New Drugs, Old Targets: Tweaking the Dopamine System to Treat Psychostimulant Use Disorders.

The abuse of illicit psychostimulants such as cocaine and methamphetamine continues to pose significant health and societal challenges. Despite considerable efforts to develop medications to treat psychostimulant use disorders, none have proven effective, leaving an underserved patient population and unanswered questions about what mechanism(s) of action should be targeted for developing pharmacotherapies. As both cocaine and methamphetamine rapidly increase dopamine (DA) levels in mesolimbic brain regions, leading to euphoria that in some can lead to addiction, targets in which this increased dopaminergic tone may be mitigated have been explored. Further, understanding and targeting mechanisms underlying relapse are fundamental to the success of discovering medications that reduce the reinforcing effects of the drug of abuse, decrease the negative reinforcement or withdrawal/negative affect that occurs during abstinence, or both. Atypical inhibitors of the DA transporter and partial agonists/antagonists at DA D3 receptors are described as two promising targets for future drug development.

Dual DAT and sigma receptor inhibitors attenuate cocaine effects on nucleus accumbens dopamine dynamics in rats.

Psychostimulant use disorders (PSUD) are prevalent; however, no FDA-approved medications have been made available for treatment. Previous studies have shown that dual inhibitors of the dopamine transporter (DAT) and sigma receptors significantly reduce the behavioral/reinforcing effects of cocaine, which have been associated with stimulation of extracellular dopamine (DA) levels resulting from DAT inhibition. Here, we employ microdialysis and fast scan cyclic voltammetry (FSCV) procedures to investigate the effects of dual inhibitors of DAT and sigma receptors in combination with cocaine on nucleus accumbens shell (NAS) DA dynamics in naïve male Sprague Dawley rats. In microdialysis studies, administration of rimcazole (3, 10 mg/kg; i.p.) or its structural analog SH 3-24 (1, 3 mg/kg; i.p.), compounds that are dual inhibitors of DAT and sigma receptors, significantly reduced NAS DA efflux stimulated by increasing doses of cocaine (0.1, 0.3, 1.0 mg/kg; i.v.). Using the same experimental conditions, in FSCV tests, we show that rimcazole pretreatments attenuated cocaine-induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Under the same conditions, JJC8-091, a modafinil analog and dual inhibitor of DAT and sigma receptors, similarly attenuated cocaine-induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Our results provide the neurochemical groundwork towards understanding actions of dual inhibitors of DAT and sigma receptors on DA dynamics that likely mediate the behavioral effects of psychostimulants like cocaine.

Contrasting the Reinforcing Effects of the Novel Dopamine Transport Inhibitors JJC8-088 and JJC8-091 in Monkeys: Potential Translation to Medication Assisted Treatment.

Despite considerable efforts, there remains no FDA-approved medications for cocaine use disorder (CUD). One strategy to mitigate cocaine craving and relapse is to elevate dopamine (DA). The DA transport inhibitor and releaser d-amphetamine has been shown to decrease cocaine self-administration (SA), although it has abuse liability. Recently, several modafinil analogues reduced cocaine SA in rats and monkeys, including JJC8-088, characterized as "cocaine like" in rats, and JJC8-091, characterized as "atypical" and not SA by rats. The present studies evaluated the reinforcing effects of both compounds in monkeys under several conditions. For Experiment 1, four male cocaine-experienced rhesus monkeys self-administered cocaine (0.001-0.3 mg/kg/injection), JJC8-088 (0.001-0.3 mg/kg/injection), and JJC8-091 (0.1-3.0 mg/kg/injection) under a progressive-ratio (PR) schedule of reinforcement. Both JJC compounds functioned as reinforcers with equal reinforcing strength to cocaine. Although JJC8-091 was less potent than cocaine, JJC8-088 and cocaine had similar potencies. For Experiment 2, one male and two females drug-naïve cynomolgus monkeys responded on a fixed-ratio schedule of food reinforcement. JJC8-091 was self-administered at rates higher than saline in all three monkeys. In Experiment 3, monkeys from Experiment 2 responded under a concurrent drug vs. food choice paradigm and given access to cocaine or JJC8-091 under these conditions. At doses equal to or one-half log-units higher than doses used in Experiment 2, cocaine, but not JJC8-091, was chosen over food. Together, these results demonstrate that while JJC8-091 may be reinforcing under some conditions, its reinforcing strength, in the presence of an alternative reinforcer, is substantially less than cocaine. Significance Statement JJC8-088 and JJC8-091 have shown efficacy is reducing cocaine self-administration in rats and in nonhuman primates. This study found that both compounds maintained self-administration in monkeys responding under several conditions. However, when given access to an alternative reinforcer during the self-administration session, JJC8-091 was not reinforcing, suggesting that JJC8-091 may be a viable candidate for CUD since, in the human population, alternatives to drug use are often available.

