Genetic and clonal dissection of murine small cell lung carcinoma progression by genome sequencing.

Small cell lung carcinoma (SCLC) is a highly lethal, smoking-associated cancer with few known targetable genetic alterations. Using genome sequencing, we characterized the somatic evolution of a genetically engineered mouse model (GEMM) of SCLC initiated by loss of Trp53 and Rb1. We identified alterations in DNA copy number and complex genomic rearrangements and demonstrated a low somatic point mutation frequency in the absence of tobacco mutagens. Alterations targeting the tumor suppressor Pten occurred in the majority of murine SCLC studied, and engineered Pten deletion accelerated murine SCLC and abrogated loss of Chr19 in Trp53; Rb1; Pten compound mutant tumors. Finally, we found evidence for polyclonal and sequential metastatic spread of murine SCLC by comparative sequencing of families of related primary tumors and metastases. We propose a temporal model of SCLC tumorigenesis with implications for human SCLC therapeutics and the nature of cancer-genome evolution in GEMMs.

Callous-unemotional traits and pre-ejection period in response to reward.

Callous-unemotional (CU) traits have important utility in distinguishing individuals exhibiting more severe and persistent antisocial behavior, and our understanding of reward processing and CU traits contributes to behavioral modification. However, research on CU traits often investigated reward alongside punishment and examined solely on average reward reactivity, neglecting the reward response pattern over time such as habituation. This study assessed individuals' pre-ejection period (PEP), a sympathetic nervous system cardiac-linked biomarker with specificity to reward, during a simple reward task to investigate the association between CU traits and both average reward reactivity and reward response pattern over time (captured as responding trajectory). A heterogeneous sample of 126 adult males was recruited from a major metropolitan area in the US. Participants reported their CU traits using the Inventory of Callous-Unemotional Traits and completed a simple reward task while impedance cardiography and electrocardiogram were recorded to derive PEP. The results revealed no significant association between average PEP reward reactivity and CU traits. However, CU traits predicted both linear and quadratic slopes of the PEP reactivity trajectory: individuals with higher CU traits had slower habituation initially, followed by a rapid habituation in later blocks. Findings highlight the importance of modeling the trajectory of PEP reward response when studying CU traits. We discussed the implications of individuals with high CU traits having the responding pattern of slower initial habituation followed by rapid habituation to reward and the possible mechanisms.

Unique and interactive effects of threat and deprivation on latent trait cortisol among emerging adults.

Though considerable work supports the Dimensional Model of Adversity and Psychopathology, prior research has not tested whether the dimensions-threat (e.g., abuse) and deprivation (e.g., neglect)-are uniquely related to salivary trait indicators of hypothalamic pituitary adrenal (HPA) axis activity. We examined the unique and interactive effects of threat and deprivation on latent trait cortisol (LTC)-and whether these effects were modified by co-occurring adversities. Emerging adults (n = 90; Mage = 19.36 years; 99.88% cisgender women) provided salivary cortisol samples four times a day (waking, 30 min and 45 min postwaking, bedtime) over three 3-day measurement waves over 13 weeks. Contextual life stress interviews assessed early adversity. Though the effects varied according to the conceptualization of early adversity, overall, threat-but not deprivation, nor other co-occurring adversities-was uniquely associated with the across-wave LTC. Specifically, the incidence and frequency of threat were each negatively related to the across-wave LTC. Threat severity was also associated with the across-wave LTC, but only among those with no deprivation. Finally, the effects of threat were modified by other co-occurring adversities. Findings suggest that threat has unique implications for individual differences in HPA axis activity among emerging adults, and that co-occurring adversities modify such effects.

Comparative neurogenetics of dog behavior complements efforts towards human neuropsychiatric genetics.

Domestic dogs display a wide array of heritable behaviors that have intermediate genetic complexity thanks to a long history of human-influenced selection. Comparative genetics in dogs could address the scarcity of non-human neurogenetic systems relevant to human neuropsychiatric disorders, which are characterized by mental, emotional, and behavioral symptoms and involve vastly complex genetic and non-genetic risk factors. Our review describes the diverse behavioral "phenome" of domestic dogs, past and ongoing sources of behavioral selection, and the state of canine behavioral genetics. We highlight two naturally disordered behavioral domains that illustrate how dogs may prove useful as a comparative, forward neurogenetic system: canine age-related cognitive dysfunction, which can be examined more rapidly given the attenuated lifespan of dogs, and compulsive disorders, which may have genetic roots in purpose-bred behaviors. Growing community science initiatives aimed at the companion dog population will be well suited to investigating such complex behavioral phenotypes and offer a comparative resource that parallels human genomic initiatives in scale and dimensionality.

Early adversity and depressive symptoms among early adolescent girls: the mediating role of exposure to recent interpersonal acute stress.

