3,197 research outputs found
Comment to "Weak instruments robust tests in GMM and the New Keynesian Phillips curve" by Frank Kleibergen and Sophocles Mavroeidis
No full textI discuss the identifiability of a structural New Keynesian Phillips curve when it is embedded in a small scale dynamic stochastic general equilibrium model. Identification problems emerge because not all the structural parameters are recoverable from the semi-structural ones and because the objective functions I consider are poorly behaved. The solution and the moment mappings are responsible for the problems.Identification, DSGE models, New Keynesian Phillips curve, Identification robust estimation methods
Characteristics of outdoor falls among older people: A qualitative study
No full textBackground Falls are a major threat to older people’s health and wellbeing. Approximately half of falls occur in outdoor environments but little is known about the circumstances in which they occur. We conducted a qualitative study to explore older people’s experiences of outdoor falls to develop understanding of how they may be prevented. Methods We conducted nine focus groups across the UK (England, Wales, and Scotland). Our sample was from urban and rural settings and different environmental landscapes. Participants were aged 65+ and had at least one outdoor fall in the past year. We analysed the data using framework and content analyses. Results Forty-four adults aged 65 – 92 took part and reported their experience of 88 outdoor falls. Outdoor falls occurred in a variety of contexts, though reports suggested the following scenarios may have been more frequent: when crossing a road, in a familiar area, when bystanders were around, and with an unreported or unknown attribution. Most frequently, falls resulted in either minor or moderate injury, feeling embarrassed at the time of the fall, and anxiety about falling again. Ten falls resulted in fracture, but no strong pattern emerged in regard to the contexts of these falls. Anxiety about falling again appeared more prevalent among those that fell in urban settings and who made more visits into their neighbourhood in a typical week. Conclusions This exploratory study has highlighted several aspects of the outdoor environment that may represent risk factors for outdoor falls and associated fear of falling. Health professionals are recommended to consider outdoor environments as well as the home setting when working to prevent falls and increase mobility among older people
Efeitos da administração sistêmica de 5-HT e 8-OH-DPAT sobre os estados de vigília e sono de pombos (Columba livia)
No full textDissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas. Programa de Pós-Graduação em NeurociênciasInvestigar a participação dos mecanismos serotonérgicos sobre a regulação dos estados de sono e vigília em pombos por meio da caracterização comportamental e eletrográfica hipocampal dos estados de sono e vigília após administração sistêmica de 5-HT ou 8-OH-DPAT e quantificação dos efeitos da administração de 5-HT ou 8-OH-DPAT sobre a atividade eletrográfica hipocampal dos diferentes estados identificados
Efeitos comportamentais e sobre a expressão da proteina Fos em neurônios serotonérgicos após injeções intracerebroventriculares de serotonina em pombos (Columba livia)
No full textDissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Programa de Pós-Graduação em Neurociências, Florianópolis, 2010Em mamíferos, os circuitos serotonérgicos têm sido relacionados à modulação de comportamentos ingestivos e dos estados de sono e vigília. No presente trabalho, foram examinadas as respostas comportamentais e ingestivas e também o padrão de expressão da proteína Fos no tronco encefálico, após injeção intracerebroventricular de serotonina (5-HT, 50, 150 ou 300 nmol/2µl) em pombos (Columba lívia) com livre acesso à água e alimento. As injeções de 5-HT provocaram marcante sequência comportamental que consistiu em veemente ingestão de água dentro dos primeiros 15 minutos após os tratamentos, seguida por comportamentos de manutenção e então por prolongados períodos de comportamentos típicos de sono. Estes efeitos foram de curto-prazo: os padrões de ingestão de água foram similares entre animais tratados com 5-HT ou veículo 2, 3 e 24 h após as injeções. Nenhum efeito consistente foi observado sobre a ingestão de alimento. A densidade de células imunorreativas à Fos (Fos+) ou tanto à Fos e a triptofano hidroxilase (Fos+/TPH+) foram examinadas em seis áreas do tronco encefálico rostral em pombos com livre acesso à água e alimento que foram tratados com 5-HT (5-HTW) ou veículo. Um grupo controle adicional foi tratado com 5-HT, mas não teve acesso à água nas duas horas seguintes à injeção (5-HTØ). Na rafe pontina, a densidade Fos+ foi positivamente correlacionada com índices de comportamentos típicos de sono e aumentou tanto nos animais 5-HTW como