Analysis of the diverse antigenic landscape of the malaria protein RH5 identifies a potent vaccine-induced human public antibody clonotype.

The highly conserved and essential Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) has emerged as the leading target for vaccines against the disease-causing blood stage of malaria. However, the features of the human vaccine-induced antibody response that confer highly potent inhibition of malaria parasite invasion into red blood cells are not well defined. Here, we characterize 236 human IgG monoclonal antibodies, derived from 15 donors, induced by the most advanced PfRH5 vaccine. We define the antigenic landscape of this molecule and establish that epitope specificity, antibody association rate, and intra-PfRH5 antibody interactions are key determinants of functional anti-parasitic potency. In addition, we identify a germline IgG gene combination that results in an exceptionally potent class of antibody and demonstrate its prophylactic potential to protect against P. falciparum parasite challenge in vivo. This comprehensive dataset provides a framework to guide rational design of next-generation vaccines and prophylactic antibodies to protect against blood-stage malaria.

Deeper and stronger North Atlantic Gyre during the Last Glacial Maximum.

Subtropical gyre (STG) depth and strength are controlled by wind stress curl and surface buoyancy forcing1,2. Modern hydrographic data reveal that the STG extends to a depth of about 1 km in the Northwest Atlantic, with its maximum depth defined by the base of the subtropical thermocline. Despite the likelihood of greater wind stress curl and surface buoyancy loss during the Last Glacial Maximum (LGM)3, previous work suggests minimal change in the depth of the glacial STG4. Here we show a sharp glacial water mass boundary between 33° N and 36° N extending down to between 2.0 and 2.5 km-approximately 1 km deeper than today. Our findings arise from benthic foraminiferal δ18O profiles from sediment cores in two depth transects at Cape Hatteras (36-39° N) and Blake Outer Ridge (29-34° N) in the Northwest Atlantic. This result suggests that the STG, including the Gulf Stream, was deeper and stronger during the LGM than at present, which we attribute to increased glacial wind stress curl, as supported by climate model simulations, as well as greater glacial production of denser subtropical mode waters (STMWs). Our data suggest (1) that subtropical waters probably contributed to the geochemical signature of what is conventionally identified as Glacial North Atlantic Intermediate Water (GNAIW)5-7 and (2) the STG helped sustain continued buoyancy loss, water mass conversion and northwards meridional heat transport (MHT) in the glacial North Atlantic.

Ketamine and Major Ketamine Metabolites Function as Allosteric Modulators of Opioid Receptors.

Ketamine is a glutamate receptor antagonist that was developed over 50 years ago as an anesthetic agent. At subanesthetic doses, ketamine and some metabolites are analgesics and fast-acting antidepressants, presumably through targets other than glutamate receptors. We tested ketamine and its metabolites for activity as allosteric modulators of opioid receptors expressed as recombinant receptors in heterologous systems and with native receptors in rodent brain; signaling was examined by measuring GTP binding, ß-arrestin recruitment, MAPK activation, and neurotransmitter release. Although micromolar concentrations of ketamine alone had weak agonist activity at µ opioid receptors, the combination of submicromolar concentrations of ketamine with endogenous opioid peptides produced robust synergistic responses with statistically significant increases in efficacies. All three opioid receptors (µ, δ, and κ) showed synergism with submicromolar concentrations of ketamine and either methionine-enkephalin (Met-enk), leucine-enkephalin (Leu-enk), and/or dynorphin A17 (Dyn A17), albeit the extent of synergy was variable between receptors and peptides. S-ketamine exhibited higher modulatory effects compared with R-ketamine or racemic ketamine, with ∼100% increase in efficacy. Importantly, the ketamine metabolite 6-hydroxynorketamine showed robust allosteric modulatory activity at µ opioid receptors; this metabolite is known to have analgesic and antidepressant activity but does not bind to glutamate receptors. Ketamine enhanced potency and efficacy of Met-enkephalin signaling both in mouse midbrain membranes and in rat ventral tegmental area neurons as determined by electrophysiology recordings in brain slices. Taken together, these findings support the hypothesis that some of the therapeutic effects of ketamine and its metabolites are mediated by directly engaging the endogenous opioid system. SIGNIFICANCE STATEMENT: This study found that ketamine and its major biologically active metabolites function as potent allosteric modulators of µ, δ, and κ opioid receptors, with submicromolar concentrations of these compounds synergizing with endogenous opioid peptides, such as enkephalin and dynorphin. This allosteric activity may contribute to ketamine's therapeutic effectiveness for treating acute and chronic pain and as a fast-acting antidepressant drug.

