A pilot trial of a brief intervention for cannabis use supplemented with a substance-free activity session or relaxation training.

OBJECTIVE: Cannabis use is increasing among college students and commonly co-occurs with anxiety symptoms in this age group. Interventions that reduce anxiety may also reduce cannabis use. Behavioral economic theory suggests that substance use reductions are most likely when there is an increase in substance-free reinforcement. This randomized pilot trial evaluated the efficacy of a brief motivational intervention (BMI) for cannabis supplemented by either a substance-free activity session (SFAS) or a relaxation training (RT) session for reducing cannabis use, problems, craving, and anxiety symptoms. METHOD: One hundred thirty-two college students (Mage = 19.9; 54% female; 67% White, 31% Black) who reported five or more past-month cannabis use days were randomized to: (a) assessment-only (AO); (b) BMI plus SFAS; or (c) BMI plus RT. Participants in the BMI conditions received two individual counselor-administered sessions plus a brief phone booster session. Outcomes were evaluated 1- and 6-months postintervention. RESULTS: Relative to assessment, both BMI + SFAS and BMI + RT were associated with significant reductions in cannabis problems and craving at 1-month follow-up, and significant reductions in anxiety at 6-month follow-up. Relative to AO, BMI + RT was associated with significant reductions in cannabis use at 1-month follow-up. There were no differences between BMI conditions. CONCLUSIONS: This pilot trial was not adequately powered to conclusively evaluate relative efficacy but provides preliminary support for the short-term efficacy of both two-session interventions for reducing anxiety and cannabis-related risk among nontreatment seeking emerging adults. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Differential impact of doxorubicin dose on cell death and autophagy pathways during acute cardiotoxicity.

Doxorubicin (DOX) is an effective anthracycline used in chemotherapeutic regimens for a variety of haematological and solid tumors. However, its utility remains limited by its well-described, but poorly understood cardiotoxicity. Despite numerous studies describing various forms of regulated cell death and their involvement in DOX-mediated cardiotoxicity, the predominate form of cell death remains unclear. Part of this inconsistency lies in a lack of standardization of in vivo and in vitro model design. To this end, the objective of this study was to characterize acute low- and high-dose DOX exposure on cardiac structure and function in C57BL/6 N mice, and evaluate regulated cell death pathways and autophagy both in vivo and in cardiomyocyte culture models. Acute low-dose DOX had no significant impact on cardiac structure or function; however, acute high-dose DOX elicited substantial cardiac necrosis resulting in diminished cardiac mass and volume, with a corresponding reduced cardiac output, and without impacting ejection fraction or fibrosis. Low-dose DOX consistently activated caspase-signaling with evidence of mitochondrial permeability transition. However, acute high-dose DOX had only modest impact on common necrotic signaling pathways, but instead led to an inhibition in autophagic flux. Intriguingly, when autophagy was inhibited in cultured cardiomyoblasts, DOX-induced necrosis was enhanced. Collectively, these observations implicate inhibition of autophagy flux as an important component of the acute necrotic response to DOX, but also suggest that acute high-dose DOX exposure does not recapitulate the disease phenotype observed in human cardiotoxicity.

Exogenous ketone ester administration attenuates systemic inflammation and reduces organ damage in a lipopolysaccharide model of sepsis.

AIMS: Sepsis is a life-threatening condition of organ dysfunction caused by dysregulated inflammation which predisposes patients to developing cardiovascular disease. The ketone ß-hydroxybutyrate is reported to be cardioprotective in cardiovascular disease and this may be due to their signaling properties that contribute to reducing inflammation. While exogenous ketone esters (KE) increase blood ketone levels, it remains unknown whether KEs can reduce the enhanced inflammatory response and multi-organ dysfunction that is observed in sepsis. Thus, this study assesses whether a recently developed and clinically safe KE can effectively improve the inflammatory response and organ dysfunction in sepsis. METHODS AND RESULTS: To assess the anti-inflammatory effects of a KE, we utilized a model of lipopolysaccharide (LPS)-induced sepsis in which an enhanced inflammatory response results in multi-organ dysfunction. Oral administration of KE for three days prior to LPS-injection significantly protected mice against the profound systemic inflammation compared to their vehicle-treated counterparts. In assessing organ dysfunction, KE protected mice from sepsis-induced cardiac dysfunction as well as renal dysfunction and fibrosis. Furthermore, KE administration attenuated the sepsis-induced inflammation in the heart, kidney, and liver. Moreover, these protective effects occurred independent of changes to enzymes involved in ketone metabolism. CONCLUSION: These data show that the use of an exogenous KE attenuates the dysregulated systemic and organ inflammation as well as organ dysfunction in a model of severe inflammation. We postulate that this exogenous KE is an appealing and promising approach to capitalize on the protective anti-inflammatory effects of ketones in sepsis and/or other inflammatory responses.

