Boosting the Hydrodeoxygenation Activity and Selectivity of Ni/(M)-SBA-15 Catalysts by Chemical Alteration of the Support.

The influence of the acid sites in the hydrodeoxygenation of anisole performed over Ni catalysts supported on SBA-15 modified with metal oxides (Ni/M-SBA-15, M = Ti, Zr, Al, or Nb) was demonstrated. Catalysts were characterized by SEM-EDX, nitrogen physisorption, XRD, UV-visible DRS, TPR, TPD of ammonia, IR-Py, O2 chemisorption, and high-resolution transmission electron microscopy. The mesoporous structure and the hexagonal arrangement of the supports were maintained in the catalysts. Ni catalysts supported on modified M-SBA-15 exhibited a higher metal-support interaction, an increase in the acidity and, as a consequence, improved selectivity to cyclohexane. The deoxygenation reaction rate constants increased as Ni/SBA-15 < Ni/Ti-SBA-15 < Ni/Nb-SBA-15 < Ni/Zr-SBA-15 < Ni/Al-SBA-15, which is attributed to the increase in the amount and strength of acid sites, especially of the Brønsted ones, which promotes the cleavage of the C-O bond. It is also important to keep the metal/acid sites together to obtain high activity and selectivity to hydrodeoxygenated products.

Maximal Respiratory Pressure Reference Equations in Healthy Adults and Cut-off Points for Defining Respiratory Muscle Weakness.

INTRODUCTION: Maximal inspiratory and expiratory pressures (PImax/PEmax) reference equations obtained in healthy people are needed to correctly interpret respiratory muscle strength. Currently, no clear cut-off points defining respiratory muscle weakness are available. We aimed to establish sex-specific reference equations for PImax/PEmax in a large sample of healthy adults and to objectively determine cut-off points for respiratory muscle weakness. METHODS: A multicentre cross-sectional study was conducted across 14 Spanish centres. Healthy non-smoking volunteers aged 18-80 years stratified by sex and age were recruited. PImax/PEmax were assessed using uniform methodology according to international standards. Multiple linear regressions were used to obtain reference equations. Cut-off points for respiratory muscle weakness were established by using T-scores. RESULTS: The final sample consisted of 610 subjects (314 females; 48 [standard deviation, SD: 17] years). Reference equations for PImax/PEmax included body mass index and a squared term of the age as independent variables for both sexes (p<0.01). Cut-off points for respiratory muscle weakness based on T-scores ≥2.5 SD below the peak mean value achieved at a young age were: 62 and 83cmH2O for PImax and 81 and 109cmH2O for PEmax in females and males, respectively. CONCLUSION: These reference values, based on the largest dataset collected in a European population to date using uniform methodology, help identify cut-off points for respiratory muscle weakness in females and males. These data will help to better identify the presence of respiratory muscle weakness and to determine indications for interventions to improve respiratory muscle function.

Methodological guidelines for the calculation of a Water-Energy-Food nexus index for seafood products.

Indicators from life cycle assessment methodologies (i.e., footprints) have emerged as useful tools for identifying and communicating the environmental impacts of a system thanks to they are accessible and intuitive and easy to understand to non-expert public. However, the focus on a single environmental problem is one of their main drawbacks. From this idea arises the concept of Water-Energy-Food (WEF) nexus, with the aim of raising awareness of the connections between the universal rights to water supply, energy security and food provision. Regarding the latter, the fisheries sector stands out as a fundamental pillar in the fight against malnutrition. In this sense, the European project "blue growth" aims to ensure that the development of the marine sector is not linked to the degradation of its ecosystems. However, although producers and authorities are willing to communicate the sustainability of products, there is still no standard methodology for reporting it. With the purpose of remedying this current situation, this paper aims to provide technical guidance to calculate a single WEF nexus index for ecolabelling seafood products in the European framework (Atlantic area). Therefore, through this, it is expected to create a useful communication channel between producers and consumers through an easy-to-read ecolabel. Nonetheless, certain aspects, such as the footprints selected or the calculation procedures selected have to be reconsidered to refine the methodology proposed, apart from broadening the approach to other food sectors with the aim that the proposed eco-certification can be present in major supply and retail chains.