nos animais 5-HTØ. No núcleo da linha média pontomesencefálica, o linearis caudalis, as marcações Fos+ e Fos+/TPH+ foram negativamente correlacionadas com os comportamentos típicos de sono e foram reduzidas nos animais 5-HTØ. Na área de A8, a densidade de Fos+/TPH+ foi reduzida VII em ambos os grupos tratados com 5-HT e foi positivamente correlacionada com a ingestão de alimento e negativamente correlacionada com o sono. Estes dados indicam que efeitos hiperdípsicos e hipnóticos de injeções ICV de 5-HT em pombos com livre acesso à água e alimento resultam da inibição da atividade tônica de neurônios serotonérgicos no tronco encefálico. Além disso, indicam que pode existir em aves, semelhante a mamíferos, uma influência inibitória de neurônios serotonérgicos sobre o comer, o beber e sobre o sono, possivelmente relacionados à sequência de saciedade pós-prandial e que a coordenação deste cenário fisiológico por circuitos serotonérgicos pode representar um atributo altamente preservado no encéfalo de amniótas.In mammals, serotonergic circuits have been shown to play important roles in the control of ingestive behaviors and sleep-waking states. In the present work, the behavioral and ingestive responses as well as the pattern of Fos-like activity in the brainstem following intracerebroventricular (ICV) injections of serotonin (5-HT at 50, 150 or 300 nmol/2 µl) were examined in free-feeding/free-drinking pigeons (Columba livia). 5-HT injections evoked a remarkable behavioral sequence that consists of vehement drinking behavior within the first 15 min after injections, followed by preening and then by prolonged periods of sleep-like behavior. These effects are short-lived: the patterns of ingestive behavior are similar in 5-HT- and vehicle-treated animals at 2, 3 and 24 h after treatments. No consistent effect on feeding behavior was observed. The density of cells immunoreactive to Fos (Fos+) or to both Fos and tryptophan hydroxylase (Fos+/TPH+) were examined in six areas of the rostral brainstem of ree-feeding/freedrinking birds treated with 5-HT (5-HTW) or vehicle. An additional control group was treated with 5-HT without access to water during the 2 hours after the treatment (5-HTØ). In the pontine raphe, Fos+ density positively correlated to sleep behavioral indexes and increased in both 5-HTW and 5-HTØ animals. In the midline nucleus linearis caudalis, Fos+ and Fos+/TPH+ labeling negatively correlated to sleep-like behaviors and were reduced in 5-HTØ animals. In the A8 area, Fos+/TPH+ cell density was reduced in both 5-HTW and 5-HTØ animals and was positively correlated to food intake whereas negatively correlated to sleep. These data indicate that hyperdipsic and hypnotic effects of ICV 5-HT in free-feeding pigeons results from inhibition of the tonic activity of serotonergic neurons in brainstem. Moreover, it indicates that it may exist in IX birds, as in mammals, an inhibitory influence of serotonergic neurons on feeding, drinking and sleep behaviors, possibly related to the postprandial Behavioral Satiety Sequence and that the coordination of this physiological set by central 5-HT circuits may represent a highly conserved attribute of the amniote brain
Risk analysis of High-Temperature Aquifer Thermal Energy Storage (HT-ATES)
No full textThe storage of heat in aquifers, also referred to as Aquifer Thermal Energy Storage (ATES), bears a high potential to bridge the seasonal gap between periods of highest thermal energy demand and supply. With storage temperatures higher than 50 °C, High-Temperature (HT) ATES is capable to facilitate the integration of (non-)renewable heat sources into complex energy systems. While the complexity of ATES technology is positively correlated to the required storage temperature, HT-ATES faces multidisciplinary challenges and risks impeding a rapid market uptake worldwide. Therefore, the aim of this study is to provide an overview and analysis of these risks of HT-ATES to facilitate global technology adoption. Risk are identified considering experiences of past HT-ATES projects and analyzed by ATES and geothermal energy experts. An online survey among 38 international experts revealed that technical risks are expected to be less critical than legal, social and organizational risks. This is confirmed by the lessons learned from past HT-ATES projects, where high heat recovery values were achieved, and technical feasibility was demonstrated. Although HT-ATES is less flexible than competing technologies such as pits or buffer tanks, the main problems encountered are attributed to a loss of the heat source and fluctuating or decreasing heating demands. Considering that a HT-ATES system has a lifetime of more than 30 years, it is crucial to develop energy concepts which take into account the conditions both for heat sources and heat sinks. Finally, a site-specific risk analysis for HT-ATES in the city of Hamburg revealed that some risks strongly depend on local boundary conditions. A project-specific risk management is therefore indispensable and should be addressed in future research and project developments.Accepted Author ManuscriptWater Resource