Change in alcohol demand following a brief intervention predicts change in alcohol use: A latent growth curve analysis.

BACKGROUND: The association between behavioral economic demand and various alcohol use outcomes is well established. However, few studies have examined whether changes in demand occur following a brief alcohol intervention (BAI), and whether this change predicts alcohol outcomes over the long term. METHODS: Parallel process piecewise latent growth curve models were examined in a sample of 393 heavy drinking emerging adults (60.8% women; 85.2% white; Mage  = 18.77). In these models, two linear slopes represented rates of change in alcohol use, heavy drinking episodes, alcohol-related problems, and demand (intensity and highest expenditure across all price points or Omax ) from baseline to 1 month (slope 1) and 1 month to 16 months (slope 2). Mediation analyses were conducted to estimate the effect of a BAI on 16-month alcohol outcomes through slope 1 demand. RESULTS: A two-session BAI predicted significant reductions in all five outcomes from baseline to 1-month follow-up. Although no further reduction was observed from the 1-month to the 16-month follow-up, there was no regression to baseline levels. Slope 1 demand intensity, but not Omax , significantly mediated the association between BAI and both outcomes-heavy drinking episodes (Est. = -0.23, SE = 0.08, p < 0.01) and alcohol-related problems (Est. = -0.15, SE = 0.07, p < 0.05)-at the 16-month follow-up. CONCLUSIONS: Reducing high valuation of alcohol among heavy drinking emerging adults within the first month following BAI is critical for the long-term efficacy of the intervention. A two-session BAI was associated with enduring reductions in alcohol demand, and the change in demand intensity, but not Omax , was associated with sustained reductions in heavy drinking and alcohol-related problems.

The molecular mosaic of regulated cell death in the cardiovascular system.

Cell death is now understood to be a highly regulated process that contributes to normal development and tissue homeostasis, alongside its role in the etiology of various pathological conditions. Through detailed molecular analysis, we have come to know that all cells do not always die in the same way, and that there are at least 7 processes involved, including: apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, and autophagy-mediated cell death. These processes act as pieces in the mosaic of cardiomyocyte cell death, which come together depending on context and stimulus. This review details each individual process, as well as highlights how they come together to produce various cardiac pathologies. By knowing how the pieces go together we can aim towards the development of efficacious therapeutics, which will enable us to prevent cardiomyocyte loss in the face of stress, both reducing mortality and improving quality of life.

Analogs of Marinopyrrole A Show Enhancement to Observed In Vitro Potency against Acute Toxoplasma gondii Infection.

The apicomplexan parasite Toxoplasma gondii is the causative agent of toxoplasmosis, a globally distributed infection with severe clinical consequences for immunocompromised individuals and developing fetuses. There are few available treatments, and these are associated with potentially severe adverse effects. Marinopyrrole A, a compound discovered in a marine Streptomyces species, has previously been found to exhibit potent antimicrobial activity, prompting our interest in exploring efficacy against Toxoplasma gondii. We found that marinopyrrole A was a highly potent anti-Toxoplasma molecule, with an in vitro 50% maximal inhibitory concentration (IC50) of 0.31 µM, corresponding to a higher potency than that of the current standard of care (pyrimethamine); however, addition of 20% serum led to abrogation of potency, and toxicity to human cell lines was observed. Yet, application of marinopyrrole A to an in vivo lethal acute infection model facilitated significantly enhanced survival at doses of 5, 10, and 20 mg/kg. We then tested a series of marinopyrrole A analogs (RL002, RL003, and RL125) and demonstrated significantly increased potency in vitro, with IC50 values ranging from 0.09 to 0.17 µM (3.6- to 6.8-fold increase relative to pyrimethamine). No detectable cytotoxicity was observed up to 50 µM in human foreskin fibroblasts, with cytotoxicity in HepG2 cells ranging from ∼28 to 50 µM, corresponding to >200-fold selectivity for parasites over host cells. All analogs additionally showed reduced sensitivity to serum. Further, RL003 potently inhibited in vitro-generated bradyzoites at 0.245 µM. Taken together, these data support further development of marinopyrrole A analogs as promising anti-Toxoplasma molecules to further combat this prevalent infection.