Effects of Hydroxychloroquine on endOthelial function in eLDerly with sleep apnea (HOLD): study protocol for a randomized clinical trial.

BACKGROUND: Sleep apnea and coronary artery disease are prevalent and relevant diseases. The mechanism by which sleep apnea leads to coronary artery disease remains unclear. Intermittent hypoxia, caused by sleep apnea, leads to inflammation and consequent endothelial dysfunction. Endothelial dysfunction precedes the development of atherosclerotic disease and the occurrence of cardiovascular events. Agents that potentially act to improve endothelial function can help prevent cardiovascular events. Patients using immunomodulators due to rheumatic diseases have a lower prevalence of cardiovascular diseases. However, the potential cardioprotective effect of these drugs in patients without autoimmune diseases is not clear. Hydroxychloroquine (HCQ) is an immunomodulator used to treat rheumatoid arthritis and systemic lupus erythematosus. In addition to its anti-inflammatory properties, HCQ reduces cholesterol and blood glucose levels and has antithrombotic effects. The drug is inexpensive and widely available. Adverse effects of HCQ are rare and occur more frequently with high doses. OBJECTIVE: In this randomized clinical trial, the effect of HCQ treatment on endothelial function will be tested in seniors with sleep apnea. METHODS: We will recruit participants over the age of 65 and with moderate-severe sleep apnea from an ongoing cohort. We chose to use this sample already evaluated for sleep apnea for reasons of convenience, but also because the elderly with sleep apnea are vulnerable to heart disease. Endothelial function will be assessed by examining flow-mediated dilation of the brachial artery, the gold standard method, considered an independent predictor of cardiovascular events in the general population and by peripheral arterial tonometry, the most recent and most easily obtained method. Hydroxychloroquine will be used at a dose of 400 mg/daily for 8 weeks. DISCUSSION: Our study aims to obtain evidence, albeit preliminary, of the efficacy of hydroxychloroquine in improving endothelial function and reducing cardiovascular risk markers. If the improvement occurs, we plan to design a randomized multicenter clinical trial to confirm the findings. TRIAL REGISTRATION: ClinicalTrials.gov NCT04161339 . Registered on November 2019.

Multi-product strategy to enhance the environmental profile of the canning industry towards circular economy.

The sustainable and continued production of enough food to feed the entire world's population is one of the main concerns in the food industry. Spain, and in particular Galicia, which is an eminently fishing region characterised by the consumption of large quantities of fish, both fresh and processed, must face the challenge of shifting its seafood productive fabric towards a circular economy. To achieve this objective, the first task is to demonstrate that circular economy principles allow to reduce the environmental impacts associated with seafood production. In this sense, this study proposes the environmental evaluation of the skipjack tuna (Katsuwonus pelamis) value chain within a canning industry located in Galicia through the LCA methodology from an attributional perspective, including the valorisation processes for biowaste (edible and inedible by-products). Results indicate that the main crucial subsystems of the value chain are tuna fishing and the canning process, as it was expected considering other similar studies on seafood products. Moreover, this specific case study demonstrates that the multi-product strategy applied to the canning sector is environmentally viable. Thus, although the environmental impacts of the entire system are increased by including further valorisation operations, the environmental loads assigned to the main product (canned tuna) decrease compared to the one-product system by assigning environmental burdens to other value-added products (tuna pâté, fishmeal, and fish oil).

Life cycle assessment of fish and seafood processed products - A review of methodologies and new challenges.