Improving identification of HT-ATES performance drivers and -barriers
No full textHigh temperature aquifer thermal energy storage (HT-ATES) can potentially solve the mismatch between heat supply and demand. It can provide a large scale seasonal heat storage solution. Thereby it enables an increase in full load hours of the base heat source, which can benefit project performance on both costs and emissions. However, the limited number of successful pilot projects indicates the technology has not escaped its state of infancy. There is a gap from concept to implementation, which is signified by the disagreement of experts on performance drivers and barriers of HT-ATES. This research aims to narrow the described knowledge gap, by improving identification of HT-ATES performance drivers and barriers. Thereby it strives to improve decision making of HT-ATES implementation, and further enhance future HT-ATES application in heating projects. The broad scope of research demands both a diagnostic and design-orientated approach, and fits seamlessly with a multi-criteria decision analysis. The analysis entails the stages of creating, evaluating, comparing and ranking of case-specific scenarios. Parametric variation changes the conditions for HT-ATES implementation across the scenarios. A simulation model is developed and connected to a groundwater model to apply the parametric variation, to create the different scenarios, and consequently to produce the quantitative information for further evaluation. During the stages of creating, evaluating, comparing and ranking, the methodology systematically produces new results on the opportunities and risks introduced by HT-ATES, and additionally on the HT-ATES performance drivers and barriers. The results show that HT-ATES enables the opportunity of improving project performance with respect to the internal rate of return and emissions. Groundwater impact remains the greatest risk, but it can be minimised with smart decision making. To support the decision maker and to overcome the risk of groundwater impact, the research proposes several performance-enhancing, non-explicit guidelines. The guidelines focus on realising an HT-ATES implementation, where project performance with respect to internal rate of return, emissions and groundwater impact are balanced. Thereby they explain the major HT-ATES performance drivers and barriers. The guidelines are summarised below. The decision maker is recommended to .. 1. .. minimise the uncertainty, through thorough subsurface characterization before implementation. Secondly, to focus on aquifers with a minimum depth of 200 [m] and a minimum hydraulic conductivity of 5 [m/d] 2. .. assure network return temperatures during peak demand are below expected storage temperatures 3. .. not consider project life-times exceeding 20 years 4. .. assure yearly maximum base source heat production is always lower than yearly consumer heat demand 5. .. to strive for a flat demand curve and apply peak-shaving, by means of, for example, variable heat prices Currently, the guidelines have the purpose of giving direction to the decision maker, but they will become more explicit once the methodology is improved, and the uncertainty and number of assumptions in the model is decreased.Electrical Engineering | Sustainable Energy Technolog
O papel dos receptores 5-HT1A nas respostas ingestivas e hipnogênica provocadas pela injeção intracerebroventricular de serotonina em pombos (Columba livia): discriminação entre receptores pré e pós-sinápticos
No full textTese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Programa de Pós-Graduação em Neurociências, Florianópolis, 2014.Introdução: diversos estudos demonstram que os circuitos serotonérgicos inibem a ingestão de alimentos e o sono em aves e mamíferos. A injeção intracerebroventricular (ICV) de 5-HT em pombos, entretanto, provoca efeitos diferentes: aumento na ingestão de água e na duração do sono. Nós associamos estas respostas à atuação de receptores 5-HT1A, pois a ativação destes receptores produz respostas similares. No entanto, os receptores 5-HT1A podem estar localizados no neurônio serotonérgico (autorreceptores) ou em outros neurônios (heterorreceptores). Dependendo da sua localização, a ativação destes receptores produz efeitos diferentes. Portanto, o nosso objetivo foi avaliar a participação dos receptores 5-HT1A nas respostas dipsogênica e hipnogênica provocadas pela 5-HT, na tentativa de especificar as respostas desencadeadas pela 5-HT à atuação de auto ou heterorreceptores. Métodos: os animais (pombos adultos, Columba lívia, de ambos os sexos, pesando entre 400-550 g) foram