system levels in socio-technical systems in high risk industries. This paper provides new knowledge on 1) how functional and dysfunctional trust and distrust are grounded in the empirical realities of high risk industries, 2) how different perspectives on trust and distrust act together and bring new knowledge on how society control risk.

  17. Interpersonal emotion regulation.

    Science.gov (United States)

    Zaki, Jamil; Williams, W Craig

    2013-10-01

    Contemporary emotion regulation research emphasizes intrapersonal processes such as cognitive reappraisal and expressive suppression, but people experiencing affect commonly choose not to go it alone. Instead, individuals often turn to others for help in shaping their affective lives. How and under what circumstances does such interpersonal regulation modulate emotional experience? Although scientists have examined allied phenomena such as social sharing, empathy, social support, and prosocial behavior for decades, there have been surprisingly few attempts to integrate these data into a single conceptual framework of interpersonal regulation. Here we propose such a framework. We first map a "space" differentiating classes of interpersonal regulation according to whether an individual uses an interpersonal regulatory episode to alter their own or another person's emotion. We then identify 2 types of processes--response-dependent and response-independent--that could support interpersonal regulation. This framework classifies an array of processes through which interpersonal contact fulfills regulatory goals. More broadly, it organizes diffuse, heretofore independent data on "pieces" of interpersonal regulation, and identifies growth points for this young and exciting research domain.

  18. Regulation of the stress response in early vertebrates

    NARCIS (Netherlands)

    Huising, M.O.; Metz, J.R.; Mazon, de A.F.; Verburg-van Kemenade, B.M.L.; Flik, G.

    2005-01-01

    The acute stress response is a key regulatory system for the maintenance of homeostatic equilibrium that is activated upon an imminent or ongoing disturbance of the "milieu intérieur". In general, the stress response in bony fish is similar to that of mammals. The recent cloning and characterization

  19. Regulation of T cell motility in vitro and in vivo by LPA and LPA2.

    Directory of Open Access Journals (Sweden)

    Sara A Knowlden

    Full Text Available Lysophosphatidic acid (LPA and the LPA-generating enzyme autotaxin (ATX have been implicated in lymphocyte trafficking and the regulation of lymphocyte entry into lymph nodes. High local concentrations of LPA are thought to be present in lymph node high endothelial venules, suggesting a direct influence of LPA on cell migration. However, little is known about the mechanism of action of LPA, and more work is needed to define the expression and function of the six known G protein-coupled receptors (LPA 1-6 in T cells. We studied the effects of 18∶1 and 16∶0 LPA on naïve CD4+ T cell migration and show that LPA induces CD4+ T cell chemorepulsion in a Transwell system, and also improves the quality of non-directed migration on ICAM-1 and CCL21 coated plates. Using intravital two-photon microscopy, lpa2-/- CD4+ T cells display a striking defect in early migratory behavior at HEVs and in lymph nodes. However, later homeostatic recirculation and LPA-directed migration in vitro were unaffected by loss of lpa2. Taken together, these data highlight a previously unsuspected and non-redundant role for LPA2 in intranodal T cell motility, and suggest that specific functions of LPA may be manipulated by targeting T cell LPA receptors.

  20. A mathematical model towards understanding the mechanism of neuronal regulation of wake-NREMS-REMS states.

    Directory of Open Access Journals (Sweden)

    Rupesh Kumar

    Full Text Available In this study we have constructed a mathematical model of a recently proposed functional model known to be responsible for inducing waking, NREMS and REMS. Simulation studies using this model reproduced sleep-wake patterns as reported in normal animals. The model helps to explain neural mechanism(s that underlie the transitions between wake, NREMS and REMS as well as how both the homeostatic sleep-drive and the circadian rhythm shape the duration of each of these episodes. In particular, this mathematical model demonstrates and confirms that an underlying mechanism for REMS generation is pre-synaptic inhibition from substantia nigra onto the REM-off terminals that project on REM-on neurons, as has been recently proposed. The importance of orexinergic neurons in stabilizing the wake-sleep cycle is demonstrated by showing how even small changes in inputs to or from those neurons can have a large impact on the ensuing dynamics. The results from this model allow us to make predictions of the neural mechanisms of regulation and patho-physiology of REMS.

  1. Emerging Roles of Regulators of G Protein Signaling (RGS) Proteins in the Immune System.

    Science.gov (United States)

    Druey, Kirk M

    2017-01-01

    The regulators of G protein signaling (RGS) proteins are a large, evolutionarily conserved group of intracellular proteins expressed in every cell type and tissue throughout the body including the immune system. Through their signature GTPase-activating protein (GAP) activity on heterotrimeric G proteins and interactions with signaling complexes and membrane constituents (e.g., lipids), RGS proteins determine the intensity and duration of G protein-coupled receptor-induced responses. They may also have a function in generating intracellular signaling gradients necessary for the directional migration of leukocytes to inflamed tissues containing local accumulations of chemoattractants. Although physiological functions of most RGS proteins in leukocytes and lymphoid organs are largely unknown, it appears thus far that deficiency of individual RGS proteins in mice does not affect homeostatic immune responses in the absence of immunogenic challenge and/or microbial infection. Although aberrant expression of some RGS proteins has been linked to dysregulated immunity and/or neoplasia in humans, there are no human diseases attributed to specific RGS dysfunction. Here, we highlight mostly published work describing expression and functions of the core group of RGS proteins that were among the first discovered, in both innate and adaptive immune processes, with particular emphasis on cell trafficking. © 2017 Elsevier Inc. All rights reserved.

  2. Adipose Type One Innate Lymphoid Cells Regulate Macrophage Homeostasis through Targeted Cytotoxicity.

    Science.gov (United States)

    Boulenouar, Selma; Michelet, Xavier; Duquette, Danielle; Alvarez, David; Hogan, Andrew E; Dold, Christina; O'Connor, Donal; Stutte, Suzanne; Tavakkoli, Ali; Winters, Desmond; Exley, Mark A; O'Shea, Donal; Brenner, Michael B; von Andrian, Ulrich; Lynch, Lydia

    2017-02-21

    Adipose tissue has a dynamic immune system that adapts to changes in diet and maintains homeostatic tissue remodeling. Adipose type 1 innate lymphoid cells (AT1-ILCs) promote pro-inflammatory macrophages in obesity, but little is known about their functions at steady state. Here we found that human and murine adipose tissue harbor heterogeneous populations of AT1-ILCs. Experiments using parabiotic mice fed a high-fat diet (HFD) showed differential trafficking of AT1-ILCs, particularly in response to short- and long-term HFD and diet restriction. At steady state, AT1-ILCs displayed cytotoxic activity toward adipose tissue macrophages (ATMs). Depletion of AT1-ILCs and perforin deficiency resulted in alterations in the ratio of inflammatory to anti-inflammatory ATMs, and adoptive transfer of AT1-ILCs exacerbated metabolic disorder. Diet-induced obesity impaired AT1-ILC killing ability. Our findings reveal a role for AT1-ILCs in regulating ATM homeostasis through cytotoxicity and suggest that this function is relevant in both homeostasis and metabolic disease. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. TOR Complex 2-Ypk1 Signaling Maintains Sphingolipid Homeostasis by Sensing and Regulating ROS Accumulation

    Directory of Open Access Journals (Sweden)

    Brad J. Niles

    2014-02-01

    Full Text Available Reactive oxygen species (ROS are produced during normal metabolism and can function as signaling molecules. However, ROS at elevated levels can damage cells. Here, we identify the conserved target of rapamycin complex 2 (TORC2/Ypk1 signaling module as an important regulator of ROS in the model eukaryotic organism, S. cerevisiae. We show that TORC2/Ypk1 suppresses ROS produced both by mitochondria as well as by nonmitochondrial sources, including changes in acidification of the vacuole. Furthermore, we link vacuole-related ROS to sphingolipids, essential components of cellular membranes, whose synthesis is also controlled by TORC2/Ypk1 signaling. In total, our data reveal that TORC2/Ypk1 act within a homeostatic feedback loop to maintain sphingolipid levels and that ROS are a critical regulatory signal within this system. Thus, ROS sensing and signaling by TORC2/Ypk1 play a central physiological role in sphingolipid biosynthesis and in the maintenance of cell growth and viability.

  4. An optimized method for measuring hypocretin-1 peptide in the mouse brain reveals differential circadian regulation of hypocretin-1 levels rostral and caudal to the hypothalamus.

    Science.gov (United States)

    Justinussen, J L; Holm, A; Kornum, B R

    2015-12-03

    The hypocretin/orexin system regulates, among other things, sleep and energy homeostasis. The system is likely regulated by both homeostatic and circadian mechanisms. Little is known about local differences in the regulation of hypocretin activity. The aim of this study was to establish an optimized peptide quantification method for hypocretin-1 extracted from different mouse brain areas and use this method for investigating circadian fluctuations of hypocretin-1 levels in these areas. The results show that hypocretin-1 peptide can be extracted from small pieces of intact tissue, with sufficient yield for measurements in a standard radioimmunoassay. Utilizing the optimized method, it was found that prepro-hypocretin mRNA and peptide show circadian fluctuations in the mouse brain. This study further demonstrates that the hypocretin-1 peptide level in the frontal brain peaks during dark as does prepro-hypocretin mRNA in the hypothalamus. However, in midbrain and brainstem tissue caudal to the hypothalamus, there was less circadian fluctuation and a tendency for higher levels during the light phase. These data suggest that regulation of the hypocretin system differs between brain areas. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  5. Cellular zinc fluxes and the regulation of apoptosis/gene-directed cell death.

    Science.gov (United States)

    Truong-Tran, A Q; Ho, L H; Chai, F; Zalewski, P D

    2000-05-01

    The maintenance of discrete subcellular pools of zinc (Zn) is critical for the functional and structural integrity of cells. Among the important biological processes influenced by Zn is apoptosis, a process that is important in cellular homeostasis (an important cellular homeostatic process). It has also been identified as a major mechanism contributing to cell death in response to toxins and in disease, offering hope that novel therapies that target apoptotic pathways may be developed. Because Zn levels in the body can be increased in a relatively nontoxic manner, it may be possible to prevent or ameliorate degenerative disorders that are associated with high rates of apoptotic cell death. This review begins with brief introductions that address, first, the cellular biology of Zn, especially the critical labile Zn pools, and, second, the phenomenon of apoptosis. We then review the evidence relating Zn to apoptosis and address three major hypotheses: (1) that a specific pool or pools of intracellular labile Zn regulates apoptosis; (2) that systemic changes in Zn levels in the body, due to dietary factors, altered physiological states or disease, can influence cell susceptibility to apoptosis, and (3) that this altered susceptibility to apoptosis contributes to pathophysiological changes in the body. Other key issues are the identity of the molecular targets of Zn in the apoptotic cascade, the types of cells and tissues most susceptible to Zn-regulated apoptosis, the role of Zn as a coordinate regulator of mitosis and apoptosis and the apparent release of tightly bound intracellular pools of Zn during the later stages of apoptosis. This review concludes with a section highlighting areas of priority for future studies.

  6. Peripheral serotonin regulates maternal calcium trafficking in mammary epithelial cells during lactation in mice.

    Directory of Open Access Journals (Sweden)

    Jimena Laporta

    Full Text Available Lactation is characterized by massive transcellular flux of calcium, from the basolateral side of the mammary alveolar epithelium (blood into the ductal lumen (milk. Regulation of calcium transport during lactation is critical for maternal and neonatal health. The monoamine serotonin (5-HT is synthesized by the mammary gland and functions as a homeostatic regulation of lactation. Genetic ablation of tryptophan hydroxylase 1 (Tph1, which encodes the rate-limiting enzyme in non-neuronal serotonin synthesis, causes a deficiency in circulating serotonin. As a consequence maternal calcium concentrations decrease, mammary epithelial cell morphology is altered, and cell proliferation is decreased during lactation. Here we demonstrate that serotonin deficiency decreases the expression and disrupts the normal localization of calcium transporters located in the apical (PMCA2 and basolateral (CaSR, ORAI-1 membranes of the lactating mammary gland. In addition, serotonin deficiency decreases the mRNA expression of calcium transporters located in intracellular compartments (SERCA2, SPCA1 and 2. Mammary expression of serotonin receptor isoform 2b and its downstream pathways (PLCβ3, PKC and MAP-ERK1/2 are also decreased by serotonin deficiency, which might explain the numerous phenotypic alterations described above. In most cases, addition of exogenous 5-hydroxy-L-tryptophan to the Tph1 deficient mice rescued the phenotype. Our data supports the hypothesis that serotonin is necessary for proper mammary gland structure and function, to regulate blood and mammary epithelial cell transport of calcium during lactation. These findings can be applicable to the treatment of lactation-induced hypocalcemia in dairy cows and can have profound implications in humans, given the wide-spread use of selective serotonin reuptake inhibitors as antidepressants during pregnancy and lactation.

  7. Transient receptor potential melastatin 8 (TRPM8 channels are involved in body temperature regulation

    Directory of Open Access Journals (Sweden)

    Gavva Narender R

    2012-05-01

    Full Text Available Abstract Background Transient receptor potential cation channel subfamily M member 8 (TRPM8 is activated by cold temperature in vitro and has been demonstrated to act as a ‘cold temperature sensor’ in vivo. Although it is known that agonists of this ‘cold temperature sensor’, such as menthol and icilin, cause a transient increase in body temperature (Tb, it is not known if TRPM8 plays a role in Tb regulation. Since TRPM8 has been considered as a potential target for chronic pain therapeutics, we have investigated the role of TRPM8 in Tb regulation. Results We characterized five chemically distinct compounds (AMG0635, AMG2850, AMG8788, AMG9678, and Compound 496 as potent and selective antagonists of TRPM8 and tested their effects on Tb in rats and mice implanted with radiotelemetry probes. All five antagonists used in the study caused a transient decrease in Tb (maximum decrease of 0.98°C. Since thermoregulation is a homeostatic process that maintains Tb about 37°C, we further evaluated whether repeated administration of an antagonist attenuated the decrease in Tb. Indeed, repeated daily administration of AMG9678 for four consecutive days showed a reduction in the magnitude of the Tb decrease Day 2 onwards. Conclusions The data reported here demonstrate that TRPM8 channels play a role in Tb regulation. Further, a reduction of magnitude in Tb decrease after repeated dosing of an antagonist suggests that TRPM8’s role in Tb maintenance may not pose an issue for developing TRPM8 antagonists as therapeutics.

  8. Federal Aviation Regulations - National Aviation Regulations of Russia

    Science.gov (United States)

    Chernykh, O.; Bakiiev, M.

    2018-03-01

    Chinese Aerospace Engineering is currently developing cooperation with Russia on a wide-body airplane project that has directed the work towards better understanding of Russian airworthiness management system. The paper introduces national Aviation regulations of Russia, presents a comparison of them with worldwide recognized regulations, and highlights typical differences. They have been found to be: two general types of regulations used in Russia (Aviation Regulations and Federal Aviation Regulations), non-unified structure of regulations on Aircraft Operation management, various separate agencies responsible for regulation issuance instead of one national aviation authority, typical confusions in references. The paper also gives a list of effective Russian Regulations of both types.

  9. Nuclear regulation in transition

    International Nuclear Information System (INIS)

    Tomain, J.P.

    1986-01-01

    The current state of nuclear regulations in the USA is examined. Since Three Mile Island the regulation of the nuclear power industry has been undergoing a noticeable transition. It will be argued here that the transition is characterized by two indicia. First, the primary focus of state and federal regulators has been on the financial aspects of the industry: this is best seen in the context of decisions allocating the costs of nuclear plant cancellations. Second, decisionmaking power has been decentralized: although the regulatory history of nuclear power demonstrates the tradition of centralized decisionmaking power (i.e., formerly the primary decisionmaking body was the Atomic Energy Commission), now States share decisionmaking power with the Nuclear Regulatory Commission. In Section 1 a brief legislative history of nuclear regulation is presented to establish the assertion that nuclear regulation, both de jure and de facto, was centralized. Next, Section 2 canvasses recent United States Supreme Court opinions regarding nuclear regulation. The Court frequently acts as policymaker through the consequences of its opinions, if not by its intent. In the area of nuclear policymaking, the Court has paid allegiance recently both to the tradition of centralization and to the movement toward decentralization. This dualism is reflected in other federal court decisions as well which will be briefly mentioned. Continuing the analysis of Federal regulation, Section 3 examines the current reform efforts of the NRC. Section 4 presents an examination of State responses to nuclear plant cancellations. In this section, State administrative agency and court decisions will be examined and recent State legislation will be discussed. (author)

  10. The circadian regulation of sleep: impact of a functional ADA-polymorphism and its association to working memory improvements.

    Directory of Open Access Journals (Sweden)

    Carolin F Reichert

    Full Text Available Sleep is regulated in a time-of-day dependent manner and profits working memory. However, the impact of the circadian timing system as well as contributions of specific sleep properties to this beneficial effect remains largely unexplored. Moreover, it is unclear to which extent inter-individual differences in sleep-wake regulation depend on circadian phase and modulate the association between sleep and working memory. Here, sleep electroencephalography (EEG was recorded during a 40-h multiple nap protocol, and working memory performance was assessed by the n-back task 10 times before and after each scheduled nap sleep episode. Twenty-four participants were genotyped regarding a functional polymorphism in adenosine deaminase (rs73598374, 12 G/A-, 12 G/G-allele carriers, previously associated with differences in sleep-wake regulation. Our results indicate that genotype-driven differences in sleep depend on circadian phase: heterozygous participants were awake longer and slept less at the end of the biological day, while they exhibited longer non rapid eye movement (NREM sleep and slow wave sleep concomitant with reduced power between 8-16 Hz at the end of the biological night. Slow wave sleep and NREM sleep delta EEG activity covaried positively with overall working memory performance, independent of circadian phase and genotype. Moreover, REM sleep duration benefitted working memory particularly when occurring in the early morning hours and specifically in heterozygous individuals. Even though based on a small sample size and thus requiring replication, our results suggest genotype-dependent differences in circadian sleep regulation. They further indicate that REM sleep, being under strong circadian control, boosts working memory performance according to genotype in a time-of-day dependent manner. Finally, our data provide first evidence that slow wave sleep and NREM sleep delta activity, majorly regulated by sleep homeostatic mechanisms, is

  11. The circadian regulation of sleep: impact of a functional ADA-polymorphism and its association to working memory improvements.

    Science.gov (United States)

    Reichert, Carolin F; Maire, Micheline; Gabel, Virginie; Hofstetter, Marcel; Viola, Antoine U; Kolodyazhniy, Vitaliy; Strobel, Werner; Goetz, Thomas; Bachmann, Valérie; Landolt, Hans-Peter; Cajochen, Christian; Schmidt, Christina

    2014-01-01

    Sleep is regulated in a time-of-day dependent manner and profits working memory. However, the impact of the circadian timing system as well as contributions of specific sleep properties to this beneficial effect remains largely unexplored. Moreover, it is unclear to which extent inter-individual differences in sleep-wake regulation depend on circadian phase and modulate the association between sleep and working memory. Here, sleep electroencephalography (EEG) was recorded during a 40-h multiple nap protocol, and working memory performance was assessed by the n-back task 10 times before and after each scheduled nap sleep episode. Twenty-four participants were genotyped regarding a functional polymorphism in adenosine deaminase (rs73598374, 12 G/A-, 12 G/G-allele carriers), previously associated with differences in sleep-wake regulation. Our results indicate that genotype-driven differences in sleep depend on circadian phase: heterozygous participants were awake longer and slept less at the end of the biological day, while they exhibited longer non rapid eye movement (NREM) sleep and slow wave sleep concomitant with reduced power between 8-16 Hz at the end of the biological night. Slow wave sleep and NREM sleep delta EEG activity covaried positively with overall working memory performance, independent of circadian phase and genotype. Moreover, REM sleep duration benefitted working memory particularly when occurring in the early morning hours and specifically in heterozygous individuals. Even though based on a small sample size and thus requiring replication, our results suggest genotype-dependent differences in circadian sleep regulation. They further indicate that REM sleep, being under strong circadian control, boosts working memory performance according to genotype in a time-of-day dependent manner. Finally, our data provide first evidence that slow wave sleep and NREM sleep delta activity, majorly regulated by sleep homeostatic mechanisms, is linked to working

  12. Neuroendocrine Regulation of Metabolism.

    Science.gov (United States)

    Cornejo, M P; Hentges, S T; Maliqueo, M; Coirini, H; Becu-Villalobos, D; Elias, C F

    2016-07-01

    Given the current environment in most developed countries, it is a challenge to maintain a good balance between calories consumed and calories burned, although maintenance of metabolic balance is key to good health. Therefore, understanding how metabolic regulation is achieved and how the dysregulation of metabolism affects health is an area of intense research. Most studies focus on the hypothalamus, which is a brain area that acts as a key regulator of metabolism. Among the nuclei that comprise the hypothalamus, the arcuate nucleus is one of the major mediators in the regulation of food intake. The regulation of energy balance is also a key factor ensuring the maintenance of any species as a result of the dependence of reproduction on energy stores. Adequate levels of energy reserves are necessary for the proper functioning of the hypothalamic-pituitary-gonadal axis. This review discusses valuable data presented in the 2015 edition of the International Workshop of Neuroendocrinology concerning the fundamental nature of the hormonal regulation of the hypothalamus and the impact on energy balance and reproduction. © 2016 British Society for Neuroendocrinology.