Anomalously weak Labrador Sea convection and Atlantic overturning during the past 150 years.

The Atlantic meridional overturning circulation (AMOC) is a system of ocean currents that has an essential role in Earth's climate, redistributing heat and influencing the carbon cycle1, 2. The AMOC has been shown to be weakening in recent years 1 ; this decline may reflect decadal-scale variability in convection in the Labrador Sea, but short observational datasets preclude a longer-term perspective on the modern state and variability of Labrador Sea convection and the AMOC1, 3-5. Here we provide several lines of palaeo-oceanographic evidence that Labrador Sea deep convection and the AMOC have been anomalously weak over the past 150 years or so (since the end of the Little Ice Age, LIA, approximately AD 1850) compared with the preceding 1,500 years. Our palaeoclimate reconstructions indicate that the transition occurred either as a predominantly abrupt shift towards the end of the LIA, or as a more gradual, continued decline over the past 150 years; this ambiguity probably arises from non-AMOC influences on the various proxies or from the different sensitivities of these proxies to individual components of the AMOC. We suggest that enhanced freshwater fluxes from the Arctic and Nordic seas towards the end of the LIA-sourced from melting glaciers and thickened sea ice that developed earlier in the LIA-weakened Labrador Sea convection and the AMOC. The lack of a subsequent recovery may have resulted from hysteresis or from twentieth-century melting of the Greenland Ice Sheet 6 . Our results suggest that recent decadal variability in Labrador Sea convection and the AMOC has occurred during an atypical, weak background state. Future work should aim to constrain the roles of internal climate variability and early anthropogenic forcing in the AMOC weakening described here.

Proteasome Inhibitor Drugs.

Proteasomes are large, multicatalytic protein complexes that cleave cellular proteins into peptides. There are many distinct forms of proteasomes that differ in catalytically active subunits, regulatory subunits, and associated proteins. Proteasome inhibitors are an important class of drugs for the treatment of multiple myeloma and mantle cell lymphoma, and they are being investigated for other diseases. Bortezomib (Velcade) was the first proteasome inhibitor to be approved by the US Food and Drug Administration. Carfilzomib (Kyprolis) and ixazomib (Ninlaro) have recently been approved, and more drugs are in development. While the primary mechanism of action is inhibition of the proteasome, the downstream events that lead to selective cell death are not entirely clear. Proteasome inhibitors have been found to affect protein turnover but at concentrations that are much higher than those achieved clinically, raising the possibility that some of the effects of proteasome inhibitors are mediated by other mechanisms.

Erratum: In situ Signature of Cyclotron Resonant Heating in the Solar Wind [Phys. Rev. Lett. 129, 165101 (2022)].

This corrects the article DOI: 10.1103/PhysRevLett.129.165101.

Recent, national trends in US adolescent use of menthol and non-menthol cigarettes.

OBJECTIVE: In light of the current U.S. Food and Drug Administration (FDA) proposal to ban menthol cigarettes, this study updates trends in menthol cigarette use among adolescents age 13-18 years up to the year 2020. The study considers a potential role for the ban to reduce black/non-black disparities in menthol cigarette use, as well as a counterargument that a ban is not necessary because menthol use is already diminishing. METHODS: Data are from annual, cross-sectional, nationally representative Monitoring the Future (MTF) surveys of 85 547 8th, 10th and 12th grade students surveyed between 2012 and 2020. Analyses include trends in past 30-day menthol and non-menthol cigarette smoking among the total adolescent population, as well as stratified by race/ethnicity. RESULTS: Declines in adolescent menthol and non-menthol cigarette smoking continued through 2020 so that in 2018-2020 past 30-day prevalence for each was less than 1% for non-Hispanic black adolescents and less than 2.2% for non-black adolescents. For non-Hispanic black adolescents no smoking declines in mentholated or non-mentholated cigarette use from 2015-2017 to 2018-2020 were statistically significant, in part because prevalence levels approached a floor effect and had little room to fall further. Menthol levels were lower for non-Hispanic black versus all other adolescents in all study years. CONCLUSIONS: Continuing declines in adolescent menthol prevalence indicate that both menthol prevalence and also black/non-black disparities in its use are steadily decreasing. However, these decreases in adolescence will take decades to reach later ages through generational replacement. Efforts to accelerate menthol decreases will require new initiatives to increase cessation among adult menthol users.