Population genomic structure of a widespread, urban-dwelling mammal: The eastern grey squirrel (Sciurus carolinensis).

Urbanization is a persistent and widespread driver of global environmental change, potentially shaping evolutionary processes due to genetic drift and reduced gene flow in cities induced by habitat fragmentation and small population sizes. We tested this prediction for the eastern grey squirrel (Sciurus carolinensis), a common and conspicuous forest-dwelling rodent, by obtaining 44K SNPs using reduced representation sequencing (ddRAD) for 403 individuals sampled across the species' native range in eastern North America. We observed moderate levels of genetic diversity, low levels of inbreeding, and only a modest signal of isolation-by-distance. Clustering and migration analyses show that estimated levels of migration and genetic connectivity were higher than expected across cities and forested areas, specifically within the eastern portion of the species' range dominated by urbanization, and genetic connectivity was less than expected within the western range where the landscape is fragmented by agriculture. Landscape genetic methods revealed greater gene flow among individual squirrels in forested regions, which likely provide abundant food and shelter for squirrels. Although gene flow appears to be higher in areas with more tree cover, only slight discontinuities in gene flow suggest eastern grey squirrels have maintained connected populations across urban areas in all but the most heavily fragmented agricultural landscapes. Our results suggest urbanization shapes biological evolution in wildlife species depending strongly on the composition and habitability of the landscape matrix surrounding urban areas.

Ensuring Intervention Fidelity of an Attention Control Arm in a Multisite Randomized Controlled Trial.

BACKGROUND: Intervention fidelity is a critical element of randomized controlled trials, yet reporting of intervention fidelity among attention control arms is limited. Lack of fidelity to attention control procedures can affect study outcomes by either overestimating or underestimating the efficacy of the intervention under examination. OBJECTIVES: This brief report describes the approach researchers took to promote fidelity to the attention control arm of a pediatric palliative care randomized controlled trial funded by the National Institutes of Health. METHODS: The Informational Meetings for Planning and Coordinating Treatment trial aims to determine the efficacy of a communication intervention that uses care team dyads (i.e., physicians partnered with nurses or advanced practice providers) to engage parents of children with cancer who have a poor prognosis in structured conversations about prognostic information, goals of care, and care planning. The intervention is compared with an attention control arm, which provides parents with structured conversations on common pediatric cancer education topics, such as talking to their child about their cancer, clinical trials, cancer treatment, side effects, and so forth. National Institutes of Health guidelines for assessing and implementing strategies to promote intervention fidelity were used to design (a) the attention control arm of a randomized controlled trial, (b) related attention control arm training, and (c) quality assurance monitoring. RESULTS: Attention control study procedures were designed to mirror that of the intervention arm (i.e., same number, frequency, and time spent in study visits). Cluster randomization was used to allocate care team dyads to one arm of the randomized controlled trial. Care team dyads assigned to the attention control arm participated in online training sessions to learn attention control procedures, the different roles of research team members, and quality assurance methods. Fidelity to attention control procedures is assessed by both the interveners themselves and a quality assurance team. DISCUSSION: Study design, training, and delivery are all critical to attention control fidelity. Baseline training often needs to be supplemented with booster training when time gaps occur between study start-up and implementation. Quality assurance procedures are essential to determine whether interveners consistently deliver attention control procedures correctly.