A combined laboratory and field test of a smartphone breath alcohol device and blood alcohol concentration estimator to facilitate moderate drinking among young adults.

OBJECTIVE: Innovative strategies are needed to reduce young adult drinking. Real-time feedback via mobile health (mHealth) technology (e.g., smartphone devices/apps) may facilitate moderate drinking, yet requires evidence of feasibility, acceptability, and usability. METHOD: Young adults reporting frequent heavy drinking (N = 99, Mage = 23, 51% male) participated in a manualized, brief, motivational interview on recent typical and peak blood alcohol concentration (BAC), then were randomized to use 1 of the 3 forms of technology: (a) smartphone breathalyzer device/app; (b) app that estimates BAC based on factors including sex, weight, number/types of drinks over time; or (c) self-text messaging after each drink. Technologies were tested initially in small-group laboratory alcohol self-administration sessions. Participants then completed a 2-week field test wherein they had free access to all three technologies. Participants reported on usability and acceptability. RESULTS: Laboratory alcohol self-administration did not differ significantly by technology condition. The smartphone breathalyzer and BAC estimator app had favorable acceptability and usability. Participants used at least one form of technology on 67% of drinking days in the field period. In exploratory analyses, alcohol use during the field period was significantly lower than the baseline including a decrease of nearly one drink per drinking day. CONCLUSIONS: These findings support the feasibility of research combining lab and field methods to test moderate drinking technologies in young adults. Findings further support the acceptability and usability of these technologies, along with young adults' openness to using them. Exploratory results suggest potential efficacy of combined mobile technology intervention to be tested in subsequent controlled studies. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Cannabidiol Suppresses Cytokine Storm and Protects Against Cardiac and Renal Injury Associated with Sepsis.

Background: Cytokine release syndrome, also termed "cytokine storm," is the leading cause of morbidity and mortality among patients with various conditions such as sepsis. While cytokine storm is associated with multiple organ damage, acute cardiac and renal injury represents a hallmark of cytokine storm. Since recent reports have suggested that cannabidiol (CBD) may assist in the treatment of inflammatory diseases, our objective was to examine the effect of CBD on cytokine storm-induced cardiac and renal injury using the lipopolysaccharide (LPS)-induced sepsis mouse model. Materials and Methods: At 8 weeks of age, mice were randomly assigned to receive CBD (15 mg/kg) or vehicle one hour before a single injection of either phosphate-buffered saline or LPS (10 mg/kg) for an additional 24 h. Results: Our results show that CBD improves cardiac function and reduces renal injury in a mouse model of cytokine storm. Moreover, our data indicate that CBD significantly reduces systemic and renal inflammation to contribute to the improvements observed in a cytokine storm-model of cardiac and renal injury. Conclusions: Overall, the findings of this study suggest that CBD could be repurposed to reduce morbidity in patients with cytokine storm particularly in severe infections such as sepsis.

Misoprostol treatment prevents hypoxia-induced cardiac dysfunction through a 14-3-3 and PKA regulatory motif on Bnip3.