Life cycle assessment (LCA) has been widely applied in many different sectors, but the marine products and seafood segment have received relatively little attention in the past. In recent decades, global fish production experienced sustained growth and peaked at about 179 million tonnes in 2018. Consequently, increased interest in the environmental implications of fishery products along the supply chain, namely from capture to end of life, was recently experienced by society, industry and policy-makers. This timely review aims to describe the current framework of LCA and its application to the seafood sector that mainly focused on fish extraction and processing, but it also encompassed the remaining stages. An excess of 60 studies conducted over the last decade, along with some additional publications, were comprehensively reviewed; these focused on the main LCA methodological choices, including but not limited to, functional unit, system boundaries allocation methods and environmental indicators. The review identifies key recommendations on the progression of LCA for this increasingly important sustaining seafood sector. Specifically, these recommendations include (i) the need for specific indicators for fish-related activities, (ii) the target species and their geographical origin, (iii) knowledge and technology transfer and, (iv) the application and implementation of key recommendations from LCA research that will improve the accuracy of LCA models in this sector. Furthermore, the review comprises a section addressing previous and current challenges of the seafood sector. Wastewater treatment, ghost fishing or climate change, are also the objects of discussion together with advocating support for the water-energy-food nexus as a valuable tool to minimize environmental negativities and to frame successful synergies.

Unraveling the environmental impacts of bioactive compounds and organic amendment from grape marc.

In a society that produces large amounts of solid waste, the search for new methods of valorisation has led to the development of techniques that make it possible to obtain new products from waste. In the case of bio-waste, biological treatment such as anaerobic digestion or composting appear to be suitable options for producing bio-energy or bio-fertilizers respectively. Vermicomposting is a method of converting solid organic waste into resources through bio-oxidation and stabilization of the organic waste by earthworms. The purpose of this study is to establish the environmental impacts of a complete route for the valorisation of grape pomace in order to identify environmental hotspots. In this valorisation route, different value-added products are produced with potential application in the cosmetic, food and pharmaceutical sectors. Priority was given to the use of primary data in the elaboration of the data inventories needed to perform the life cycle assessment (LCA). The main findings from this study reported that the energy requirement of the distillation process is an important hot spot of the process. Although the valorisation route has some poor results in terms of the two environmental indicators (carbon footprint and normalised impact index), when economic revenues were included in this analysis, its environmental performance was better than that of other alternatives for bio-waste recovery.

Environmental assessment of viticulture waste valorisation through composting as a biofertilisation strategy for cereal and fruit crops.

Composting is a solid waste management alternative that avoids the emission of methane associated with its disposal in landfill and reduces or eliminates the need for chemical fertilisers if compost is applied. The main objective of this study was to analyse the environmental burdens of composting as a way to achieve a more circular valorisation of wine waste. To do so, with the purpose of identifying optimal operational conditions and determining the "hotspots" of the process, the life cycle assessment (LCA) methodology was used. The consumption of diesel fuel in machinery was determined to be the main critical point in the environmental effects of the system, followed by the transport and distribution of the compost. After the application of compost instead of mineral fertilisers, corn, tomato and strawberry crops would have a better environmental performance in most impact categories. In this sense, a maximum improvement of 65% in terrestrial ecotoxicity is achieved in strawberry cultivation. In light of the results obtained, it is demonstrated that composting is a suitable way of organic waste valorisation according to Circular Economy principles.

Exploring the STOP-BANG questionnaire for obstructive sleep apnea screening in seniors.

STUDY OBJECTIVES: The accuracy of obstructive sleep apnea (OSA) screening instruments in seniors may change as the predictive role of sex, age, and body mass index (BMI) changes with aging. We investigated the diagnostic performance of the STOP-BANG questionnaire in older individuals with aging-adapted scores and thresholds. METHODS: Independent community-dwelling adults aged 65 years or older were screened for OSA. The STOP-BANG questionnaire was tested with different configurations and compared to the apnea-hypopnea index (AHI) obtained from home sleep apnea testing (HSAT). Epworth Sleepiness Scale (ESS) and Athens Insomnia Scale (AIS) were tested as possible supplementary screening criteria. RESULTS: We recruited 458 individuals with a mean age of 71 ± 5 years, 41% men, BMI of 28.5 ± 4.6 kg/m². Mild, moderate, and severe OSA were present in, respectively, 34%, 30%, and 19% of the sample. The STOP questions had an area under the curve (AUC) of the receiver operating characteristic curve significantly lower than the STOP-BANG and the STOP+BMI > 28 kg/m² (STOP-B28). Both STOP-BANG and STOP-B28 had high sensitivity and low specificity in all OSA levels with similar AUC to predict AHI ≥ 5 events/h, 0.64. ESS and AIS were nonsignificant as adjunctive instruments. CONCLUSIONS: Novel modifications of a standard instrument created the STOP-B28, a simpler-to-obtain and similarly performing variation of the STOP-BANG using fewer inputs, and useful to exclude OSA. Screening seniors via questionnaires to detect OSA is problematic. Considering the 83% OSA prevalence in this age group, it may be a sensible option to indicate objective tests, oximetry, HSAT, or even polysomnography, as a first step in OSA investigation.