3,4-Methylenedioxypyrovalerone High-Responder Phenotype as a Tool to Evaluate Candidate Medications for Stimulant Use Disorder.

Despite decades of research, there are no medications approved by the United States Food and Drug Administration to treat stimulant use disorders. Self-administration procedures are widely used to screen candidate medications for stimulant use disorder, although preclinical reductions in stimulant self-administration have not translated to meaningful reductions in stimulant use in humans. One possible reason for this discordance is that most preclinical studies evaluate candidate medications under conditions that promote predictable, and well-regulated patterns of drug-taking rather than the dysregulated and/or compulsive patterns of drug-taking characteristic of a stimulant use disorder. A subset of rats ("high-responders") that self-administer 3,4-methelyendioxypyrovalerone (MDPV), a monoamine uptake inhibitor, develop high levels of dysregulated drug-taking consistent with behaviors related to stimulant use disorders. Because MDPV acts on dopamine, serotonin (5-HT), and sigma receptor systems, the current studies compared the potency and effectiveness of a dopamine D3 receptor partial agonist (VK4-40) or antagonist (VK4-116), a sigma receptor antagonist (BD1063), a dopamine D2/D3/sigma receptor antagonist (haloperidol), and a 5-HT2C receptor agonist (CP-809,101) to reduce MDPV (0.0032-0.1 mg/kg/infusion) self-administration in high- and low-responding rats as well as rats self-administering cocaine (0.032-1 mg/kg/infusion). VK4-40, VK4-116, haloperidol, and CP-809,101 were equipotent and effective at reducing drug-taking in all three groups of rats, including the high-responders; however, VK4-116 and CP-809,101 were less potent at reducing drug-taking in female compared with male rats. Together, these studies suggest that drugs targeting dopamine D3 or 5-HT2C receptors can effectively reduce dysregulated patterns of stimulant use, highlighting their potential utility for treating stimulant use disorders. SIGNIFICANCE STATEMENT: There are no United States Food and Drug Administration-approved treatments for stimulant use disorder, perhaps in part because candidate medications are most often evaluated in preclinical models using male subjects with well-regulated drug-taking. In an attempt to better model aberrant drug taking, this study found compounds acting at dopamine D3 or 5-HT2C receptors can attenuate drug-taking in male and female rats that self-administered two different stimulants and exhibited either a high or low substance use disorder-like phenotype.

The Effects of the Dopamine Transporter Ligands JJC8-088 and JJC8-091 on Cocaine versus Food Choice in Rhesus Monkeys.