  13. Npas4 regulates excitatory-inhibitory balance within neural circuits through cell-type-specific gene programs.

    Science.gov (United States)

    Spiegel, Ivo; Mardinly, Alan R; Gabel, Harrison W; Bazinet, Jeremy E; Couch, Cameron H; Tzeng, Christopher P; Harmin, David A; Greenberg, Michael E

    2014-05-22

    The nervous system adapts to experience by inducing a transcriptional program that controls important aspects of synaptic plasticity. Although the molecular mechanisms of experience-dependent plasticity are well characterized in excitatory neurons, the mechanisms that regulate this process in inhibitory neurons are only poorly understood. Here, we describe a transcriptional program that is induced by neuronal activity in inhibitory neurons. We find that, while neuronal activity induces expression of early-response transcription factors such as Npas4 in both excitatory and inhibitory neurons, Npas4 activates distinct programs of late-response genes in inhibitory and excitatory neurons. These late-response genes differentially regulate synaptic input to these two types of neurons, promoting inhibition onto excitatory neurons while inducing excitation onto inhibitory neurons. These findings suggest that the functional outcomes of activity-induced transcriptional responses are adapted in a cell-type-specific manner to achieve a circuit-wide homeostatic response. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Cell-cycle-dependent Xenopus TRF1 recruitment to telomere chromatin regulated by Polo-like kinase

    Science.gov (United States)

    Nishiyama, Atsuya; Muraki, Keiko; Saito, Motoki; Ohsumi, Keita; Kishimoto, Takeo; Ishikawa, Fuyuki

    2006-01-01

    Telomeres are regulated by a homeostatic mechanism that includes telomerase and telomeric repeat binding proteins, TRF1 and TRF2. Recently, it has been hypothesized that telomeres assume distinct configurations in a cell-cycle-dependent manner, although direct biochemical evidence is lacking. Here we demonstrated that Xenopus TRF1 (xTRF1) associates with telomere chromatin specifically in mitotic Xenopus egg extracts, and dissociates from it upon mitotic exit. Both the N-terminal TRF-homology (TRFH) domain and the linker region connecting the TRFH domain and the C-terminal Myb domain are required for this cell-cycle-dependent association of xTRF1 with chromatin. In contrast, Xenopus TRF2 (xTRF2) associates with chromatin throughout the cell cycle. We showed that Polo-like kinase (Plx1) phosphorylates xTRF1 in vitro. Moreover, the mitotic xTRF1–chromatin association was significantly impaired when Plx1 was immunodepleted from the extracts. Finally, high telomerase activities were detected in association with replicating interphase chromatin compared with mitotic chromatin. These results indicate that telomere chromatin is actively regulated by cell-cycle-dependent processes, and provide an insight for understanding how telomeres undergo DNA metabolisms during the cell cycle. PMID:16424898

  15. Radiation emitting devices regulations

    International Nuclear Information System (INIS)

    1970-01-01

    The Radiation Emitting Devices Regulations are the regulations referred to in the Radiation Emitting Devices Act and relate to the operation of devices. They include standards of design and construction, standards of functioning, warning symbol specifications in addition to information relating to the seizure and detention of machines failing to comply with the regulations. The radiation emitting devices consist of the following: television receivers, extra-oral dental x-ray equipment, microwave ovens, baggage inspection x-ray devices, demonstration--type gas discharge devices, photofluorographic x-ray equipment, laser scanners, demonstration lasers, low energy electron microscopes, high intensity mercury vapour discharge lamps, sunlamps, diagnostic x-ray equipment, ultrasound therapy devices, x-ray diffraction equipment, cabinet x-ray equipment and therapeutic x-ray equipment

  16. Safety regulations in Japan

    International Nuclear Information System (INIS)

    Kondo, S.

    1987-01-01

    In Japan, it is provided in the Law for Regulations of Nuclear Source Material, Nuclear Fuel Material and Reactors (referred as LRNR) that the licensee shall establish the safety regulations for individual plant by themselves regarding the operating management of nuclear reactor facility to secure the concrete safety of the nuclear power plant, that he shall receive an authorization of responsible government agencies (Minister of International Trade and Industry for commercial power station) and that this regulation shall be kept by the licensee and its employees. Furthermore, it is also provided in the same law that the licensee shall voluntarily nominate a chief reactor engineer to supervise the safety of reactor operation and that those who are engaged to the reactor operation shall obey the chief reactor engineer's instruction for the safety of reactor operation. These two factors are the base of the voluntary security system for reactor safety

  17. Volume regulation in epithelia

    DEFF Research Database (Denmark)

    Larsen, Erik Hviid; Hoffmann, Else Kay

    2016-01-01

    We review studies on regulatory volume decrease (RVD) and regulatory volume increase (RVI) of major ion and water transporting vertebrate epithelia. The rate of RVD and RVI is faster in cells of high osmotic permeability like amphibian gallbladder and mammalian proximal tubule as compared...... function of iso-osmotic fluid transport that depends on Na+ recirculation. The causative relationship is discussed for a fluid-absorbing and a fluid-secreting epithelium of which the Na+ recirculation mechanisms have been identified. A large number of transporters and ion channels involved in cell volume...... regulation are cloned. The volume-regulated anion channel (VRAC) exhibiting specific electrophysiological characteristics seems exclusive to serve cell volume regulation. This is contrary to K+ channels as well as cotransporters and exchange mechanisms that may serve both transepithelial transport and cell...

  18. Regulating multiple externalities

    DEFF Research Database (Denmark)

    Waldo, Staffan; Jensen, Frank; Nielsen, Max

    2016-01-01

    Open access is a well-known externality problem in fisheries causing excess capacity and overfishing. Due to global warming, externality problems from CO2 emissions have gained increased interest. With two externality problems, a first-best optimum can be achieved by using two regulatory...... instruments. However, solving the open-access externality problem also affects CO2 emissions. By using a bio-economic model covering Iceland, Norway, Denmark, Sweden, and the Faroe Islands, it is shown that regulations of the open-access externality problem have a large effect on both economic performance...... and CO2 emissions, while an additional CO2 regulation only has minor effects. The second-best solution achieved by only regulating open access reduces emissions by approximately 50% compared to current fisheries, with the exception of Iceland, which already has a well-developed fisheries management...

  19. Staff rules and regulations

    CERN Multimedia

    HR Department

    2007-01-01

    The 11th edition of the Staff Rules and Regulations, dated 1 January 2007, adopted by the Council and the Finance Committee in December 2006, is currently being distributed to departmental secretariats. The Staff Rules and Regulations, together with a summary of the main modifications made, will be available, as from next week, on the Human Resources Department's intranet site: http://cern.ch/hr-web/internal/admin_services/rules/default.asp The main changes made to the Staff Rules and Regulations stem from the five-yearly review of employment conditions of members of the personnel. The changes notably relate to: the categories of members of the personnel (e.g. removal of the local staff category); the careers structure and the merit recognition system; the non-residence, installation and re-installation allowances; the definition of family, family allowances and family-related leave; recognition of partnerships; education fees. The administrative circulars, some of which are being revised following the ...

  20. Public regulators and CSR

    DEFF Research Database (Denmark)

    Buhmann, Karin

    2016-01-01

    analysis of an expansion of law into the normative framing of what constitutes responsible business conduct, we demonstrate a process of juridification entailing a legal framing of social expectations of companies, a proliferation of law into the field of business ethics, and an increased regulation by law......The social licence to operate (SLO) concept is little developed in the academic literature so far. Deployment of the term was made by the United National (UN) Guiding Principles on Business and Human Rights and the UN ‘Protect, Respect and Remedy’ Framework, which apply SLO as an argument...... for responsible business conduct, connecting to social expectations and bridging to public regulation. This UN guidance has had a significant bearing on how public regulators seek to influence business conduct beyond Human Rights to broader Corporate Social Responsibility (CSR) concerns. Drawing on examples...

  1. The central governor model of exercise regulation teaches us precious little about the nature of mental fatigue and self-control failure

    Directory of Open Access Journals (Sweden)

    Michael eInzlicht

    2016-05-01

    Full Text Available Self-control is considered broadly important for many domains of life. One of its unfortunate features, however, is that it tends to wane over time, with little agreement about why this is the case. Recently, there has been a push to address this problem by looking to the literature in exercise physiology, specifically the work on the central governor model of physical fatigue. Trying to explain how and why mental performance wanes over time, the central governor model suggests that exertion is throttled by some central nervous system mechanism that receives information about energetic bodily needs and motivational drives to regulate exertion and, ultimately, to prevent homeostatic breakdown, chiefly energy depletion. While we admire the spirit of integration and the attempt to shed light on an important topic in psychology, our concern is that the central governor model is very controversial in exercise physiologists, with increasing calls to abandon it altogether, making it a poor fit for psychology. Our concerns are threefold. First, while we agree that preservation of bodily homeostasis makes for an elegant ultimate account, the fact that such important homeostatic concerns can be regularly overturned with even slight incentives (e.g., a smile renders the ultimate account impotent and points to other ultimate functions for fatigue. Second, despite the central governor being thought to take as input information about the metabolic needs of the body, there is no credible evidence that mental effort actually consumes inordinate amounts of energy that are not already circulating in the brain. Third, recent modifications of the model make the central governor appear like an all-knowing homunculus and unfalsifiable in principle, thus contributing very little to our understanding of why people tend to disengage from effortful tasks over time. We note that the latest models in exercise physiology have actually borrowed concepts and models from

  2. The Impact of Regulating Social Science Research with Biomedical Regulations

    Science.gov (United States)

    Durosinmi, Brenda Braxton

    2011-01-01

    The Impact of Regulating Social Science Research with Biomedical Regulations Since 1974 Federal regulations have governed the use of human subjects in biomedical and social science research. The regulations are known as the Federal Policy for the Protection of Human Subjects, and often referred to as the "Common Rule" because 18 Federal…

  3. Regulated underground storage tanks

    International Nuclear Information System (INIS)

    1992-06-01

    This guidance package is designed to assist DOE Field operations by providing thorough guidance on the underground storage tank (UST) regulations. [40 CFR 280]. The guidance uses tables, flowcharts, and checklists to provide a ''roadmap'' for DOE staff who are responsible for supervising UST operations. This package is tailored to address the issues facing DOE facilities. DOE staff should use this guidance as: An overview of the regulations for UST installation and operation; a comprehensive step-by-step guidance for the process of owning and operating an UST, from installation to closure; and a quick, ready-reference guide for any specific topic concerning UST ownership or operation

  4. Nuclear regulations and environment

    International Nuclear Information System (INIS)

    Oliveira, Antonio A.

    2001-01-01

    After an historical overview of the nuclear regulation system in Argentina a description is made of the country's Nuclear Regulatory Authority (ARN) and of its regulation and control functions. Its organic structure is also outlined. A detailed report is given of the environmental monitoring activities in the sites of the operating Argentine nuclear power plants as well as those of the nuclear research centres. A special reference is made of the monitoring of the relevant uranium mining districts in Argentina. The radon determination in houses of several regions of the country is also mentioned

  5. Nuclear regulation and safety

    International Nuclear Information System (INIS)

    Hendrie, J.M.

    1982-01-01

    Nuclear regulation and safety are discussed from the standpoint of a hypothetical country that is in the process of introducing a nuclear power industry and setting up a regulatory system. The national policy is assumed to be in favor of nuclear power. The regulators will have responsibility for economic, reliable electric production as well as for safety. Reactor safety is divided into three parts: shut it down, keep it covered, take out the afterheat. Emergency plans also have to be provided. Ways of keeping the core covered with water are discussed

  6. Metabolic regulation of yeast

    Science.gov (United States)

    Fiechter, A.

    1982-12-01

    Metabolic regulation which is based on endogeneous and exogeneous process variables which may act constantly or time dependently on the living cell is discussed. The observed phenomena of the regulation are the result of physical, chemical, and biological parameters. These parameters are identified. Ethanol is accumulated as an intermediate product and the synthesis of biomass is reduced. This regulatory effect of glucose is used for the aerobic production of ethanol. Very high production rates are thereby obtained. Understanding of the regulation mechanism of the glucose effect has improved. In addition to catabolite repression, several other mechanisms of enzyme regulation have been described, that are mostly governed by exogeneous factors. Glucose also affects the control of respiration in a third class of yeasts which are unable to make use of ethanol as a substrate for growth. This is due to the lack of any anaplerotic activity. As a consequence, diauxic growth behavior is reduced to a one-stage growth with a drastically reduced cell yield. The pulse chemostat technique, a systematic approach for medium design is developed and medium supplements that are essential for metabolic control are identified.

  7. Understanding medical device regulation.

    Science.gov (United States)

    Galgon, Richard E

    2016-12-01

    The purpose of this article is to provide a structural and functional understanding of the systems used for the regulation of medical devices in the USA and European Union (EU). Safe and effective anesthesia care depends heavily on medical devices, including simple, low risk devices to complex life-supporting and life-sustaining devices. In the USA and EU, the Food and Drug Administration and European Commission, respectively, provide regulatory oversight to ensure medical devices are reasonably safe and effective when used for their intended purposes. Unfortunately, practicing anesthesiologists generally have little or no understanding of how medical devices are regulated, nor do they have sufficient knowledge of available adverse event reporting systems. The US and EU medical device regulatory systems are similar in many ways, but differ in important ways too, which impacts the afforded level of safety and effectiveness assurance. In both systems, medical devices are classified and regulated on a risk basis, which fundamentally differs from drug regulation, where uniform requirements are imposed. Anesthesia providers must gain knowledge of these systems and be active players in both premarket and postmarket activities, particularly with regard to vigilance and adverse event/device failure reporting.

  8. Legislation and regulation

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2001-09-01

    This document presents the fulfilling of the Brazilian obligations under the Convention on Nuclear Safety. The Chapter 3 of the document contains some details about the Brazilian legislation and regulation, the legislative and regulatory framework, regulatory body and responsibility of the license holder.

  9. Allosteric Regulation of Proteins

    Indian Academy of Sciences (India)

    For example, the structural changes that allowed for allosteric regulation of haemoglobin were re- vealed through structural elucidation of the protein in free and oxygen-bound forms by X-ray crystallography. Following this,. X-ray crystallography has been utilized to study a variety of al- losteric proteins including ATCase. 2.

  10. Regulations in radiation protection

    International Nuclear Information System (INIS)

    1986-01-01

    On the occasion of the twenty fifth anniversary of the Dutch Society for Radiation Protection, a symposium was held about Regulations in Radiation Protection. The program consisted of six contributions of which four are included in this publication. The posters presented are published in NVS-nieuws, 1985, vol. 11(5). (G.J.P.)

  11. Federal Gasoline Regulations

    Science.gov (United States)

    The Clean Air Act requires EPA to regulate fuels and fuel additives for use in mobile sources if such fuel, fuel additive or any emission products causes or contributes to air or water pollution that may endanger the public health or welfare.

  12. Regulation of serum phosphate

    Science.gov (United States)

    Lederer, Eleanor

    2014-01-01

    The regulation of serum phosphate, an acknowledged risk factor for chronic kidney disease and cardiovascular mortality, is poorly understood. The discovery of fibroblast growth factor 23 (FGF23) as a key regulator of renal phosphate handling and activation of vitamin D has revolutionized our comprehension of phosphate homeostasis. Through as yet undetermined mechanisms, circulating and dietary phosphate appear to have a direct effect on FGF23 release by bone cells that, in turn, causes renal phosphate excretion and decreases intestinal phosphate absorption through a decrease in vitamin D production. Thus, the two major phosphaturic hormones, PTH and FGF23, have opposing effects on vitamin D production, placing vitamin D at the nexus of phosphate homeostasis. While our understanding of phosphate homeostasis has advanced, the factors determining regulation of serum phosphate level remain enigmatic. Diet, time of day, season, gender, age and genetics have all been identified as significant contributors to serum phosphate level. The effects of these factors on serum phosphate have major implications for what is understood as ‘normal’ and for studies of phosphate homeostasis and metabolism. Moreover, other hormonal mediators such as dopamine, insulin-like growth factor, and angiotensin II also affect renal handling of phosphate. How the major hormone effects on phosphate handling are regulated and how the effect of these other factors are integrated to yield the measurable serum phosphate are only now beginning to be studied. PMID:24973411

  13. Focus on PTEN Regulation

    Science.gov (United States)

    Bermúdez Brito, Miriam; Goulielmaki, Evangelia; Papakonstanti, Evangelia A.

    2015-01-01

    The role of phosphatase and tensin homolog on chromosome 10 (PTEN) as a tumor suppressor has been for a long time attributed to its lipid phosphatase activity against PI(3,4,5)P3, the phospholipid product of the class I PI3Ks. Besides its traditional role as a lipid phosphatase at the plasma membrane, a wealth of data has shown that PTEN can function independently of its phosphatase activity and that PTEN also exists and plays a role in the nucleus, in cytoplasmic organelles, and extracellularly. Accumulating evidence has shed light on diverse physiological functions of PTEN, which are accompanied by a complex regulation of its expression and activity. PTEN levels and function are regulated transcriptionally, post-transcriptionally, and post-translationally. PTEN is also sensitive to regulation by its interacting proteins and its localization. Herein, we summarize the current knowledge on mechanisms that regulate the expression and enzymatic activity of PTEN and its role in human diseases. PMID:26284192

  14. Vehicle recycling regulations

    DEFF Research Database (Denmark)

    Smink, Carla

    2007-01-01

    The number of end-of-life vehicles (ELVs) in the EU is increasing continously. Around 75 percent of an ELV are recyclable metals. The forecast growth in the number of ELVs calls for regulation that aims to minimise the environmental impact of a car. Using Denmark as an example, this article...

  15. Emotion regulation during isolation

    Czech Academy of Sciences Publication Activity Database

    Poláčková Šolcová, Iva; Šolcová, Iva

    2012-01-01

    Roč. 47, Suppl. 1 (2012) ISSN 0020-7594. [International Congress of Psychology /30./. 22.07.2012-27.07.2012, Cape Town] R&D Projects: GA ČR(CZ) GAP407/11/2226 Institutional support: RVO:68081740 Keywords : emotion regulation * isolation * Mars500 Subject RIV: AN - Psychology

  16. Regulating nuclear fuel waste

    International Nuclear Information System (INIS)

    1995-01-01

    When Parliament passed the Atomic Energy Control Act in 1946, it erected the framework for nuclear safety in Canada. Under the Act, the government created the Atomic Energy Control Board and gave it the authority to make and enforce regulations governing every aspect of nuclear power production and use in this country. The Act gives the Control Board the flexibility to amend its regulations to adapt to changes in technology, health and safety standards, co-operative agreements with provincial agencies and policy regarding trade in nuclear materials. This flexibility has allowed the Control Board to successfully regulate the nuclear industry for more than 40 years. Its mission statement 'to ensure that the use of nuclear energy in Canada does not pose undue risk to health, safety, security and the environment' concisely states the Control Board's primary objective. The Atomic Energy Control Board regulates all aspects of nuclear energy in Canada to ensure there is no undue risk to health, safety, security or the environment. It does this through a multi-stage licensing process

  17. Allosteric Regulation of Proteins

    Indian Academy of Sciences (India)

    ... Lecture Workshops · Refresher Courses · Symposia · Live Streaming. Home; Journals; Resonance – Journal of Science Education; Volume 22; Issue 1. Allosteric Regulation of Proteins: A Historical Perspective on the Development of Concepts and Techniques. General Article Volume 22 Issue 1 January 2017 pp 37-50 ...

  18. Regulation of gene expression by 17β-estradiol in the arcuate nucleus of the mouse through ERE-dependent and ERE-independent mechanisms.