divididos em 5 grupos/experimentos diferentes. Experimento 1: 16 pombos foram divididos em dois grupos de acordo com o pré-tratamento e receberam: MM77 (antagonista de heterorreceptores 5-HT1A; 0, 23 ou 69 nmol), ou WAY100635 (WAY, antagonista de auto e heterorreceptores 5-HT1A; 0, 0,1, 0,3 ou 1 nmol) e 20 min. após foram tratados com 5-HT (50 e 150 nmol) ou 8-OH-DPAT (30 nmol; agonista de receptores 5-HT1A/7). Logo após o tratamento, o registro comportamental começou e a ingestão de alimentos foi verificada 60 min. após a última injeção. Experimento 2: 12 pombos foram divididos em 2 grupos e submetidos à cirurgia para injeção ICV (bilateral) da neurotoxina de neurônios serotonérgicos 5,7-dihidroxitriptamina (5,7-DHT, 200µg/injeção) ou de seu veículo. Após 12 dias, os animais começaram a ser testados com 5-HT (150 nmol), 8-OH-DPAT (30 nmol) ou veículo (ácido ascórbico 1% em NaCl 0,9%) com intervalo de 7 dias entre as injeções. Estes animais foram mortos 28 dias após a cirurgia e o conteúdo encefálico de 5-HT foi analisado para verificar os efeitos da lesão. Adicionalmente, nós utilizamos outros 18 animais divididos em três grupos, a) 6 animais naïve que foram mortos para servir como controle para os níveis basais de 5-HT e outros dois grupos (N: 6/grupo) que foram submetidos à cirurgia (injeção de 5,7-DHT ou do veículo) e perfundidos 12 dias após a cirurgia para verificar os efeitos da toxina sobre a densidade de neurônios serotonérgicos. Experimento 3: Secções do tronco e do hipotálamo de 6 animais não submetidos a qualquer manipulação experimental foram processados pela técnica de autorradiografia para detectar a distribuição dos sítios de ligação ao agonista tritiado [3H] 8-OH-DPAT. Experimento 4: 15 pombos com cânulas guia direcionadas ao ventrículo lateral direito foram divididos em 3 grupos e tratados com: 8-OH-DPAT (30 nmol) e tiveram livre acesso (N:5) ou foram privados de água após a injeção (N:5) e veículo (N:5). 90 min. após a injeção os animais foram perfundidos e as secções do tronco encefálico processadas para detecção da proteína Fos em neurônios serotonérgicos e não serotonérgicos, e secções do hipotálamo processadas para detectar somente a expressão da proteína Fos. Experimento 5: 10 pombos com cânulas guia direcionadas ao ventrículo lateral direito foram divididos em 3 grupos e tratados com: 5-HT (150 nmol) e tiveram livre acesso (N:5) ou foram privados de água após a injeção (N:5). 90 min. após, os animais foram perfundidos e secções contendo o hipotálamo foram processadas para a detecção da proteína Fos. Resultados: tanto a 5-HT como o 8-OH-DPAT provocaram intensa ingestão de água e aumento na duração do sono. O 8-OH-DPAT ainda aumentou a ingestão de alimento. Os efeitos ingestivos e hipnogênico dos tratamentos foram parcial ou totalmente afetados pelos antagonistas evidenciando a participação dos receptores 5-HT1A nas alterações comportamentais provocadas pela 5-HT. Entretanto, os dados farmacológicos não nos permitiram especificar entre a ação de auto ou heterorreceptores, mas indicam que a interação entre os dois receptores parece ser um importante aspecto do controle exercido pelos circuitos serotonérgicos sobre os comportamentos ingestivos. Apesar de diminuir drasticamente a densidade de neurônios serotonérgicos, a lesão não afetou as alterações provocadas pelos tratamentos o que sugere que em animais com a função serotonérgica prejudicada, receptores 5-HT1A localizados em neurônios não serotonérgicos parecem ser os responsáveis pelos efeitos dos tratamentos. Além disso, os antagonistas e a lesão dos neurônios serotonérgicos também aumentaram o sono dos animais indicando um efeito inibitório tônico dos neurônios serotonérgicos sobre o sono. Os tratamentos também aumentaram a atividade Fos em regiões hipotalâmicas ricas em receptores 5-HT1A e que parecem estar envolvidas com o controle da ingestão de alimento, dos fluídos corporais e do sono. Conclusão: As respostas dipsogênica e hipnogênica desencadeadas pela injeção de 5-HT parecem ser mediadas parcialmente tanto por auto como por heterorreceptores 5-HT1A. Aparentemente, estas respostas são mediadas por receptores 5-HT1A localizados em estruturas encefálicas (no tronco e no hipotálamo) envolvidas com o controle dos comportamentos ingestivos e de sono em aves. Nossos resultados revelaram sutis diferenças na atividade celular produzidas pela 5-HT e pelo 8-OH-DPAT que sugerem que outros receptores serotonérgicos também participam das respostas comportamentais organizadas pela 5-HT. Além disso, os resultados obtidos com a lesão sugerem que os receptores 5-HT1A parecem apresentar diferenças funcionais espécie-específicas, o que pode ser reflexo de diferentes pressões seletivas experimentadas por aves e mamíferos ao longo da evolução dos vertebrados.Abstract : Introduction: several studies have demonstrated the inhibitory role of serotonergic circuits on ingestive