Unusual Vascular Ring in the Fetus.

We present the clinical course and echocardiographic and genetic findings of two fetuses with an unusual vascular ring, created by a left aortic arch with a right arterial duct and an aberrant right subclavian artery. One fetus was diagnosed with 22q11.2 microdeletion and the other became symptomatic in infancy. It is important to consider the position of the arterial ductal ligament in patients who present with tracheoesophageal compressive symptoms in the presence of a left aortic arch. These cases also highlight that a vascular ring formed from a left arch may have similar associations to a vascular ring formed by a right aortic arch.

Inequities in coronavirus disease 2019 (COVID-19) Vaccination Rates Among Adolescents in Massachusetts: A Cross-sectional Study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has disproportionately affected more socioeconomically disadvantaged persons and areas. We sought to determine how certain sociodemographic factors were correlated to adolescents' COVID-19 vaccination rates in towns and cities ("communities") in the Commonwealth of Massachusetts. METHODS: Data on COVID-19 vaccination rates were obtained over a 20-week period from 30 March 2021 to 10 August 2021. Communities' adolescent (ages 12-19) vaccination rates were compared across quintiles of community-level income, COVID-19 case rate, and proportion of non-Hispanic Black or Hispanic individuals. Other variables included population density and earlier COVID-19 vaccination rates of adolescents and adults, averaged from 30 March to 11 May to determine their effects on vaccination rates on 10 August. Linear and logistic regression was used to estimate individual effects of variables on adolescent vaccination rates. RESULTS: Higher median household income, lower proportion of Black or Hispanic individuals, higher early adolescent COVID-19 vaccination rates, and higher early adult COVID-19 vaccination rates were associated with higher later adolescent COVID-19 vaccination rates. Income per $10 000 (adjusted odds ratio [aOR] = 1.01 [95% confidence interval [CI] = 1.01-1.02]), proportion of Hispanic individuals (aOR = 1.33 [95% CI: 1.13-1.56]), early adolescent COVID-19 vaccination rates (aOR = 5.28 [95% CI: 4.67-5.96]), and early adult COVID-19 vaccination rates (aOR = 2.31 [95% CI: 2.02-2.64]) were associated with higher adolescent COVID-19 vaccination on 10 August, whereas proportion of Black individuals approached significance (aOR = 1.26 [95% CI: .98-1.61]). CONCLUSIONS: Vaccination efforts for adolescents in Massachusetts should focus on boosting vaccination rates early in communities with the lowest incomes and greatest proportion of Hispanic individuals and consider targeting communities with a greater proportion of Black individuals.

In Situ Signature of Cyclotron Resonant Heating in the Solar Wind.

The dissipation of magnetized turbulence is an important paradigm for describing heating and energy transfer in astrophysical environments such as the solar corona and wind; however, the specific collisionless processes behind dissipation and heating remain relatively unconstrained by measurements. Remote sensing observations have suggested the presence of strong temperature anisotropy in the solar corona consistent with cyclotron resonant heating. In the solar wind, in situ magnetic field measurements reveal the presence of cyclotron waves, while measured ion velocity distribution functions have hinted at the active presence of cyclotron resonance. Here, we present Parker Solar Probe observations that connect the presence of ion-cyclotron waves directly to signatures of resonant damping in observed proton-velocity distributions using the framework of quasilinear theory. We show that the quasilinear evolution of the observed distribution functions should absorb the observed cyclotron wave population with a heating rate of 10^{-14} W/m^{3}, indicating significant heating of the solar wind.

Chronic Environmental Perturbation Influences Microbial Community Assembly Patterns.

Acute environmental perturbations are reported to induce deterministic microbial community assembly, while it is hypothesized that chronic perturbations promote development of alternative stable states. Such acute or chronic perturbations strongly impact on the pre-adaptation capacity to the perturbation. To determine the importance of the level of microbial pre-adaptation and the community assembly processes following acute or chronic perturbations in the context of hydrocarbon contamination, a model system of pristine and polluted (hydrocarbon-contaminated) sediments was incubated in the absence or presence (discrete or repeated) of hydrocarbon amendment. The community structure of the pristine sediments changed significantly following acute perturbation, with selection of different phylotypes not initially detectable. Conversely, historically polluted sediments maintained the initial community structure, and the historical legacy effect of chronic pollution likely facilitated community stability. An alternative stable state was also reached in the pristine sediments following chronic perturbation, further demonstrating the existence of a legacy effect. Finally, ecosystem functional resilience was demonstrated through occurrence of hydrocarbon degradation by different communities in the tested sites, but the legacy effect of perturbation also strongly influenced the biotic response. This study therefore demonstrates the importance of perturbation chronicity on microbial community assembly processes and reveals ecosystem functional resilience following environmental perturbation.

