RESUMEN
The three-spined stickleback (Gasterosteus aculeatus) is a teleost fish and a model organism in evolutionary ecology, useful for both laboratory and natural experiments. It is especially valued for the substantial intraspecific variation in morphology, behaviour and genetics. Classic work of Swarup (1958) has described the development in the laboratory of embryos from a single freshwater population, but this was carried out at higher temperature than many stickleback would encounter in the wild and variation between populations was not addressed. Here we describe the development of embryos from two sympatric, saltwater ecotypes of stickleback from North Uist, Scotland raised at 14°C, the approximate temperature of North Uist lochs in the breeding season. The two ecotypes were (a) a large, migratory form in which the adults are completely plated with bony armour and (b) a smaller, low-plated form that is resident year-round in saltwater lagoons. By monitoring embryos every 24-hours post fertilisation, important characteristics of development were observed and photographed to provide a reference for North Uist ecotypes at this temperature. Hatching success was greater than 85% and did not differ between resident and migratory stickleback, but migratory eggs hatched significantly earlier than the resident ecotype. Our work provides a framework that can now be used to compare stickleback populations that may also grow in distinct environmental conditions, to help understand the breadth of normal developmental features and to characterise abnormal development.
Asunto(s)
Migración Animal , Smegmamorpha , Animales , Smegmamorpha/fisiología , Smegmamorpha/crecimiento & desarrollo , Migración Animal/fisiología , Temperatura , Escocia , Embrión no Mamífero , Ecotipo , FemeninoRESUMEN
Extracellular vesicles (EVs) play a crucial role in pregnancy, revealed by the presence of placental-derived EVs in maternal blood, their in vitro functionality, and their altered cargo in pregnancy pathologies. These EVs are thought to be involved in the development of pregnancy pathologies, such as pre-eclampsia, pre-term birth, and fetal growth restriction, and have been suggested as a source of biomarkers for gestational diseases. However, to accurately interpret their function and biomarker potential, it is necessary to critically evaluate the EV isolation and characterization methodologies used in pregnant cohorts. In this systematic scoping review, we collated the results from 152 studies that have investigated EVs in the blood of pregnant women, and provide a detailed analysis of the EV isolation and characterization methodologies used. Our findings indicate an overall increase in EV concentrations in pregnant compared to non-pregnant individuals, an increased EV count as gestation progresses, and an increased EV count in some pregnancy pathologies. We highlight the need for improved standardization of methodology, greater focus on gestational changes in EV concentrations, and further investigations into the functionality of EVs. Our review suggests that EVs hold great promise as diagnostic and translational tools for gestational diseases. However, to fully realize their potential, it is crucial to improve the standardization and reliability of EV isolation and characterization methodologies, and to gain a better understanding of their functional roles in pregnancy pathologies.
Asunto(s)
Vesículas Extracelulares , Preeclampsia , Embarazo , Femenino , Humanos , Placenta , Reproducibilidad de los Resultados , Preeclampsia/diagnósticoRESUMEN
HIC-Vac is an international network of researchers dedicated to developing human infection challenge studies to accelerate vaccine development against pathogens of high global impact. The HIC-Vac Annual Meeting (3rd and 4th November 2022) brought together stakeholders including researchers, ethicists, volunteers, policymakers, industry partners, and funders with a strong representation from low- and middle-income countries. The network enables sharing of research findings, especially in endemic regions. Discussions included pandemic preparedness and the role of human challenge to accelerate vaccine development during outbreak, with industry speakers emphasising the great utility of human challenge in vaccine development. Public consent, engagement, and participation in human challenge studies were addressed, along with the role of embedded social science and empirical studies to uncover social, ethical, and regulatory issues around human infection challenge studies. Study volunteers shared their experiences and motivations for participating in studies. This report summarises completed and ongoing human challenge studies across a variety of pathogens and demographics, and addresses other key issues discussed at the meeting.