Although there are no Food and Drug Administration-approved treatments for cocaine use disorder, several modafinil analogs have demonstrated promise in reducing cocaine self-administration and reinstatement in rats. Furthermore, the range of dopamine transporter (DAT) compounds provides an opportunity to develop pharmacotherapeutics without abuse liability. This study extended the comparison of JJC8-088 and JJC8-091, the former compound having higher DAT affinity and predicted abuse liability, to rhesus monkeys using a concurrent cocaine versus food schedule of reinforcement. First, binding to striatal DAT was examined in cocaine-naïve monkey tissue. Next, intravenous pharmacokinetics of both JJC compounds were evaluated in cocaine-experienced male monkeys (n = 3/drug). In behavioral studies, acute and chronic administration of both compounds were evaluated in these same monkeys responding under a concurrent food versus cocaine (0 and 0.003-0.1 mg/kg per injection) schedule of reinforcement. In nonhuman primate striatum, JJC8-088 had higher DAT affinity compared with JJC8-091 (14.4 ± 9 versus 2730 ± 1270 nM, respectively). Both JJC compounds had favorable plasma pharmacokinetics for behavioral assessments, with half-lives of 1.1 hours and 3.5 hours for JJC8-088 (0.7 mg/kg, i.v.) and JJC8-091 (1.9 mg/kg, i.v.), respectively. Acute treatment with both compounds shifted the cocaine dose-response curve to the left. Chronic treatment with JJC8-088 decreased cocaine choice in two of the three monkeys, whereas JJC8-091 only modestly reduced cocaine allocation in one monkey. Differences in affinities of JJC8-091 DAT binding in monkeys compared with rats may account for the poor rodent-to-monkey translation. Future studies should evaluate atypical DAT blockers in combination with behavioral interventions that may further decrease cocaine choice. SIGNIFICANCE STATEMENT: Cocaine use disorder (CUD) remains a significant public health problem with no Food and Drug Administration-approved treatments. The ability of drugs that act in the brain in a similar manner to cocaine, but with lower abuse liability, has clinical implications for a treatment of CUD.

Designing and validating novel communication measures for pediatric, adolescent, and young adult oncology care and research: The PedCOM measures.

BACKGROUND: High-quality communication in pediatric and adolescent cancer is the standard of care. Yet, we lack pediatric-specific communication measures. We designed self-report and caregiver-report communication measures for use in pediatric oncology settings. METHODS: We recruited adolescent and young adults (AYAs; 12-24 years) with cancer and parents of children and AYAs between 1 month post-diagnosis and 2 months after completing treatment. Participants completed measures including 58 questions addressing eight previously characterized communication functions. For each function, we conducted factor analysis, and assessed reliability and construct validity. Based on psychometric properties, we created final long-form (31 items) and short-form (eight items) communication measures (PedCOM) for both self- and caregiver-report. RESULTS: Participants included 200 parents and 88 AYAs. The final 31-item and eight-item PedCOM measures for parents and AYAs demonstrated good unidimensional model fit. Each communication function (e.g., building relationships) demonstrated high reliability, coefficient alphas ranged from .83 to .93 for parents and .85 to .93 for AYAs. The overall 31-item and eight-item PedCOM measures also demonstrated high reliability (alphas >.9). For construct validity, PedCOM-Parent-31 and PedCOM-Parent-8 correlated positively with satisfaction with care, trust, emotional self-management, and decisional satisfaction, and negatively with anxiety and caregiver burden. PedCOM-AYA-31 and PedCOM-AYA-8 correlated positively with satisfaction with care, trust, emotional self-management, symptoms self-management, and decisional satisfaction, and negatively with anxiety. DISCUSSION: We developed valid and reliable measures of communication functions for parents and AYAs with cancer. These measures can support organizations and stakeholder groups that are striving to improve the quality of cancer care.

Consistency of Eye Coloration Across Different Relationship Partners.

Studies have indicated that people are attracted to partners who resemble themselves or their parents, in terms of physical traits including eye color. We might anticipate this inclination to be relatively stable, giving rise to a sequential selection of similar partners who then represent an individual's "type". We tested this idea by examining whether people's sequential partners resembled each other at the level of eye color. We gathered details of the eye colors of the partners of participants (N = 579) across their adult romantic history (N = 3250 relationships), in three samples, comprising two samples which made use of self-reports from predominantly UK-based participants, and one which made use of publicly available information about celebrity relationship histories. Recorded partner eye colors comprised black (N = 39 partners), dark brown (N = 884), light brown (N = 393), hazel (N = 224), blue (N = 936), blue green (N = 245), grey (N = 34), and green (N = 229). We calculated the proportion of identical eye colors within each participant's relationship history, and compared that to 100,000 random permutations of our dataset, using t-tests to investigate if the eye color of partners across an individual's relationship history was biased relative to chance (i.e., if there was greater consistency, represented by higher calculated proportions of identical eye colors, in the original dataset than in the permutations). To account for possible eye color reporting errors and ethnic group matching, we ran the analyses restricted to White participants and to high-confidence eye color data; we then ran the analyses again in relation to the complete dataset. We found some limited evidence for some consistency of eye color across people's relationship histories in some of the samples only when using the complete dataset. We discuss the issues of small effect sizes, partner-report bias, and ethnic group matching in investigating partner consistency across time.