and sleep behaviors both in mammals and birds. Intracerebroventricular (ICV) injections of serotonin (5-HT), however, evoked oposite effects: increased water intake and sleep. We associated these responses to 5-HT1A receptors, because the activation of these receptors caused similar responses. However, the 5-HT1A receptor is located on serotonergic neurons (as autoreceptor) as well as on different neurons (as heteroreceptor), and produces different effects based on its location. Therefore, we decided to investigate the participation of 5-HT1A receptor on dipsogenic and hypnogenic 5-HT-mediated responses to try discriminate the role of auto and heteroreceptors. Methods: the animals (adult pigeons, Columba lívia, both sex, 400-550g of body weight) were divided in 5 groups. Each group represented one different experiment. Experiment 1: 16 pigeons were divided in two groups according on the antagonist used as pretreatment and were injected with: MM77 (0, 23 or 69 nmol, heteroreceptor antagonist), or WAY100635 (WAY, 0, 0.1, 0.3 or 1 nmol, 5-HT1A auto and heterorreceptor antagonist) and 20 min. afterwards injected with 5-HT (0, 50 or 150 nmol) or 8-OH-DPAT (30 nmol). The animals behaviors were registered during the first hour after the last injection and the food and water intake was evaluated at the end of this period. Experiment 2: 12 pigeons were divided in 2 groups and were stereotaxically implanted with an ICV cannula guide (bilateral) to receive the serotonergic neurotoxin 5,7-Dihydroxytryptamine (5,7-DHT, 200µg/injection) or its vehicle. Past 12 days the tests with 5-HT (150 nmol), 8-OH-DPAT (30 nmol) or vehicle (1% ascorbic acid in 0.9 NaCl) started, with seven days apart each other. These animals were killed 28 days after the surgery and the encephalic levels of 5-HT were analised to verify possible degenerative effects of 5,7-DHT. Moreover, we used other 18 animals divided in three groups, a) six naïve pigeons that were killed to be used as reference of the basal levels of 5-HT and another 2 groups that were inject with 5.7-DHT (N: 6) or its vehicle (N:6) and were perfused 12 days later to verify the 5,7-DHT effects on serotonergic neurons. Experiment 3: six naïve pigeons were killed and had their brains dissecated and brainstem and hypothalamic sections reacted by autoradiographic approach to demonstrate the distribution of 5-HT1A binding sites with the selective radioligand [3H] 8-OH-DPAT. Experiment 4: 15 pigeons with ICV cannula guide implanted were divided in three groups and treated with: 8-OH-DPAT (30 nmol) withfree (N:5) or without acess to water after the injection (N:5), and vehicle (N:5). 90 min. later the animals were perfused and brainstem sections reacted to detect Fos protein expression in serotonergic and in non-serotonergic neurons, and hypothalamic sections processed to detect Fos activation. Experiment 5: 10 pigeons with ICV cannula guide implanted were divided in three groups and treated with: 5-HT (150 nmol) with free (N:5) or without acess to water after the injection (N:5). 90 min. later the animals were perfused and hypothalamic sections processed to detect the Fos activation. Results: both 5-HT and 8-OH-DPAT evoked huge increase in water intake and sleep duration. The 8-OH-DPAT injection also produce hyperphagic responses. The ingestive and hypnogenic effects of the treatments were partially or totally inhibited by the antagonists, sugesting the participation of 5-HT1A receptors on behavioral changes produced by 5-HT. However, the pharmacologic data did not permit specify between the action of 5-HT1A auto or heteroreceptors, but indicate the interaction between these two receptors as an important aspect of serotonergic control upon ingestive behavior. Besides its impressive effects on serotonergic neurons density, the 5,7-DHT lesion did not affect the behavioral changes caused by the treatments, suggesting that in animals with anormal serotonergic function, 5-HT1A receptors located in non-serotonergic neurons seem to be related to the treatments effects. Additionally, the antagonists and the 5,7-DHT lesion increased the sleep, indicating one tonic inhibitory effect of serotonergic circuits on sleep. The treatments also increased the Fos protein activation in hypothalamic regions with high 5-HT1A binding sites density that seem to be involved with food, body fluid and sleep regulation. Conclusion: the dipsogenic and hypnogenic responses evoked by 5-HT seem to be mediated partially by both 5-HT1A auto and heteroreceptors. Apparently, these responses are regulated by 5-HT1A receptors located on encephalic (hypothalamic and brainstem) regions directly or indirectly involved with ingestive and sleep/wake cycle regulation in birds. Our results also indicate small differences in the neuronal activity evoked by 5-HT and by 8-OH-DPAT suggesting that other serotonergic receptor also participate in behavioral responses organized by 5-HT. Moreover, the results produced by 5,7-DHT lesion indicate that 5-HT1A receptors seem present specie-specific functional differences that could represent different seletive pressions experimented by birds and mammal during vertebrate evolution