RESUMEN
On-site Sewage Disposal Systems (OSDS) are globally common, and in Hawai'i they present a risk of contamination to drinking water sources and nearshore waters. State legislation has commanded that all cesspools are to be banned by 2050, thus requiring tens of thousands of systems to be converted in the coming decades. This project followed a participatory structured decision-making (SDM) approach to collaboratively design cost-effective and equitable solutions for thousands of cesspools in the high elevation areas of north Maui, Hawai'i. Participatory workshops with a diverse group of stakeholders set ten objectives and brainstormed 33 alternatives, for which the technical team then modeled groundwater nutrients, costs, and equity. All alternatives posed trade-offs, though composting toilets performed best across most objectives, albeit with high maintenance burden. Discounting innovative toilets, the multi-objective analysis suggests that the state should invest in cluster sewering of high-density communities, followed by incentivizing septic tank solutions in properties with the highest effluent flow first, then expanding across the area. The total project cost (installation and operation/maintenance) would be $183-258 million, depending upon the sewer-septic combination. An efficiency frontier reveals sub-par combinations, including aerobic treatment units and passive absorption systems, which cost much more and deliver lower mass flux reduction than more cost-effective alternatives. This study contributes a novel case of rural sanitation to the literature in which decision support tools are used to facilitate evidence-based, collaborative decision-making for sanitation planning. The state could use a similar participatory SDM process when approaching other communities to discuss their cesspool upgrade strategies. Broadening the use of decision analytic techniques can have wider ecological, economic, and social benefits for the state and contexts beyond Hawai'i, as SDM provides a transparent and rigorous, evidence-based decision-theoretic framework to explore multiple values and strategies to address difficult resource management problems.
Asunto(s)
Agua Potable , Agua Subterránea , Administración de Residuos , Hawaii , Formulación de Políticas , SaneamientoRESUMEN
Despite over half a century of research, respiratory syncytial virus (RSV)-induced bronchiolitis remains a major cause of hospitalisation in infancy, while vaccines and specific therapies still await development. Our understanding of mucosal immune responses to RSV continues to evolve, but recent studies again highlight the role of Type-2 immune responses in RSV disease and hint at the possibility that it dampens Type-1 antiviral immunity. Other immunoregulatory pathways implicated in RSV disease highlight the importance of focussing on localised mucosal responses in the respiratory mucosa, as befits a virus that is essentially confined to the ciliated respiratory epithelium. In this review, we discuss studies of mucosal immune cell infiltration and production of inflammatory mediators in RSV bronchiolitis and relate these studies to observations from peripheral blood. We also discuss the advantages and limitations of studying the nasal mucosa in a disease that is most severe in the lower airway. A fresh focus on studies of RSV pathogenesis in the airway mucosa is set to revolutionise our understanding of this common and important infection.
Asunto(s)
Bronquiolitis , Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Humanos , Inmunidad Mucosa , Mucosa Nasal/patologíaRESUMEN
BACKGROUND: Hyaluronic acid (HA) fillers have been studied extensively on the face; however, their safety and efficacy on the neck has not yet been evaluated in a prospective trial in the United States. OBJECTIVE: Analyze the efficacy and safety of a HA filler for static horizontal neck rhytides using either a cannula or needle. MATERIALS AND METHODS: Twenty-six subjects were randomized to receive up to 1 mL of the HA filler Restylane Refyne (HARR, n = 20) or saline (n = 6) using a cannula on one side and a needle on the other with optional repeat treatment. Subjects were graded using the Transverse Neck Line Scale, Canfield photography, and the Global Aesthetic Improvement Scale. RESULTS: A significant improvement 30 days after the last treatment was achieved on the Transverse Neck Line Scale when comparing HARR with saline according to the blind evaluator, subjects, and investigator without any significant side effects. In addition, the blind evaluator, subjects, and investigator rated the side of the neck injected with a needle as having significantly greater improvement than the cannula. CONCLUSION: The hyaluronic acid filler, Restylane Refyne, achieved significant improvement in static horizontal neck rhytides using either a cannula or needle without any serious side effects, although the needle was more effective.