    Science.gov (United States)

    Yang, Jennifer A; Mamounis, Kyle J; Yasrebi, Ali; Roepke, Troy A

    2016-03-01

    17β-Estradiol (E2) modulates gene expression in the hypothalamic arcuate nucleus (ARC) to control homeostatic functions. In the ARC, estrogen receptor (ER) α is highly expressed and is an important contributor to E2's actions, controlling gene expression through estrogen response element (ERE)-dependent and -independent mechanisms. The objective of this study was to determine if known E2-regulated genes are regulated through these mechanisms. The selected genes have been shown to regulate homeostasis and have been separated into three subsections: channels, receptors, and neuropeptides. To determine if ERE-dependent or ERE-independent mechanisms regulate gene expression, two transgenic mouse models, an ERα knock-out (ERKO) and an ERα knock-in/knock-out (KIKO), which lacks a functional ERE binding domain, were used in addition to their wild-type littermates. Females of all genotypes were ovariectomized and injected with oil or estradiol benzoate (E2B). Our results suggest that E2B regulates multiple genes through these mechanisms. Of note, Cacna1g and Kcnmb1 channel expression was increased by E2B in WT females only, suggesting an ERE-dependent regulation. Furthermore, the NKB receptor, Tac3r, was suppressed by E2B in WT and KIKO females but not ERKO females, suggesting that ERα-dependent, ERE-independent signaling is necessary for Tac3r regulation. The adrenergic receptor Adra1b was suppressed by E2B in all genotypes indicating that ERα is not the primary receptor for E2B's actions. The neuropeptide Tac2 was suppressed by E2B through ERE-dependent mechanisms. These results indicate that E2B activates both ERα-dependent and independent signaling in the ARC through ERE-dependent and ERE-independent mechanisms to control gene expression. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Ethanol Exposure RegulatesGabra1Expression via Histone Deacetylation at the Promoter in Cultured Cortical Neurons.

    Science.gov (United States)

    Bohnsack, John Peyton; Patel, Vraj K; Morrow, A Leslie

    2017-10-01

    γ -Aminobutyric acid A receptors (GABA A -Rs) mediate the majority of inhibitory neurotransmission in the adult brain. The α 1-containing GABA A -Rs are the most prominent subtype in the adult brain and are important in both homeostatic function and several disease pathologies including alcohol dependence, epilepsy, and stress. Ethanol exposure causes a decrease of α 1 transcription and peptide expression both in vivo and in vitro, but the mechanism that controls the transcriptional regulation is unknown. Because ethanol is known to activate epigenetic regulation of gene expression, we tested the hypothesis that ethanol regulates α 1 expression through histone modifications in cerebral cortical cultured neurons. We found that class I histone deacetylases (HDACs) regulate ethanol-induced changes in α 1 gene and protein expression as pharmacologic inhibition or knockdown of HDAC1-3 prevents the effects of ethanol exposure. Targeted histone acetylation associated with the Gabra1 promoter using CRISPR (clustered regularly interspaced palindromic repeat) dCas9-P300 (a nuclease-null Cas9 fused with a histone acetyltransferase) increases histone acetylation and prevents the decrease of Gabra1 expression. In contrast, there was no effect of a mutant histone acetyltransferase or generic transcriptional activator or targeting P300 to a distant exon. Conversely, using a dCas9-KRAB construct that increases repressive methylation (H3K9me3) does not interfere with ethanol-induced histone deacetylation. Overall our results indicate that ethanol deacetylates histones associated with the Gabra1 promoter through class I HDACs and that pharmacologic, genetic, or epigenetic intervention prevents decreases in α 1 expression in cultured cortical neurons. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  20. Differential regulation of spontaneous and evoked inhibitory synaptic transmission in somatosensory cortex by retinoic acid.

    Science.gov (United States)

    Yee, Ada X; Chen, Lu

    2016-11-01

    Retinoic acid (RA), a developmental morphogen, has emerged in recent studies as a novel synaptic signaling molecule that acts in mature hippocampal neurons to modulate excitatory and inhibitory synaptic transmission in the context of homeostatic synaptic plasticity. However, it is unclear whether RA is capable of modulating neural circuits outside of the hippocampus, and if so, whether the mode of RA's action at synapses is similar to that within the hippocampal network. Here we explore for the first time RA's synaptic function outside the hippocampus and uncover a novel function of all-trans retinoic acid at inhibitory synapses. Acute RA treatment increases spontaneous inhibitory synaptic transmission in L2/3 pyramidal neurons of the somatosensory cortex, and this effect requires expression of RA's receptor RARα both pre- and post-synaptically. Intriguingly, RA does not seem to affect evoked inhibitory transmission assayed with either extracellular stimulation or direct activation of action potentials in presynaptic interneurons at connected pairs of interneurons and pyramidal neurons. Taken together, these results suggest that RA's action at synapses is not monotonous, but is diverse depending on the type of synaptic connection (excitatory versus inhibitory) and circuit (hippocampal versus cortical). Thus, synaptic signaling of RA may mediate multi-faceted regulation of synaptic plasticity. In addition to its classic roles in brain development, retinoic acid (RA) has recently been shown to regulate excitatory and inhibitory transmission in the adult brain. Here, the authors show that in layer 2/3 (L2/3) of the somatosensory cortex (S1), acute RA induces increases in spontaneous but not action-potential evoked transmission, and that this requires retinoic acid receptor (RARα) both in presynaptic PV-positive interneurons and postsynaptic pyramidal (PN) neurons. © 2016 Wiley Periodicals, Inc.

  1. Anion Exchanger 2 Regulates Dectin-1-Dependent Phagocytosis and Killing of Candida albicans.

    Directory of Open Access Journals (Sweden)

    Katia Urso

    Full Text Available Anion exchanger 2 (Ae2; gene symbol, Slc4a2 is a plasma membrane Cl-/HCO3- exchanger expressed in the gastrointestinal tract, kidney and bone. We have previously shown that Ae2 is required for the function of osteoclasts, bone resorbing cells of the macrophage lineage, to maintain homeostatic cytoplasmic pH and electroneutrality during acid secretion. Macrophages require endosomal acidification for pathogen killing during the process known as phagocytosis. Chloride is thought to be the principal ion responsible for maintaining electroneutrality during organelle acidification, but whether Cl-/HCO3- exchangers such as Ae2 contribute to macrophage function is not known. In this study we investigated the role of Ae2 in primary macrophages during phagocytosis. We find that Ae2 is expressed in macrophages where it regulates intracellular pH and the binding of Zymosan, a fungal cell wall derivative. Surprisingly, the transcription and surface expression of Dectin-1, the major phagocytic receptor for Candida albicans (C. albicans and Zymosan, is reduced in the absence of Ae2. As a consequence, Zymosan-induced Tnfα expression is also impaired in Ae2-deficient macrophages. Similar to Ae2 deficiency, pharmacological alkalinization of lysosomal pH with bafilomycin A decreases both Dectin-1 mRNA and cell surface expression. Finally, Ae2-deficient macrophages demonstrate defective phagocytosis and killing of the human pathogenic fungus C. albicans. Our results strongly suggest that Ae2 is a critical factor in the innate response to C. albicans. This study represents an important contribution to a better understanding of how Dectin-1 expression and fungal clearance is regulated.

  2. A formal description of middle ear pressure-regulation.

    Science.gov (United States)

    Doyle, William J

    2017-10-01

    Middle ear (ME) pressure-regulation (MEPR) is a homeostatic mechanism that maintains the ME-environment pressure-gradient (MEEPG) within a range optimized for "normal" hearing. Describe MEPR using equations applicable to passive, inter-compartmental gas-exchange and determine if the predictions of that description include the increasing ME pressure observed under certain conditions and interpreted by some as evidencing gas-production by the ME mucosa. MEPR was modeled as the combined effect of passive gas-exchanges between the ME and: perilymph via the round window membrane, the ambient environment via the tympanic membrane, and the local blood via the ME mucosa and of gas flow between the ME and nasopharynx during Eustachian tube openings. The first 3 of these exchanges are described at the species level using the Fick's diffusion equation and the last as a bulk gas transfer governed by Poiseuille's equation. The model structure is a time-iteration of the equation: P ME g(t=(i+1)Δt)  = ∑ s (P ME s(t=iΔt) +(1/(β ME s V ME )∑ P (Қ P s (P C s(t=(iΔt) -P ME s(t=(iΔt) )). There, P ME g(t=iΔt) and P ME s(t=iΔt) are the ME total and species-pressures at the indexed times, P C s(t=iΔt) is the species-pressure for each exchange-compartment, β ME s V ME is the product of the ME species-capacitance and volume, Қ P s is the pathway species-conductance, and ∑ S and ∑ P are operators for summing the expression over all species or exchange pathways. When calibrated to known values, the model predicts the empirically measured ME species-pressures and the observed time-trajectories for total ME pressure and the MEEPG under a wide variety of physiologic, pathologic and non-physiologic conditions. Passive inter-compartmental gas exchange is sole and sufficient to describe MEPR. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Environmental considerations and regulations

    International Nuclear Information System (INIS)

    Blanco, R.E.

    1976-01-01

    Methods used to control the radiological impact of the nuclear fuel cycle are described. This control is exercised through the application of a series of federal laws and regulations that are used as the basis for licensing nuclear facilities. The control is exercised more directly by the use of radwaste treatment equipment at the nuclear facilities to limit the release of radioactive materials. Federal laws and regulations are summarized and their applications in licensing actions are discussed. Radiological doses from materials released from licensed facilities are compared with doses from natural background. A series of cost/benefit engineering surveys are being made to determine the cost and effectiveness of radwaste systems for decreasing the release of radioactive materials from model fuel cycle facilities and to determine the benefits in terms of reduction in dose commitment to individuals and populations in surrounding areas

  4. Markets, religion, regulation

    DEFF Research Database (Denmark)

    Fischer, Johan

    2016-01-01

    of regulation, certification and standardization on a global scale. Building on research on global kosher (a Hebrew term meaning “fit” or “proper”), halal (an Arabic word that literally means “permissible” or “lawful”) and Hindu vegetarianism this paper argues that these economies or markets to a large extent......Most recent scholarship on moral economies or religious markets argues for the compatibility of economies/markets and religious practices in particular national or regional contexts. However, over the last couple of decades or so religious markets have entered a new phase characterized by new forms...... are conditioned by and themselves condition forms of transnational governmentality, that is, new and often overlapping practices of government and grassroots politics. I explore religious economies and markets at three interrelated levels of the social scale: state and non-state regulation, the marketplace...

  5. Probiotics and Appetite Regulation

    DEFF Research Database (Denmark)

    Bjerg, Anne Toksvig

    resistance and blood lipid profile among others. Probiotics which are health promoting bacteria can potentially be used to affect the GM and thereby change metabolic outcomes of the host. Animal studies have shown associations between intake of probiotics and appetite regulation, but currently no human...... studies have investigated this effect. Supplementation with different probiotic strains have been shown to have an effect on blood lipid profiles in both animals and humans and the mechanisms behind have been studied in vitro and in rodents. The aim of the present thesis was to examine in an ex vivo...... intestine, in an animal study and in two human studies the effect of the probiotic bacteria Lactobacillus paracasei subsp. paracasei L. casei W8 (W8) on appetite regulation, blood lipids and blood fatty acids. In addition, it was investigated if W8 had an effect on the fecal microbiota of the human...

  6. Regulating prefrontal cortex activation

    DEFF Research Database (Denmark)

    Aznar, Susana; Klein, Anders Bue

    2013-01-01

    The prefrontal cortex (PFC) is involved in mediating important higher-order cognitive processes such as decision making, prompting thereby our actions. At the same time, PFC activation is strongly influenced by emotional reactions through its functional interaction with the amygdala...... and the striatal circuitry, areas involved in emotion and reward processing. The PFC, however, is able to modulate amygdala reactivity via a feedback loop to this area. A role for serotonin in adjusting for this circuitry of cognitive regulation of emotion has long been suggested based primarily on the positive...... pharmacological effect of elevating serotonin levels in anxiety regulation. Recent animal and human functional magnetic resonance studies have pointed to a specific involvement of the 5-hydroxytryptamine (5-HT)2A serotonin receptor in the PFC feedback regulatory projection onto the amygdala. This receptor...

  7. Regulation of Meiotic Recombination

    Energy Technology Data Exchange (ETDEWEB)

    Gregory p. Copenhaver

    2011-11-09

    Meiotic recombination results in the heritable rearrangement of DNA, primarily through reciprocal exchange between homologous chromosome or gene conversion. In plants these events are critical for ensuring proper chromosome segregation, facilitating DNA repair and providing a basis for genetic diversity. Understanding this fundamental biological mechanism will directly facilitate trait mapping, conventional plant breeding, and development of genetic engineering techniques that will help support the responsible production and conversion of renewable resources for fuels, chemicals, and the conservation of energy (1-3). Substantial progress has been made in understanding the basal recombination machinery, much of which is conserved in organisms as diverse as yeast, plants and mammals (4, 5). Significantly less is known about the factors that regulate how often and where that basal machinery acts on higher eukaryotic chromosomes. One important mechanism for regulating the frequency and distribution of meiotic recombination is crossover interference - or the ability of one recombination event to influence nearby events. The MUS81 gene is thought to play an important role in regulating the influence of interference on crossing over. The immediate goals of this project are to use reverse genetics to identify mutants in two putative MUS81 homologs in the model plant Arabidopsis thaliana, characterize those mutants and initiate a novel forward genetic screen for additional regulators of meiotic recombination. The long-term goal of the project is to understand how meiotic recombination is regulated in higher eukaryotes with an emphasis on the molecular basis of crossover interference. The ability to monitor recombination in all four meiotic products (tetrad analysis) has been a powerful tool in the arsenal of yeast geneticists. Previously, the qrt mutant of Arabidopsis, which causes the four pollen products of male meiosis to remain attached, was developed as a facile system

  8. Risk, uncertainty and regulation.

    Science.gov (United States)

    Krebs, John R

    2011-12-13

    This paper reviews the relationship between scientific evidence, uncertainty, risk and regulation. Risk has many different meanings. Furthermore, if risk is defined as the likelihood of an event happening multiplied by its impact, subjective perceptions of risk often diverge from the objective assessment. Scientific evidence may be ambiguous. Scientific experts are called upon to assess risks, but there is often uncertainty in their assessment, or disagreement about the magnitude of the risk. The translation of risk assessments into policy is a political judgement that includes consideration of the acceptability of the risk and the costs and benefits of legislation to reduce the risk. These general points are illustrated with reference to three examples: regulation of risk from pesticides, control of bovine tuberculosis and pricing of alcohol as a means to discourage excessive drinking.

  9. ELECTRON EMISSION REGULATING MEANS

    Science.gov (United States)

    Brenholdt, I.R.

    1957-11-19

    >An electronic regulating system is described for controlling the electron emission of a cathode, for example, the cathode in a mass spectrometer. The system incorporates a transformer having a first secondary winding for the above-mentioned cathode and a second secondary winding for the above-mentioned cathode and a second secondary winding load by grid controlled vacuum tubes. A portion of the electron current emitted by the cathode is passed through a network which develops a feedback signal. The system arrangement is completed by using the feedback signal to control the vacuum tubes in the second secondary winding through a regulator tube. When a change in cathode emission occurs, the feedback signal acts to correct this change by adjusting the load on the transformer.

  10. Financial Investment Services Regulation

    Directory of Open Access Journals (Sweden)

    Gabriela Anghelache

    2006-04-01

    Full Text Available This article includes the latest regulations regarding the financial investments services. After presenting some elements about prudence and conduct rules, the peculiar aspects of the presentation form and of the contract, with all the forms demanded by such transaction, are analyzed. Afterwards, the focus is set on the transparency and integrity of the operations. Another aspect is about the free circulation of services and about the role of the clearing fund, being distinguished all thesensitive elements this fund raises.

  11. Payday lending regulation

    OpenAIRE

    Alex Kaufman

    2013-01-01

    To date the debate over payday lending has focused on whether access to such lending is on net beneficial or harmful to consumer welfare. However, payday loans are not one product but many, and different forms of lending may have different welfare implications. The current diversity in payday lending stems from the diverse ways in which states have regulated the industry. This paper attempts to quantify the effects that various regulatory approaches have had on lending terms and usage. Using ...

  12. Empowerment and regulation

    DEFF Research Database (Denmark)

    Jacobsen, Rikke Becker; Wilson, Douglas Clyde; Ramirez-Monsalve, Paulina

    2012-01-01

    Using a perspective from the sociology of knowledge, this study identifies some ‘dilemmas of participatory research’. We look at how social relationships between fishers and scientists develop around the exchange of fishers’ knowledge in particular institutional contexts. We survey the general ty......’ fishers to support the effective management of the fishing commons and the bureaucratic need to regulate the fishery as an industry....

  13. Improving CS regulations.

    Energy Technology Data Exchange (ETDEWEB)

    Nesse, R.J.; Scheer, R.M.; Marasco, A.L.; Furey, R.

    1980-10-01

    President Carter issued Executive Order 12044 (3/28/78) that required all Federal agencies to distinguish between significant and insignificant regulations, and to determine whether a regulation will result in major impacts. This study gathered information on the impact of the order and the guidelines on the Office of Conservation and Solar Energy (CS) regulatory practices, investigated problems encountered by the CS staff when implementing the order and guidelines, and recommended solutions to resolve these problems. Major tasks accomplished and discussed are: (1) legislation, Executive Orders, and DOE Memoranda concerning Federal administrative procedures relevant to the development and analysis of regulations within CS reviewed; (2) relevant DOE Orders and Memoranda analyzed and key DOE and CS staff interviewed in order to accurately describe the current CS regulatory process; (3) DOE staff from the Office of the General Counsel, the Office of Policy and Evaluation, the Office of the Environment, and the Office of the Secretary interviewed to explore issues and problems encountered with current CS regulatory practices; (4) the regulatory processes at five other Federal agencies reviewed in order to see how other agencies have approached the regulatory process, dealt with specific regulatory problems, and responded to the Executive Order; and (5) based on the results of the preceding four tasks, recommendations for potential solutions to the CS regulatory problems developed. (MCW)

  14. Staff rules and regulations

    CERN Multimedia

    HR Department

    2007-01-01

    The 11th edition of the Staff Rules and Regulations, dated 1 January 2007, adopted by the Council and the Finance Committee in December 2006, is currently being distributed to departmental secretariats. The Staff Rules and Regulations, together with a summary of the main modifications made, will be available, as from next week, on the Human Resources Department's intranet site: http://cern.ch/hr-web/internal/admin_services/rules/default.asp The main changes made to the Staff Rules and Regulations stem from the five-yearly review of employment conditions of members of the personnel. The changes notably relate to: the categories of members of the personnel (e.g. removal of the local staff category); the careers structure and the merit recognition system; the non-residence, installation and re-installation allowances; the definition of family, family allowances and family-related leave; recognition of partnerships; education fees. The administrative circulars, some of which are being revised following the m...

  15. Nuclear Safety Regulations

    International Nuclear Information System (INIS)

    Novosel, N.; Prah, M.

    2008-01-01

    Beside new Ordinance on the control of nuclear material and special equipment ('Official Gazette' No. 15/08), from 2006 State Office for Nuclear Safety (SONS) adopted Ordinance on performing nuclear activities ('Official Gazette' No. 74/06) and Ordinance on special requirements which expert organizations must fulfil in order to perform certain activities in the field of nuclear safety ('Official Gazette' No. 74/06), based on Nuclear Safety Act ('Official Gazette' No. 173/03). The Ordinance on performing nuclear activities regulates the procedure of notification of the intent to perform nuclear activities, submitting the application for the issue of a licence to perform nuclear activities, and the procedure for issuing decisions on granting a licence to perform a nuclear activity. The Ordinance also regulates the content of the forms for notification of the intent to perform nuclear activities, as well as of the application for the issue of a licence to perform the nuclear activity and the method of keeping the register of nuclear activities. According to the Nuclear Safety Act, nuclear activities are the production, processing, use, storage, disposal, transport, import, export, possession or other handling of nuclear material or specified equipment. The Ordinance on special requirements which expert organizations must fulfil in order to perform certain activities in the field of nuclear safety regulates these mentioned conditions, whereas compliance is established by a decision passed by the SONS. Special requirements which expert organizations must fulfil in order to perform certain activities in the field of nuclear safety are organizational, technical, technological conditions and established system of quality assurance. In 2007, State Office for Nuclear Safety finalized the text of new Ordinance on conditions for nuclear safety and protection with regard to the siting, design, construction, use and decommissioning of a facility in which a nuclear activity is

  16. The international radioactive transportation regulations: A model for national regulations

    International Nuclear Information System (INIS)

    Pope, R.B.; Rawl, R.R.