Transcriptional profiling of apple fruit in response to heat treatment: involvement of a defense response during Penicillium expansum
No full textHeat treatment of harvested fruit has been demonstrated to be an effective and a safe approach for managing postharvest decay. In the present study, the effect of a hot water treatment (HT) (45. °C for 10. min) on the response of apple to blue mold infection was investigated. HT was applied to 'Ultima Gala' apples using 2 different methods. Wounded apples were: (1) inoculated with a Penicillium expansum spore suspension and then heat-treated after 1, 4 and 24. h (Inoc-HT); or (2) first heat-treated and then inoculated with a P. expansum spore suspension after 1, 4 and 24. h (HT-Inoc). All treated/inoculated apples were stored at 20. °C for 6 days. Significant reductions in fruit rot incidence, up to 100%, were observed using the Inoc-HT protocol at 4 and 24. h while a 30% reduction in blue mold incidence was found at 1 and 4. h using the HT-Inoc method. In vitro experiments showed no evident lethal effect of HT at 45. °C for 10. min on the germination of P. expansum conidia, indicating that this pathogen has a high heat tolerance. In order to investigate the molecular mechanisms involved in fruit response to heat treatment, an apple microarray was used to conduct a global transcriptional analysis of gene expression in apple at 0, 15, 30. min, 1, 4, 8 and 24. h after the heat treatment. The results provided evidence that at 1 and 4. h after heating, the HT apples had the highest number of differentially expressed genes. A significant upregulation of heat shock proteins, heat shock cognate protein, and heat shock transcription factor genes, involved in thermotolerance were observed. This indicates that the apple fruit respond to the heat treatment in a programmed manner and suggests that the genes responsible for thermotolerance may also be involved in the induced resistance response
Transforming Ates To Ht-Ates, Insights From Dutch Pilot Project
No full textAquifer Thermal Energy Storage (ATES) systems combined with a heat pump save energy for space heating and cooling of buildings. In most countries the temperature of the stored heat is allowed up to 25-30°C. However, when heat is available at higher temperatures (e.g. waste heat, solar heat), it is more efficient to store higher temperatures because that improves heat pump performance or makes it unnecessary. Therefore, interest in HT-ATES development is growing. Next to developing new HT-ATES projects, there is also a large potential for additional energy savings by transforming ‘regular’ low-temperature LT-ATES systems to a HT-ATES. Such a transformation is tested for a greenhouse system in the Netherlands. This greenhouse has a LT-ATES system operational since 2012, and from 2015 onwards heat is stored in the warm well at temperatures up to 45°C. In this HT-ATES transformation pilot, water quality parameters are closely monitored as well as temperature distribution in the subsurface (using DTS). Together with the operators, the results from the ATES monitoring are used to continuously improve system performance. Numerical groundwater and heat flow simulations of actual and expected well pumping data are used to evaluate how well operation can be optimized. In this paper, the optimization using monitoring results and simulations is discussed as well as general and site specific lessons/conclusions for such transformations.Water Resource
Characterization of the 5-HT(7) receptor as a new therapeutic target for the treatment of pain
No full text[eng] The work showed in this Thesis has been part of the “5-HT7 and neuropathic pain” project in the pharmaceutical company Esteve. Thus, the aim of this Thesis was in line with the goal of the 5-HT7 project at Esteve, focused on drug discovery of 5-HT7 receptor ligands for the treatment of neuropathic pain.
Taking the advantage of a genetic approach (5-HT7 receptor knockout mice) and pharmacological tools (5-HT7 receptor ligands) we investigated at the preclinical level the role of 5-HT7 receptors in nociception and the therapeutic interest of 5-HT7 receptor ligands on pain treatment. The 5-HT7 receptor ligands used were SB-258719 and SB-269970 as 5- HT7 receptor antagonists, and AS-19, MSD-5a, E-55888 and E-57431 as 5-HT7 receptor agonists. E-55888 and E-57431 developed by Esteve were described for the first time and their binding profile and functionality (cAMP formation) were examined. In vivo behavioural studies were performed in mice and rats subjected to nociceptive, inflammatory, neurogenic or neuropathic pain conditions.