Asunto(s)
Técnicas Cosméticas , Rellenos Dérmicos , Envejecimiento de la Piel , Cánula , Técnicas Cosméticas/efectos adversos , Rellenos Dérmicos/efectos adversos , Humanos , Ácido Hialurónico/efectos adversos , Estudios Prospectivos , Resultado del TratamientoRESUMEN
The purpose of this study was to examine the effects of a single acute dose of yohimbine hydrochloride on repeated anaerobic sprint ability. Physically active females (n = 18) completed two separate repeated supramaximal sprint trials each with a different single-dose treatment: placebo (PL; gluten-free corn starch) or yohimbine hydrochloride (YHM; 2.5 mg). For each trial, participants consumed their respective treatment 20 min before exercise. Following a warm-up, participants completed 3 × 15 s Wingate anaerobic tests (WAnTs) separated by 2 min of active recovery. A capillary blood sample was obtained pre- and immediately post-exercise to measure blood concentrations of lactate (LA), epinephrine (EPI), and norepinephrine (NE). Heart rate (HR) and rate of perceived exertion (RPE) were measured following each WAnT. Findings showed that mean power (p < 0.001; η2 = 0.024), total work (p < 0.001; η2 = 0.061), and HR (p < 0.001; η2 = 0.046), were significantly higher with YHM supplementation versus PL. Fatigue index (p < 0.001; η2 = 0.054) and post-exercise LA (p < 0.001; d = 1.26) were significantly lower with YHM compared to PL. YHM resulted in significantly higher EPI concentrations versus PL (p < 0.001; η2 = 0.225) pre- and post-exercise while NE only increased as a function of time (p < 0.001; η2 = 0.227) and was unaffected by treatment. While RPE increased after each WAnT, no differences between treatments were observed (p = 0.539; η2 < 0.001). Together, these results suggest that acute YHM ingestion imparts ergogenic benefits which may be mediated by lower blood LA and fatigue concomitantly occurring with blood EPI increases. Thus, YHM may improve sprint performance although more mechanistic study is warranted to accentuate underlying processes mediating performance enhancement.
Asunto(s)
Rendimiento Atlético , Sustancias para Mejorar el Rendimiento , Rendimiento Atlético/fisiología , Suplementos Dietéticos , Método Doble Ciego , Prueba de Esfuerzo , Fatiga , Femenino , Humanos , Sustancias para Mejorar el Rendimiento/farmacología , YohimbinaRESUMEN
ISSUE ADDRESSED: Population cancer screening rates are around 50% for the general population and even lower in rural areas. This study aimed to explore knowledge, attitudes, behaviours, motivators and barriers to breast, bowel and cervical screening participation in under-screened men and women. METHODS: We used a qualitative research design. Focus groups were segmented by age, sex and screening participation. Participants were under-screened in at least one of the cancer screening programs, with separate groups for each of the programs. The discussion guides were designed around the Health Belief Model and group discussions were coded using a thematic content analysis approach. RESULTS: Fourteen focus groups were held with 80 participants. Key themes were that the concept of cancer screening was not well understood, a low priority for preventive health behaviours, issues relating to local general practitioners (GP) and screening was unpleasant, embarrassing and/or inconvenient. A key determinant of participation in cancer screening was exposure to prompts to action, and it was evident that participants often required multiple prompts before they took action. CONCLUSIONS: Opportunities that develop attitudes to health that place disease prevention as a high priority; improve understanding of the benefit of screening in terms of early detection and treatment; improve GP availability and the patient-practitioner relationship; and the development of messages for each of the screening programs should be further explored as factors that may influence rural population screening rates. SO WHAT?: Addressing health attitudes, beliefs, knowledge, health practitioner and test-related barriers and improving messaging may increase cancer screening participation in under-screened rural populations.
Asunto(s)
Detección Precoz del Cáncer , Neoplasias del Cuello Uterino , Femenino , Conocimientos, Actitudes y Práctica en Salud , Humanos , Masculino , Tamizaje Masivo , Investigación Cualitativa , Población Rural , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/prevención & controlRESUMEN
Marine plastic pollution has emerged as one of the most pressing environmental challenges of our time. Although there has been a surge in global investment for implementing interventions to mitigate plastic pollution, there has been little attention given to the cost of these interventions. We developed a decision support framework to identify the economic, social, and ecological costs and benefits of plastic pollution interventions for different sectors and stakeholders. We calculated net cost as a function of six cost and benefit categories with the following equation: cost of implementing an intervention (direct, indirect, and nonmonetary costs) minus recovered costs and benefits (monetary and nonmonetary) produced by the interventions. We applied our framework to two quantitative case studies (a solid waste management plan and a trash interceptor) and four comparative case studies, evaluating the costs of beach cleanups and waste-to-energy plants in various contexts, to identify factors that influence the costs of plastic pollution interventions. The socioeconomic context of implementation, the spatial scale of implementation, and the time scale of evaluation all influence costs and the distribution of costs across stakeholders. Our framework provides an approach to estimate and compare the costs of a range of interventions across sociopolitical and economic contexts.