Systemic hypoxia is a common element in most perinatal emergencies and is a known driver of Bnip3 expression in the neonatal heart. Bnip3 plays a prominent role in the evolution of necrotic cell death, disrupting ER calcium homeostasis and initiating mitochondrial permeability transition (MPT). Emerging evidence suggests a cardioprotective role for the prostaglandin E1 analog misoprostol during periods of hypoxia, but the mechanisms for this protection are not completely understood. Using a combination of mouse and cell models, we tested if misoprostol is cardioprotective during neonatal hypoxic injury by altering Bnip3 function. Here we report that hypoxia elicits mitochondrial-fragmentation, MPT, reduced ejection fraction, and evidence of necroinflammation, which were abrogated with misoprostol treatment or Bnip3 knockout. Through molecular studies we show that misoprostol leads to PKA-dependent Bnip3 phosphorylation at threonine-181, and subsequent redistribution of Bnip3 from mitochondrial Opa1 and the ER through an interaction with 14-3-3 proteins. Taken together, our results demonstrate a role for Bnip3 phosphorylation in the regulation of cardiomyocyte contractile/metabolic dysfunction, and necroinflammation. Furthermore, we identify a potential pharmacological mechanism to prevent neonatal hypoxic injury.

Trajectories of reward availability moderate the impact of brief alcohol interventions on alcohol severity in heavy-drinking young adults.

BACKGROUND: Behavioral economic theory predicts that low access to environmental reward is a risk factor for alcohol use disorder (AUD). The Substance-Free Activity Session (SFAS) is a behavioral economic supplement to standard brief alcohol interventions that attempts to increase environmental reward and may therefore have beneficial effects, particularly for individuals with low levels of environmental reward. METHODS: Participants were 393 college students who reported at least 2 heavy-drinking episodes in the past month. Participants were randomly assigned to 1 of 3 conditions following a baseline assessment: a standard alcohol-focused brief motivational intervention plus relaxation training session (BMI + RT), BMI plus Substance-Free Activity Session (BMI + SFAS), or an assessment-only control condition (AO). In a secondary analysis of the data from this study, we used person-centered statistical techniques to describe trajectories of alcohol severity and environmental reward over a 16-month follow-up and examined whether environmental reward levels moderated the effectiveness of the interventions. RESULTS: Piecewise growth mixture modeling identified 2 trajectories of reward availability: low increasing (LR; n = 120) and high stable (HR; n = 273). Depressive symptoms, cannabis use, sensation seeking, and low life satisfaction were associated with a greater probability of classification in the LR trajectory. Alcohol severity was greater in the LR trajectory than the HR trajectory. For students in the LR trajectory, at 1, 6, and 12 months, BMI + SFAS led to greater increases in reward availability and reduced levels of alcohol severity compared with the BMI + RT and AO conditions and at 16 months compared with AO. CONCLUSIONS: Young adults with low levels of environmental reward are at heightened risk for greater alcohol severity and may show greater benefit from brief alcohol interventions that focus on increasing substance-free reward than individuals who are not deficient in reward availability.

Not all symptoms of alcohol dependence are developmentally equivalent: Implications for the false-positives problem.

OBJECTIVE: Recent studies have examined the extent to which alcohol dependence (AD) criteria prospectively predict the course of AD. Critically, these studies have lacked a developmental perspective. However, the differential performance of criteria by age might indicate overendorsement in younger individuals. The current study examined AD criteria in terms of persistence and prediction of AD course and alcohol use by age in order to identify criteria that are likely to be overly endorsed by younger individuals. METHOD: The current study used longitudinal data from the National Epidemiologic Survey on Alcohol and Related Conditions to depict age differences in rates of new onset, recurrence, and persistence for each AD criterion, thereby showing how these three factors contribute to the overall age-prevalence curve of each criterion. Additionally, we tested age moderation of the predictive association between each criterion at baseline and new onset, recurrence, and persistence of syndromal AD. RESULTS: Some criteria (particularly, persistent desire or unsuccessful efforts to cut down or control drinking, and drinking despite physical/psychological problems) are both less persistent and less predictive of AD course among younger adults compared to older adults. CONCLUSIONS: These findings raise the possibility of elevated rates of false-positive AD among younger adults and suggest ways to improve the assessment of AD criteria. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

A new trick for an old dog? Myocardial-specific roles for prostaglandins as mediators of ischemic injury and repair.