    1990-06-01

    The International Atomic Energy Agency's (IAEA) Regulations for the Safe Transport of Radioactive Material, Safety Series No. 6 (herein after denoted as the ''International Regulations'') serve as the model for the regulations for individual countries and international modal organizations controlling the packaging and transportation of radioactive materials. The purpose of this paper is to outline the background and history of the International Regulations, the general principles behind the requirements of the International Regulations, the structure and general contents of the latest edition of the International Regulations, and the roles of various international bodies in the development and implementation of the International Regulations and the current status of regulatory and supportive document development at both the international and domestic level. This review will provide a basis for users and potential users to better understand the source and application of the International Regulations. 1 tab

  17. The Regulation of Street Foods

    DEFF Research Database (Denmark)

    Forkour, John Boulard; Samuelsen, Helle; Yeboah, Eric Henry

    2017-01-01

    There has been a lot of research on the relationship between regulators and street vendors, often portraying regulators as bullies of vulnerable vendors. However, there is little documentation on urban regulators and their challenges as they implement their mandates. This paper investigates...... the challenges and negotiating strategies of regulators of street-vended foods in Ghana and analyses the implication for their relationship with street food vendors. The paper reveals that regulators operate in a context of limited resources, leading to a general feeling of neglect. In coping, regulators adopt...... strategies that encourage harassment of vendors and increase tensions between vendors and regulators. Thus, this study establishes relations between the challenges and negotiating strategies of regulators and the poor relations that exist...

  18. Epigenetic Regulation in Plants

    Science.gov (United States)

    Pikaard, Craig S.; Mittelsten Scheid, Ortrun

    2014-01-01

    The study of epigenetics in plants has a long and rich history, from initial descriptions of non-Mendelian gene behaviors to seminal discoveries of chromatin-modifying proteins and RNAs that mediate gene silencing in most eukaryotes, including humans. Genetic screens in the model plant Arabidopsis have been particularly rewarding, identifying more than 130 epigenetic regulators thus far. The diversity of epigenetic pathways in plants is remarkable, presumably contributing to the phenotypic plasticity of plant postembryonic development and the ability to survive and reproduce in unpredictable environments. PMID:25452385

  19. [Regulation of terpene metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Croteau, R.

    1992-01-01

    This report describes accomplishments over the past year on understanding of terpene synthesis in mint plants and sage. Specifically reported are the fractionation of 4-S-limonene synthetase, the enzyme responsible for the first committed step to monoterpene synthesis, along with isolation of the corresponding RNA and DNA cloning of its gene; the localization of the enzyme within the oil glands, regulation of transcription and translation of the synthetase, the pathway to camphor biosynthesis,a nd studies on the early stages and branch points of the isoprenoid pathway.

  20. Wiring regulations in brief

    CERN Document Server

    Tricker, Ray

    2012-01-01

    Tired of trawling through the Wiring Regs?Perplexed by Part P?Confused by cables, conductors and circuits?Then look no further! This handy guide provides an on-the-job reference source for Electricians, Designers, Service Engineers, Inspectors, Builders, Students, DIY enthusiastsTopic-based chapters link areas of working practice - such as cables, installations, testing and inspection, special locations - with the specifics of the Regulations themselves. This allows quick and easy identification of the official requirements relating to the situati

  1. Regulation under Uncertainty

    DEFF Research Database (Denmark)

    Sabel, Charles; Herrigel, Gary; Hull Kristensen, Peer

    2017-01-01

    As production and design disintegrate and become more collaborative, involving dynamic relations between customers and firms supplying complex subsystems and service, products and production methods become more innovative but also more hazardous. The inadvertent co-production of latent hazards...... generation of the implicated components or installations are updated accordingly. In this essay we develop these arguments and look closely at changes in the Norwegian offshore oil and gas industry and its regulator, the Petroleum Safety Authority to better understand the coevolution of vertically...

  2. Nuclear regulation - the Canadian approach

    International Nuclear Information System (INIS)

    Jennekens, J.

    1981-09-01

    Although the Atomic Energy Control Board was established 35 years ago the basic philosophy of nuclear regulation in Canada and the underlying principles of the regulatory process remain essentially unchanged. This paper outlines the Canadian approach to nuclear regulation and explains in practical terms how the principles of regulation are applied. (author)

  3. Endocrine-disrupting chemicals and the regulation of energy balance.

    Science.gov (United States)

    Nadal, Angel; Quesada, Ivan; Tudurí, Eva; Nogueiras, Rubén; Alonso-Magdalena, Paloma

    2017-09-01

    Energy balance involves the adjustment of food intake, energy expenditure and body fat reserves through homeostatic pathways. These pathways include a multitude of biochemical reactions, as well as hormonal cues. Dysfunction of this homeostatic control system results in common metabolism-related pathologies, which include obesity and type 2 diabetes mellitus. Metabolism-disrupting chemicals (MDCs) are a particular class of endocrine-disrupting chemicals that affect energy homeostasis. MDCs affect multiple endocrine mechanisms and thus different cell types that are implicated in metabolic control. MDCs affect gene expression and the biosynthesis of key enzymes, hormones and adipokines that are essential for controlling energy homeostasis. This multifaceted spectrum of actions precludes compensatory responses and favours metabolic disorders. Herein, we review the main mechanisms used by MDCs to alter energy balance. This work should help to identify new MDCs, as well as novel targets of their action.

  4. A Novel Egr-1-Agrin Pathway and Potential Implications for Regulation of Synaptic Physiology and Homeostasis at the Neuromuscular Junction

    Directory of Open Access Journals (Sweden)

    Ryen MacDonald

    2017-08-01

    Full Text Available Synaptic transmission requires intricate coordination of the components involved in processing of incoming signals, formation and stabilization of synaptic machinery, neurotransmission and in all related signaling pathways. Changes to any of these components cause synaptic imbalance and disruption of neuronal circuitry. Extensive studies at the neuromuscular junction (NMJ have greatly aided in the current understanding of synapses and served to elucidate the underlying physiology as well as associated adaptive and homeostatic processes. The heparan sulfate proteoglycan agrin is a vital component of the NMJ, mediating synaptic formation and maintenance in both brain and muscle, but very little is known about direct control of its expression. Here, we investigated the relationship between agrin and transcription factor early growth response-1 (Egr-1, as Egr-1 regulates the expression of many genes involved in synaptic homeostasis and plasticity. Using chromatin immunoprecipitation (ChIP, cell culture with cell lines derived from brain and muscle, and animal models, we show that Egr-1 binds to the AGRN gene locus and suppresses its expression. When compared with wild type (WT, mice deficient in Egr-1 (Egr-1−/− display a marked increase in AGRN mRNA and agrin full-length and cleavage fragment protein levels, including the 22 kDa, C-terminal fragment in brain and muscle tissue homogenate. Because agrin is a crucial component of the NMJ, we explored possible physiological implications of the Egr-1-agrin relationship. In the diaphragm, Egr-1−/− mice display increased NMJ motor endplate density, individual area and area of innervation. In addition to increased density, soleus NMJs also display an increase in fragmented and faint endplates in Egr-1−/− vs. WT mice. Moreover, the soleus NMJ electrophysiology of Egr-1−/− mice revealed increased quantal content and motor testing showed decreased movement and limb muscle strength compared with

  5. Strategisk compliance og regulering

    DEFF Research Database (Denmark)

    Kühn Pedersen, Mogens

    2016-01-01

    Denne artikel introducerer strategisk compliance og påpeger dens samspil med klassiske og nyere former for reguleringer i digital værdiskabelse. Konteksten er den digitale økonomi, som vokser frem imellem den materielle økonomis bærepiller: Virksomheder og markeder, men består af en helt ny...... materialitet, som er det digitale univers og dets modsvarighed i nye krav til compliance. Den nye materialitet stiller nye krav, hvad angår digitale processer og transaktioner. Klassisk regulering, som aktører ikke selv kan ændre, støder på egenregulering, hvor aktørerne selv opsætter regler for at skabe...... digital værdi. Dette kalder på strategisk compliance. Med digitalisering er strategisk compliance sat på dagsordnen i reguleringsdebatten. Vi hævder, at regulering og egenregulering kan komme til at virke komplementært i det post-industrielle, digitaliserede samfund....

  6. Translational regulation in nutrigenomics.

    Science.gov (United States)

    Liu, Botao; Qian, Shu-Bing

    2011-11-01

    The emergence of genome-wide analysis to interrogate cellular DNA, RNA, and protein content has revolutionized the study of the control network that mediates cellular homeostasis. Nutrigenomics addresses the effect of nutrients on gene expression, which provides a basis for understanding the biological activity of dietary components. Translation of mRNAs represents the last step of genetic flow and primarily defines the proteome. Translational regulation is thus critical for gene expression, in particular, under nutrient excess or deficiency. Until recently, it was unclear how the global effects of translational control are influenced by nutrient signaling. An emerging concept of translational reprogramming addresses how to maintain the expression of specific proteins during pathophysiological conditions by translation of selective mRNAs. Here we describe recent advances in our understanding of translational control, nutrient signaling, and their dysregulation in aging and cancer. The mechanistic understanding of translational regulation in response to different nutrient conditions may help identify potential dietary and therapeutic targets to improve human health.

  7. [Regulation of terpene metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Croteau, R.

    1991-01-01

    During the last grant period, we have completed studies on the key pathways of monoterpene biosynthesis and catabolism in sage and peppermint, and have, by several lines of evidence, deciphered the rate-limiting step of each pathway. We have at least partially purified and characterized the relevant enzymes of each pathway. We have made a strong case, based on analytical, in vivo, and in vitro studies, that terpene accumulation depends upon the balance between biosynthesis and catabolism, and provided supporting evidence that these processes are developmentally-regulated and very closely associated with senescence of the oil glands. Oil gland ontogeny has been characterized at the ultrastructural level. We have exploited foliar-applied bioregulators to delay gland senescence, and have developed tissue explant and cell culture systems to study several elusive aspects of catabolism. We have isolated pure gland cell clusters and localized monoterpene biosynthesis and catabolism within these structures, and have used these preparations as starting materials for the purification to homogeneity of target regulatory'' enzymes. We have thus developed the necessary background knowledge, based on a firm understanding of enzymology, as well as the necessary experimental tools for studying the regulation of monoterpene metabolism at the molecular level. Furthermore, we are now in a position to extend our systematic approach to other terpenoid classes (C[sub 15]-C[sub 30]) produced by oil glands.

  8. Regulations and Procedures Manual

    Energy Technology Data Exchange (ETDEWEB)

    Young, Lydia J. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

    2011-07-25

    The purpose of the Regulations and Procedures Manual (RPM) is to provide LBNL personnel with a reference to University and Lawrence Berkeley National Laboratory (LBNL or Laboratory) policies and regulations by outlining normal practices and answering most policy questions that arise in the day-to-day operations of Laboratory organizations. Much of the information in this manual has been condensed from detail provided in LBNL procedure manuals, Department of Energy (DOE) directives, and Contract DE-AC02-05CH11231. This manual is not intended, however, to replace any of those documents. RPM sections on personnel apply only to employees who are not represented by unions. Personnel policies pertaining to employees represented by unions may be found in their labor agreements. Questions concerning policy interpretation should be directed to the LBNL organization responsible for the particular policy. A link to the Managers Responsible for RPM Sections is available on the RPM home page. If it is not clear which organization is responsible for a policy, please contact Requirements Manager Lydia Young or the RPM Editor.

  9. Regulations and Procedures Manual

    Energy Technology Data Exchange (ETDEWEB)

    Young, Lydia [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

    2010-09-30

    The purpose of the Regulations and Procedures Manual (RPM) is to provide Laboratory personnel with a reference to University and Lawrence Berkeley National Laboratory policies and regulations by outlining the normal practices and answering most policy questions that arise in the day-to-day operations of Laboratory departments. Much of the information in this manual has been condensed from detail provided in Laboratory procedure manuals, Department of Energy (DOE) directives, and Contract DE-AC02-05CH11231. This manual is not intended, however, to replace any of those documents. The sections on personnel apply only to employees who are not represented by unions. Personnel policies pertaining to employees represented by unions may be found in their labor agreements. Questions concerning policy interpretation should be directed to the department responsible for the particular policy. A link to the Managers Responsible for RPM Sections is available on the RPM home page. If it is not clear which department should be called, please contact the Associate Laboratory Director of Operations.

  10. The homeostatic psyche: Freudian theory and somatic markers.

    Science.gov (United States)

    Arminjon, Mathieu; Ansermet, François; Magistretti, Pierre

    2010-11-01

    After years of reciprocal lack of interest, if not opposition, neuroscience and psychoanalysis are poised for a renewed dialogue. This article discusses some aspects of the Freudian metapsychology and its link with specific biological mechanisms. It highlights in particular how the physiological concept of homeostasis resonates with certain fundamental concepts of psychoanalysis. Similarly, the authors underline how the Freud and Damasio theories of brain functioning display remarkable complementarities, especially through their common reference to Meynert and James. Furthermore, the Freudian theory of drives is discussed in the light of current neurobiological evidences of neural plasticity and trace formation and of their relationships with the processes of homeostasis. The ensuing dynamics between traces and homeostasis opens novel avenues to consider inner life in reference to the establishment of fantasies unique to each subject. The lack of determinism, within a context of determinism, implied by plasticity and reconsolidation participates in the emergence of singularity, the creation of uniqueness and the unpredictable future of the subject. There is a gap in determinism inherent to biology itself. Uniqueness and discontinuity: this should today be the focus of the questions raised in neuroscience. Neuroscience needs to establish the new bases of a "discontinuous" biology. Psychoanalysis can offer to neuroscience the possibility to think of discontinuity. Neuroscience and psychoanalysis meet thus in an unexpected way with regard to discontinuity and this is a new point of convergence between them. Copyright © 2010 Elsevier Ltd. All rights reserved.

  11. A homeostatic function of CXCR2 signalling in articular cartilage.

    Science.gov (United States)

    Sherwood, Joanna; Bertrand, Jessica; Nalesso, Giovanna; Poulet, Blandine; Pitsillides, Andrew; Brandolini, Laura; Karystinou, Alexandra; De Bari, Cosimo; Luyten, Frank P; Pitzalis, Costantino; Pap, Thomas; Dell'Accio, Francesco

    2015-12-01

    ELR+ CXC chemokines are heparin-binding cytokines signalling through the CXCR1 and CXCR2 receptors. ELR+ CXC chemokines have been associated with inflammatory arthritis due to their capacity to attract inflammatory cells. Here, we describe an unsuspected physiological function of these molecules in articular cartilage homeostasis. Chemokine receptors and ligands were detected by immunohistochemistry, western blotting and RT-PCR. Osteoarthritis was induced in wild-type and CXCR2(-/-) mice by destabilisation of the medial meniscus (DMM). CXCR1/2 signalling was inhibited in vitro using blocking antibodies or siRNA. Chondrocyte phenotype was analysed using Alcian blue staining, RT-PCR and western blotting. AKT phosphorylation and SOX9 expression were upregulated using constitutively active AKT or SOX9 plasmids. Apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay. CXCL6 was expressed in healthy cartilage and was retained through binding to heparan sulfate proteoglycans. CXCR2(-/-) mice developed more severe osteoarthritis than wild types following DMM, with increased chondrocyte apoptosis. Disruption of CXCR1/2 in human and CXCR2 signalling in mouse chondrocytes led to a decrease in extracellular matrix production, reduced expression of chondrocyte differentiation markers and increased chondrocyte apoptosis. CXCR2-dependent chondrocyte homeostasis was mediated by AKT signalling since forced expression of constitutively active AKT rescued the expression of phenotypic markers and the apoptosis induced by CXCR2 blockade. Our study demonstrates an important physiological role for CXCR1/2 signalling in maintaining cartilage homeostasis and suggests that the loss of ELR+ CXC chemokines during cartilage breakdown in osteoarthritis contributes to the characteristic loss of chondrocyte phenotypic stability. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  12. The homeostatic astroglia emerges from evolutionary specialization of neural cells

    DEFF Research Database (Denmark)

    Verkhratsky, Alexei; Nedergaard, Maiken

    2016-01-01

    Evolution of the nervous system progressed through cellular diversification and specialization of functions. Conceptually, the nervous system is composed from electrically excitable neuronal networks connected with chemical synapses and non-excitable glial cells that provide for homeostasis...... and defence. Astrocytes are integrated into neural networks through multipartite synapses; astroglial perisynaptic processes closely enwrap synaptic contacts and control homeostasis of the synaptic cleft, supply neurons with glutamate and GABA obligatory precursor glutamine and contribute to synaptic...... plasticity, learning and memory. In neuropathology, astrocytes may undergo reactive remodelling or degeneration; to a large extent, astroglial reactions define progression of the pathology and neurological outcome.This article is part of the themed issue 'Evolution brings Ca(2+) and ATP together to control...

  13. Homeostatic scaling of excitability in recurrent neural networks.

    NARCIS (Netherlands)

    Remme, M.W.H.; Wadman, W.J.

    2012-01-01

    Neurons adjust their intrinsic excitability when experiencing a persistent change in synaptic drive. This process can prevent neural activity from moving into either a quiescent state or a saturated state in the face of ongoing plasticity, and is thought to promote stability of the network in which

  14. Mathematical Modeling of the Glucose Homeostatic System in Humans

    Science.gov (United States)

    1972-07-01

    of carbohydrates), glycogenolysis (break-down of glycogen to glucose-1-phosphate) and gluconeogenesis (formation of glucose from non-carbohydrate...extreme hypoglycemia. Since a major function of the liver involves gluconeogenesis , it is clear that any model of carbohydrate metabolism should include...physiological in vivo rates in experimental literature, and extrapolation of data from experiments on rat and dog tissue. The assumptions on his vector

  15. Homeostatic roles of naturally occurring antibodies: an overview.

    Science.gov (United States)

    Lutz, Hans U

    2007-12-01

    Immunoglobulins may have been developed in evolution to provide specificity for clearing body waste in the first animals with three germ layers. Tissue homeostasis in vertebrates comprises clearance of proteins released from lysed cells, elimination of altered plasma proteins, of senescent and apoptotic cells. Rather specific IgM and IgG naturally occurring antibodies (NAbs) to cytoplasmic and cytoskeletal proteins bind to proteins released from lysing cells and the IgG NAbs are slightly upregulated upon demand. Some of these NAbs along with complement have devastating effects when massive amounts of intracellular proteins are released during an infarct or an ischemia/reperfusion experiment. IgM NAbs to neoepitopes on plasma proteins/lipids help clear denatured proteins and are protective. IgG NAbs to an exposed protein, band 3 from red blood cells, bind to oligomerized band 3 and due to an affinity for C3 within their framework preferentially form C3b2-IgG complexes from nascent C3b. Thus, anti-band 3 NAbs gain potency by using avidity and generating a potent precursor of the amplifying C3 convertase. IgM NAbs to neoepitopes, which are generated by oxidized lipids forming Schiff bases with proteins, are protective and help clear this waste in atherosclerosis, but IgG antibodies (NAbs?) of the same specificity promote disease.

  16. Exploring the Homeostatic and Sensory Roles of the Immune System.

    Science.gov (United States)

    Marques, Rafael Elias; Marques, Pedro Elias; Guabiraba, Rodrigo; Teixeira, Mauro Martins

    2016-01-01

    Immunology developed under the notion of the immune system exists to fight pathogens. Recently, the discovery of interactions with commensal microbiota that are essential to human health initiated a change in this old paradigm. Here, we argue that the immune system has major physiological roles extending far beyond defending the host. Immune and inflammatory responses share the core property of sensing, defining the immune system also as a sensory system. The inference with the immune system collects, interprets, and stores information, while creating an identity of self, places it in close relationship to the nervous system, which suggests that these systems may have a profound evolutionary connection.

  17. Dietary regulation of Keap1/Nrf2/ARE pathway: focus on plant-derived compounds and trace minerals.

    Science.gov (United States)

    Stefanson, Amanda L; Bakovic, Marica

    2014-09-19

    It has become increasingly evident that chronic inflammation underpins the development of many chronic diseases including cancer, cardiovascular disease and type 2 diabetes. Oxidative stress is inherently a biochemical dysregulation of the redox status of the intracellular environment, which under homeostatic conditions is a reducing environment, whereas inflammation is the biological response to oxidative stress in that the cell initiates the production of proteins, enzymes, and other compounds to restore homeostasis. At the center of the day-to-day biological response to oxidative stress is the Keap1/Nrf2/ARE pathway, which regulates the transcription of many antioxidant genes that preserve cellular homeostasis and detoxification genes that process and eliminate carcinogens and toxins before they can cause damage. The Keap1/Nrf2/ARE pathway plays a major role in health resilience and can be made more robust and responsive by certain dietary factors. Transient activation of Nrf2 by dietary electrophilic phytochemicals can upregulate antioxidant and chemopreventive enzymes in the absence of actual oxidative stress inducers. Priming the Keap1/Nrf2/ARE pathway by upregulating these enzymes prior to oxidative stress or xenobiotic encounter increases cellular fitness to respond more robustly to oxidative assaults without activating more intense inflammatory NFκB-mediated responses.

  18. Intramyocellular ceramides and skeletal muscle mitochondrial respiration are partially regulated by Toll-like receptor 4 during hindlimb unloading.