Identifying long-term and imminent suicide predictors in a general population and a clinical sample with machine learning.

BACKGROUND: Machine learning (ML) is increasingly used to predict suicide deaths but their value for suicide prevention has not been established. Our first objective was to identify risk and protective factors in a general population. Our second objective was to identify factors indicating imminent suicide risk. METHODS: We used survival and ML models to identify lifetime predictors using the Cohort of Norway (n=173,275) and hospital diagnoses in a Saskatoon clinical sample (n=12,614). The mean follow-up times were 17 years and 3 years for the Cohort of Norway and Saskatoon respectively. People in the clinical sample had a longitudinal record of hospital visits grouped in six-month intervals. We developed models in a training set and these models predicted survival probabilities in held-out test data. RESULTS: In the general population, we found that a higher proportion of low-income residents in a county, mood symptoms, and daily smoking increased the risk of dying from suicide in both genders. In the clinical sample, the only predictors identified were male gender and older age. CONCLUSION: Suicide prevention probably requires individual actions with governmental incentives. The prediction of imminent suicide remains highly challenging, but machine learning can identify early prevention targets.

Matrix stiffening induces a pathogenic QKI-miR-7-SRSF1 signaling axis in pulmonary arterial endothelial cells.

Pulmonary arterial hypertension (PAH) refers to a set of heterogeneous vascular diseases defined by elevation of pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR), leading to right ventricular (RV) remodeling and often death. Early increases in pulmonary artery stiffness in PAH drive pathogenic alterations of pulmonary arterial endothelial cells (PAECs), leading to vascular remodeling. Dysregulation of microRNAs can drive PAEC dysfunction. However, the role of vascular stiffness in regulating pathogenic microRNAs in PAH is incompletely understood. Here, we demonstrated that extracellular matrix (ECM) stiffening downregulated miR-7 levels in PAECs. The RNA-binding protein quaking (QKI) has been implicated in the biogenesis of miR-7. Correspondingly, we found that ECM stiffness upregulated QKI, and QKI knockdown led to increased miR-7. Downstream of the QKI-miR-7 axis, the serine and arginine-rich splicing factor 1 (SRSF1) was identified as a direct target of miR-7. Correspondingly, SRSF1 was reciprocally upregulated in PAECs exposed to stiff ECM and was negatively correlated with miR-7. Decreased miR-7 and increased QKI and SRSF1 were observed in lungs from patients with PAH and PAH rats exposed to SU5416/hypoxia. Lastly, miR-7 upregulation inhibited human PAEC migration, whereas forced SRSF1 expression reversed this phenotype, proving that miR-7 depended upon SRSF1 to control migration. In aggregate, these results define the QKI-miR-7-SRSF1 axis as a mechanosensitive mechanism linking pulmonary arterial vascular stiffness to pathogenic endothelial function. These findings emphasize implications relevant to PAH and suggest the potential benefit of developing therapies that target this miRNA-dependent axis in PAH.

Salmonella-induced thrombi in mice develop asynchronously in the spleen and liver and are not effective bacterial traps.

Thrombosis is a frequent, life-threatening complication of systemic infection associated with multiple organ damage. We have previously described a novel mechanism of inflammation-driven thrombosis induced by Salmonella Typhimurium infection of mice. Thrombosis in the liver develops 7 days after infection, persisting after the infection resolves, and is monocytic cell dependent. Unexpectedly, thrombosis was not prominent in the spleen at this time, despite carrying a similar bacterial burden as the liver. In this study, we show that thrombosis does occur in the spleen but with strikingly accelerated kinetics compared with the liver, being evident by 24 hours and resolving rapidly thereafter. The distinct kinetics of thrombosis and bacterial burden provides a test of the hypothesis that thrombi form in healthy vessels to trap or remove bacteria from the circulation, often termed immunothrombosis. Remarkably, despite bacteria being detected throughout infected spleens and livers in the early days of infection, immunohistological analysis of tissue sections show that thrombi contain very low numbers of bacteria. In contrast, bacteria are present throughout platelet aggregates induced by Salmonella in vitro. Therefore, we show that thrombosis develops with organ-specific kinetics and challenge the universality of immunothrombosis as a mechanism to capture bacteria in vivo.

