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A software platform for real-time and adaptive neuroscience experiments.
Get PDFCurrent neuroscience research is often limited to testing predetermined hypotheses and post hoc analysis of already collected data. Adaptive experimental designs, in which modeling drives ongoing data collection and selects experimental manipulations, offer a promising alternative. However, such adaptive paradigms require tight integration between software and hardware under real-time constraints. We introduce improv, a software platform for flexible integration of modeling, data collection, analysis pipelines, and live experimental control. We demonstrate both in silico and in vivo how improv enables efficient experimental designs for discovery and validation across various model organisms and data types. We used improv to orchestrate real-time behavioral analyses, rapid functional typing of neural responses via calcium imaging, optimal visual stimulus selection, and model-driven optogenetic photostimulation of visually responsive neurons in the zebrafish brain. Together, these results demonstrate the power of improv to integrate modeling with data collection and experimental control to achieve next-generation adaptive experiments
A cryptic pocket in CB1 drives peripheral and functional selectivity
Get PDFThe current opioid overdose epidemic highlights the urgent need to develop safer and more effective treatments for chronic pain1. Cannabinoid receptor type 1 (CB1) is a promising non-opioid target for pain relief, but its clinical use has been limited by centrally mediated psychoactivity and tolerance. We overcame both issues by designing peripherally restricted CB1 agonists that minimize arrestin recruitment. We achieved these goals by computationally designing positively charged derivatives of the potent CB1 agonist MDMB-Fubinaca2. We designed these ligands to occupy a cryptic pocket identified through molecular dynamics simulations—an extended binding pocket that opens rarely and leads to the conserved signalling residue D2.50 (ref. 3). We used structure determination, pharmacological assays and molecular dynamics simulations to verify the binding modes of these ligands and to determine the molecular mechanism by which they achieve this dampening of arrestin recruitment. Our lead ligand, VIP36, is highly peripherally restricted and demonstrates notable efficacy in three mouse pain models, with 100-fold dose separation between analgesic efficacy and centrally mediated side effects. VIP36 exerts analgesic efficacy through peripheral CB1 receptors and shows limited analgesic tolerance. These results show how targeting a cryptic pocket in a G-protein-coupled receptor can lead to enhanced peripheral selectivity, biased signalling, desired in vivo pharmacology and reduced adverse effects. This has substantial implications for chronic pain treatment but could also revolutionize the design of drugs targeting other G-protein-coupled receptors
Prenatal Choline Attenuates the Elevated Adiposity and Glucose Intolerance Caused by Prenatal Alcohol Exposure
Get PDFPrenatal alcohol exposure (PAE) causes neurobehavioral deficits and metabolic syndrome in later life. Prenatal choline supplementation (PCS) improves those behavioral deficits. Here we test whether PCS also ameliorates the attendant metabolic syndrome, using an established mouse model that mirrors aspects of alcohol-related neurodevelopmental disorders. Pregnant dams were exposed to alcohol (3 g/kg) from gestational days 8.5–17.5; some dams received additional choline (175% of requirement) by a daily injection. Offspring were followed through to the age of 86 wks with respect to their body composition and glucose tolerance. We found that PAE affected these outcomes in a sex-dependent manner. Male PAE offspring exhibited an increased fat mass, liver enlargement, elevated fasting glucose, and glucose intolerance. Female PAE offspring exhibited an increased fat mass, but the glucose tolerance and fasting values were unaffected. Regardless of sex, PCS attenuated all these metabolic measures. PCS was shown previously to elevate methyl-related choline metabolites and improve fetal growth, suggesting that it acts by attenuating the in utero stressors that otherwise program the fetus for metabolic syndrome in later life. Importantly, PCS also improved the adiposity, fasting glucose, and glucose tolerance in control offspring consuming the fixed-nutrient AIN-93G diet, suggesting that its choline content (1 g/kg) may be inadequate for optimal rodent health
Design approaches for developing quality checklists in healthcare organizations: A scoping review