    Science.gov (United States)

    Kwon, Oh Sung; Nelson, Daniel S; Barrows, Katherine M; O'Connell, Ryan M; Drummond, Micah J

    2016-11-01

    Physical inactivity and disuse result in skeletal muscle metabolic disruption, including insulin resistance and mitochondrial dysfunction. The role of the Toll-like receptor 4 (TLR4) signaling pathway in contributing to metabolic decline with muscle disuse is unknown. Therefore, our goal was to determine whether TLR4 is an underlying mechanism of insulin resistance, mitochondrial dysfunction, and skeletal muscle ceramide accumulation following muscle disuse in mice. To address this hypothesis, we subjected (n = 6-8/group) male WT and TLR4 -/- mice to 2 wk of hindlimb unloading (HU), while a second group of mice served as ambulatory wild-type controls (WT CON, TLR4 -/- CON). Mice were assessed for insulin resistance [homeostatic model assessment-insulin resistance (HOMA-IR), glucose tolerance], and hindlimb muscles (soleus and gastrocnemius) were used to assess muscle sphingolipid abundance, mitochondrial respiration [respiratory control ratio (RCR)], and NF-κB signaling. The primary finding was that HU resulted in insulin resistance, increased total ceramides, specifically Cer18:0 and Cer20:0, and decreased skeletal muscle mitochondrial respiration. Importantly, TLR4 -/- HU mice were protected from insulin resistance and altered NF-κB signaling and were partly resistant to muscle atrophy, ceramide accumulation, and decreased RCR. Skeletal muscle ceramides and RCR were correlated with insulin resistance. We conclude that TLR4 is an upstream regulator of insulin sensitivity, while partly upregulating muscle ceramides and worsening mitochondrial respiration during 2 wk of HU.

  19. Dietary Regulation of Keap1/Nrf2/ARE Pathway: Focus on Plant-Derived Compounds and Trace Minerals

    Directory of Open Access Journals (Sweden)

    Amanda L. Stefanson

    2014-09-01

    Full Text Available It has become increasingly evident that chronic inflammation underpins the development of many chronic diseases including cancer, cardiovascular disease and type 2 diabetes. Oxidative stress is inherently a biochemical dysregulation of the redox status of the intracellular environment, which under homeostatic conditions is a reducing environment, whereas inflammation is the biological response to oxidative stress in that the cell initiates the production of proteins, enzymes, and other compounds to restore homeostasis. At the center of the day-to-day biological response to oxidative stress is the Keap1/Nrf2/ARE pathway, which regulates the transcription of many antioxidant genes that preserve cellular homeostasis and detoxification genes that process and eliminate carcinogens and toxins before they can cause damage. The Keap1/Nrf2/ARE pathway plays a major role in health resilience and can be made more robust and responsive by certain dietary factors. Transient activation of Nrf2 by dietary electrophilic phytochemicals can upregulate antioxidant and chemopreventive enzymes in the absence of actual oxidative stress inducers. Priming the Keap1/Nrf2/ARE pathway by upregulating these enzymes prior to oxidative stress or xenobiotic encounter increases cellular fitness to respond more robustly to oxidative assaults without activating more intense inflammatory NFκB-mediated responses.

  20. The role of Rel/NF-kappa B proteins in viral oncogenesis and the regulation of viral transcription.

    Science.gov (United States)

    Mosialos, G

    1997-04-01

    Rel/NF-kappa B is a ubiquitous transcription factor that consists of multiple polypeptide subunits, and is subject to complex regulatory mechanisms that involve protein-protein interactions, phosphorylation, ubiquitination, proteolytic degradation, and nucleocytoplasmic translocation. The sophisticated control of Rel/NF-kappa B activity is not surprising since this transcription factor is involved in a wide array of cellular responses to extracellular cues, associated with growth, development, apoptosis, and pathogen invasion. Thus, it is not unexpected that this versatile cellular homeostatic switch would be affected by a variety of viral pathogens, which have evolved mechanisms to utilize various aspects of Rel/NF-kappa B activity to facilitate their replication, cell survival and possibly evasion of immune responses. This review will cover the molecular mechanisms that are utilized by mammalian oncogenic viruses to affect the activity of Rel/NF-kappa B transcription factors and the role of Rel/NF-kappa B in the regulation of viral gene expression and replication.

  1. EphA4 is Involved in Sleep Regulation but Not in the Electrophysiological Response to Sleep Deprivation.

    Science.gov (United States)

    Freyburger, Marlène; Pierre, Audrey; Paquette, Gabrielle; Bélanger-Nelson, Erika; Bedont, Joseph; Gaudreault, Pierre-Olivier; Drolet, Guy; Laforest, Sylvie; Blackshaw, Seth; Cermakian, Nicolas; Doucet, Guy; Mongrain, Valérie

    2016-03-01

    Optimal sleep is ensured by the interaction of circadian and homeostatic processes. Although synaptic plasticity seems to contribute to both processes, the specific players involved are not well understood. The EphA4 tyrosine kinase receptor is a cell adhesion protein regulating synaptic plasticity. We investigated the role of EphA4 in sleep regulation using electrocorticography in mice lacking EphA4 and gene expression measurements. EphA4 knockout (KO) mice, Clock(Δ19/Δ19) mutant mice and littermates, C57BL/6J and CD-1 mice, and Sprague-Dawley rats were studied under a 12 h light: 12 h dark cycle, under undisturbed conditions or 6 h sleep deprivation (SLD), and submitted to a 48 h electrophysiological recording and/or brain sampling at different time of day. EphA4 KO mice showed less rapid eye movement sleep (REMS), enhanced duration of individual bouts of wakefulness and nonrapid eye movement sleep (NREMS) during the light period, and a blunted daily rhythm of NREMS sigma activity. The NREMS delta activity response to SLD was unchanged in EphA4 KO mice. However, SLD increased EphA4 expression in the thalamic/hypothalamic region in C57BL/6J mice. We further show the presence of E-boxes in the promoter region of EphA4, a lower expression of EphA4 in Clock mutant mice, a rhythmic expression of EphA4 ligands in several brain areas, expression of EphA4 in the suprachiasmatic nuclei of the hypothalamus (SCN), and finally an unchanged number of cells expressing Vip, Grp and Avp in the SCN of EphA4 KO mice. Our results suggest that EphA4 is involved in circadian sleep regulation. © 2016 Associated Professional Sleep Societies, LLC.

  2. pH modulation of glial glutamate transporters regulates synaptic transmission in the nucleus of the solitary tract

    Science.gov (United States)

    McCrimmon, Donald R.; Martina, Marco

    2013-01-01

    The nucleus of the solitary tract (NTS) is the major site for termination of visceral sensory afferents contributing to homeostatic regulation of, for example, arterial pressure, gastric motility, and breathing. Whereas much is known about how different neuronal populations influence these functions, information about the role of glia remains scant. In this article, we propose that glia may contribute to NTS functions by modulating excitatory neurotransmission. We found that acidification (pH 7.0) depolarizes NTS glia by inhibiting K+-selective membrane currents. NTS glia also showed functional expression of voltage-sensitive glutamate transporters, suggesting that extracellular acidification regulates synaptic transmission by compromising glial glutamate uptake. To test this hypothesis, we evoked glutamatergic slow excitatory potentials (SEPs) in NTS neurons with repetitive stimulation (20 pulses at 10 Hz) of the solitary tract. This SEP depends on accumulation of glutamate following repetitive stimulation, since it was potentiated by blocking glutamate uptake with dl-threo-β-benzyloxyaspartic acid (TBOA) or a glia-specific glutamate transport blocker, dihydrokainate (DHK). Importantly, extracellular acidification (pH 7.0) also potentiated the SEP. This effect appeared to be mediated through a depolarization-induced inhibition of glial transporter activity, because it was occluded by TBOA and DHK. In agreement, pH 7.0 did not directly alter d-aspartate-induced responses in NTS glia or properties of presynaptic glutamate release. Thus acidification-dependent regulation of glial function affects synaptic transmission within the NTS. These results suggest that glia play a modulatory role in the NTS by integrating local tissue signals (such as pH) with synaptic inputs from peripheral afferents. PMID:23615553

  3. Is self-regulation possible

    International Nuclear Information System (INIS)

    Barkenbus, J.N.

    1983-01-01

    The Nuclear Regulatory Commission's increasingly prescriptive regulation of the nuclear industry can have deleterious effects, perhaps the most serious being the shift in responsibility for safety from the utility to the NRC. Several factors account for this type of regulation including the nature and structure of the nuclear industry, public opinion and bureaucratic incentives, and the nature of the technology itself. The opportunities to create heightened industry self-regulation (performance-based regulation) deserve further examination. The key to self-regulation is to structure incentives so that it is clearly within the nuclear utilities' interests to build and operate nuclear power facilities in the safest manner possible. 27 references

  4. Regulation as delegation

    Directory of Open Access Journals (Sweden)

    Oren Bar-Gill

    2016-03-01

    Full Text Available Objective to consider the conception of reverse delegation when the government acts a principal and an individual ndash an agent from the point of view of behavioral PrincipalAgent Theory. Methods statistical method sociological polling. Results In diverse areas ndash from retirement savings to consumer credit to prescription drug use to fuel economy and energy efficiency rules to tobacco consumption to food and beverage consumption ndash government makes decisions for us or endeavors to help us make better decisions thus serving as our agent. From the point of view of PrincipalAgent Theory and behavioral PrincipalAgent Theory a great deal of modern regulation can be helpfully evaluated as a hypothetical delegation. Shifting from personal decisions to public goods problems the authors view the idea of reverse delegation with the government as principal and the individuals as agents. They show that the essence of delegation changes depending on the context. The article describes conditions under which various approaches will make sense. Scientific novelty the paper is devoted to the foreign experience of regulation through delegation by the example of a country with developed market economy the USA. It shows the prospects of such approach in solving both the public and the private tasks. Application of PrincipalAgent Theory and behavioral PrincipalAgent Theory is viewed to distinguish between such types of hypothetical delegation as information default rules incentives precommitments mandates and prohibitions. The article considers the benefits and costs of delegation and circumstances in which one or another approach makes sense. Practical significance PrincipalAgent Theory is widely used in economics and political science and can serve as a convenient tool to consider the optimal scale and essence of the assistance rendered to us by the government as our agent. The paper is of interest for the Russian legal science as the institution of

  5. Volume Regulated Channels

    DEFF Research Database (Denmark)

    Klausen, Thomas Kjær

    , controlled cell death and cellular migration. Volume regulatory mechanisms has long been in focus for regulating cellular proliferation and my thesis work have been focusing on the role of Cl- channels in proliferation with specific emphasis on ICl, swell. Pharmacological blockage of the ubiquitously...... but are also essential for a number of physiological processes such as proliferation, controlled cell death, migration and endocrinology. The thesis have been focusing on two Channels, namely the swelling activated Cl- channel (ICl, swell) and the transient receptor potential Vanilloid (TRPV4) channel. I: Cl...... understood. Potential agonist binding sites have been proposed in transmembrane domains 3 and 4, in congruence with agonist binding sites of TRPV1. However, the functional relationship between TRPV4 and agonist binding is not yet understood. In this thesis is further elaborate the structure...

  6. NRC's license renewal regulations

    International Nuclear Information System (INIS)

    Akstulewicz, Francis

    1991-01-01

    In order to provide for the continuity of the current generation of nuclear power plant operating licenses and at the same time ensure the health and safety of the public, and the quality of the environment, the US Nuclear Regulatory Commission (NRC) established a goal of developing and issuing regulations and regulatory guidance for license renewal in the early 1990s. This paper will discuss some of those activities underway to achieve this goal. More specifically, this paper will discuss the Commission's regulatory philosophy for license renewal and the two major license renewal rule makings currently underway. The first is the development of a new Part 54 to address procedural and technical requirements for license renewal; the second is a revision to existing Part 51 to exclude environmental issues and impacts from consideration during the license renewal process. (author)

  7. Regulation of Terpene Metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Rodney Croteau

    2004-03-14

    OAK-B135 Research over the last four years has progressed fairly closely along the lines initially proposed, with progress-driven expansion of Objectives 1, 2 and 3. Recent advances have developed from three research thrusts: 1. Random sequencing of an enriched peppermint oil gland cDNA library has given access to a large number of potential pathway and regulatory genes for test of function; 2. The availability of new DNA probes and antibodies has permitted investigation of developmental regulation and organization of terpenoid metabolism; and 3. The development of a transformation system for peppermint by colleagues at Purdue University has allowed direct transgenic testing of gene function and added a biotechnological component to the project. The current status of each of the original research objectives is outlined below.

  8. NCAM regulates cell motility

    DEFF Research Database (Denmark)

    Prag, Søren; Lepekhin, Eugene A; Kolkova, Kateryna

    2002-01-01

    Cell migration is required during development of the nervous system. The regulatory mechanisms for this process, however, are poorly elucidated. We show here that expression of or exposure to the neural cell adhesion molecule (NCAM) strongly affected the motile behaviour of glioma cells...... independently of homophilic NCAM interactions. Expression of the transmembrane 140 kDa isoform of NCAM (NCAM-140) caused a significant reduction in cellular motility, probably through interference with factors regulating cellular attachment, as NCAM-140-expressing cells exhibited a decreased attachment...... to a fibronectin substratum compared with NCAM-negative cells. Ectopic expression of the cytoplasmic part of NCAM-140 also inhibited cell motility, presumably via the non-receptor tyrosine kinase p59(fyn) with which NCAM-140 interacts. Furthermore, we showed that the extracellular part of NCAM acted as a paracrine...

  9. Higher regulators, algebraic

    CERN Document Server

    Bloch, Spencer J

    2000-01-01

    This book is the long-awaited publication of the famous Irvine lectures. Delivered in 1978 at the University of California at Irvine, these lectures turned out to be an entry point to several intimately-connected new branches of arithmetic algebraic geometry, such as regulators and special values of L-functions of algebraic varieties, explicit formulas for them in terms of polylogarithms, the theory of algebraic cycles, and eventually the general theory of mixed motives which unifies and underlies all of the above (and much more). In the 20 years since, the importance of Bloch's lectures has not diminished. A lucky group of people working in the above areas had the good fortune to possess a copy of old typewritten notes of these lectures. Now everyone can have their own copy of this classic work.

  10. Meat and Appetite Regulation

    DEFF Research Database (Denmark)

    Kehlet, Ursula Nana

    D thesis was to investigate the effects of fiber addition to meatballs and the effects of cooking methods of pork on appetite regulation. The PhD thesis is based on three human meal test studies and one analytical study related to the characteristics of fiber meat products. In paper I, the objective...... pork products are also characterized as high fat products containing more than 10 g fat per 100 g. In this context, the Danish meat industry puts a lot of effort into developing meat products with a healthier nutritional profile. Thus, it is relevant to provide scientific evidence of the satiating...... effects of new formulations of pork products. Different strategies can be applied to potentially enhance the satiating properties of pork. Processed meat products such as meatballs can serve as a matrix for the addition of fiber ingredients. Based on their high protein and fiber contents, high...

  11. Mitosis and its regulation

    Directory of Open Access Journals (Sweden)

    Frías Vázquez Sara

    2014-07-01

    Full Text Available Cell division by mitosis is essential for the development of organisms and their reproduction; it is also neces- sary that each new cell is genetically identical to that from which it comes. In eukaryotes this is achieved by the presence of complex mechanisms that ensure the integrity of genomic material and their proper segregation during mitosis. The traditional view of mitosis has been divided into different stages that were characterized by morphological studies in dividing cells; advances in molecular biology have led beyond this characterization, so that we now know a range of participant molecules. This article will discuss the process of mitosis, both at the cellular and molecular level and a brief summary of the molecular players that regulate this process.

  12. Robust regulering af destillationskolonner

    DEFF Research Database (Denmark)

    Nielsen, Kim

    1987-01-01

    Sharke og Dixons metode benyttes til minimalrealisering af Laplace-overføringsmatricer. Ud fra denne metode til minimalrealisering opnåes en tilstandsbeskrivelse med første ordens Pade'-approximation af tidsforsinkelsen i Laplace-overføringsfunktionsmatricerne. Ud fra A.N Hansens frekvensanalyser...... bør denne regulator dog undersøges med eksakt beskrivelse af tidsforsinkelsen, hvilket ikke er nået indenfor denne opgave, væsenligst på grund af problemer med MIMOFAD Konklusion. Med Sharked og Dixons metode er der opnået kendskab til en simpel metode til minimalrealisering af Laplace......-overføringsmatricer. Metoden munder ud i et simpelt program der foretager minimalrealisering af Laplace-overføringsfunktionsmatricer med reelle adskildte poler. Anvendelsen af programmet resulterer i en tilstandsbeskrivelse af Laplace-overføringsfunktioner for velbeskrevne kolonner i litteraturen. Den opnåede...

  13. Probiotics and Appetite Regulation

    DEFF Research Database (Denmark)

    Bjerg, Anne Toksvig

    Summary There is emerging focus on the gut microbiota’s (GM) effects on health. GM is suggested to be a contributing factor to the rapid development of obesity and its related diseases like type 2 diabetes and cardiovascular disease. The omposition of the GM has been associated with weight, insulin...... resistance and blood lipid profile among others. Probiotics which are health promoting bacteria can potentially be used to affect the GM and thereby change metabolic outcomes of the host. Animal studies have shown associations between intake of probiotics and appetite regulation, but currently no human...... participants and if changes in GM could be associated with blood lipid profile. The effect of W8 on release of glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2) and peptide YY (PYY) was investigated by perfusion of W8 into an isolated porcine intestine. The expression of mRNA for the glucagon...

  14. [Regulation of terpene metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Croteau, R.

    1989-11-09

    Terpenoid oils, resins, and waxes from plants are important renewable resources. The objective of this project is to understand the regulation of terpenoid metabolism using the monoterpenes (C[sub 10]) as a model. The pathways of monoterpene biosynthesis and catabolism have been established, and the relevant enzymes characterized. Developmental studies relating enzyme levels to terpene accumulation within the oil gland sites of synthesis, and work with bioregulators, indicate that monoterpene production is controlled by terpene cyclases, the enzymes catalyzing the first step of the monoterpene pathway. As the leaf oil glands mature, cyclase levels decline and monoterpene biosynthesis ceases. Yield then decreases as the monoterpenes undergo catabolism by a process involving conversion to a glycoside and transport from the leaf glands to the root. At this site, the terpenoid is oxidatively degraded to acetate that is recycled into other lipid metabolites. During the transition from terpene biosynthesis to catabolism, the oil glands undergo dramatic ultrastructural modification. Degradation of the producing cells results in mixing of previously compartmentized monoterpenes with the catabolic enzymes, ultimately leading to yield decline. This regulatory model is being applied to the formation of other terpenoid classes (C[sub 15] C[sub 20], C[sub 30], C[sub 40]) within the oil glands. Preliminary investigations on the formation of sesquiterpenes (C[sub 15]) suggest that the corresponding cyclases may play a lesser role in determining yield of these products, but that compartmentation effects are important. From these studies, a comprehensive scheme for the regulation of terpene metabolism is being constructed. Results from this project wail have important consequences for the yield and composition of terpenoid natural products that can be made available for industrial exploitation.

  15. Endocannabinoids in cerebrovascular regulation.

    Science.gov (United States)

    Benyó, Zoltán; Ruisanchez, Éva; Leszl-Ishiguro, Miriam; Sándor, Péter; Pacher, Pál

    2016-04-01

    The cerebral blood flow is tightly regulated by myogenic, endothelial, metabolic, and neural mechanisms under physiological conditions, and a large body of recent evidence indicates that inflammatory pathways have a major influence on the cerebral blood perfusion in certain central nervous system disorders, like hemorrhagic and ischemic stroke, traumatic brain injury, and vascular dementia. All major cell types involved in cerebrovascular control pathways (i.e., smooth muscle, endothelium, neurons, astrocytes, pericytes, microglia, and leukocytes) are capable of synthesizing endocannabinoids and/or express some or several of their target proteins [i.e., the cannabinoid 1 and 2 (CB1 and CB2) receptors and the transient receptor potential vanilloid type 1 ion channel]. Therefore, the endocannabinoid system may importantly modulate the regulation of cerebral circulation under physiological and pathophysiological conditions in a very complex manner. Experimental data accumulated since the late 1990s indicate that the direct effect of cannabinoids on cerebral vessels is vasodilation mediated, at least in part, by CB1 receptors. Cannabinoid-induced cerebrovascular relaxation involves both a direct inhibition of smooth muscle contractility and a release of vasodilator mediator(s) from the endothelium. However, under stress conditions (e.g., in conscious restrained animals or during hypoxia and hypercapnia), cannabinoid receptor activation was shown to induce a reduction of the cerebral blood flow, probably via inhibition of the electrical and/or metabolic activity of neurons. Finally, in certain cerebrovascular pathologies (e.g., subarachnoid hemorrhage, as well as traumatic and ischemic brain injury), activation of CB2 (and probably yet unidentified non-CB1/non-CB2) receptors appear to improve the blood perfusion of the brain via attenuating vascular inflammation.