Circadian rhythms in the plant host influence rhythmicity of rhizosphere microbiota.

BACKGROUND: Recent studies demonstrated that microbiota inhabiting the plant rhizosphere exhibit diel changes in abundance. To investigate the impact of plant circadian rhythms on bacterial and fungal rhythms in the rhizosphere, we analysed temporal changes in fungal and bacterial communities in the rhizosphere of Arabidopsis plants overexpressing or lacking function of the circadian clock gene LATE ELONGATED HYPOCOTYL (LHY). RESULTS: Under diel light-dark cycles, the knock-out mutant lhy-11 and the gain-of-function mutant lhy-ox both exhibited gene expression rhythms with altered timing and amplitude compared to wild-type plants. Distinct sets of bacteria and fungi were found to display rhythmic changes in abundance in the rhizosphere of both of these mutants, suggesting that abnormal patterns of rhythmicity in the plant host caused temporal reprogramming of the rhizosphere microbiome. This was associated with changes in microbial community structure, including changes in the abundance of fungal guilds known to impact on plant health. Under constant environmental conditions, microbial rhythmicity persisted in the rhizosphere of wild-type plants, indicating control by a circadian oscillator. In contrast, loss of rhythmicity in lhy-ox plants was associated with disrupted rhythms for the majority of rhizosphere microbiota. CONCLUSIONS: These results show that aberrant function of the plant circadian clock is associated with altered rhythmicity of rhizosphere bacteria and fungi. In the long term, this leads to changes in composition of the rhizosphere microbiome, with potential consequences for plant health. Further research will be required to understand the functional implications of these changes and how they impact on plant health and productivity.

Are There Prevalent Sex Differences in Psychostimulant Use Disorder? A Focus on the Potential Therapeutic Efficacy of Atypical Dopamine Uptake Inhibitors.

Psychostimulant use disorders (PSUD) affect a growing number of men and women and exert sizable public health and economic burdens on our global society. Notably, there are some sex differences in the onset of dependence, relapse rates, and treatment success with PSUD observed in preclinical and clinical studies. The subtle sex differences observed in the behavioral aspects of PSUD may be associated with differences in the neurochemistry of the dopaminergic system between sexes. Preclinically, psychostimulants have been shown to increase synaptic dopamine (DA) levels and may downregulate the dopamine transporter (DAT). This effect is greatest in females during the high estradiol phase of the estrous cycle. Interestingly, women have been shown to be more likely to begin drug use at younger ages and report higher levels of desire to use cocaine than males. Even though there is currently no FDA-approved medication, modafinil, a DAT inhibitor approved for use in the treatment of narcolepsy and sleep disorders, has shown promise in the treatment of PSUD among specific populations of affected individuals. In this review, we highlight the therapeutic potential of modafinil and other atypical DAT inhibitors focusing on the lack of sex differences in the actions of these agents.

Expanding the frame around social dynamics and glucocorticoids: From hierarchies within the nest to competitive interactions among species.