Get PDFQuality checklists have demonstrated benefits in healthcare and other high-reliability organizations, but there remains a gap in the understanding of design approaches and levels of stakeholder engagement in the development of these quality checklists. This scoping review aims to synthesize the current knowledge base regarding the use of various design approaches for developing quality checklists in healthcare. Secondary objectives are to explore theoretical frameworks, design principles, stakeholder involvement and engagement, and characteristics of the design methods used for developing quality checklists. The review followed the Preferred Reporting Items for Systematic Reviews 2020 checklist. Seven databases (PubMed, APA PsycInfo, CINAHL, Embase, Scopus, ACM Digital Library, and IEEE Xplore) were searched for studies using a comprehensive search strategy developed in collaboration with a health sciences librarian. Search terms included "checklist" and "user-centered design" and their related terms. The IAP2 Spectrum of Participation Framework was used to categorize studies by level of stakeholder engagement during data extraction. Twenty-nine studies met the inclusion criteria for this review. Twenty-three distinct design methods were identified that were predominantly non-collaborative in nature (e.g., interviews, surveys, and other methods that involved only one researcher and one participant at a given time). Analysis of the levels of stakeholder engagement revealed a gap in studies that empowered their stakeholders in the quality checklist design process. Highly effective, clear, and standardized methodologies are needed for the design of quality checklists. Future work needs to explore how stakeholders can be empowered in the design process, and how different levels of stakeholder engagement might impact implementation outcomes
Impacts of Improved Cookstove Interventions on Personal Exposure to Carbon Monoxide and Particulate Matter in Zambia
Get PDFEighty‐four percent of sub‐Saharan African households rely on polluting fuels (e.g., wood, charcoal) for cooking, leading to high levels of household air pollution (HAP). While switching to modern fuels/stoves could decrease HAP levels, they are not always available or affordable. Improved biomass cookstoves could provide an intermediate step supporting transitions from traditional biomass to clean burning fuels/stoves. We conducted two stove intervention trials in Lusaka, Zambia using targeted marketing/incentives to motivate participants to use improved biomass stoves, either the Mimi Moto (pellet) or the EcoZoom (charcoal). Before the intervention, 65% of participants exclusively used charcoal, while 27% relied on electricity to some extent for cooking. We measured 24‐hr personal exposure to CO ( n = 747) and PM 2.5 ( n = 90) of primary cooks. We implemented several statistical approaches to estimate the effects of interventions on exposure: household‐specific endline minus baseline exposure, ranksum testing, difference‐in‐differences analyses, and cross‐sectional analyses. We found that switching from traditional charcoal stoves to either intervention stove was not associated with significantly reduced exposures. However, cooks using electric stoves independent of the intervention did have significantly lower CO exposures than those using traditional charcoal, with greater electric stove use corresponding to greater exposure reductions. Variability in exposure was dominated by seasonal, regional, and neighborhood differences rather than household stove/fuel choices. A focus on HAP exposure from cooking in urban settings is unlikely to yield expected exposure reductions. Policy makers should consider pollution reduction policies/interventions that target ambient air quality in tandem with HAP‐mitigating strategies to address air pollution health burden. Plain Language Summary In 2019, almost 7 million deaths worldwide were linked to air pollution. In sub‐Saharan Africa, 84% of households use polluting fuels like wood and charcoal for cooking, which leads to high levels of air pollution. While cleaner energy options such as electricity could reduce pollution, they are often not accessible or affordable. Improved biomass cookstoves might offer an intermediate solution, helping people transition from traditional fuels to cleaner options. We conducted two studies in Lusaka, Zambia to encourage traditional stove users to switch to improved biomass stoves, either the Mimi Moto (using wood pellets) or EcoZoom (using charcoal). We measured exposure to carbon monoxide and particulate matter among household cooks. We found that switching to improved stoves did not significantly reduce exposures compared to traditional charcoal use. However, cooks using electric stoves did have lower exposures, with greater exposure reductions as more meals were cooked with electricity. Factors such as season and neighborhood also had substantial impacts on exposure. This suggests that focusing only on reducing pollution from cooking in urban areas may not be enough to improve health. Policymakers should consider broader strategies that also target outdoor air quality to effectively address the health risks of air pollution. Key Points In two interventions, the use of improved biomass stoves was not associated with reduced personal exposures Household cooks using existing electric stoves did have significantly lower exposures than traditional charcoal users Changes in exposure were dominated by seasonal, regional, and neighborhood differences rather than household stove/fuel choice
Development of LC-MS/MS Database Based on 250 Potentially Highly Neuroactive Compounds and Their Metabolites