  16. TFEB regulates lysosomal proteostasis.

    Science.gov (United States)

    Song, Wensi; Wang, Fan; Savini, Marzia; Ake, Ashley; di Ronza, Alberto; Sardiello, Marco; Segatori, Laura

    2013-05-15

    Loss-of-function diseases are often caused by destabilizing mutations that lead to protein misfolding and degradation. Modulating the innate protein homeostasis (proteostasis) capacity may lead to rescue of native folding of the mutated variants, thereby ameliorating the disease phenotype. In lysosomal storage disorders (LSDs), a number of highly prevalent alleles have missense mutations that do not impair the enzyme's catalytic activity but destabilize its native structure, resulting in the degradation of the misfolded protein. Enhancing the cellular folding capacity enables rescuing the native, biologically functional structure of these unstable mutated enzymes. However, proteostasis modulators specific for the lysosomal system are currently unknown. Here, we investigate the role of the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and function, in modulating lysosomal proteostasis in LSDs. We show that TFEB activation results in enhanced folding, trafficking and lysosomal activity of a severely destabilized glucocerebrosidase (GC) variant associated with the development of Gaucher disease (GD), the most common LSD. TFEB specifically induces the expression of GC and of key genes involved in folding and lysosomal trafficking, thereby enhancing both the pool of mutated enzyme and its processing through the secretory pathway. TFEB activation also rescues the activity of a β-hexosaminidase mutant associated with the development of another LSD, Tay-Sachs disease, thus suggesting general applicability of TFEB-mediated proteostasis modulation to rescue destabilizing mutations in LSDs. In summary, our findings identify TFEB as a specific regulator of lysosomal proteostasis and suggest that TFEB may be used as a therapeutic target to rescue enzyme homeostasis in LSDs.

  17. The AMPK enzyme-complex: from the regulation of cellular energy homeostasis to a possible new molecular target in the management of chronic inflammatory disorders.

    Science.gov (United States)

    Antonioli, Luca; Colucci, Rocchina; Pellegrini, Carolina; Giustarini, Giulio; Sacco, Deborah; Tirotta, Erika; Caputi, Valentina; Marsilio, Ilaria; Giron, Maria Cecilia; Németh, Zoltán H; Blandizzi, Corrado; Fornai, Matteo

    2016-01-01

    Adenosine monophosphate-activated protein kinase (AMPK), known as an enzymatic complex that regulates the energetic metabolism, is emerging as a pivotal enzyme and enzymatic pathway involved in the regulation of immune homeostatic networks. It is also involved in the molecular mechanisms underlying the pathophysiology of chronic inflammatory diseases. AMPK is expressed in several immune cell types including macrophages, lymphocytes, neutrophils and dendritic cells, and governs a broad array of cell functions, which include cytokine production, chemotaxis, cytotoxicity, apoptosis and proliferation. Based on its wide variety of immunoregulatory actions, the AMPK system has been targeted to reveal its impact on the course of immune-related diseases, such as atherosclerosis, psoriasis, joint inflammation and inflammatory bowel diseases. The identification of AMPK subunits responsible for specific anti-inflammatory actions and the understanding of the underlying molecular mechanisms will promote the generation of novel AMPK activators, endowed with improved pharmacodynamic and pharmacokinetic profiles. These new tools will aid us to utilize AMPK pathway activation in the management of acute and chronic inflammatory diseases, while minimizing potential adverse reactions related to the effects of AMPK on metabolic energy.

  18. Standard types of regulation loops; Chaines de regulation types

    Energy Technology Data Exchange (ETDEWEB)

    Bertrand, M. [ENSAM, Centre d`Enseignement et de Recherche de Lille, 59 - Lille (France)

    1997-12-01

    The aim of this paper is to give help in the analysis of industrial regulation problems using different types of real installations. The increasing complexity of industrial systems requires the use of a decomposition-recomposition procedure using a scheme with different blocs. Examples are given to help the non-specialist users in the mastery of essential choices and in the distinction between operational and material separations. The examples concern: the heating loop of a central heating installation, the sensors and actuators of industrial systems (the temperature regulation of a tubular furnace, the electro-hydraulic positioning systems used in machine tools, forming, aeronautics etc.., the regulation of a mixing system for hot and cold fluids, and the regulation of a fluidizing system. The usual types of regulation loops are presented with the different steps of the resolution of a regulation problem. (J.S.) 7 refs.

  19. Fasting and refeeding differentially regulate NLRP3 inflammasome activation in human subjects.

    Science.gov (United States)

    Traba, Javier; Kwarteng-Siaw, Miriam; Okoli, Tracy C; Li, Jessica; Huffstutler, Rebecca D; Bray, Amanda; Waclawiw, Myron A; Han, Kim; Pelletier, Martin; Sauve, Anthony A; Siegel, Richard M; Sack, Michael N

    2015-11-03

    Activation of the NLRP3 inflammasome is associated with metabolic dysfunction, and intermittent fasting has been shown to improve clinical presentation of NLRP3 inflammasome-linked diseases. As mitochondrial perturbations, which function as a damage-associated molecular pattern, exacerbate NLRP3 inflammasome activation, we investigated whether fasting blunts inflammasome activation via sirtuin-mediated augmentation of mitochondrial integrity. We performed a clinical study of 19 healthy volunteers. Each subject underwent a 24-hour fast and then was fed a fixed-calorie meal. Blood was drawn during the fasted and fed states and analyzed for NRLP3 inflammasome activation. We enrolled an additional group of 8 healthy volunteers to assess the effects of the sirtuin activator, nicotinamide riboside, on NLRP3 inflammasome activation. In the fasting/refeeding study, individuals showed less NLRP3 inflammasome activation in the fasted state compared with that in refed conditions. In a human macrophage line, depletion of the mitochondrial-enriched sirtuin deacetylase SIRT3 increased NLRP3 inflammasome activation in association with excessive mitochondrial ROS production. Furthermore, genetic and pharmacologic SIRT3 activation blunted NLRP3 activity in parallel with enhanced mitochondrial function in cultured cells and in leukocytes extracted from healthy volunteers and from refed individuals but not in those collected during fasting. Together, our data indicate that nutrient levels regulate the NLRP3 inflammasome, in part through SIRT3-mediated mitochondrial homeostatic control. Moreover, these results suggest that deacetylase-dependent inflammasome attenuation may be amenable to targeting in human disease. ClinicalTrials.gov NCT02122575 and NCT00442195. Division of Intramural Research, NHLBI of the NIH.

  20. Regulation of hippocampal and behavioral excitability by cyclin-dependent kinase 5.

    Directory of Open Access Journals (Sweden)

    Ammar H Hawasli

    2009-06-01

    Full Text Available Cyclin-dependent kinase 5 (Cdk5 is a proline-directed serine/threonine kinase that has been implicated in learning, synaptic plasticity, neurotransmission, and numerous neurological disorders. We previously showed that conditional loss of Cdk5 in adult mice enhanced hippocampal learning and plasticity via modulation of calpain-mediated N-methyl-D-aspartic acid receptor (NMDAR degradation. In the present study, we characterize the enhanced synaptic plasticity and examine the effects of long-term Cdk5 loss on hippocampal excitability in adult mice. Field excitatory post-synaptic potentials (fEPSPs from the Schaffer collateral CA1 subregion of the hippocampus (SC/CA1 reveal that loss of Cdk5 altered theta burst topography and enhanced post-tetanic potentiation. Since Cdk5 governs NMDAR NR2B subunit levels, we investigated the effects of long-term Cdk5 knockout on hippocampal neuronal excitability by measuring NMDAR-mediated fEPSP magnitudes and population-spike thresholds. Long-term loss of Cdk5 led to increased Mg(2+-sensitive potentials and a lower threshold for epileptiform activity and seizures. Biochemical analyses were performed to better understand the role of Cdk5 in seizures. Induced-seizures in wild-type animals led to elevated amounts of p25, the Cdk5-activating cofactor. Long-term, but not acute, loss of Cdk5 led to decreased p25 levels, suggesting that Cdk5/p25 may be activated as a homeostatic mechanism to attenuate epileptiform activity. These findings indicate that Cdk5 regulates synaptic plasticity, controls neuronal and behavioral stimulus-induced excitability and may be a novel pharmacological target for cognitive and anticonvulsant therapies.

  1. Senescence-Inflammatory Regulation of Reparative Cellular Reprogramming in Aging and Cancer.

    Science.gov (United States)

    Menendez, Javier A; Alarcón, Tomás

    2017-01-01

    The inability of adult tissues to transitorily generate cells with functional stem cell-like properties is a major obstacle to tissue self-repair. Nuclear reprogramming-like phenomena that induce a transient acquisition of epigenetic plasticity and phenotype malleability may constitute a reparative route through which human tissues respond to injury, stress, and disease. However, tissue rejuvenation should involve not only the transient epigenetic reprogramming of differentiated cells, but also the committed re-acquisition of the original or alternative committed cell fate. Chronic or unrestrained epigenetic plasticity would drive aging phenotypes by impairing the repair or the replacement of damaged cells; such uncontrolled phenomena of in vivo reprogramming might also generate cancer-like cellular states. We herein propose that the ability of senescence-associated inflammatory signaling to regulate in vivo reprogramming cycles of tissue repair outlines a threshold model of aging and cancer. The degree of senescence/inflammation-associated deviation from the homeostatic state may delineate a type of thresholding algorithm distinguishing beneficial from deleterious effects of in vivo reprogramming. First, transient activation of NF-κB-related innate immunity and senescence-associated inflammatory components (e.g., IL-6) might facilitate reparative cellular reprogramming in response to acute inflammatory events. Second, para-inflammation switches might promote long-lasting but reversible refractoriness to reparative cellular reprogramming. Third, chronic senescence-associated inflammatory signaling might lock cells in highly plastic epigenetic states disabled for reparative differentiation. The consideration of a cellular reprogramming-centered view of epigenetic plasticity as a fundamental element of a tissue's capacity to undergo successful repair, aging degeneration or malignant transformation should provide challenging stochastic insights into the current

  2. Regulation of the power sector

    CERN Document Server

    2013-01-01

    Regulation of the Power Sector is a unified, consistent and comprehensive treatment of the theories and practicalities of regulation in modern power-supply systems. The need for generation to occur at the time of use occasioned by the impracticality of large-scale electricity storage coupled with constant and often unpredictable changes in demand make electricity-supply systems large, dynamic and complex and their regulation a daunting task. Conceptually arranged in four parts, this book addresses both traditional regulatory frameworks and also liberalized and re-regulated environments. First, an introduction gives a full characterization of power supply including engineering, economic and regulatory viewpoints. The second part presents the fundamentals of regulation and the third looks at the regulation of particular components of the power sector in detail. Advanced topics and subjects still open or subject to dispute form the content of the fourth part. In a sector where regulatory design is the key driver...

  3. Regulations for RA reactor operation

    International Nuclear Information System (INIS)

    1980-09-01

    Regulations for RA reactor operation are written in accordance with the legal regulations defined by the Law about radiation protection and related legal acts, as well as technical standards according to the IAEA recommendations. The contents of this book include: fundamental data about the reactor; legal regulations for reactor operation; organizational scheme for reactor operation; general and detailed instructions for operation, behaviour in the reactor building, performing experiments; operating rules for operation under steady state and accidental conditions [sr

  4. Financial Private Regulation and Enforcement

    OpenAIRE

    MILLER, Geoffrey

    2011-01-01

    This paper has been delivered within the context of the research project "Transnational Private Regulatory Regimes: Constitutional foundations and governance design". This paper considers the topic of private regulation and enforcement for internationally active financial services firms. The paper documents the following types of regulation and enforcement that involve significant private input: house rules, contracts, internal compliance, management-based regulation, private standard-sett...

  5. Electricity regulation and economic growth

    OpenAIRE

    Costa, M. Teresa (Maria Teresa), 1951-; Garcia-Quevedo, Jose; Trujillo-Baute, Elisa

    2018-01-01

    The main objective of this paper is to analyse the effect of electricity regulation on economic growth. Although the relationship between electricity consumption and economic growth has been extensively analysed in the empirical literature, this framework has not been used to estimate the effect of electricity regulation on economic growth. Understanding this effect is essential for the assessment of regulatory policy. Specifically, we assess the effects of two major areas of regulation, rene...

  6. Auditing and bank capital regulation

    OpenAIRE

    Edward Simpson Prescott

    2004-01-01

    Auditing is introduced into a model of bank capital regulation. Deterministic and stochastic auditing strategies are studied. Contrary to intuition, auditing of bank risk should be focused on the safest banks because they hold the least amount of capital. Risky banks, which hold more capital, need to be audited less. The importance of auditing by regulators and penalties for non-compliance are discussed in light of the Basel II capital regulation proposals. Emphasis is placed on the importanc...

  7. Regulation by permit

    International Nuclear Information System (INIS)

    Anon.

    1991-01-01

    This chapter discusses the key elements of the operating permit program. It begins with an overview of the program and the deadlines for establishing the program. It then discusses the basic program elements, including (1) the sources covered by the program; (2) the requirements that must be contained in the new operating permits; (3) the protections afforded those possessing CAA operating permits; (4) the consequences of the failure to obtain or to comply with an operating permit; and (5) the roles of EPA, the public, and contiguous states in issuing and enforcing operating permits. This chapter then reviews the other operating permit requirements of the 1990 Amendments that will be integrated over time with the basic Title V permit program. These other requirements include the acid deposition and air toxic permit programs. In addition, many states currently have operating permit requirements that will be integrated with the new permit program of the 1990 Amendments. Finally, this chapter discusses the preconstruction permit program that applies to proposed new and modified major sources of air pollutants regulated under the Act

  8. Mechanisms Regulating Glioma Invasion

    Science.gov (United States)

    Paw, Ivy; Carpenter, Richard C.; Watabe, Kounosuke; Debinski, Waldemar; Lo, Hui-Wen

    2015-01-01

    Glioblastoma (GBM) is the most aggressive, deadliest, and most common brain malignancy in adults. Despite the advances made in surgical techniques, radiotherapy and chemotherapy, the median survival for GBM patients has remained at a mere 14 months. GBM poses several unique challenges to currently available treatments for the disease. For example, GBM cells have the propensity to aggressively infiltrate/invade into the normal brain tissues and along the vascular tracks, which prevents complete resection of all malignant cells and limits the effect of localized radiotherapy while sparing normal tissue. Although anti-angiogenic treatment exerts anti-edematic effect in GBM, unfortunately, tumors progress with acquired increased invasiveness. Therefore, it is an important task to gain a deeper understanding of the intrinsic and post-treatment invasive phenotypes of GBM in hopes that the gained knowledge would lead to novel GBM treatments that are more effective and less toxic. This review will give an overview of some of the signaling pathways that have been shown to positively and negatively regulate GBM invasion, including, the PI3K/Akt, Wnt, sonic hedgehog-GLI1, and microRNAs. The review will also discuss several approaches to cancer therapies potentially altering GBM invasiveness. PMID:25796440

  9. Between regulation and independence

    International Nuclear Information System (INIS)

    Ladoucette, Ph. de

    2007-01-01

    This article stresses, first, on the differences between electricity and gas in terms of storability and place of production before introducing the gas sector and its reorganization and re-structuration in the framework of energy markets deregulation. Then, it presents the actions carried out by the commission of energy regulation (CRE) intended to improve the operation of the gas market: improvement of transparency, incitation to invest in transportation infrastructures, organisation of the downstream market and development of regional gas markets. Since July 1, 2007, the opening of gas market is juridically and technically complete. The role of CRE is also to inform the consumers and to warrant a non-discriminatory access to infrastructures in a context of sound competition. On this point, the new situation is satisfactory but improvements are needed to increase the offer. The future objectives of CRE is to maintain a climate favorable to investments, to implement stable and efficient conditions of access to infrastructures and, finally, to regularly work at the European scale for the building up of a domestic gas market synonymous of security of supplies, sustainable development and competitiveness. (J.S.)

  10. Personality and Emotion Regulation Strategies

    Directory of Open Access Journals (Sweden)

    Esti Hayu Purnamaningsih

    2017-01-01

    Full Text Available The emotions has many important functions in our life such as in relation of interpersonal communication, and health. In interpersonal communicative function aimed to signal to other information about internal state. Emotions manifests in specific cognitive, behavioural, and physiological reactions, thus closely related to health. There is wide variety of ways for individuals to regulate their emotion. In this regard, there are two kinds of emotion regulation strategy; first Antecedent-focused emotion regulation consisting of situation selection, situation modification, attentional deployment, cognitive change and second, Response-focused emotion regulation consisting of suppression. The purpose of this research is to investigate personality factors relate with emotion regulation strategies. 339 students from Faculty of Psychology, Universitas Gadjah Mada were participating in this study and given The Big Five Personality Factors (Ramdhani, 2012, adaptation, and the modified version of the Emotion Regulation Scale was used, Emotion Regulation Questionnaire (John & Gross, 2004 which measure personality and emotion regulation respectively. Using multiple regression analysis, the study indicated that personality predicts emotion regulation strategies.

  11. Regulating the nursing associate profession.

    Science.gov (United States)

    Glasper, Alan

    2017-11-23

    Emeritus Professor Alan Glasper, University of Southampton, discusses the Government's consultation on changes to the Nursing and Midwifery Order 2001 and the legislation to regulate nursing associates.

  12. Utility regulation and competition policy

    International Nuclear Information System (INIS)

    Robinson, Colin

    2002-03-01

    Contents: 1. The New Electricity Trading Arrangements in England and Wales: A Review - David Currie, 2. A Critique of Rail Regulation - Dieter Helm, 3. Moving to a Competitive Market in Water - Colin Robinson, 4. The New Gas Trading Arrangements - George Yarrow, 5. A Review of Privatization and Regulation Experience in Britain - Irwin M. Stelzer, 6. Converging Communications: Implications for Regulation - Mark Armstrong, 7. Opening European Electricity and Gas Markets - Graham Shuttleworth, 8. Concurrency or Convergence? Competition and Regulation Under the Competition Act 1998 - Tom Sharpe QC, 9. Ten Years of European Merger Control - Paul Seabright. (Author)

  13. Drinking Water Contaminants -- Standards and Regulations

    Science.gov (United States)

    ... Agency Search Search Contact Us Share Drinking Water Contaminants – Standards and Regulations EPA identifies contaminants to regulate ... other partners to implement these SDWA provisions. Regulated Contaminants National Primary Drinking Water Regulations (NPDWRs) - table of ...

  14. Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone attenuates postincisional pain by regulating macrophage polarization

    Energy Technology Data Exchange (ETDEWEB)

    Hasegawa-Moriyama, Maiko, E-mail: hase-mai@m3.kufm.kagoshima-u.ac.jp [Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Ohnou, Tetsuya; Godai, Kohei; Kurimoto, Tae; Nakama, Mayo; Kanmura, Yuichi [Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan)

    2012-09-14

    Highlights: Black-Right-Pointing-Pointer Rosiglitazone attenuated postincisional pain. Black-Right-Pointing-Pointer Rosiglitazone alters macrophage polarization to F4/80{sup +}CD206{sup +} M2 macrophages at the incisional sites. Black-Right-Pointing-Pointer Transplantation of rosiglitazone-treated macrophages produced analgesic effects. -- Abstract: Acute inflammation triggered by macrophage infiltration to injured tissue promotes wound repair and may induce pain hypersensitivity. Peroxisome proliferator-activated receptor {gamma} (PPAR){gamma} signaling is known to regulate heterogeneity of macrophages, which are often referred to as classically activated (M1) and alternatively activated (M2) macrophages. M1 macrophages have considerable antimicrobial activity and produce a wide variety of proinflammatory cytokines. In contrast, M2 macrophages are involved in anti-inflammatory and homeostatic functions linked to wound healing and tissue repair. Although it has been suggested that PPAR{gamma} agonists attenuate pain hypersensitivity, the molecular mechanism of macrophage-mediated effects of PPAR{gamma} signaling on pain development has not been explored. In this study, we investigated the link between the phenotype switching of macrophage polarization induced by PPAR{gamma} signaling and the development of acute pain hypersensitivity. Local administration of rosiglitazone significantly ameliorated hypersensitivity to heat and mechanical stimuli, and paw swelling. Consistent with the down-regulation of nuclear factor {kappa}B (NF{kappa}B) phosphorylation by rosiglitazone at the incisional sites, the number of F4/80{sup +}iNOS{sup +} M1 macrophages was decreased whereas numbers of F4/80{sup +}CD206{sup +} M2 macrophages were increased in rosiglitazone-treated incisional sites 24 h after the procedure. In addition, gene induction of anti-inflammatory M2-macrophage-associated markers such as arginase1, FIZZ1 and interleukin (IL)-10 were significantly increased, whereas

  15. Role of vascular regulation disturbances in the occurrence perinatal complications in high-risk pregnancies

    Directory of Open Access Journals (Sweden)

    Kaminsky V.V.