Un Marco de Decisión para Estimar el Costo de Intervenciones en la Contaminación Marina por Plástico Resumen La contaminación marina por plásticos ha emergido como uno de los retos ambientales más prioritarios de nuestro tiempo. Mientras ha habido un aumento en la inversión global para implementar intervenciones para mitigar la contaminación por plásticos, se ha dado poca atención al costo de estas intervenciones. Desarrollamos un marco de soporte a las decisiones para identificar los costos y beneficios económicos, sociales y ecológicos de las intervenciones en la contaminación por plástico para diferentes sectores y partes interesadas. Calculamos el costo neto como una función de 6 categorías de costo y beneficio con la siguiente ecuación: costo de la implementación de una intervención (costos directos, indirectos y no monetarios) menos los costos y beneficios recuperados (monetarios y no monetarios) producidos por las intervenciones. Aplicamos nuestro marco a 2 estudios de caso cuantitativos (un plan de manejo de residuos sólidos y un interceptor de basura) y 4 casos de estudio comparativos evaluando los costos de limpieza de playas y plantas de transformación de desechos a energía en varios contextos para identificar los factores que influyen en los costos de las intervenciones de la contaminación por plástico. El contexto socioeconómico de la implementación, la escala espacial de la implementación y la escala de tiempo de evaluación influyen en los costos y distribución de costos entre las partes interesadas. Nuestro marco proporciona una aproximación para estimar y comparar los costos de una gama de intervenciones en contextos sociopolíticos y económicos.
Asunto(s)
Conservación de los Recursos Naturales , Plásticos , Contaminación Ambiental/prevención & controlRESUMEN
Protected areas are highly heterogeneous in their effectiveness at buffering human pressure, which may hamper their ability to conserve species highly sensitive to human activities. Here, we use 60 million bird observations from eBird to estimate the sensitivity to human pressure of each bird species breeding in the Americas. Concerningly, we find that ecoregions hosting large proportions of high-sensitivity species, concentrated in tropical biomes, do not have more intact protected habitat. Moreover, 266 high-sensitivity species have little or no intact protected habitat within their distributions. Finally, we show that protected area intactness is decreasing faster where high-sensitivity species concentrate. Our results highlight a major mismatch between species conservation needs and the coverage of intact protected habitats, which likely hampers the long-term effectiveness of protected areas at retaining species. We highlight ecoregions where protection and management of intact habitats, complemented by restoration, is urgently needed.
Asunto(s)
Conservación de los Recursos Naturales , Ecosistema , Américas , Animales , Biodiversidad , Aves , HumanosRESUMEN
One of the basic purposes of protected areas and other effective area-based conservation interventions is to achieve conservation impact, the sum of avoided biodiversity loss and promoted recovery relative to outcomes without protection. In the context of the Convention on Biological Diversity's negotiations on the post-2020 Global Biodiversity Framework, we find that targets for area-based interventions are framed overwhelmingly with measures that fail to inform decision-makers about impact and that risk diverting limited resources away from achieving it. We show that predicting impact in space and time is feasible and can provide the basis for global guidance for jurisdictions to develop targets for conservation impact and shift investment priorities to areas where impact can be most effectively achieved.
Asunto(s)
Biodiversidad , Conservación de los Recursos Naturales , EcosistemaRESUMEN
Background: With advances in sequencing technology and decreasing costs, the number of phage genomes that have been sequenced has increased markedly in the past decade. Materials and Methods: We developed an automated retrieval and analysis system for phage genomes (https://github.com/RyanCook94/inphared) to produce the INfrastructure for a PHAge REference Database (INPHARED) of phage genomes and associated metadata. Results: As of January 2021, 14,244 complete phage genomes have been sequenced. The INPHARED data set is dominated by phages that infect a small number of bacterial genera, with 75% of phages isolated on only 30 bacterial genera. There is further bias, with significantly more lytic phage genomes (â¼70%) than temperate (â¼30%) within our database. Collectively, this results in â¼54% of temperate phage genomes originating from just three host genera. With much debate on the carriage of antibiotic resistance genes and their potential safety in phage therapy, we searched for putative antibiotic resistance genes. Frequency of antibiotic resistance gene carriage was found to be higher in temperate phages than in lytic phages and again varied with host. Conclusions: Given the bias of currently sequenced phage genomes, we suggest to fully understand phage diversity, efforts should be made to isolate and sequence a larger number of phages, in particular temperate phages, from a greater diversity of hosts.