Get PDFBackground: Environmental chemicals are hypothesized to contribute to the development of neurodevelopmental disorders; however, only a fraction of the thousands of chemicals in common commercial use have validated assays. We recently developed the Environmental NeuRoactIve Chemicals (ENRICH) list of 250 chemicals prioritized for further testing due to their high likelihood of neuroactivity and human exposure, as derived through analysis across eight neuroactivity, exposure, and detection databases. Measuring some of these compounds in human biological media remains challenging due to the lack of information regarding their metabolites and detection frequencies. Methods: We created an LC-MS/MS database based on the targets in the ENRICH list using S9 human liver fractions to metabolize compounds individually and in groups into newly and previously discovered phase I metabolites. Results: The final database consisted of 274 compounds with 94 parent compounds and 182 metabolites being featured. A total of 55 novel metabolites were discovered. The confidence of the compounds, which were annotated correctly within the database, was high, increasing the odds of positive identifications within future exposomic work. The confidence of the annotations fell between the levels 1–3, with levels one and two consisting of 87% of the database. Conclusions: The creation of this database creates the opportunity for future biological studies centered around the impact these compounds and their metabolites have on the brain and for a better understanding of neurodevelopmental disorders and their origins
Defining the evolving field of culinary medicine across multiple domains
Get PDFCulinary medicine is an evolving field that spans multiple professions and settings. Prior definitions of culinary medicine may not reflect the expansion of this discipline or the variety of key stakeholders engaged in culinary medicine. To address the need for an updated definition of what culinary medicine means, a working group consisting of a variety of roles and professional/community settings was assembled to reach a consensus definition that is reflective of the current landscape of culinary medicine. Definitions that are tailored to the variety of stakeholders participating in culinary medicine are beneficial to engagement within and across professions in support of programming, clinical care, and access to healthy food with the ultimate goal of empowering patients/consumers to make healthier food choices
Real-world use of classic and non-classic psychedelics in Hispanic/Latino adults with Obsessive-Compulsive Disorder: International findings from the LATINO Study.
Get PDFOBJECTIVE: Despite growing research on the potential mental health benefits of psychedelics, there has been limited study of these drugs in populations with obsessive-compulsive disorder (OCD) and with Hispanic and Latin American (H/L) ancestry. METHODS: Demographic and clinical assessments were conducted as part of the Latin American Trans-ancestry Initiative for OCD genomics (LATINO) Study in H/L participants with OCD living throughout the Americas. Self-reported data on the prevalence of naturalistic psychedelic use and associated outcomes on OCD symptoms were collected in a subsample of 2,639 adults. Descriptive statistics and regression analyses were used to assess psychedelic use, predictors of use, and predictors of OCD symptom change attributed to psychedelics. RESULTS: Across 11 countries, 9% of respondents reported using psychedelics or related substances for treatment. Most respondents (72%) had received traditionally available treatments for OCD (e.g., psychiatric medication and/or psychotherapy). Psilocybin, LSD, and MDMA were the most used psychedelics. Psychedelic users compared to non-users were more likely to be male, have received non-ERP therapy for OCD, and have a comorbid psychiatric diagnosis. Outcomes of psychedelic use for OCD-related symptoms varied widely by drug and were difficult to predict but were reported as most favorable for "classic" serotonergic psychedelics. CONCLUSIONS: Real-world evidence suggests that H/L adults are exploring psychedelics as a treatment for OCD, though further work is needed to establish the conditions for safe and effective use in this population. Increased research and practical harm reduction in this area is critical as public interest in psychedelic drugs continues to surge
Health Communication to Improve Social Interaction: Resources
Get PDFResources from our research, "Health Communication to Improve Social Interaction: Promoting Health Equity Admidst Rising Economic Inequality."
Moisture-responsive root-branching pathways identified in diverse maize breeding germplasm
Get PDFPlants grow complex root systems to extract unevenly distributed resources from soils. Spatial differences in soil moisture are perceived by root tips, leading to the patterning of new root branches toward available water in a process called hydropatterning. Little is known about hydropatterning behavior and its genetic basis in crop plants. Here, we developed an assay to measure hydropatterning in maize and revealed substantial differences between tropical/subtropical and temperate maize breeding germplasm that likely resulted from divergent selection. Genetic analysis of hydropatterning confirmed the regulatory role of auxin and revealed that the gaseous hormone ethylene locally inhibits root branching from air-exposed tissues. Our results demonstrate how distinct signaling pathways translate spatial patterns of water availability to developmental programs that determine root architecture