The small lipid-derived paracrine signaling molecules known as prostaglandins have been recognized for their ability to modulate many facets of cardiovascular physiology since their initial discovery more than 85 years ago. Although the role of prostaglandins in the vasculature has gained significant attention across time, a handful of historical studies have also directly implicated the cardiomyocyte in both prostaglandin synthesis and release. Recently, our understanding of how prostaglandin receptor modulation impacts and contributes to myocardial structure and function has gained attention while leaving most other components of myocardial prostaglandin metabolism and signaling unexplored. This mini-review highlights both the key historical studies that underpin modern prostaglandin research in the heart, while concurrently presenting the latest findings related to how prostaglandin metabolism and signaling impact myocardial injury and repair.

BNIP3L/Nix-induced mitochondrial fission, mitophagy, and impaired myocyte glucose uptake are abrogated by PRKA/PKA phosphorylation.

Lipotoxicity is a form of cellular stress caused by the accumulation of lipids resulting in mitochondrial dysfunction and insulin resistance in muscle. Previously, we demonstrated that the mitophagy receptor BNIP3L/Nix is responsive to lipotoxicity and accumulates in response to a high-fat (HF) feeding. To provide a better understanding of this observation, we undertook gene expression array and shot-gun metabolomics studies in soleus muscle from rodents on an HF diet. Interestingly, we observed a modest reduction in several autophagy-related genes. Moreover, we observed alterations in the fatty acyl composition of cardiolipins and phosphatidic acids. Given the reported roles of these phospholipids and BNIP3L in mitochondrial dynamics, we investigated aberrant mitochondrial turnover as a mechanism of impaired myocyte insulin signaling. In a series of gain-of-function and loss-of-function experiments in rodent and human myotubes, we demonstrate that BNIP3L accumulation triggers mitochondrial depolarization, calcium-dependent activation of DNM1L/DRP1, and mitophagy. In addition, BNIP3L can inhibit insulin signaling through activation of MTOR-RPS6KB/p70S6 kinase inhibition of IRS1, which is contingent on phosphatidic acids and RHEB. Finally, we demonstrate that BNIP3L-induced mitophagy and impaired glucose uptake can be reversed by direct phosphorylation of BNIP3L by PRKA/PKA, leading to the translocation of BNIP3L from the mitochondria and sarcoplasmic reticulum to the cytosol. These findings provide insight into the role of BNIP3L, mitochondrial turnover, and impaired myocyte insulin signaling during an overfed state when overall autophagy-related gene expression is reduced. Furthermore, our data suggest a mechanism by which exercise or pharmacological activation of PRKA may overcome myocyte insulin resistance.Abbreviations: BCL2: B cell leukemia/lymphoma 2; BNIP3L/Nix: BCL2/adenovirus E1B interacting protein 3-like; DNM1L/DRP1: dynamin 1-like; FUNDC1: FUN14 domain containing 1; IRS1: insulin receptor substrate 1; MAP1LC3A/LC3: microtubule-associated protein 1 light chain 3 alpha; MFN1: mitofusin 1; MFN2: mitofusin 2; MTOR: mechanistic target of rapamycin kinase; OPA1: OPA1 mitochondrial dynamin like GTPase; PDE4i: phosphodiesterase 4 inhibitor; PLD1: phospholipase D1; PLD6: phospholipase D family member 6; PRKA/PKA: protein kinase, AMP-activated; PRKCD/PKCδ: protein kinase C, delta; PRKCQ/PKCθ: protein kinase C, theta; RHEB: Ras homolog enriched in brain; RPS6KB/p70S6K: ribosomal protein S6 kinase; SQSTM1/p62: sequestosome 1; YWHAB/14-3-3ß: tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein beta.

Statistically derived patterns of behavioral economic risk among heavy-drinking college students: A latent profile analysis.