RESUMEN
Transplacental antibody transfer from mother to fetus provides protection from infection in the first weeks of life, and the four different subclasses of IgG (IgG1, IgG2, IgG3, and IgG4) have diverse roles in protection against infection. In this study, we evaluated concentrations and transplacental transfer ratios of the IgG subclasses in a healthy UK-based cohort of mother-cord pairs, and investigated associations with maternal, obstetric, and fetal factors. In agreement with previous studies, we found a strong association between maternal and cord IgG for all subclasses. We report a transfer efficiency hierarchy of IgG1>IgG3>IgG4=IgG2 in our study population, and our review of the literature demonstrates that there is no consensus in the hierarchy of subclass transfer, despite the commonly made statement that the order is IgG1>IgG4>IgG3>IgG2. We report additional data regarding negative associations between elevated maternal IgG concentrations and maternal/cord transfer ratios, finding an effect on IgG1, IgG2, and IgG3 subclasses. Levels of IgG subclasses were the same between venous and arterial blood samples from the umbilical cord, but there was a significantly higher level of total IgG in arterial blood. We found no correlation between placental FcRn protein levels and IgG transfer in our cohort, suggesting that IgG is the main determinant of observed differences in transplacental transfer ratios at term. Neonatal IgG1 and IgG4 levels were increased with later gestation at delivery, independent of any increase in transplacental transfer, indicating that the benefit of later gestation is through accumulation of these subclasses in the fetus. Neonatal IgG2 levels and transfer ratios were reduced in rhesus-negative pregnancies, suggesting that administered anti-D antibodies may compete for transplacental transfer of this subclass. Maternal influenza vaccination resulted in elevated maternal and neonatal levels of IgG4, whereas maternal Tdap vaccination had no impact on neonatal levels of the subclasses, nor transfer. However, within Tdap vaccinated pregnancies, later gestation at Tdap vaccination was associated with higher transplacental transfer. Our study provides information regarding levels and transfer of IgG subclasses in healthy term pregnancies and demonstrates the importance of recording detailed clinical information in studies of antibody transfer, including parity, ethnicity, and timing of maternal vaccine delivery.
Asunto(s)
Sangre Fetal/inmunología , Inmunidad Materno-Adquirida , Inmunoglobulina G/sangre , Intercambio Materno-Fetal , Circulación Placentaria/inmunología , Adulto , Vacunas contra Difteria, Tétanos y Tos Ferina Acelular/administración & dosificación , Vacunas contra Difteria, Tétanos y Tos Ferina Acelular/inmunología , Femenino , Humanos , Inmunogenicidad Vacunal , Inmunoglobulina G/clasificación , Recién Nacido , Vacunas contra la Influenza/administración & dosificación , Vacunas contra la Influenza/inmunología , Londres , Masculino , Persona de Mediana Edad , Embarazo , Vacunación , Adulto JovenRESUMEN
Plastic pollution is a planetary threat, affecting nearly every marine and freshwater ecosystem globally. In response, multilevel mitigation strategies are being adopted but with a lack of quantitative assessment of how such strategies reduce plastic emissions. We assessed the impact of three broad management strategies, plastic waste reduction, waste management, and environmental recovery, at different levels of effort to estimate plastic emissions to 2030 for 173 countries. We estimate that 19 to 23 million metric tons, or 11%, of plastic waste generated globally in 2016 entered aquatic ecosystems. Considering the ambitious commitments currently set by governments, annual emissions may reach up to 53 million metric tons per year by 2030. To reduce emissions to a level well below this prediction, extraordinary efforts to transform the global plastics economy are needed.