    2016-03-01

    disorders during induced pregnancy in women with hepatobiliary disorders. Conclusions. In the context of homeostatic imbalance in this group of women violation of the endothelium and vascular regulation factors underlie the pathogenesis of reproductive, obstetric and perinatal complications, which is the theoretical precondition for the development of a pathogenetic substantiation of complex prevention and treatment of complications, aimed at correcting the violations.

  16. Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone attenuates postincisional pain by regulating macrophage polarization

    International Nuclear Information System (INIS)

    Hasegawa-Moriyama, Maiko; Ohnou, Tetsuya; Godai, Kohei; Kurimoto, Tae; Nakama, Mayo; Kanmura, Yuichi

    2012-01-01

    Highlights: ► Rosiglitazone attenuated postincisional pain. ► Rosiglitazone alters macrophage polarization to F4/80 + CD206 + M2 macrophages at the incisional sites. ► Transplantation of rosiglitazone-treated macrophages produced analgesic effects. -- Abstract: Acute inflammation triggered by macrophage infiltration to injured tissue promotes wound repair and may induce pain hypersensitivity. Peroxisome proliferator-activated receptor γ (PPAR)γ signaling is known to regulate heterogeneity of macrophages, which are often referred to as classically activated (M1) and alternatively activated (M2) macrophages. M1 macrophages have considerable antimicrobial activity and produce a wide variety of proinflammatory cytokines. In contrast, M2 macrophages are involved in anti-inflammatory and homeostatic functions linked to wound healing and tissue repair. Although it has been suggested that PPARγ agonists attenuate pain hypersensitivity, the molecular mechanism of macrophage-mediated effects of PPARγ signaling on pain development has not been explored. In this study, we investigated the link between the phenotype switching of macrophage polarization induced by PPARγ signaling and the development of acute pain hypersensitivity. Local administration of rosiglitazone significantly ameliorated hypersensitivity to heat and mechanical stimuli, and paw swelling. Consistent with the down-regulation of nuclear factor κB (NFκB) phosphorylation by rosiglitazone at the incisional sites, the number of F4/80 + iNOS + M1 macrophages was decreased whereas numbers of F4/80 + CD206 + M2 macrophages were increased in rosiglitazone-treated incisional sites 24 h after the procedure. In addition, gene induction of anti-inflammatory M2-macrophage-associated markers such as arginase1, FIZZ1 and interleukin (IL)-10 were significantly increased, whereas M1-macrophage-related molecules such as integrin αX, IL-1β, MIP2α and leptin were decreased at rosiglitazone-treated incisional sites

  17. Sleep Regulation, Physiology and Development, Sleep Duration and Patterns, and Sleep Hygiene in Infants, Toddlers, and Preschool-Age Children.

    Science.gov (United States)

    Bathory, Eleanor; Tomopoulos, Suzy

    2017-02-01

    Sleep problems are common, reported by a quarter of parents with children under the age of 5 years, and have been associated with poor behavior, worse school performance, and obesity, in addition to negative secondary effects on maternal and family well-being. Yet, it has been shown that pediatricians do not adequately address sleep in routine well-child visits, and underdiagnose sleep issues. Pediatricians receive little formal training in medical school or in residency regarding sleep medicine. An understanding of the physiology of sleep is critical to a pediatrician׳s ability to effectively and confidently counsel patients about sleep. The biological rhythm of sleep and waking is regulated through both circadian and homeostatic processes. Sleep also has an internal rhythmic organization, or sleep architecture, which includes sleep cycles of REM and NREM sleep. Arousal and sleep (REM and NREM) are active and complex neurophysiologic processes, involving both neural pathway activation and suppression. These physiologic processes change over the life course, especially in the first 5 years. Adequate sleep is often difficult to achieve, yet is considered very important to optimal daily function and behavior in children; thus, understanding optimal sleep duration and patterns is critical for pediatricians. There is little experimental evidence that guides sleep recommendations, rather normative data and expert recommendations. Effective counseling on child sleep must account for the child and parent factors (child temperament, parent-child interaction, and parental affect) and the environmental factors (cultural, geographic, and home environment, especially media exposure) that influence sleep. To promote health and to prevent and manage sleep problems, the American Academy of Pediatrics (AAP) recommends that parents start promoting good sleep hygiene, with a sleep-promoting environment and a bedtime routine in infancy, and throughout childhood. Thus, counseling

  18. Plasmacytoid Dendritic Cells Mediate the Regulation of Inflammatory Type T Cell Response for Optimal Immunity against Respiratory Chlamydia Pneumoniae Infection

    Science.gov (United States)

    Joyee, Antony George; Yang, Xi

    2013-01-01

    Chlamydia pneumoniae (Cpn) infection is a leading cause for a variety of respiratory diseases and has been implicated in the pathogenesis of chronic inflammatory diseases. The regulatory mechanisms in host defense against Cpn infection are less understood. In this study, we investigated the role of plasmacytoid dendritic cells (pDCs) in immune regulation in Cpn respiratory tract infection. We found that in vivo depletion of pDCs increased the severity of infection and lung pathology. Mice depleted of pDC had greater body weight loss, higher lung bacterial burden and excessive tissue inflammation compared to the control mice. Analysis of specific T cell cytokine production pattern in the lung following Cpn infection revealed that pDC depleted mice produced significantly higher amounts of inflammatory cytokines, especially TNF-α, but lower IL-10 compared to the controls. In particular, pDC depleted mice showed pathogenic T cell responses characterized by inflammatory type-1 (CD8 and CD4) and inflammatory Th2 cell responses. Moreover, pDC depletion dramatically reduced CD4 regulatory T cells (Tregs) in the lungs and draining lymph nodes. Furthermore, pDC-T cell co-culture experiments showed that pDCs isolated from Cpn infected mice were potent in inducing IL-10 producing CD4 Tregs. Together, these findings provide in vivo evidence for a critical role of pDCs in homeostatic regulation of immunity during Cpn infection. Our findings highlight the importance of a ‘balanced’ immune response for host protective immunity and preventing detrimental immunopathology during microbial infections. PMID:24386207

  19. Membrane Microdomains and Cytoskeleton Organization Shape and Regulate the IL-7 Receptor Signalosome in Human CD4 T-cells*

    Science.gov (United States)

    Tamarit, Blanche; Bugault, Florence; Pillet, Anne-Hélène; Lavergne, Vincent; Bochet, Pascal; Garin, Nathalie; Schwarz, Ulf; Thèze, Jacques; Rose, Thierry

    2013-01-01

    Interleukin (IL)-7 is the main homeostatic regulator of CD4 T-lymphocytes (helper) at both central and peripheral levels. Upon activation by IL-7, several signaling pathways, mainly JAK/STAT, PI3K/Akt and MAPK, induce the expression of genes involved in T-cell differentiation, activation, and proliferation. We have analyzed the early events of CD4 T-cell activation by IL-7. We have shown that IL-7 in the first few min induces the formation of cholesterol-enriched membrane microdomains that compartmentalize its activated receptor and initiate its anchoring to the cytoskeleton, supporting the formation of the signaling complex, the signalosome, on the IL-7 receptor cytoplasmic domains. Here we describe by stimulated emission depletion microscopy the key roles played by membrane microdomains and cytoskeleton transient organization in the IL-7-regulated JAK/STAT signaling pathway. We image phospho-STAT5 and cytoskeleton components along IL-7 activation kinetics using appropriate inhibitors. We show that lipid raft inhibitors delay and reduce IL-7-induced JAK1 and JAK3 phosphorylation. Drug-induced disassembly of the cytoskeleton inhibits phospho-STAT5 formation, transport, and translocation into the nucleus that controls the transcription of genes involved in T-cell activation and proliferation. We fit together the results of these quantitative analyses and propose the following mechanism. Activated IL-7 receptors embedded in membrane microdomains induce actin-microfilament meshwork formation, anchoring microtubules that grow radially from rafted receptors to the nuclear membrane. STAT5 phosphorylated by signalosomes are loaded on kinesins and glide along the microtubules across the cytoplasm to reach the nucleus 2 min after IL-7 stimulation. Radial microtubules disappear 15 min later, while transversal microtubules, independent of phospho-STAT5 transport, begin to bud from the microtubule organization center. PMID:23329834

  20. The evolution of nuclear regulation

    International Nuclear Information System (INIS)

    Martin, A.

    1997-01-01

    The already not so young history of nuclear regulations shows patterns and specific causes that have characterized and influenced its own evolution as well as the industry itself. Today's regulation is facing relevant challenges with potential significant effects. The quest for higher regulatory efficiency brings up the increasing need to base future actions on firmly established strategies. (Author) 7 refs

  1. Regulation of gas infrastructure expansion

    NARCIS (Netherlands)

    De Joode, J.

    2012-01-01

    The topic of this dissertation is the regulation of gas infrastructure expansion in the European Union (EU). While the gas market has been liberalised, the gas infrastructure has largely remained in the regulated domain. However, not necessarily all gas infrastructure facilities – such as gas

  2. The Organization of Regulated Production

    DEFF Research Database (Denmark)

    Jansen, Jos; Jeon, Doh-Shin; Menicucci, Domenico

    2008-01-01

    We analyze the choice between vertical separation (VS) and vertical integration (VI) when two regulated firms produce complementary inputs with correlated costs and are protected by ex post break-even constraints. First, in the absence of collusion the regulator prefers VI (VS) for negative...

  3. Regulating Pornography: A Public Dilemma.

    Science.gov (United States)

    Thompson, Margaret E.; And Others

    1990-01-01

    Examines attitudes toward sex and pornography by means of a telephone survey of Dane County, Wisconsin, adults. Describes survey questions about sexual attitudes, perceived effects of pornography, and pornography regulation. Concludes that adults who feel more strongly that pornography has negative effects are more opposed to its regulation. (SG)

  4. REGULATION OF NATIONAL QUALIFICATIONS SYSTEMS

    Directory of Open Access Journals (Sweden)

    Anna A. Muravyeva

    2014-01-01

    Full Text Available The paper looks into the diverse aspects of qualifications system regulation, designed for balancing the supply and demand in the labor and educational service markets. Both the objects and mechanisms of such regulation are described. Special attention is given to institutions, involved in regulation of qualifications, and their jurisdiction. Another emphasis is on the industry-related regulation of qualifications which proved to be effective both on the national and European level. Such structures were first established on the national levels to regulate the qualifications and ensure their comparability and compatibility, given the economic globalization and growing labor and academic mobility. The author points out the role of the ministries of education and labor in maintaining a steady qualifications system, and outlines the positive experience of Great Britain using the industry councils for continuing development of qualifications system.

  5. Designing Next Generation Telecom Regulation

    DEFF Research Database (Denmark)

    Henten, Anders; Samarajiva, Rohan

    – ICT convergence regulation and multisector utility regulation. Whatever structure of next generation telecom regulation is adopted, all countries will need to pay much greater attention to the need for increased coordination of policy directions and regulatory activities both across the industries......Continuously expanding applications of information and communication technologies (ICT) are transforming local, national, regional and international economies into network economies, the foundation for information societies. They are being built upon expanded and upgraded national telecom networks...... to creating an environment to foster a massive expansion in the coverage and capabilities of the information infrastructure networks, with national telecom regulators as the key implementers of the policies of reform. The first phase of reform has focused on industry specific telecom policy and regulation...

  6. Assessing self-regulation strategies

    DEFF Research Database (Denmark)

    de Vet, Emely; de Ridder, Denise T. D.; Stok, Marijn

    2014-01-01

    Background: Applying self-regulation strategies have proven important in eating behaviors, but it remains subject to investigation what strategies adolescents report to use to ensure healthy eating, and adequate measures are lacking. Therefore, we developed and validated a self-regulation...... participants were aged between 10 and 17 years. Results: Study 1 resulted in a 24-item questionnaire assessing adolescent-reported use of six specific strategies for healthy eating that represent three general self-regulation approaches. Study 2 showed that the easy-to-administer theory-based TESQ-E has...... general self-regulation and motivation measures. Conclusions: The TESQ-E provides a reliable and valid measure to assess six theory-based self-regulation strategies that adolescents may use to ensure their healthy eating....

  7. RNA-guided transcriptional regulation

    Science.gov (United States)

    Church, George M.; Mali, Prashant G.; Esvelt, Kevin M.

    2016-02-23

    Methods of modulating expression of a target nucleic acid in a cell are provided including introducing into the cell a first foreign nucleic acid encoding one or more RNAs complementary to DNA, wherein the DNA includes the target nucleic acid, introducing into the cell a second foreign nucleic acid encoding a nuclease-null Cas9 protein that binds to the DNA and is guided by the one or more RNAs, introducing into the cell a third foreign nucleic acid encoding a transcriptional regulator protein or domain, wherein the one or more RNAs, the nuclease-null Cas9 protein, and the transcriptional regulator protein or domain are expressed, wherein the one or more RNAs, the nuclease-null Cas9 protein and the transcriptional regulator protein or domain co-localize to the DNA and wherein the transcriptional regulator protein or domain regulates expression of the target nucleic acid.

  8. The regulator's view

    International Nuclear Information System (INIS)

    Sendin, P.

    2004-01-01

    Spanish experience holds a relatively important position in the field of the decommissioning of nuclear and radioactive facilities. Nuclear facilities are subject to a system of prior authorization by the competent authorities before they come into service and to subsequent regulation and control during their operating life. Nuclear and radioactive facilities that stop operating, for technical or financial reasons or because they are compelled to, remain subject to this regulatory control system as long as the competent authorities consider that their residual radioactivity represents a potential source of radiological hazard to the individuals affected or entails an unacceptable environmental risk. The decommissioning of nuclear facilities is contemplated in Spain a further or an additional step of their life cycle in which, in principle, the whole regulatory framework in force during the previous stages - sitting, construction, commissioning, operation, etc. - remains applicable. The term decommissioning is used to delineate the final stage of the life of a definitely non-operational facility and also to introduce a new licensing regime and a new regulatory control scheme. In the regulatory context, the decommissioning of a facility is understood as a set of administrative and technical actions and processes whose purpose, once a facility has been withdrawn from service, is to release it from regulatory control and so to relieve the former licensee of its previous responsibilities relating to the facility's safety. With the increasing age of nuclear and radioactive facilities in service, and as the number of facilities reaching the end of their operating life rises, the administrative process required in order to decommissioning them safely has become a real challenge in all countries, especially in those like Spain with an old nuclear power programme. Let me first give you a quick overview of the Spanish regulatory decommissioning framework. Then I will try to

  9. Self-regulation versus State Regulation in Swedish Industrial Relations

    OpenAIRE

    Kjellberg, Anders

    2017-01-01

    The Swedish model of industrial relations is distinguished by a high degree of self-regulation with roots around the turn of the century 1900. Under the threat of state regulation, the labour market parties in the 1930s, and again in the late 1990s, found they had a common interest in self-regulation. The 1938 Saltsjöbaden Agreement between the blue-collar confederation LO and the employer confederation SAF had its predecessors in the 1905 Engineering Agreement and the December Compromise LO-...

  10. Regulated electricity retailing in Chile

    Energy Technology Data Exchange (ETDEWEB)

    Galetovic, Alexander, E-mail: alexander@galetovic.cl [Facultad de Ciencias Economicas y Empresariales, Universidad de los Andes, Santiago, Chile. Av. San Carlos de Apoquindo 2200, Las Condes, Santiago (Chile); Munoz, Cristian M., E-mail: cmunozm@aes.com [AES Gener and Departamento de Ingenieria Electrica, Universidad Catolica de Chile (Chile)

    2011-10-15

    While some countries have unbundled distribution and retailing, skeptics argue that the physical attributes of electricity make retailers redundant. Instead, it is claimed that passive pass through of wholesale prices plus regulated charges for transmission and distribution suffice for customers to benefit from competitive generation markets. We review the Chilean experience with regulated retailing and pass through of wholesale prices. We argue that when energy wholesale prices are volatile and prices are stabilized, distortions emerge. Regulated retailers gain little by mitigating or correcting them. On the contrary, sometimes price distortions increase their profits. We estimate the cost of three distortions that neither regulated retailers nor the regulator have shown any interest in correcting. - Highlights: > We review Chile's experience with regulated electricity retailing. > Distortions emerge when energy wholesale prices are volatile and prices stabilized. > Regulated retailers gain little by mitigating or correcting distortions. > Sometimes price distortions increase retailers' profits. > We estimate the cost of three distortions, which retailers have not corrected.

  11. Grandfather regulations, new source bias, and state air toxics regulations

    International Nuclear Information System (INIS)

    Levinson, Arik

    1999-01-01

    This paper uses plant-level data from the Census of Manufactures and the variation in toxic air pollution regulations across states to measure the effects of laws that are more stringent for new sources of pollution than for existing sources (so-called 'grandfather' regulations). Of particular interest is the resulting 'new source bias' and its effects on capital vintage and investment. Two industries are examined: commercial printing, which has a local product market; and paint manufacturing, which has a more national market. In general, there seem to be no statistically significant differences in capital vintage or investment between plants in states that grandfather new sources of pollution, plants in states that have no air toxics regulations, and plants in states that regulate both new and existing sources

  12. Introduction to international radio regulations

    International Nuclear Information System (INIS)

    Radicella, S.M.

    2003-01-01

    These lecture notes contain an overview of basic problems of the International Radio Regulations. Access to the existing information infrastructure, and to that of the future Information Society, depends critically on radio, especially in poor, remote and sparsely populated regions with under-developed telecommunication infrastructure. How the spectrum of radio frequencies is regulated has profound impact on the society, its security, prosperity, and culture. The radio regulations represent a very important framework for an adequate use of radio and should be known by all of those working in the field

  13. Designing Next Generation Telecom Regulation

    DEFF Research Database (Denmark)

    Henten, Anders; Samarajiva, Rohan; Melody, William H.

    2003-01-01

    This article critically examines the multiple rationales for telecom, IT, media convergence regulation, on the one hand, and multisector utility regulation, on the other, and the practical questions of implementation they pose, with a view to contributing to informed policy and regulatory decisions...... to the regulatory process such as scarcity of regulatory resources and safeguards for regulatory independence, are examined. It is concluded that ICT and media convergence issues are primarily about improving the efficiency of market economies, and how changes in regulation can facilitate this process. Multi...

  14. Nanometrology - challenges for health regulation

    Directory of Open Access Journals (Sweden)

    Jailton Carreteiro Damasceno

    2013-11-01

    Full Text Available The relationship between metrology, nanotechnology and nanoscience and sanitary regulation is discussed from the point of view of its importance and the interrelationship between the themes for the development of products and services involving nanotech-nology. The discussion involves the main techniques for measuring dimensional, chemical and biological properties of materials, and presents some of the challenges for the future. Issues such as processes of standardization and regulation in Europe, U.S. and Brazil are also addressed, providing an overview of how these processes are related to sanitary regulation.

  15. Network Regulation and Support Schemes

    DEFF Research Database (Denmark)

    Ropenus, Stephanie; Schröder, Sascha Thorsten; Jacobsen, Henrik

    2009-01-01

    At present, there exists no explicit European policy framework on distributed generation. Various Directives encompass distributed generation; inherently, their implementation is to the discretion of the Member States. The latter have adopted different kinds of support schemes, ranging from feed-in...... tariffs to market-based quota systems, and network regulation approaches, comprising rate-of-return and incentive regulation. National regulation and the vertical structure of the electricity sector shape the incentives of market agents, notably of distributed generators and network operators...

  16. Hydrography - Boating Special Regulation Streams

    Data.gov (United States)

    NSGIC Education | GIS Inventory — This layer contains those streams/rivers within Pennsylvania that have specifc special regulations related to boating as defined by the Pennsylvania Fish and Boat...

  17. Attachment and Dyadic Regulation Processes.

    Science.gov (United States)

    Overall, Nickola C; Simpson, Jeffry A

    2015-02-01

    Insecurely attached people have relatively unhappy and unstable romantic relationships, but the quality of their relationships depends on how their partners regulate them. Some partners find ways to regulate the emotional and behavioral reactions of insecurely attached individuals, which promotes greater relationship satisfaction and security. We discuss attachment theory and interdependence dilemmas, and then explain how and why certain responses by partners assuage the cardinal concerns of insecure individuals in key interdependent situations. We then review recent studies illustrating how partners can successfully regulate the reactions of anxiously and avoidantly attached individuals, yielding more constructive interactions. We finish by considering how these regulation processes can create a more secure dyadic environment, which helps to improve relationships and attachment security across time.

  18. Regulations concerning nuclear facilities decommissioning

    International Nuclear Information System (INIS)

    Habib, F.