High levels of 3 behavioral economic indices (delay discounting, alcohol demand, and proportionate substance-related reinforcement) are consistently associated with greater alcohol misuse and alcohol-related problems. However, it is unclear whether and how these variables jointly increase the risk for alcohol-related outcomes among college students who engage in heavy episodic drinking (HED; 4/5+ drinks for women/men, respectively). The current study used a person-centered approach to identify similar patterns of behavioral economic domains among heavy-drinking college students and investigate the relationship between these empirically derived classes and alcohol-related outcomes. A sample of 393 college students (60.8% female, 78.9% White/Caucasian) reporting at least 2 heavy drinking episodes in the previous month completed measures of alcohol use and problems, demographics, delay discounting, and alcohol reward value (alcohol demand and proportionate substance-related reinforcement). Latent profile analyses revealed that a 3-class solution provided the best fit to the data: a low reward value, high discounting (LRHD) class (n = 53), a moderate reward value, low discounting (MRLD) class (n = 214), and a high reward value, high discounting (HRHD) class (n = 126). Members of the HRHD class reported significantly greater alcohol consumption, past-month HED episodes, alcohol-related problems, and symptoms of alcohol use disorder than those in the MRLD and LRHD classes. The results suggest that there are 3 constellations of behavioral economic processes and that, consistent with the reinforcer pathology model, students who overvalue alcohol-related reward and discount the future more steeply are at the greatest risk for alcohol misuse and alcohol-related problems. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

In Vitro Selection Implicates ROP1 as a Resistance Gene for an Experimental Therapeutic Benzoquinone Acyl Hydrazone in Toxoplasma gondii.

Toxoplasma gondii is a globally distributed apicomplexan parasite and the causative agent of toxoplasmosis in humans. While pharmaceuticals exist to combat acute infection, they can produce serious adverse reactions, demonstrating a need for enhanced therapies. KG8 is a benzoquinone acyl hydrazone chemotype identified from a previous chemical screen for which we previously showed in vitro and in vivo efficacy against T. gondii However, the genetic target and mechanism of action of KG8 remain unknown. To investigate potential targets, we generated resistant T. gondii lines by chemical mutagenesis followed by in vitro selection. Whole-genome sequencing of resistant clones revealed a P207S mutation in the gene encoding rhoptry organelle protein 1 (ROP1) in addition to two lesser resistance-conferring mutations in the genes for rhoptry organelle protein 8 (ROP8) and a putative ADP/ATP carrier protein (TGGT1_237700). Expressing ROP1P207S in parental parasites was sufficient to confer significant (10.3-fold increased half-maximal effective concentration [EC50]) KG8 resistance. After generating a library of mutants carrying hypermutated rop1 alleles followed by KG8 pressure, we sequenced the most resistant clonal isolate (>16.9-fold increased EC50) and found independent recapitulation of the P207S mutation, along with three additional mutations in the same region. We also demonstrate that a rop1 knockout strain is insensitive to KG8. These data implicate ROP1 as a putative resistance gene of KG8. This work further identifies a compound that can be used in future studies to better understand ROP1 function and highlights this novel chemotype as a potential scaffold for the development of improved T. gondii therapeutics.

Misoprostol attenuates neonatal cardiomyocyte proliferation through Bnip3, perinuclear calcium signaling, and inhibition of glycolysis.

Systemic hypoxia resulting from preterm birth, altered lung development, and cyanotic congenital heart disease is known to impede the regulatory and developmental pathways in the neonatal heart. While the molecular mechanisms are still unknown, hypoxia induces aberrant cardiomyocyte proliferation, which may be initially adaptive, but can ultimately program the heart to fail in early life. Recent evidence suggests that the prostaglandin E1 analogue, misoprostol, is cytoprotective in the hypoxia-exposed neonatal heart by impacting alternative splicing of the Bcl-2 family member Bnip3, resulting in the generation of a variant lacking the third exon (Bnip3ΔExon3 or small Nip; sNip). Using a rodent model of neonatal hypoxia, in combination with rat primary neonatal cardiomyocytes (PVNCs) and H9c2 cells, we sought to determine if misoprostol can prevent cardiomyocyte proliferation and what the key molecular mechanisms might be in this pathway. In PVNCs, exposure to 10% oxygen induced myocyte proliferation concurrent with molecular markers of cell-cycle progression, such as Cyclin-D1, which were prevented by misoprostol treatment. Furthermore, we describe a critical role for sNip in opposing cardiomyocyte proliferation through several mechanisms, including reduced expression of the proliferative MEF2C-myocardin-BMP10 pathway, accumulation of nuclear calcium leading to NFATc3 activation, and increased expression of the cardiac maturation factor BMP2. Intriguingly, misoprostol and sNip inhibited hypoxia-induced glycolytic flux, which directly influenced myocyte proliferation. These observations were further supported by knockdown studies, where hypoxia-induced cardiomyocyte proliferation is restored in misoprostol-treated cells by an siRNA targeting sNip. Finally, in postnatal day (PND)-10 rat pups exposed to hypoxia, we observed histological evidence of increased nuclei number and increased PPH3 staining, which were completely attenuated by misoprostol treatment. Collectively, this data demonstrates how neonatal cardiomyocyte proliferation can be pharmacologically modulated by misoprostol treatment, which may have important implications for both neonatal and regenerative medicine.