Asunto(s)
Agua Dulce/análisis , Plásticos/análisis , Agua de Mar/análisis , Residuos/análisis , Contaminación Química del Agua/análisis , Monitoreo del Ambiente , Administración de ResiduosRESUMEN
The awareness of the need for robust impact evaluations in conservation is growing and statistical matching techniques are increasingly being used to assess the impacts of conservation interventions. Used appropriately matching approaches are powerful tools, but they also pose potential pitfalls. We outlined important considerations and best practice when using matching in conservation science. We identified 3 steps in a matching analysis. First, develop a clear theory of change to inform selection of treatment and controls and that accounts for real-world complexities and potential spillover effects. Second, select the appropriate covariates and matching approach. Third, assess the quality of the matching by carrying out a series of checks. The second and third steps can be repeated and should be finalized before outcomes are explored. Future conservation impact evaluations could be improved by increased planning of evaluations alongside the intervention, better integration of qualitative methods, considering spillover effects at larger spatial scales, and more publication of preanalysis plans. Implementing these improvements will require more serious engagement of conservation scientists, practitioners, and funders to mainstream robust impact evaluations into conservation. We hope this article will improve the quality of evaluations and help direct future research to continue to improve the approaches on offer.
Emparejamiento Estadístico para la Ciencia de la Conservación Resumen Hay más conciencia sobre la necesidad de evaluaciones de impacto más rigurosas y las técnicas de emparejamiento estadístico se están usan con más frecuencia para evaluar los impactos de intervenciones de conservación. Las técnicas de emparejamiento pueden ser herramientas poderosas si son utilizadas correctamente, pero también pueden llevar a conclusiones erróneas. En este artículo describimos consideraciones importantes para realizar estudios de conservación que utilizan técnicas de emparejamiento estadístico. Identificamos tres pasos dentro de un análisis de emparejamiento. Primero, es importante desarrollar una teoría del cambio que considere las complejidades del mundo real y las posibles consecuencias indirectas para poder seleccionar unidades de tratamiento y controles. Segundo, es clave seleccionar las covarianzas y la estrategia de emparejamiento apropiadas. Tercero, evaluar la calidad del emparejamiento a través de una serie de revisiones. El segundo y el tercer paso pueden ser repetidos y deben concluirse antes de que se exploren los resultados. Evaluaciones de impacto de intervenciones de conservación podrían mejorarse con una mejor planeación de las evaluaciones junto con la intervención, una mejor integración de los métodos cualitativos, mejor consideración de consecuencias indirectas a grandes escalas espaciales y un incremento en la publicación de planes pre-analíticos. La implementación de estas mejoras requerirá de un compromiso más serio por parte de científicos de la conservación, y de practicantes y financiadores. Esperamos que este artículo mejore la calidad de evaluaciones y ayude a guiar futuras investigaciones e intervenciones de conservación.
Asunto(s)
Conservación de los Recursos NaturalesRESUMEN
Upon the FDA approval for inhaled nitric oxide (iNO) in 1999 to treat persistent pulmonary hypertension in neonates, iNO has proven to be a beneficial therapeutic in multiple diseases. We aim to review applications of iNO that have modeled its protective and therapeutic attributes, as well as highlight preliminary studies that could allude to future avenues of use. Numerous publications have reported specific incidences where iNO therapy has proved advantageous, while some applications have potential after further validation. Establishing guidelines on dosing, duration, and defined clinical uses are crucial for the future of iNO. Delivery of iNO has been controlled by a sole distributor, and comes with high cost, and lack of portability. A shift in patents has allowed for new designs for iNO device synthesis, with many new developments of iNO medical devices that will likely change the future of iNO in a medical setting.
Asunto(s)
Óxido Nítrico , Administración por Inhalación , Humanos , Recién NacidoRESUMEN
Developing new medications for the treatment of cocaine dependence continues to be a research priority. Compelling evidence indicates that mixed opioid receptor agonists, particularly bifunctional compounds that target nociceptin/orphanin FQ peptide (NOP) and mu opioid receptors, may be useful for the treatment of cocaine addiction. Here, we verify that potent and selective pharmacological activation of NOP receptors is sufficient to reduce relevant facets of cocaine addiction in animal models. Accordingly, we determined whether systemic injections of the small molecule AT-312 (0, 1, 3 mg/kg) could reduce operant cocaine self-administration, motivation for cocaine, and vulnerability to cocaine relapse in rats. Results indicate that a potent and selective NOP receptor agonist was equally efficacious in reducing the number of cocaine infusions in short (1-hour), as well as long (6-hour) access sessions. When tested on an economic-demand reinforcement schedule, AT-312 reduced Q0 , the parameter that describes the amount of drug consumed at zero price, while leaving the parameter α, a measure of motivation for drug consumption, unaltered. Furthermore, AT-312 successfully reduced conditioned reinstatement of cocaine seeking. In contrast, the NOP receptor agonist did not modify food self-administration. Blockade of the NOP receptor with the antagonist SB-612111 prevented the effect of AT-312 in decreasing cocaine-reinforced responding under a 2-hour fixed ratio 1 schedule, suggesting a NOP receptor-mediated mechanism. This work demonstrates that potent and selective activation of NOP receptors is sufficient to decrease cocaine taking and seeking behaviors in rats.