Dry reforming of methane over nickel supported on Nd-ceria: enhancement of the catalytic properties and coke resistance.

Nickel (5 wt%) supported on Nd-doped ceria was studied as catalysts in the DRM reaction at stoichiometric conditions in the range of 600-800 °C. Ce1-x Nd x O2-δ supports with different Nd contents (x = 0, 0.05, 0.1 and 0.2) were successfully synthesized. The role of oxygen vacancies by the incorporation of Nd3+ into the ceria lattice was investigated. These species were quantified by XRD and Raman spectroscopy, showing a linear dependence as a function of Nd content. Ni/Nd-ceria catalysts were prepared by wet impregnation. Although formation of oxygen vacancies, as well as microstructural features of the support (smaller crystallite sizes, higher surface area, and developed mesoporous structure) were improved as a function of the Nd content, no significant differences were observed in the catalytic properties of Ni/Nd-ceria in the DRM reaction. Despite this, compared to undoped ceria, all the Nd-doped CeO2 catalysts present an enhanced activity and stability, and the best catalytic performance was observed in the Ni/Ce0.95Nd0.05O2-δ sample. Quantification of carbon residues in spent catalysts showed, as expected, lower amounts in the Ni/Nd-ceria samples; nevertheless, among them, the catalyst with the higher amount of oxygen vacancies, is the one with the higher carbon residues. Incorporation of Nd in ceria changes the acid/base properties, diminishing the gasification capacity of the carbonaceous species. These results emphasize that the activity and stability in the Ni/Nd-ceria catalysts for the DRM reaction depend on two key factors, the redox and the acid/base properties of the CeO2 supports, offering insights about the necessary and adequate balance between these properties.

[Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) Consensus for post-COVID-19 Clinical Follow-up]. / Documento de consenso de la Sociedad Española de Neumología y Cirugía Torácica (SEPAR) para el seguimiento clínico post-COVID-19.

SARS-CoV-2 infection can cause a range of respiratory sequelae, especially in patients who have had severe Covid-19 pneumonia. Given the high number of patients who have developed this infection over a short period of time, numerous post-Covid-19 follow-up visits are being carried out, but no clinical follow-up protocol has been established to advise on the complementary tests to be performed and the frequency of these procedures. This consensus document was drawn up by professionals from different areas of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) in order to assist the clinician in identifying possible respiratory complications that may occur during the months following the acute disease, and to protocolize their follow-up and additional tests to be performed. It recommends examinations and interventions to be carried out at various stages in the post-Covid-19 period, and details the specific objectives of these procedures. Primarily, we aim to ensure that patients receive timely clinical follow-up, following a pre-established schedule that takes into account the severity of the disease and the likelihood of long-term sequelae. Another objective is to avoid overloading the health system by eschewing examinations and/or consultations that are, in many cases, unnecessary. Finally, we define criteria for referring patients with specific established sequelae (interstitial lung disease, pulmonary vascular disease, bronchiectasis) to the corresponding specialized units.

Integrated evaluation of wine lees valorization to produce value-added products.