The effect of the social environment on individual state or condition has largely focused on glucocorticoid levels (GCs). As metabolic hormones whose production can be influenced by nutritional, physical, or psychosocial stressors, GCs are a valuable (though singular) measure that may reflect the degree of "stress" experienced by an individual. Most work to date has focused on how social rank influences GCs in group-living species or how predation risk influences GCs in prey. This work has been revealing, but a more comprehensive assessment of the social environment is needed to fully understand how different features of the social environment influence GCs in both group living and non-group living species and across life history stages. Just as there can be intense within-group competition among adult conspecifics, it bears appreciating there can also be competition among siblings from the same brood, among adult conspecifics that do not live in groups, or among heterospecifics. In these situations, dominance hierarchies typically emerge, albeit, do dominants or subordinate individuals or species have higher GCs? We examine the degree of support for hypotheses derived from group-living species about whether differential GCs between dominants and subordinates reflect the "stress of subordination" or "costs of dominance" in these other social contexts. By doing so, we aim to test the generality of these two hypotheses and propose new research directions to broaden the lens that focuses on social hierarchies and GCs.

Preferential Gs protein coupling of the galanin Gal1 receptor in the µ-opioid-Gal1 receptor heterotetramer.

Recent studies have proposed that heteromers of µ-opioid receptors (MORs) and galanin Gal1 receptors (Gal1Rs) localized in the mesencephalon mediate the dopaminergic effects of opioids. The present study reports converging evidence, using a peptide-interfering approach combined with biophysical and biochemical techniques, including total internal reflection fluorescence microscopy, for a predominant homodimeric structure of MOR and Gal1R when expressed individually, and for their preference to form functional heterotetramers when co-expressed. Results show that a heteromerization-dependent change in the Gal1R homodimeric interface leads to a switch in G-protein coupling from inhibitory Gi to stimulatory Gs proteins. The MOR-Gal1R heterotetramer, which is thus bound to Gs via the Gal1R homodimer and Gi via the MOR homodimer, provides the framework for a canonical Gs-Gi antagonist interaction at the adenylyl cyclase level. These novel results shed light on the intense debate about the oligomeric quaternary structure of G protein-coupled receptors, their predilection for heteromer formation, and the resulting functional significance.

Pharmacological targeting of G protein-coupled receptor heteromers.

A main rationale for the role of G protein-coupled receptor (GPCR) heteromers as targets for drug development is the putative ability of selective ligands for specific GPCRs to change their pharmacological properties upon GPCR heteromerization. The present study provides a proof of concept for this rationale by demonstrating that heteromerization of dopamine D1 and D3 receptors (D1R and D3R) influences the pharmacological properties of three structurally similar selective dopamine D3R ligands, the phenylpiperazine derivatives PG01042, PG01037 and VK4-116. By using D1R-D3R heteromer-disrupting peptides, it could be demonstrated that the three D3R ligands display different D1R-D3R heteromer-dependent pharmacological properties: PG01042, acting as G protein-biased agonist, counteracted D1R-mediated signaling in the D1R-D3R heteromer; PG01037, acting as a D3R antagonist cross-antagonized D1R-mediated signaling in the D1R-D3R heteromer; and VK4-116 specifically acted as a ß-arrestin-biased agonist in the D1R-D3R heteromer. Molecular dynamics simulations predicted potential molecular mechanisms mediating these qualitatively different pharmacological properties of the selective D3R ligands that are dependent on D1R-D3R heteromerization. The results of in vitro experiments were paralleled by qualitatively different pharmacological properties of the D3R ligands in vivo. The results supported the involvement of D1R-D3R heteromers in the locomotor activation by D1R agonists in reserpinized mice and L-DOPA-induced dyskinesia in rats, highlighting the D1R-D3R heteromer as a main pharmacological target for L-DOPA-induced dyskinesia in Parkinson's disease. More generally, the present study implies that when suspecting its pathogenetic role, a GPCR heteromer, and not its individual GPCR units, should be considered as main target for drug development.

Symptoms and daily experiences reported by children with cancer using a game-based app.