    1984-10-01

    After a short presentation of the French nuclear regulations, a short overview of their application is given. Finally, are presented the points related to the fiscality specific of nuclear basis facilities [fr

  19. Electronic Code of Federal Regulations

    Data.gov (United States)

    National Archives and Records Administration — The Electronic Code of Federal Regulations (e-CFR) is the codification of the general and permanent rules published in the Federal Register by the executive...

  20. Nanomaterials: Regulation and Risk Assessment

    DEFF Research Database (Denmark)

    Hansen, Steffen Foss; Grieger, Khara Deanne; Baun, Anders

    2013-01-01

    The topics of regulation and risk assessment of nanomaterials have never been more relevant and controversial in Europe than they are at this point in time. In this entry, we present and discuss a number of major pieces of legislation relevant for the regulation of nanomaterials, including REACH...... triggered by thresholds values not tailored to the nanoscale but based on bulk material; and 3) limitations related to lack of metrological tools, (eco)toxicological data, and environmental exposure limits as required by, e.g., REACH, the pharmaceuticals regulation, and the recast of the Novel Foods...... Regulation. Chemical risk assessment provides a fundamental element in support of existing legislation. Risk assessment is normally said to consist of four elements, i.e., hazard identification, dose–response assessment, exposure assessment, and risk characterization. Each of these four elements hold...

  1. Comparison of some European regulations

    Energy Technology Data Exchange (ETDEWEB)

    Argyriadis, K. [Germanisher Lloyd, Hamburg (Germany)

    1996-09-01

    Fatigue calculations are an essential part in certification of a wind turbine. Manufacturers have to fulfill recommendations of several different regulations throughout Europe with the result that the design has often to be altered to satisfy them. In general three national (D/GL, NL, DK), and two international (GL, IEC) regulations are in use, with the IEC standard getting more importance with wind energy deploying to more in regions with no yet clearly defined national standards (India, Spain). The Germanischer Lloyd made calculations for wind turbines they are certifying and in one case we compared the resulting damages for different regulations and classes on a 600 kW, three bladed, stall regulated wind turbine. (EG) 18 refs.

  2. Regulation on control systems tests

    International Nuclear Information System (INIS)

    Grau, J.; Navarro, J.M.

    1978-01-01

    Requirements under regulation applicable to the testing of control systems and controlled equipments in the case of USA nuclear projects are examined. They are reviewed, in particular, the following standards and criteria: 10 Code of Federal Regulations 50, Appendix A, General Design Criteria 20 and 21; IEEE Standards 279 and 308; IEEE Standard 338; US Regulatory Guides 1.22 and 1.118.(J.E.de C.)

  3. Epigenetic regulation of persistent pain

    Science.gov (United States)

    Bai, Guang; Ren, Ke; Dubner, Ronald

    2014-01-01

    Persistent or chronic pain is tightly associated with various environmental changes and linked to abnormal gene expression within cells processing nociceptive signaling. Epigenetic regulation governs gene expression in response to environmental cues. Recent animal model and clinical studies indicate that epigenetic regulation plays an important role in the development/maintenance of persistent pain and, possibly the transition of acute pain to chronic pain, thus shedding light in a direction for development of new therapeutics for persistent pain. PMID:24948399

  4. How should Bitcoin be regulated ?

    OpenAIRE

    SHCHERBAK, Sergii

    2014-01-01

    The lack of clarity about Bitcoin’s legal framework has meant that none of the regulators across the EU have yet achieved sufficient clarity in the legal treatment of Bitcoin and its stakeholders. This uncertainty poses a number of substantial risks to Bitcoin stakeholders and creates challenges for regulatory authorities. Therefore, there is a need for a clear strategy for Bitcoin’s regulation aiming to ensure the maximum possible balance between the interests of Bitcoin stakeholders longing...

  5. Civilsamfundets ABC: R for Regulering

    DEFF Research Database (Denmark)

    Meyer, Gitte; Lund, Anker Brink

    2016-01-01

    Hvad er civilsamfundet? Anker Brink Lund og Gitte Meyer fra CBS Center for Civil Society Studies gennemgår civilsamfundet bogstav for bogstav. Vi er nået til R for Regulering.......Hvad er civilsamfundet? Anker Brink Lund og Gitte Meyer fra CBS Center for Civil Society Studies gennemgår civilsamfundet bogstav for bogstav. Vi er nået til R for Regulering....

  6. Money Laundering and its Regulation

    OpenAIRE

    Alberto E. Chong; Florencio López-de-Silanes

    2007-01-01

    The recent wave of terrorist attacks has increased the attention paid to money laundering activities. Using several methodologies, this paper investigates empirically the determinants of money laundering and its regulation in over 80 countries by assembling a cross-country dataset on proxies for money laundering and the prevalence of feeding activities. The paper additionally constructs specific money laundering regulation indices based on available information on laws and their mechanisms of...

  7. 7 CFR 29.29 - Regulations.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 2 2010-01-01 2010-01-01 false Regulations. 29.29 Section 29.29 Agriculture Regulations of the Department of Agriculture AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing... INSPECTION Regulations Definitions § 29.29 Regulations. Rules and regulations of the Secretary under the Act. ...

  8. 7 CFR 987.48 - Container regulation.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 8 2010-01-01 2010-01-01 false Container regulation. 987.48 Section 987.48... IN RIVERSIDE COUNTY, CALIFORNIA Order Regulating Handling Container Regulation § 987.48 Container regulation. Whenever the Committee deems it advisable to establish a container regulation for any variety of...

  9. Polysialic Acid Regulates Sympathetic Outflow by Facilitating Information Transfer within the Nucleus of the Solitary Tract.

    Science.gov (United States)

    Bokiniec, Phillip; Shahbazian, Shila; McDougall, Stuart J; Berning, Britt A; Cheng, Delfine; Llewellyn-Smith, Ida J; Burke, Peter G R; McMullan, Simon; Mühlenhoff, Martina; Hildebrandt, Herbert; Braet, Filip; Connor, Mark; Packer, Nicolle H; Goodchild, Ann K

    2017-07-05

    posttranslational modification, glycosylation. How these glycans influence brain function is only now beginning to be elucidated. The adult nucleus of the solitary tract has abundant polysialic acid (polySia) and is a major site of integration, receiving viscerosensory information which controls critical homeostatic functions. Our data reveal that polySia is a determinant of neuronal behavior and excitatory transmission in the nucleus of the solitary tract, regulating sympathetic nerve activity. polySia is abundantly expressed at distinct brain sites in adult, including major sensory nuclei, suggesting that sensory transmission may also be influenced via mechanisms described here. These findings hint at the importance of elucidating how other glycans influence neural function. Copyright © 2017 the authors 0270-6474/17/376559-17$15.00/0.

  10. The temporal organization of ingestive behaviour and its interaction with regulation of energy balance

    NARCIS (Netherlands)

    Strubbe, JH; van Dijk, G

    Body weight of man and animals is under homeostatic control mediated by the adjustment of food intake It is discussed in this review that besides signals reporting energy deficits, optimized programs of body clocks take part in feeding behaviour as well Circadian light- and food-entrainable clocks

  11. A C-terminally truncated form of β-catenin acts as a novel regulator of Wnt/β-catenin signaling in planarians.

    Directory of Open Access Journals (Sweden)

    Hanxia Su

    2017-10-01

    Full Text Available β-Catenin, the core element of the Wnt/β-catenin pathway, is a multifunctional and evolutionarily conserved protein which performs essential roles in a variety of developmental and homeostatic processes. Despite its crucial roles, the mechanisms that control its context-specific functions in time and space remain largely unknown. The Wnt/β-catenin pathway has been extensively studied in planarians, flatworms with the ability to regenerate and remodel the whole body, providing a 'whole animal' developmental framework to approach this question. Here we identify a C-terminally truncated β-catenin (β-catenin4, generated by gene duplication, that is required for planarian photoreceptor cell specification. Our results indicate that the role of β-catenin4 is to modulate the activity of β-catenin1, the planarian β-catenin involved in Wnt signal transduction in the nucleus, mediated by the transcription factor TCF-2. This inhibitory form of β-catenin, expressed in specific cell types, would provide a novel mechanism to modulate nuclear β-catenin signaling levels. Genomic searches and in vitro analysis suggest that the existence of a C-terminally truncated form of β-catenin could be an evolutionarily conserved mechanism to achieve a fine-tuned regulation of Wnt/β-catenin signaling in specific cellular contexts.

  12. A C-terminally truncated form of β-catenin acts as a novel regulator of Wnt/β-catenin signaling in planarians.

    Science.gov (United States)

    Su, Hanxia; Sureda-Gomez, Miquel; Rabaneda-Lombarte, Neus; Gelabert, Maria; Xie, Jianlei; Wu, Wei; Adell, Teresa

    2017-10-01

    β-Catenin, the core element of the Wnt/β-catenin pathway, is a multifunctional and evolutionarily conserved protein which performs essential roles in a variety of developmental and homeostatic processes. Despite its crucial roles, the mechanisms that control its context-specific functions in time and space remain largely unknown. The Wnt/β-catenin pathway has been extensively studied in planarians, flatworms with the ability to regenerate and remodel the whole body, providing a 'whole animal' developmental framework to approach this question. Here we identify a C-terminally truncated β-catenin (β-catenin4), generated by gene duplication, that is required for planarian photoreceptor cell specification. Our results indicate that the role of β-catenin4 is to modulate the activity of β-catenin1, the planarian β-catenin involved in Wnt signal transduction in the nucleus, mediated by the transcription factor TCF-2. This inhibitory form of β-catenin, expressed in specific cell types, would provide a novel mechanism to modulate nuclear β-catenin signaling levels. Genomic searches and in vitro analysis suggest that the existence of a C-terminally truncated form of β-catenin could be an evolutionarily conserved mechanism to achieve a fine-tuned regulation of Wnt/β-catenin signaling in specific cellular contexts.

  13. M4 muscarinic receptors regulate the dynamics of cholinergic and dopaminergic neurotransmission: relevance to the pathophysiology and treatment of related CNS pathologies.

    Science.gov (United States)

    Tzavara, Eleni T; Bymaster, Frank P; Davis, Richard J; Wade, Mark R; Perry, Kenneth W; Wess, Jurgen; McKinzie, David L; Felder, Chris; Nomikos, George G

    2004-09-01

    Dopaminergic dysfunction is an important pathogenetic factor for brain pathologies such as Parkinson's disease, ADHD, schizophrenia, and addiction as well as for metabolic disorders and anorexia. Dopaminergic neurons projecting from the midbrain to forebrain regions, such as the nucleus accumbens and the prefrontal cortex, regulate motor and cognitive functions and coordinate the patterned response of the organism to sensory, affective, and rewarding stimuli. In this study, we showed that dopaminergic neurotransmission is highly dependent on M4 cholinergic muscarinic receptor function. Using in vivo microdialysis, we found elevated dopamine (DA) basal values and enhanced DA response to psychostimulants in the nucleus accumbens of M4 knockout mice. We also demonstrated impaired homeostatic control of cholinergic activity that leads to increased basal acetylcholine efflux in the midbrain of these animals. Thus, loss of M4 muscarinic receptor control of cholinergic function effectuates a state of dopaminergic hyperexcitability. This may be responsible for pathological conditions, in which appetitive motivation as well as affective and cognitive processing is impaired. We propose that M4 receptor agonists could represent an innovative strategy for the treatment of pathologies associated with hyperdopaminergia.

  14. 2010 Carl Ludwig Distinguished Lectureship of the APS Neural Control and Autonomic Regulation Section: Central neural pathways for thermoregulatory cold defense.

    Science.gov (United States)

    Morrison, Shaun F

    2011-05-01

    Central neural circuits orchestrate the homeostatic repertoire to maintain body temperature during environmental temperature challenges and to alter body temperature during the inflammatory response. This review summarizes the research leading to a model representing our current understanding of the neural pathways through which cutaneous thermal receptors alter thermoregulatory effectors: the cutaneous circulation for control of heat loss, and brown adipose tissue, skeletal muscle, and the heart for thermogenesis. The activation of these effectors is regulated by parallel but distinct, effector-specific core efferent pathways within the central nervous system (CNS) that share a common peripheral thermal sensory input. The thermal afferent circuit from cutaneous thermal receptors includes neurons in the spinal dorsal horn projecting to lateral parabrachial nucleus neurons that project to the medial aspect of the preoptic area. Within the preoptic area, warm-sensitive, inhibitory output neurons control heat production by reducing the discharge of thermogenesis-promoting neurons in the dorsomedial hypothalamus. The rostral ventromedial medulla, including the raphe pallidus, receives projections form the dorsomedial hypothalamus and contains spinally projecting premotor neurons that provide the excitatory drive to spinal circuits controlling the activity of thermogenic effectors. A distinct population of warm-sensitive preoptic neurons controls heat loss through an inhibitory input to raphe pallidus sympathetic premotor neurons controlling cutaneous vasoconstriction. The model proposed for central thermoregulatory control provides a platform for further understanding of the functional organization of central thermoregulation.

  15. The novel CXCL12gamma isoform encodes an unstructured cationic domain which regulates bioactivity and interaction with both glycosaminoglycans and CXCR4.

    Directory of Open Access Journals (Sweden)

    Cédric Laguri

    Full Text Available BACKGROUND: CXCL12alpha, a chemokine that importantly promotes the oriented cell migration and tissue homing of many cell types, regulates key homeostatic functions and pathological processes through interactions with its cognate receptor (CXCR4 and heparan sulfate (HS. The alternative splicing of the cxcl12 gene generates a recently identified isoform, CXCL12gamma, which structure/function relationships remain unexplored. The high occurrence of basic residues that characterize this isoform suggests however that it could feature specific regulation by HS. METHODOLOGY/PRINCIPAL FINDINGS: Using surface plasmon resonance and NMR spectroscopy, as well as chemically and recombinantly produced chemokines, we show here that CXCL12gamma first 68 amino acids adopt a structure closely related to the well described alpha isoform, followed by an unfolded C-terminal extension of 30 amino acids. Remarkably, 60% of these residues are either lysine or arginine, and most of them are clustered in typical HS binding sites. This provides the chemokine with the highest affinity for HP ever observed (Kd = 0.9 nM, and ensures a strong retention of the chemokine at the cell surface. This was due to the unique combination of two cooperative binding sites, one strictly required, found in the structured domain of the protein, the other one being the C-terminus which essentially functions by enhancing the half life of the complexes. Importantly, this peculiar C-terminus also regulates the balance between HS and CXCR4 binding, and consequently the biological activity of the chemokine. CONCLUSIONS/SIGNIFICANCE: Together these data describe an unusual binding process that gives rise to an unprecedented high affinity between a chemokine and HS. This shows that the gamma isoform of CXCL12, which features unique structural and functional properties, is optimized to ensure its strong retention at the cell surface. Thus, depending on the chemokine isoform to which it binds, HS

  16. Dynamics of cocaine- and amphetamine-regulated transcript containing cell changes in the adrenal glands of two kidney, one clip rats.

    Science.gov (United States)

    Kasacka, Irena; Piotrowska, Zaneta; Janiuk, Izabela; Zbucki, Robert

    2014-10-01

    Taking into consideration the homeostatic disorders resulting from renal hypertension and the essential role of cocaine- and amphetamine-regulated transcript (CART) in maintaining homeostasis by regulating many functions of the body, the question arises as to what extent the renovascular hypertension affects the morphology and dynamics of changes of CART-containing cells in the adrenal glands. The aim of the present study was to examine the distribution, morphology, and dynamics of changes of CART-containing cells in the adrenal glands of "two kidney, one clip" (2K1C) renovascular hypertension model in rats. The studies were carried out on the adrenal glands of rats after 3, 14, 28, 42, and 91 days from the renal artery clipping procedure. To identify neuroendocrine cells, immunohistochemical reaction was performed with the use of a specific antibody against CART. It was revealed that renovascular hypertension causes changes in the endocrine cells containing CART in the adrenal glands of rats. The changes observed in the endocrine cells depend on the time when the rats with experimentally induced hypertension were examined. In the first period of hypertension, the number and immunoreactivity of CART-containing cells were decreased, while from the 28-day test, it significantly increased, as compared to the control rats. CART is relevant to the regulation of homeostasis in the cardiovascular system and seems to be involved in renovascular hypertension. The results of the present work open the possibility of new therapeutic perspectives for the treatment of arterial hypertension, since CART function is involved in their pathophysiology. © 2014 by the Society for Experimental Biology and Medicine.

  17. 76 FR 75825 - Streamlining Inherited Regulations

    Science.gov (United States)

    2011-12-05

    ... submitting comments. Mail: Research, Markets & Regulations Division, Bureau of Consumer Financial Protection... Lieu of Mail: Research, Markets & Regulations Division, Bureau of Consumer Financial Protection, 1700 G..., Counsel, Research, Markets & Regulations Division, Bureau of Consumer Financial Protection, (202) 453-7700...

  18. Regulation of autophagy by cytosolic acetyl-coenzyme A

    DEFF Research Database (Denmark)

    Mariño, Guillermo; Pietrocola, Federico; Eisenberg, Tobias

    2014-01-01

    levels inhibited maladaptive autophagy in a model of cardiac pressure overload. Depletion of AcCoA reduced the activity of the acetyltransferase EP300, and EP300 was required for the suppression of autophagy by high AcCoA levels. Altogether, our results indicate that cytosolic AcCoA functions...... proteins, as well as the induction of autophagy, a homeostatic process of self-digestion. Multiple distinct manipulations designed to increase or reduce cytosolic AcCoA led to the suppression or induction of autophagy, respectively, both in cultured human cells and in mice. Moreover, maintenance of high AcCoA...

  19. Thyroid Hormone Regulation of Metabolism

    Science.gov (United States)

    Mullur, Rashmi; Liu, Yan-Yun

    2014-01-01

    Thyroid hormone (TH) is required for normal development as well as regulating metabolism in the adult. The thyroid hormone receptor (TR) isoforms, α and β, are differentially expressed in tissues and have distinct roles in TH signaling. Local activation of thyroxine (T4), to the active form, triiodothyronine (T3), by 5′-deiodinase type 2 (D2) is a key mechanism of TH regulation of metabolism. D2 is expressed in the hypothalamus, white fat, brown adipose tissue (BAT), and skeletal muscle and is required for adaptive thermogenesis. The thyroid gland is regulated by thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH). In addition to TRH/TSH regulation by TH feedback, there is central modulation by nutritional signals, such as leptin, as well as peptides regulating appetite. The nutrient status of the cell provides feedback on TH signaling pathways through epigentic modification of histones. Integration of TH signaling with the adrenergic nervous system occurs peripherally, in liver, white fat, and BAT, but also centrally, in the hypothalamus. TR regulates cholesterol and carbohydrate metabolism through direct actions on gene expression as well as cross-talk with other nuclear receptors, including peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR), and bile acid signaling pathways. TH modulates hepatic insulin sensitivity, especially important for the suppression of hepatic gluconeogenesis. The role of TH in regulating metabolic pathways has led to several new therapeutic targets for metabolic disorders. Understanding the mechanisms and interactions of the various TH signaling pathways in metabolism will improve our likelihood of identifying effective and selective targets. PMID:24692351

  20. Balancing Public and Private Regulation

    Directory of Open Access Journals (Sweden)

    Martijn Scheltema

    2016-01-01

    Full Text Available Voluntary Sustainability Standards (VSS might develop into a viable alternative to public regulation. However, it turns on the (regulatory circumstances whether that holds true in practice. If public regulation on CSR topics is lacking, governments are unable to agree upon certain topics on a global level or diverging public regulation exists, VSS can be helpful to set global standards. Obviously, private standards will especially be helpful if they are commensurate with local public legislation (and e.g. treaties and/or are accepted by local governments. If one neglects this, numerous domestic structures might exist that frustrate VSS. Furthermore, governments have to remain vigilant as to whether these private regimes do not result in market disruption, consumer detriment or hamper trade. VSS might also compete with public arrangements which might limit the uptake of VSS. However, if public regulation exists VSS might be a viable alternative if compliance with not too compelling public norms by market participants is rather poor and the public policymaker is aiming to incentivize the better performing part of the market to embark on higher standards and thus only desires to regulate the less performing part of the market. However, of paramount importance is the effectiveness of VSS in order to be a viable alternative to public regulation. The effectiveness of VSS should be assessed using an integrated multi-disciplinary (comparative approach entailing legal, impact-assessment, legitimacy, governance and behavioural aspects. Only effective VSS in the aforementioned sense are a true alternative to public regulation.Beyond that, the legal perspective in connection with (the effectiveness of VSS is discussed, featuring FSC and UTZ Certified as an example. It is important from this perspective that VSS have a clear and sufficiently selective objective and sufficiently specific norms, are regularly evaluated, entail ‘conflict of law rules’ and