Correction to: Myocardin regulates mitochondrial calcium homeostasis and prevents permeability transition.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

High Opportunity Cost Demand as an Indicator of Weekday Drinking and Distinctly Severe Alcohol Problems: A Behavioral Economic Analysis.

INTRODUCTION: Behavioral economic theory views addiction as a reinforcer pathology characterized by excessive demand for drugs relative to alternatives. Complementary to this theory, Lamb and Ginsburg (Pharmacology Biochemistry and Behavior, 164, 2018, 62) describe addiction as a behavioral allocation disorder and predict that decisions to drink under increasingly stringent constraints are a central indicator of addiction. This study used a modified demand-curve paradigm to examine alcohol demand in the context of a next-day contingency (high opportunity cost demand) as a specific indicator of a severe pattern of alcohol problems. METHODS: Participants were 370 undergraduates (61.1% female, 86.5% white, Mage  = 18.8) reporting multiple past-month heavy drinking episodes (5/4 drinks per occasion for men/women) who completed 2 versions of an alcohol purchase task (APT), along with measures of past-month alcohol use and problems. In 1 APT (low opportunity cost), students imagined they had no next-day responsibilities, and in the other APT (high opportunity cost), they imagined having a 10:00 am test the next day. Item-response theory analyses were used to determine mild and severe alcohol problems from the Young Adult Alcohol Consequences Questionnaire (Journal of Studies on Alcohol, 67, 2006, 169), and the most and least severe binge drinking days throughout the week. RESULTS: Low opportunity cost demand (ß = 0.15, p = 0.02) significantly predicted beyond high opportunity cost demand for the least severe problems, and high opportunity cost demand (ß = 0.17, p = 0.009) significantly predicted beyond low opportunity cost demand for the most severe problems. Similarly, low opportunity cost demand (ß = 0.26, p < 0.001) was more highly associated with weekend drinking, whereas high opportunity cost demand (ß = 0.21, p = 0.001) was more highly associated with weekday drinking. CONCLUSIONS: The current results suggest high opportunity cost alcohol demand is a distinct marker of severe alcohol problems among college student heavy drinkers.

Temporal precedence of self-regulation over depression and alcohol problems: Support for a model of self-regulatory failure.

Alcohol use is highly comorbid with depression, especially among college students, whose rates of both phenomena are higher than in the general population. The self-medication hypothesis (i.e., alcohol use is negatively reinforced via the alleviation of negative affect) has dominated explanatory models of comorbidity. However, self-regulation has also demonstrated cross-sectional relationships with both depression and alcohol problems and may contribute to the development of alternative comorbidity models. Self-regulation introduces three alternative models that can be tested empirically: (a) a depressed regulation model, (b) a central nervous system depressant model, and (c) a self-regulatory failure model. The purpose of this study was to test the utility of these models (in addition to the self-medication hypothesis) by examining the temporal precedence in the relations between self-regulation, depressive symptoms, and alcohol problems among heavy-drinking college students (N = 393) over 5 assessment points (baseline, 1 month, 6 months, 12 months, and 16 months) using an autoregressive cross-lagged model. Lower self-regulation, and higher alcohol problems and depressive symptoms, prospectively predicted higher depressive symptoms. Higher alcohol problems and lower self-regulation prospectively predicted higher alcohol problems. Only self-regulation prospectively predicted self-regulation. These results were consistent across multiple time points. Findings are consistent with a self-regulatory failure model of depressive symptoms and alcohol problems. Therefore, self-regulation may be an important etiological variable and potential intervention target to reduce both alcohol problems and depressive symptoms among college students. (PsycINFO Database Record (c) 2019 APA, all rights reserved).