PURPOSE: Mobile health (mHealth) resources, including apps, are emerging as resources to support children in tracking symptoms and other health-related data. The purpose of this study was to describe symptoms and daily experiences reported by elementary school-age children receiving treatment for cancer using the newly developed Color Me Healthy app. DESIGN AND METHODS: Participants in this descriptive study were children 6-12 years of age, who were receiving cancer treatment at a free-standing children's hospital in the Intermountain West of the United States. Children were requested to use the app for at least five days between clinical visits. Children's app-reported data were extracted from individual user accounts for analysis. Quantitative data were summarized descriptively. Qualitative data were summarized using qualitative content analysis. RESULTS: Nineteen children (6-12 years; median 8 years; 7 females) completed 107 days of app use. All children reported symptoms at least once, and 14 reported at least one day with a symptom of moderate or greater severity. Daily experiences reported through the app reflected children's engagement in usual childhood experiences while also describing life with cancer, including symptoms. CONCLUSIONS: Elementary school-age children are capable of self-reporting symptoms using a symptom reporting app, providing preliminary evidence for the potential benefits and clinical relevance of mHealth resources to support health outcomes within this population. PRACTICE IMPLICATIONS: Clinicians should anticipate and support ongoing symptom management needs between clinical visits. Children's self-reported data can promote a person-centered approach to symptom assessment and management.

Effects of early-life exposure to sublethal levels of a common neonicotinoid insecticide on the orientation and migration of monarch butterflies (Danaus plexippus).

Migratory insects use a variety of innate mechanisms to determine their orientation and maintain correct bearing. For long-distance migrants, such as the monarch butterfly (Danaus plexippus), these journeys could be affected by exposure to environmental contaminants. Neonicotinoids are synthetic insecticides that work by affecting the nervous system of insects, resulting in impairment of their mobility, cognitive performance, and other physiological and behavioural functions. To examine how neonicotinoids might affect the ability of monarch butterflies to maintain a proper directional orientation on their ∼4000 km migration, we grew swamp milkweed (Asclepias incarnata) in soil that was either untreated (0 ng g-1: control) or mixed with low (15 ng g-1 of soil) or high (25 ng g-1 of soil) levels of the neonicotinoid clothianidin. Monarch caterpillars were raised on control or clothianidin-treated milkweed and, after pupation, either tested for orientation in a static flight simulator or radio-tracked in the wild during the autumn migration period. Despite clothianidin being detectable in milkweed tissue consumed by caterpillars, there was no evidence that clothianidin influenced the orientation, vector strength (i.e. concentration of direction data around the mean) or rate of travel of adult butterflies, nor was there evidence that morphological traits (i.e. mass and forewing length), testing time, wind speed or temperature impacted directionality. Although sample sizes for both flight simulator and radio-tracking tests were limited, our preliminary results suggest that clothianidin exposure during early caterpillar development does not affect the directed flight of adult migratory monarch butterflies or influence their orientation at the beginning of migration.

Toward Reducing hERG Affinities for DAT Inhibitors with a Combined Machine Learning and Molecular Modeling Approach.

Psychostimulant drugs, such as cocaine, inhibit dopamine reuptake via blockading the dopamine transporter (DAT), which is the primary mechanism underpinning their abuse. Atypical DAT inhibitors are dissimilar to cocaine and can block cocaine- or methamphetamine-induced behaviors, supporting their development as part of a treatment regimen for psychostimulant use disorders. When developing these atypical DAT inhibitors as medications, it is necessary to avoid off-target binding that can produce unwanted side effects or toxicities. In particular, the blockade of a potassium channel, human ether-a-go-go (hERG), can lead to potentially lethal ventricular tachycardia. In this study, we established a counter screening platform for DAT and against hERG binding by combining machine learning-based quantitative structure-activity relationship (QSAR) modeling, experimental validation, and molecular modeling and simulations. Our results show that the available data are adequate to establish robust QSAR models, as validated by chemical synthesis and pharmacological evaluation of a validation set of DAT inhibitors. Furthermore, the QSAR models based on subsets of the data according to experimental approaches used have predictive power as well, which opens the door to target specific functional states of a protein. Complementarily, our molecular modeling and simulations identified the structural elements responsible for a pair of DAT inhibitors having opposite binding affinity trends at DAT and hERG, which can be leveraged for rational optimization of lead atypical DAT inhibitors with desired pharmacological properties.

