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Cover page of Neurotensin receptor 1-biased ligand attenuates neurotensin-mediated excitation of ventral tegmental area dopamine neurons and dopamine release in the nucleus accumbens.

Neurotensin receptor 1-biased ligand attenuates neurotensin-mediated excitation of ventral tegmental area dopamine neurons and dopamine release in the nucleus accumbens.

(2023)

Strong expression of the G protein-coupled receptor (GPCR) neurotensin receptor 1 (NTR1) in ventral tegmental area (VTA) dopamine (DA) neurons and terminals makes it an attractive target to modulate DA neuron activity and normalize DA-related pathologies. Recent studies have identified a novel class of NTR1 ligand that shows promising effects in preclinical models of addiction. A lead molecule, SBI-0654553 (SBI-553), can act as a positive allosteric modulator of NTR1 β-arrestin recruitment while simultaneously antagonizing NTR1 Gq protein signaling. Using cell-attached recordings from mouse VTA DA neurons we discovered that, unlike neurotensin (NT), SBI-553 did not independently increase spontaneous firing. Instead, SBI-553 blocked the NT-mediated increase in firing. SBI-553 also antagonized the effects of NT on dopamine D2 auto-receptor signaling, potentially through its inhibitory effects on G-protein signaling. We also measured DA release directly, using fast-scan cyclic voltammetry in the nucleus accumbens and observed antagonist effects of SBI-553 on an NT-induced increase in DA release. Further, in vivo administration of SBI-553 did not notably change basal or cocaine-evoked DA release measured in NAc using fiber photometry. Overall, these results indicate that SBI-553 blunts NT's effects on spontaneous DA neuron firing, D2 auto-receptor function, and DA release, without independently affecting these measures. In the presence of NT, SBI-553 has an inhibitory effect on mesolimbic DA activity, which could contribute to its efficacy in animal models of psychostimulant use.

Cover page of Brain organoids, consciousness, ethics and moral status.

Brain organoids, consciousness, ethics and moral status.

(2023)

Advances in the field of human stem cells are often a source of public and ethical controversy. Researchers must frequently balance diverse societal perspectives on questions of morality with the pursuit of medical therapeutics and innovation. Recent developments in brain organoids make this challenge even more acute. Brain organoids are a new class of brain surrogate generated from human pluripotent stem cells (hPSCs). They have gained traction as a model for studying the intricacies of the human brain by using advancements in stem cell biology to recapitulate aspects of the developing human brain in vitro. However, recent observation of neural oscillations spontaneously emerging from these organoids raises the question of whether brain organoids are or could become conscious. At the same time, brain organoids offer a potentially unique opportunity to scientifically understand consciousness. To address these issues, experimental biologists, philosophers, and ethicists united to discuss the possibility of consciousness in human brain organoids and the consequent ethical and moral implications.

Cover page of Intermediate and long-term exposure to air pollution and temperature and the extracellular microRNA profile of participants in the normative aging study (NAS).

Intermediate and long-term exposure to air pollution and temperature and the extracellular microRNA profile of participants in the normative aging study (NAS).

(2023)

Background

The molecular effects of intermediate and long-term exposure to air pollution and temperature, such as those on extracellular microRNA (ex-miRNA) are not well understood but may have clinical consequences.

Objectives

To assess the association between exposure to ambient air pollution and temperature and ex-miRNA profiles.

Methods

Our study population consisted of 734 participants in the Normative Aging Study (NAS) between 1999 and 2015. We used high-resolution models to estimate four-week, eight-week, twelve-week, six-month, and one-year moving averages of PM2.5, O3, NO2, and ambient temperature based on geo-coded residential addresses. The outcome of interest was the extracellular microRNA (ex-miRNA) profile of each participant over time. We used a longitudinal quantile regression approach to estimate the association between the exposures and each ex-miRNA. Results were corrected for multiple comparisons and ex-miRNAs that were still significantly associated with the exposures were further analyzed using KEGG pathway analysis and Ingenuity Pathway Analysis.

Results

We found 151 significant associations between levels of PM2.5, O3, NO2, and ambient temperature and 82 unique ex-miRNAs across multiple quantiles. Most of the significant results were associations with intermediate-term exposure to O3, long-term exposure to PM2.5, and both intermediate and long-term exposure to ambient temperature. The exposures were most often associated with the 75th and 90th percentile of the outcomes. Pathway analyses of significant ex-miRNAs revealed their involvement in biological pathways involving cell function and communication as well as clinical diseases such as cardiovascular disease, respiratory disease, and neurological disease.

Conclusion

Our results show that intermediate and long-term exposure to all our exposures of interest were associated with changes in the ex-miRNA profile of study participants. Further studies on environmental risk factors and ex-miRNAs are warranted.

Cover page of Discordance between assessments of food cue responsiveness: Implications for assessment in youth with overweight/obesity.

Discordance between assessments of food cue responsiveness: Implications for assessment in youth with overweight/obesity.