Approaches for estimating benefits and costs of interventions in plant biosecurity across invasion phases.

Nonnative plant pests cause billions of dollars in damages. It is critical to prevent or reduce these losses by intervening at various stages of the invasion process, including pathway risk management (to prevent pest arrival), surveillance and eradication (to counter establishment), and management of established pests (to limit damages). Quantifying benefits and costs of these interventions is important to justify and prioritize investments and to inform biosecurity policy. However, approaches for these estimations differ in (1) the assumed relationship between supply, demand, and prices, and (2) the ability to assess different types of direct and indirect costs at invasion stages, for a given arrival or establishment probability. Here we review economic approaches available to estimate benefits and costs of biosecurity interventions to inform the appropriate selection of approaches. In doing so, we complement previous studies and reviews on estimates of damages from invasive species by considering the influence of economic and methodological assumptions. Cost accounting is suitable for rapid decisions, specific impacts, and simple methodological assumptions but fails to account for feedbacks, such as market adjustments, and may overestimate long-term economic impacts. Partial equilibrium models consider changes in consumer and producer surplus due to pest impacts or interventions and can account for feedbacks in affected sectors but require specialized economic models, comprehensive data sets, and estimates of commodity supply and demand curves. More intensive computable general equilibrium models can account for feedbacks across entire economies, including capital and labor, and linkages among these. The two major considerations in choosing an approach are (1) the goals of the analysis (e.g., consideration of a single pest or intervention with a limited range of impacts vs. multiple interventions, pests or sectors), and (2) the resources available for analysis such as knowledge, budget and time.

Savvy investments or formative endowments? Disentangling causal direction in the association between parental support and self-efficacy in STEM university students.

Conventional wisdom views the parent-child relationship as unilateral: Parents' actions upstream flow downstream to shape their children's development. However, scholars have proposed that this view of parenting is lopsided; children may influence their parents no less than parents influence children. We apply this bilateral perspective in a reexamination of the robust finding that confident people report having had more supportive parents. The social-cognitive explanation for this finding is that parents endow their children with support that builds confidence. However, evolutionary accounts suggest that confident children-displaying more promise and potential-ought to attract their parents' investments of support. We examined these predictions in a four-wave longitudinal study drawing on both archival and field survey data from 350 STEM students (science, technology, engineering, and mathematics) in the Philippines. Results were consistent with the bilateral perspective, in which parental support endowed children with confidence, but also children's confidence attracted parental support in equal measure. These reciprocal relations also had implications for whether or not students persisted in their computer science degrees. The results indicate that parental endowments of confidence and parental investments of support form a virtuous cycle, consistent with the perspective that self-efficacy operates not only as an intrapsychic resource allocator but also as an interpersonal resource attractor. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Five Decades of Research on Opioid Peptides: Current Knowledge and Unanswered Questions.

In the mid-1970s, an intense race to identify endogenous substances that activated the same receptors as opiates resulted in the identification of the first endogenous opioid peptides. Since then, >20 peptides with opioid receptor activity have been discovered, all of which are generated from three precursors, proenkephalin, prodynorphin, and proopiomelanocortin, by sequential proteolytic processing by prohormone convertases and carboxypeptidase E. Each of these peptides binds to all three of the opioid receptor types (µ, δ, or κ), albeit with differing affinities. Peptides derived from proenkephalin and prodynorphin are broadly distributed in the brain, and mRNA encoding all three precursors are highly expressed in some peripheral tissues. Various approaches have been used to explore the functions of the opioid peptides in specific behaviors and brain circuits. These methods include directly administering the peptides ex vivo (i.e., to excised tissue) or in vivo (in animals), using antagonists of opioid receptors to infer endogenous peptide activity, and genetic knockout of opioid peptide precursors. Collectively, these studies add to our current understanding of the function of endogenous opioids, especially when similar results are found using different approaches. We briefly review the history of identification of opioid peptides, highlight the major findings, address several myths that are widely accepted but not supported by recent data, and discuss unanswered questions and future directions for research. SIGNIFICANCE STATEMENT: Activation of the opioid receptors by opiates and synthetic drugs leads to central and peripheral biological effects, including analgesia and respiratory depression, but these may not be the primary functions of the endogenous opioid peptides. Instead, the opioid peptides play complex and overlapping roles in a variety of systems, including reward pathways, and an important direction for research is the delineation of the role of individual peptides.