Our results showed that 5-HT7 receptors per se were not involved in the nociceptive response to a normally noxius stimulus, although when co-activated together with opioid receptors potentiated the opioidergic analgesic response in nociceptive pain conditions. Indeed, 5-HT7 receptor knockout and wild-type mice showed similar sensitivity to a noxious heat stimulus, and systemic administration of the 5-HT7 receptor agonist E-55888 or the 5-HT7 receptor antagonist SB-258719 showed no effects on acute nociceptive pain using the tail flick test in mice. However, the 5-HT7 receptor agonist E-55888 enhanced the morphine-induced analgesia in this test and this potentiation was significantly reversed by the 5-HT7 receptor antagonist SB-258719.
On the other hand, we studied the role of 5-HT7 receptors in pain conditions involving central sensitization. We showed that the 5-HT7 receptor agonists AS-19, E-55888 and E-57431 inhibited capsaicin-induced mechanical hypersensitivity, nerve injury-induced mechanical and thermal hypersensitivity and reduced the phase II formalin-induced nociception. In contrast, a promotion of mechanical hypersensitivity after administration of the 5-HT7 receptor antagonists SB-258719 and SB-269970 was observed. This reduction of hypersensitivity by agonists and promotion of hypersensitivity by antagonists was reversed by antagonists and agonists, respectively. It is important to note that effectiveness of the treatment with 5-HT7 receptor agonists was not masked by non-specific motor effects, as no motor incoordination was found in the rota-rod test at the doses used and no tolerance to the effect was evidenced following repeated systemic administrations.
The antinociceptive effects exerted by systemic 5-HT7 receptor agonists seemed to be mediated by 5-HT7 receptors localized in the spinal cord. We found that intrathecal administration of the 5-HT7 receptor agonist E-57431 inhibited mechanical hypersensitivity secondary to capsaicin injection and nerve injury-induced mechanical hypersensitivity. In contrast, a pronociceptive effect was observed after local intraplantar injection of the selective 5-HT7 receptor agonist E-57431 in the capsaicin model. Thus, the antinociceptive role mediated by central 5-HT7 receptors seems to predominate over their pronociceptive role at the periphery, resulting in an overall analgesic effect when 5-HT7 receptor agonists are administered by a systemic route. In line with these spinal antinociceptive effects, we found an increased immunoreactivity of 5-HT7 receptors in the ipsilateral dorsal horn of the spinal cord in sciatic nerve-injured mice. This increased 5-HT7 receptor expression in the dorsal horn induced by nerve injury could represent a physiological, compensatory, protective spinal mechanism relevant to the control of nociception in neuropathic pain conditions.
We observed that 5-HT7 receptors co-localized with GABAergic neurons in the ipsilateral dorsal horn of the spinal cord. Therefore, we suggested that an indirect action through activation of 5-HT7 receptors localized on inhibitory interneurons may be responsible of the antinociceptive effects observed after administration of 5-HT7 receptor agonists.
Finally, using 5-HT7 receptor knockout mice, we demonstrated that the 5-HT7 receptor agonists AS-19, E-55888 and E-57431 exerted in vivo target specific effects on pain control. We observed that systemic administration of these 5-HT7 receptor agonists reduced phase II formalin-induced nociception in wild-type but not in 5-HT7 receptor knockout mice. Taken together, these data add a piece of knowledge to the role played by 5-HT7 receptors in the control of pain and point to a new potential use of 5-HT7 receptor agonists as promising drugs for the treatment of neuropathic pain.[cat] El treball mostrat en aquesta Tesi ha format part del projecte “5-HT7 i dolor neuropàtic” de l’empresa farmacèutica Esteve. Per tant, els objectius d’aquesta Tesi estan en línea amb l’objectiu del projecte 5-HT7 d’Esteve focalitzat en el descobriment de compostos amb afinitat pel receptor 5-HT7 pel tractament del dolor neuropàtic.
A partir de l’aproximació genètica amb l’ús de ratolins genoanul•lats pel receptor 5-HT7 i d’eines farmacològiques com compostos amb afinitat pel receptor 5-HT7, vàrem investigar a nivell preclínic el paper dels receptors 5-HT7 en el dolor i l’interès terapèutic dels lligands del receptor 5-HT7 en dolor. Entre els compostos utilitzats hi trobem el SB-258719 i el SB- 269970 com antagonistes pel receptor 5-HT7, i el AS-19, MSD-5a, E-55888 i el E-57431 com agonistes pel receptor 5-HT7. E-55888 i E-57431 van ser descrits per primera vegada i es va estudiar el seu perfil d’afinitat, selectivitat i funcionalitat. Es van realitzar estudis de comportament in vivo en ratolí i rata sotmesos a unes condicions de dolor nociceptiu, inflamatori, neurogènic i neuropàtic.