(2023)

Food cue responsiveness (FCR), broadly defined as behavioral, cognitive, emotional and/or physiological responses to external appetitive cues outside of physiological need, contributes to overeating and obesity among youth and adults. A variety of measures purportedly assess this construct, ranging from youth- or parent-report surveys to objective eating tasks. However, little research has assessed their convergence. It is especially important to evaluate this in children with overweight/obesity (OW/OB), as reliable and valid assessments of FCR are essential to better understand the role of this critical mechanism in behavioral interventions. The present study examined the relationship between five measures of FCR in a sample of 111 children with OW/OB (mean age = 10.6, mean BMI percentile = 96.4; 70% female; 68% white; 23% Latinx). Assessments included: objectively measured eating in the absence of hunger (EAH), parasympathetic activity when exposed to food, parent reported food responsiveness subscale from the Child Eating Behavior Questionnaire (CEBQ-FR), child self-reported Power of Food total score (C-PFS), and child self-reported Food Cravings Questionnaire total score (FCQ-T). Statistically significant spearman correlations were found between EAH and CEBQ-FR (ρ = 0.19, p < 0.05) and parasympathetic reactivity to food cues with both C-PFS (ρ = -0.32, p = 0.002) and FCQ-T (ρ = -0.34, p < 0.001). No other associations were statistically significant. These relationships remained significant in subsequent linear regression models controlling for child age and gender. The lack of concordance between measures assessing highly conceptually related constructs is of concern. Future studies should seek to elucidate a clear operationalization of FCR, examine the associations between FCR assessments in children and adolescents with a range of weight statuses, and evaluate how to best revise these measures to accurately reflect the latent construct being assessed.

Cover page of Geochemical Negative Emissions Technologies: Part I. Review

Geochemical Negative Emissions Technologies: Part I. Review

(2023)

Over the previous two decades, a diverse array of geochemical negative emissions technologies (NETs) have been proposed, which use alkaline minerals for removing and permanently storing atmospheric carbon dioxide (CO2). Geochemical NETs include CO2 mineralization (methods which react alkaline minerals with CO2, producing solid carbonate minerals), enhanced weathering (dispersing alkaline minerals in the environment for CO2 drawdown) and ocean alkalinity enhancement (manipulation of ocean chemistry to remove CO2 from air as dissolved inorganic carbon). CO2 mineralization approaches include in situ (CO2 reacts with alkaline minerals in the Earth's subsurface), surficial (high surface area alkaline minerals found at the Earth's surface are reacted with air or CO2-bearing fluids), and ex situ (high surface area alkaline minerals are transported to sites of concentrated CO2 production). Geochemical NETS may also include an approach to direct air capture (DAC) that harnesses surficial mineralization reactions to remove CO2 from air, and produce concentrated CO2. Overall, these technologies are at an early stage of development with just a few subjected to field trials. In Part I of this work we have reviewed the current state of geochemical NETs, highlighting key features (mineral resources; processes; kinetics; storage durability; synergies with other NETs such as DAC, risks; limitations; co-benefits, environmental impacts and life-cycle assessment). The role of organisms and biological mechanisms in enhancing geochemical NETs is also explored. In Part II, a roadmap is presented to help catalyze the research, development, and deployment of geochemical NETs at the gigaton scale over the coming decades.

Cover page of Geochemical Negative Emissions Technologies: Part II. Roadmap

Geochemical Negative Emissions Technologies: Part II. Roadmap

(2023)

Geochemical negative emissions technologies (NETs) comprise a set of approaches to climate change mitigation that make use of alkaline minerals to remove and/or permanently store carbon dioxide (CO2) as solid carbonate minerals or dissolved ocean bicarbonate ions. This roadmap accompanies the comprehensive review of geochemical NETs by the same authors and offers guidance for the development and deployment of geochemical NETs at gigaton per year (Gt yr.−1) scale. We lay out needs and high-priority initiatives across six key elements required for the responsible and effective deployment of geochemical NETs: (i) technical readiness, (ii) social license, (iii) demand, (iv) supply chains, (v) human capital, and (vi) infrastructure. We put forward proposals for: specific initiatives to be undertaken; their approximate costs and timelines; and the roles that various actors could play in undertaking them. Our intent is to progress toward a working consensus among researchers, practitioners, and key players about initiatives that merit resourcing and action, primarily focusing on the near-term.

Viral and antiretroviral dynamics in HIV mother-to-child transmission fluids (VADICT) – Protocol and data analysis plan for a cohort study

(2023)

Background: Pregnancy and polymorphisms in drug disposition genes alter the clearance of key antiretrovirals used as part of regimens for prevention of mother-to-child transmission of HIV (PMTCT). The clinical significance of these in women initiating therapy late in pregnancy has not been investigated. The primary objective of the Viral and Antiretroviral Dynamics in HIV Mother-To-Child Transmission Fluids (VADICT) study is to investigate viral and antiretroviral dynamics in matrices associated with mother-to-child transmission (MTCT) (plasma, genital fluid and breastmilk) in women (stratified by CYP2B6 genotypes) who initiate antiretroviral therapy (ART) before or early in pregnancy versus late in pregnancy or early postpartum. Methods: A cohort of HIV-1 infected women who initiated ART containing 600 mg efavirenz before or early in pregnancy (n = 120), during the third trimester (n = 60), or early postpartum (n = 60) will be studied.  Eligible patients will be recruited from four hospitals in Benue State, North Central Nigeria and followed until the end of breastfeeding. Procedures at follow up visits will include sample collection for drug quantification and HIV-1 RNA and DNA in plasma, genital fluid and breastmilk; adherence monitoring; and newborn and infant assessment. Using newborn exposure to maternal efavirenz at birth for validation, prenatal pharmacogenetics of efavirenz will be explored using physiologically-based pharmacokinetic modelling. Three integrated methods will be used to monitor patterns and correlates of adherence across pregnancy and the breastfeeding period. A population pharmacokinetic-pharmacodynamic model will be developed to describe the observed data and simulate what to expect in women initiating ART containing 400 mg efavirenz (recently approved for non-pregnant adults) late in pregnancy or early postpartum. Discussion: This study will help in understanding residual MTCT in women receiving ART and reasons for the rise in MTCT risk during the breastfeeding period. Trial registration: ClinicalTrials.gov: NCT03284645 (15/09/2017)