The integrated evaluation of the valorization of wine lees to produce value-added products was carried out in this study from a life-cycle perspective. The consumption of steam has been demonstrated as the main hot spot, reaching 85.7% of the impact on Fossil Depletion and 85.3% on Climate Change. Bearing in mind that four different value-added products are produced, a sensitivity analysis was carried out in order to ascertain the influence of the functional unit and the allocation method on the environmental outcomes. The performance of this system was compared to other processes that produce antioxidants from different raw materials. These processes were phycocyanin recovery from Spirulina platensis cyanobacterium, the production of the red antioxidant astaxanthin by microalgae and the valorization of the macroalgae Sargassum muticum. Wine lees valorization showed a better environmental profile throughout the entire life cycle, due to the fact that most of the operations performed are physical (solid/liquid separations, distillations, evaporations, etc.) and do not involve a large consumption of electricity or chemicals. However, there is still room for improvement, and future research should focus on optimizing the extraction of antioxidants from wine lees using two-stages aqueous systems, ultrasonic or microwave assisted extraction, in the pursuit of better performance and lower environmental impact.

Relevance of hydrogen bonding in CO2 capture enhancement within InOF-1: an energy and vibrational analysis.

The enhancement of CO2 capture due to the confinement of polar molecules within InOF-1 was previously demonstrated. In particular, the presence of MeOH produced 1.30-fold increase in the total CO2 capture. This was explained before with the presence of hydrogen bonds. However, a detailed analysis of the hydrogen bonds among µ2-OH functional groups, MeOH molecules and CO2 molecules was not elucidated; moreover, the possible mechanisms that could explain the enhancement of the capture were also not explained. In this investigation, the density functional theory (DFT) periodic calculations and experimental in situ DRIFTS results allowed us to postulate four plausible CO2 adsorption mechanisms for MeOH-functionalised InOF-1, which described the hydrogen bonds and rationalised the nature of the CO2 capture enhancement.

A template-based approach for responsibility management in executable business processes.

Process-oriented organisations need to manage the different types of responsibilities their employees may have w.r.t. the activities involved in their business processes. Despite several approaches provide support for responsibility modelling, in current Business Process Management Systems (BPMS) the only responsibility considered at runtime is the one related to performing the work required for activity completion. Others like accountability or consultation must be implemented by manually adding activities in the executable process model, which is time-consuming and error-prone. In this paper, we address this limitation by enabling current BPMS to execute processes in which people with different responsibilities interact to complete the activities. We introduce a metamodel based on Responsibility Assignment Matrices (RAM) to model the responsibility assignment for each activity, and a flexible template-based mechanism that automatically transforms such information into BPMN elements, which can be interpreted and executed by a BPMS. Thus, our approach does not enforce any specific behaviour for the different responsibilities but new templates can be modelled to specify the interaction that best suits the activity requirements. Furthermore, libraries of templates can be created and reused in different processes. We provide a reference implementation and build a library of templates for a well-known set of responsibilities.

Clima motivacional hacia el deporte y su relación con hábitos de ocio digital sedentario en estudiantes universitarios / Motivational climate in sport and its relationship with digital sedentary leisure habits in university students

Resumen El uso abusivo de videojuegos se asocia a consecuencias negativas para la salud, como son problemas músculo-esqueléticos, patología ocular o problemas cognitivos y emocionales. Ante esta problemática, múltiples estudios han demostrado como un estilo de vida activo mediante la práctica deportiva genera efectos positivos para la salud que rompen con las consecuencias del ocio digital sedentario. Este estudio de carácter descriptivo y corte transversal, realizado en una muestra de 490 estudiantes universitarios, tiene como objetivo analizar la relación entre el clima motivacional hacia el deporte y el uso problemático de videojuegos, usando como principales instrumentos los cuestionarios CERV, CHCV y PMCSQ-2. Los resultados revelaron que aquellos universitarios que obtenían mayores puntuaciones en Clima Tarea y sus subcategorías eran los que menos problemas patológicos presentaban. Por el contrario, los participantes que padecían problemas potenciales o problemas severos, así como un nivel de uso y atracción medio, obtenían medias más elevadas en Clima Ego, Reconocimiento Desigual y Rivalidad entre Miembros. Se concluye que los universitarios con metas de logro en el deporte orientadas al Ego pueden presentar mayores problemas asociados al uso de videojuegos, principalmente por su búsqueda de motivaciones extrínsecas como la sensación de victoria, obtener mejor rendimiento que otros rivales o alcanzar nuevos retos. De este modo, resulta vital orientar la práctica deportiva a las motivaciones intrínsecas con el fin de evitar el abandono en el deporte y desarrollar una práctica más hedonista que se aleje de hábitos sedentarios.