Asunto(s)
Trastornos Relacionados con Cocaína/metabolismo , Cocaína/administración & dosificación , Receptores Opioides/agonistas , Animales , Buprenorfina , Cicloheptanos/metabolismo , Indoles/metabolismo , Masculino , Piperidinas/metabolismo , Ratas , Ratas Sprague-Dawley , Esquema de Refuerzo , Autoadministración , Receptor de NociceptinaRESUMEN
BACKGROUND: The nociceptin/orphanin FQ opioid peptide (NOP) receptor and its endogenous ligand N/OFQ have been implicated in the regulation of drug and alcohol use disorders (AUD). In particular, evidence demonstrated that NOP receptor activation blocks reinforcing and motivating effects of alcohol across a range of behavioral measures, including alcohol intake, conditioned place preference, and vulnerability to relapse. METHODS: Here, we show the effects of pharmacological activation and inhibition of NOP receptors on binge-like alcohol consumption, as measured by the "drinking in the dark" (DID) model in C57BL/6J mice. RESULTS: We found that 2 potent and selective NOP agonists AT-202 (0, 0.3, 1, 3 mg/kg) and AT-312 (0, 0.3, 1 mg/kg) did not affect binge alcohol drinking at doses that do not affect locomotor activity. AT-202 also failed to alter DID behavior when administered to mice previously exposed to chronic alcohol treatment with an alcohol-containing liquid diet. Conversely, treatment with either the high affinity NOP receptor antagonist SB-612111 (0, 3, 10, 30 mg/kg) or the selective antagonist LY2817412 (0, 3, 10, 30 mg/kg) decreased binge drinking. SB-612111 was effective at all doses examined, and LY2817412 was effective at 30 mg/kg. Consistently, NOP receptor knockout mice consumed less alcohol compared to wild type. SB-612111 reduced DID and increased sucrose consumption at doses that do not appear to affect locomotor activity. However, the high dose of SB-612111 (30 mg/kg) reduced alcohol intake but failed to inhibit preference in a 2-bottle choice DID model that can assess moderate alcohol intake. CONCLUSIONS: The present results suggest that NOP receptor inhibition rather than activation may represent a valuable approach for treatment of AUD characterized by excessive alcohol consumption such as binge drinking.
Asunto(s)
Disuasivos de Alcohol/uso terapéutico , Consumo de Bebidas Alcohólicas/prevención & control , Antagonistas de Narcóticos/uso terapéutico , Receptores Opioides/efectos de los fármacos , Consumo de Bebidas Alcohólicas/genética , Consumo de Bebidas Alcohólicas/psicología , Animales , Consumo Excesivo de Bebidas Alcohólicas/tratamiento farmacológico , Consumo Excesivo de Bebidas Alcohólicas/genética , Consumo Excesivo de Bebidas Alcohólicas/psicología , Depresores del Sistema Nervioso Central/sangre , Cicloheptanos/farmacología , Oscuridad , Relación Dosis-Respuesta a Droga , Etanol/sangre , Indoles/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Piperidinas/farmacología , Receptores Opioides/agonistas , Receptores Opioides/genética , Receptor de NociceptinaRESUMEN
A cocktail of land-based sources of pollution threatens coral reef ecosystems, and addressing these has become a key management and policy challenge in the State of Hawai'i, other US territories, and globally. In West Maui, Hawai'i, nearly one quarter of all living corals were lost between 1995 and 2008. Onsite disposal systems (OSDS) for sewage leak contaminants into drinking water sources and nearshore waters. In recognition of this risk, the Hawai'i State Department of Health (DOH) is prioritizing areas for cesspool upgrades. Independently, we applied a decision analysis process to identify priority areas to address sewage pollution from OSDS in West Maui, with the objective of reducing nearshore coral reef exposure to pollution. The decision science approach is relevant to a broader context of coastal areas both statewide and worldwide which are struggling with identifying pollution mitigation actions on limited budgets.