Feasibility and acceptability of a game-based symptom-reporting app for children with cancer: perspectives of children and parents.

BACKGROUND: Children with cancer have difficulty identifying and describing the multiple symptoms they experience during hospitalization and between clinical encounters. Mobile health resources, including apps, are potential solutions to support child-centric symptom reporting. This study evaluated the feasibility and acceptability of a newly developed game-based symptom-reporting app for school-age children with cancer. PROCEDURE: Nineteen school-age children (6-12 years of age) receiving treatment for cancer at a COG institution in the Intermountain West of the United States used a game-based symptom-reporting app between clinical visits. Feasibility was evaluated through a summary of actual days of app use and interaction with each of the app's features. Children and their parents participated in interviews regarding the app's acceptability. RESULTS: Children used the app a median of 4 days (range 1-12) and interacted most frequently with the symptom reporting and the drawing features. Children enjoyed aspects of the app that supported their creativity and provided choices. Parents endorsed the interactive nature of the app and the value of the child providing his/her own report. Both children and parents identified additional opportunities to enhance the child's user experience. CONCLUSION: Study results support the preliminary feasibility and acceptability of the app. Children's and parents' responses supported the developmental relevance of the app and its role in enhancing the child's autonomy and serving as an outlet for creativity. Future directions include optimizing the child user's experience and investigating the app's role as a resource to enhance shared decision-making for symptom management.

COMPLETE (Communication Plan Early Through End of Life): Development of a Research Program to Diminish Suffering for Children at End of Life.

While overall survival has improved significantly for children with cancer over the past 75 years, cancer remains the leading cause of death from disease among children and adolescents. Further, despite the many advances in medical and nursing care, children with cancer still experience significant physical and emotional suffering over the course of their illness, especially at the end of life (EOL). Children endure significant rates of high-intensity medical interventions (e.g., intubation, intensive care unit admission) at the EOL despite many parents, adolescents, and young adult patients identifying home as their preferred location of death. Hospice care has the potential to ease suffering at the EOL and facilitate home deaths, and yet, most children still die in acute care settings without hospice care. Numerous barriers prevent timely enrollment in hospice among children with cancer who are in the EOL period. This report describes the development and testing of a palliative care/EOL communication intervention designed to overcome some of these barriers and improve EOL outcomes (i.e., earlier hospice enrollment, less use of high-intensity medical interventions, reduced pain and suffering) among children with cancer and their parents (i.e., less emotional distress and uncertainty, improved hope and healthcare satisfaction).

Into the wild: microbiome transplant studies need broader ecological reality.

Gut microbial communities (microbiomes) profoundly shape the ecology and evolution of multicellular life. Interactions between host and microbiome appear to be reciprocal, and ecological theory is now being applied to better understand how hosts and their microbiome influence each other. However, some ecological processes that underlie reciprocal host-microbiome interactions may be obscured by the current convention of highly controlled transplantation experiments. Although these approaches have yielded invaluable insights, there is a need for a broader array of approaches to fully understand host-microbiome reciprocity. Using a directed review, we surveyed the breadth of ecological reality in the current literature on gut microbiome transplants with non-human recipients. For 55 studies, we categorized nine key experimental conditions that impact the ecological reality (EcoReality) of the transplant, including host taxon match and donor environment. Using these categories, we rated the EcoReality of each transplant. Encouragingly, the breadth of EcoReality has increased over time, but some components of EcoReality are still relatively unexplored, including recipient host environment and microbiome state. The conceptual framework we develop here maps the landscape of possible EcoReality to highlight where fundamental ecological processes can be considered in future transplant experiments.