Abstract Abusive use of video games is associated with negative health consequences, such as musculoskeletal problems, eye disease, or cognitive and emotional problems. In this sense, several studies have shown that an active lifestyle based on sport practice can generate positive health effects that discontinue the consequences of sedentary digital leisure. This descriptive and cross-sectional research was conducted on a sample of 490 university students. The main objective was to determine the relationship between problematic use of video games and motivational climate in sports, using as main instruments the CERV, CHCV, and PMCSQ-2 questionnaires. The results showed that those students who got a higher score on Task Climate and its categories were the participants who presented less pathological problems. By contrast, students who had potential or severe problems, as well as a medium level of use and attraction to video games, got a higher average in Ego Climate, Uneven Recognition, and Rivalry among Members. It is concluded that university students with achievement goals in sports that are oriented to Ego can show more problems associated with the use of video games, mainly because of its pursuit of extrinsic motivations like the feeling of victory, achievement of better performance in comparison with rivals or the quest for new challenges. Therefore, it is vital to promote a sport practice associated with intrinsic motivations in order to avoid sport abandonment and develop a more hedonistic practice to avert sedentary habits.

Heteroreceptor Complexes Formed by Dopamine D1, Histamine H3, and N-Methyl-D-Aspartate Glutamate Receptors as Targets to Prevent Neuronal Death in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder causing progressive memory loss and cognitive dysfunction. Anti-AD strategies targeting cell receptors consider them as isolated units. However, many cell surface receptors cooperate and physically contact each other forming complexes having different biochemical properties than individual receptors. We here report the discovery of dopamine D1, histamine H3, and N-methyl-D-aspartate (NMDA) glutamate receptor heteromers in heterologous systems and in rodent brain cortex. Heteromers were detected by co-immunoprecipitation and in situ proximity ligation assays (PLA) in the rat cortex where H3 receptor agonists, via negative cross-talk, and H3 receptor antagonists, via cross-antagonism, decreased D1 receptor agonist signaling determined by ERK1/2 or Akt phosphorylation, and counteracted D1 receptor-mediated excitotoxic cell death. Both D1 and H3 receptor antagonists also counteracted NMDA toxicity suggesting a complex interaction between NMDA receptors and D1-H3 receptor heteromer function. Likely due to heteromerization, H3 receptors act as allosteric regulator for D1 and NMDA receptors. By bioluminescence resonance energy transfer (BRET), we demonstrated that D1 or H3 receptors form heteromers with NR1A/NR2B NMDA receptor subunits. D1-H3-NMDA receptor complexes were confirmed by BRET combined with fluorescence complementation. The endogenous expression of complexes in mouse cortex was determined by PLA and similar expression was observed in wild-type and APP/PS1 mice. Consistent with allosteric receptor-receptor interactions within the complex, H3 receptor antagonists reduced NMDA or D1 receptor-mediated excitotoxic cell death in cortical organotypic cultures. Moreover, H3 receptor antagonists reverted the toxicity induced by ß1-42-amyloid peptide. Thus, histamine H3 receptors in D1-H3-NMDA heteroreceptor complexes arise as promising targets to prevent neurodegeneration.

Equilibrative nucleoside transporter ENT1 as a biomarker of Huntington disease.

The initial goal of this study was to investigate alterations in adenosine A2A receptor (A2AR) density or function in a rat model of Huntington disease (HD) with reported insensitivity to an A2AR antagonist. Unsuspected negative results led to the hypothesis of a low striatal adenosine tone and to the search for the mechanisms involved. Extracellular striatal concentrations of adenosine were measured with in vivo microdialysis in two rodent models of early neuropathological stages of HD disease, the Tg51 rat and the zQ175 knock-in mouse. In view of the crucial role of the equilibrative nucleoside transporter (ENT1) in determining extracellular content of adenosine, the binding properties of the ENT1 inhibitor [3H]-S-(4-Nitrobenzyl)-6-thioinosine were evaluated in zQ175 mice and the differential expression and differential coexpression patterns of the ENT1 gene (SLC29A1) were analyzed in a large human cohort of HD disease and controls. Extracellular striatal levels of adenosine were significantly lower in both animal models as compared with control littermates and striatal ENT1 binding sites were significantly upregulated in zQ175 mice. ENT1 transcript was significantly upregulated in HD disease patients at an early neuropathological severity stage, but not those with a higher severity stage, relative to non-demented controls. ENT1 transcript was differentially coexpressed (gained correlations) with several other genes in HD disease subjects compared to the control group. The present study demonstrates that ENT1 and adenosine constitute biomarkers of the initial stages of neurodegeneration in HD disease and also predicts that ENT1 could constitute a new therapeutic target to delay the progression of the disease.