Els nostres resultats van mostrar que els receptors 5-HT7 per si mateixos no estaven implicats en la resposta a un estímul nociu, mentre que sí interaccionen amb el sistema opiodèrgic en condicions de dolor nociceptiu. Ratolins genoanul•lats pel receptor 5-HT7 van mostrar la mateixa sensibilitat enfront un estímul tèrmic nociu. L’administració sistèmica de l’agonista del receptor 5-HT7 E-55888 o l’antagonista del receptor 5-HT7 SB-258719 no van mostrar efecte en el dolor agut nociceptiu. En canvi, vàrem observar que els efectes antinociceptius de la morfina per via oral obtinguts en resposta a l’estímul tèrmic nociu del tail-flick, eren potenciats amb l’administració sistèmica conjunta de l’agonista del receptor 5-HT7 E-55888. Aquesta potenciació va ser revertida al mateix temps amb la coadministració de l’antagonista del receptor 5-HT7 SB-258719.
També vàrem estudiar el paper dels receptors 5-HT7 en condicions de dolor i sensibilització central. L’administració sistèmica d’agonistes selectius pel receptor 5-HT7 inhibia la hipersensibilitat mecànica induïda per capsaicina, la hipersensibilitat mecànica i tèrmica induïda per la lesió del nervi ciàtic, i el dolor induït per la fase II del model de la formalina. Això suggeria la implicació dels receptors 5-HT7 en condicions de sensibilització central. En canvi, es va observar una promoció de la hipersensibilitat mecànica amb els antagonistes del receptor 5-HT7. Tant els efectes dels agonistes i antagonistes del receptor 5-HT7 es van revertir amb la coadministració d’antagonistes i agonistes del receptor 5-HT7, respectivament. És important senyalar que les dosis amb eficàcia analgèsica dels agonistes del receptor 5-HT7 eren inferior a les dosis que produïen efectes adversos amb el test del rota-rod. A més, no es va observar tolerància de l’efecte analgèsic amb l’administració de dosis repetides de l’agonista del receptor 5-HT7 E-57431.
L’efecte analgèsic obtingut amb l’administració sistèmica dels agonistes pel receptor 5-HT7 semblava ser degut a l’activació de receptors 5-HT7 localitzats a nivell espinal. Vàrem trobar que l’administració intratecal de l’agonista del receptor 5-HT7 E-57431 inhibia la hipersensibilitat mecànica secundària a la injecció de capsaicina i la induïda per la lesió del nervi ciàtic. En canvi, es va observar un increment de la hipersensibilitat mecànica induïda per capsaicina amb la injecció local intraplantar de l’agonista del receptor 5-HT7 E-57431. En resum, l’efecte antinociceptiu obtingut a través de l’activació dels receptors 5-HT7 a nivell espinal sembla predominar respecte l’efecte pronociceptiu de la perifèria quan s’administra sistèmicament un agonista pel receptor 5-HT7. En línea amb l’efecte antinociceptiu observat a nivell espinal, vàrem trobar un increment de la immunoreactivitat dels receptors 5-HT7 de l’asta dorsal de la medul•la espinal en ratolins amb lesió del nervi ciàtic. Aquest increment en l’expressió del receptor 5-HT7 en l’asta dorsal induït per la lesió del nervi podria representar un mecanisme espinal fisiològic, compensatori i protector rellevant pel control de dolor en condicions de dolor neuropàtic.
Vàrem observar una col•localització dels receptors 5-HT7 en cèl•lules GABAèrgiques. En aquest sentit, l’activació dels receptors 5-HT7 col•localitzats en interneurones inhibitòries de l’asta dorsal de la medul•la espinal podria ser el mecanisme d’acció implicat en els efectes antinociceptius observats amb els agonistes del receptor 5-HT7.
Finalment, utilitzant ratolins genoanul•lats pel receptor 5-HT7, vàrem demostrar que els agonistes pel receptor 5-HT7 AS-19, E-55888 i E-57431 exercien efectes diana específics em el control de dolor. L’administració subcutània d’aquests agonistes pel receptor 5-HT7 reduïren la nocicepció induïda per formalina de la fase II en ratolins salvatges però no en ratolins genoanul•lats, suggerint una especificitat dels efectes obtinguts in vivo a través del receptor 5-HT7.
Aquest treball aporta un millor coneixement del paper del receptor 5-HT7 en el control del dolor i suggereix un nou potencial ús terapèutic dels agonistes pel receptor 5-HT7 com a fàrmacs prometedors pel tractament del dolor neuropàtic
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