Individuals with mild-to-moderate hip osteoarthritis walk with lower hip joint contact forces despite higher levels of muscle co-contraction compared to healthy individuals.

OBJECTIVE: To compare hip joint contact forces (HJCF), hip muscle forces, and hip muscle co-contraction levels between individuals with mild-to-moderate hip osteoarthritis (OA) and healthy controls during walking. DESIGN: Eighteen participants with mild-to-moderate hip OA and 23 healthy controls walked at a self-selected speed while motion capture and electromyographic data were synchronously collected. HJCF were computed using a calibrated electromyography-informed neuromusculoskeletal model. Hip joint contact forces, muscle forces, and co-contraction indices for flexor/extensor and adductor/abductor muscle groups were compared between groups using independent sample t-tests (P < 0.05). RESULTS: There was no between-group difference in self-selected walking speed. On average, participants with hip OA walked with 11% lower first peak (mean difference 235 [95% confidence interval (CI) 57-413] N) and 22% lower second peak (mean difference 574 [95%CI 304-844] N) HJCF compared to controls. Hip muscle forces were also significantly lower in the hip OA compared to control group at first (mean difference 224 [95%CI 66-382] N) and second (mean difference 782 [95%CI 399-1164] N) peak HJCF. Participants with hip OA exhibited higher levels of hip muscle co-contraction in both flexor/extensor and adductor/abductor muscle groups. Consistent with existing literature, hip joint angles (extension, adduction) and external moments (flexion, extension, adduction) were lower in hip OA compared to controls. CONCLUSION: Lower HJCF were detected in mild-to-moderate hip OA, primarily due to lower hip muscle force production, and despite higher levels of hip muscle co-contraction. Findings suggest that lower loading of the hip joint during walking is a feature of mild-to-moderate hip OA, which could have implications for the pathogenesis of hip OA and/or disease progression.

Influence of the Sea Surface Microlayer on Oceanic Iodine Emissions.

The influence of organic compounds on iodine (I2) emissions from the O3 + I- reaction at the sea surface was investigated in laboratory and modeling studies using artificial solutions, natural subsurface seawater (SSW), and, for the first time, samples of the surface microlayer (SML). Gas-phase I2 was measured directly above the surface of liquid samples using broadband cavity enhanced absorption spectroscopy. I2 emissions were consistently lower for artificial seawater (AS) than buffered potassium iodide (KI) solutions. Natural seawater samples showed the strongest reduction of I2 emissions compared to artificial solutions with equivalent [I-], and the reduction was more pronounced over SML than SSW. Emissions of volatile organic iodine (VOI) were highest from SML samples but remained a negligible fraction (<1%) of the total iodine flux. Therefore, reduced iodine emissions from natural seawater cannot be explained by chemical losses of I2 or hypoiodous acid (HOI), leading to VOI. An interfacial model explains this reduction by increased solubility of the I2 product in the organic-rich interfacial layer of seawater. Our results highlight the importance of using environmentally representative concentrations in studies of the O3 + I- reaction and demonstrate the influence the SML exerts on emissions of iodine and potentially other volatile species.

The great decline in adolescent cigarette smoking since 2000: consequences for drug use among US adolescents.

OBJECTIVE: Adolescent cigarette smoking declined steadily and substantially from 2000 to 2018. This paper considers the potential consequences of this 'great decline' for the prevalence of other drug use among adolescents. METHODS: Data are annual, cross-sectional, nationally representative Monitoring the Future surveys of more than 1.2 million US students in 12th, 10th and 8th grades from 2000 to 2018. Analyses include trends in the past 12 months' non-medical amphetamine, tranquillisers and opioid use overall, among ever and never cigarette smokers, and projected if adolescent cigarette smoking levels had remained at 2000 levels. RESULTS: Within groups of ever and never cigarette smokers, the prevalence for each of the three substances has either changed little or overall increased in 2018 as compared with 2000. When the two groups were combined into one pool, the overall prevalence for each of the drugs declined by about half. The decline resulted from the growing group of never smokers, whose levels of non-medical drug use over the study period were at least four times lower than the levels of ever smokers. CONCLUSIONS: The results support the 'gateway' prediction that declines in cigarette smoking among adolescents pull downward their non-medical use of amphetamines, tranquillisers and opioids. Continuing to reduce adolescent smoking through policy and programmatic prevention efforts should have further positive spillover effects on adolescent drug use.