A Significant Role of the Truncated Ghrelin Receptor GHS-R1b in Ghrelin-induced Signaling in Neurons.

The truncated non-signaling ghrelin receptor growth hormone secretagogue R1b (GHS-R1b) has been suggested to simply exert a dominant negative role in the trafficking and signaling of the full and functional ghrelin receptor GHS-R1a. Here we reveal a more complex modulatory role of GHS-R1b. Differential co-expression of GHS-R1a and GHS-R1b, both in HEK-293T cells and in striatal and hippocampal neurons in culture, demonstrates that GHS-R1b acts as a dual modulator of GHS-R1a function: low relative GHS-R1b expression potentiates and high relative GHS-R1b expression inhibits GHS-R1a function by facilitating GHS-R1a trafficking to the plasma membrane and by exerting a negative allosteric effect on GHS-R1a signaling, respectively. We found a preferential Gi/o coupling of the GHS-R1a-GHS-R1b complex in HEK-293T cells and, unexpectedly, a preferential Gs/olf coupling in both striatal and hippocampal neurons in culture. A dopamine D1 receptor (D1R) antagonist blocked ghrelin-induced cAMP accumulation in striatal but not hippocampal neurons, indicating the involvement of D1R in the striatal GHS-R1a-Gs/olf coupling. Experiments in HEK-293T cells demonstrated that D1R co-expression promotes a switch in GHS-R1a-G protein coupling from Gi/o to Gs/olf, but only upon co-expression of GHS-R1b. Furthermore, resonance energy transfer experiments showed that D1R interacts with GHS-R1a, but only in the presence of GHS-R1b. Therefore, GHS-R1b not only determines the efficacy of ghrelin-induced GHS-R1a-mediated signaling but also determines the ability of GHS-R1a to form oligomeric complexes with other receptors, promoting profound qualitative changes in ghrelin-induced signaling.

Allosteric mechanisms within the adenosine A2A-dopamine D2 receptor heterotetramer.

The structure constituted by a G protein coupled receptor (GPCR) homodimer and a G protein provides a main functional unit and oligomeric entities can be viewed as multiples of dimers. For GPCR heteromers, experimental evidence supports a tetrameric structure, comprised of two different homodimers, each able to signal with its preferred G protein. GPCR homomers and heteromers can act as the conduit of allosteric interactions between orthosteric ligands. The well-known agonist/agonist allosteric interaction in the adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) heteromer, by which A2AR agonists decrease the affinity of D2R agonists, gave the first rationale for the use of A2AR antagonists in Parkinson's disease. We review new pharmacological findings that can be explained in the frame of a tetrameric structure of the A2AR-D2R heteromer: first, ligand-independent allosteric modulations by the D2R that result in changes of the binding properties of A2AR ligands; second, differential modulation of the intrinsic efficacy of D2R ligands for G protein-dependent and independent signaling; third, the canonical antagonistic Gs-Gi interaction within the frame of the heteromer; and fourth, the ability of A2AR antagonists, including caffeine, to also exert the same allosteric modulations of D2R ligands than A2AR agonists, while A2AR agonists and antagonists counteract each other's effects. These findings can have important clinical implications when evaluating the use of A2AR antagonists. They also call for the need of monitoring caffeine intake when evaluating the effect of D2R ligands, when used as therapeutic agents in neuropsychiatric disorders or as probes in imaging studies. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'.