Early adversity confers risk for depression in part through its association with recent (i.e., proximal) acute stress. However, it remains unresolved whether: a) early adversity predicts increases in recent acute stress over time; b) all - or only certain types - of recent events mediate the relationship between early adversity and depression; and c) early adversity places individuals at greater risk for depression via greater exposure to independent (i.e., fateful) interpersonal events or via greater generation of dependent (i.e., partially self-initiated) interpersonal events (i.e., stress generation) or both. These questions were examined in a 3-wave longitudinal study of early adolescent girls (N = 125; M = 12.35 years [SD = .77]) with no history of diagnosable depression using contextual life stress and diagnostic interviews. Path analyses indicated that increases in past-year acute interpersonal, but not non-interpersonal, stress mediated the link between early adversity and depressive symptoms. The mediating role of interpersonal events was limited to independent ones, suggesting increases in interpersonal event exposure, not interpersonal stress generation, acted as a mediator. Finally, findings support prior evidence that early adversity may not directly predict future depressive symptoms. Implications for understanding the role of recent stress in the association between early adversity and adolescent depression are discussed.

i-Frame interventions enhance s-frame interventions.

We argue that i-frame interventions can and do increase support for systemic reforms, and s-frame interventions should be pursued in parallel to address key societal issues. Without accompanying i-frame interventions, s-frame interventions can fail. We offer an operant conditioning framework to generate positive spillover effects. Behavioral scientists should develop i-frame interventions that enhance, rather than compete with, s-frame interventions.

Association between adolescent oral contraceptive use and future major depressive disorder: a prospective cohort study.

BACKGROUND: Because of the widespread use of oral contraceptives (OCs) and the devastating effects of depression both on an individual and a societal level, it is crucial to understand the nature of the previously reported relationship between OC use and depression risk. Insight into the impact of analytical choices on the association is important when interpreting available evidence. Hence, we examined the association between adolescent OC use and subsequent depression risk in early adulthood analyzing all theoretically justifiable models. METHODS: Data from the prospective cohort study TRacking Adolescents' Individual Lives Survey, among women aged 13-25 years were used. Adolescent OC use (ages 16-19 years) was used as a predictor and major depressive disorder (MDD) in early adulthood (ages 20-25 years), as assessed by the Diagnostic and Statistical Manual of Mental Disorders-IV oriented Lifetime Depression Assessment Self-Report and the Composite International Diagnostic Interview, was used as an outcome. A total of 818 analytical models were analyzed using Specification Curve Analysis in 534 adolescent OC users and 191 nonusers. RESULTS: Overall, there was an association of adolescent OC use and an episode of MDD in early adulthood [median odds ratio (OR)median = 1.41; ORmin = 1.08; ORmax = 2.18, p < .001], which was driven by the group of young women with no history of MDD (ORmedian = 1.72; ORmin = 1.21; ORmax = 2.18, p < .001). CONCLUSIONS: In summary, adolescent OC use was associated with a small but robust increased risk for experiencing an episode of MDD, especially among women with no history of MDD in adolescence. Understanding the potential side effects of OCs will help women and their doctors to make informed choices when deciding among possible methods of birth control.

Receptiveness to Opposing Views: Conceptualization and Integrative Review.

The present article reviews a growing body of research on receptiveness to opposing views-the willingness to access, consider, and evaluate contradictory opinions in a relatively impartial manner. First, we describe the construct of receptiveness and consider how it can be measured and studied at the individual level. Next, we extend our theorizing to the interpersonal level, arguing that receptiveness in the course of any given interaction is mutually constituted by the dispositional tendencies and observable behaviors of the parties involved. We advance the argument that receptiveness should be conceptualized and studied as an interpersonal construct that emerges dynamically over the course of an interaction and is powerfully influenced by counterpart behavior. This interpersonal conceptualization of receptiveness has important implications for intervention design and raises a suite of novel research questions.

Assessing the role of adolescent hormonal contraceptive use on risk for depression: a 3-year longitudinal study protocol.

BACKGROUND: The incidence of depression in human females rises steadily throughout adolescence, a critical period of pubertal maturation marked by increasing levels of gonadal hormones including estrogens and progesterone. These gonadal hormones play a central role in social and emotional development and may also contribute to the increased occurrence of depression in females that begins in early adolescence. In this study, we examine whether and how introducing synthetic estrogen and progestin derivatives through the use of combined hormonal contraceptives (CHC), affects adolescent females' risk for developing depression. We further assess potential links between CHC use and alterations in stress responses and social-emotional functioning. METHODS: Using a longitudinal cohort design, we will follow a sample of adolescent females over the span of three years. Participants will be assessed at three time points: once when they are between 13 and 15 years of age, and at approximately 18 and 36 months after their initial assessment. Each time point will consist of two online sessions during which participants will complete a clinical interview that screens for key symptoms of mental health disorders, along with a series of questionnaires assessing their level of depressive symptoms and history of contraceptive use. They will also complete a standardized social-evaluative stress test and an emotion recognition task, as well as provide saliva samples to allow for assessment of their circulating free cortisol levels. DISCUSSION: In this study we will assess the effect of CHC use during adolescence on development of Major Depressive Disorder (MDD). We will control for variables previously found to or proposed to partially account for the observed relationship between CHC use and MDD, including socioeconomic status, age of sexual debut, and CHC-related variables including age of first use, reasons for use, and its duration. In particular, we will discover whether CHC use increases depressive symptoms and/or MDD, whether elevated depressive symptoms and/or MDD predict a higher likelihood of starting CHC, or both. Furthermore, this study will allow us to clarify whether alterations in stress reactivity and social-emotional functioning serve as pathways through which CHC use may result in increased risk of depressive symptoms and/or MDD.

The Cognitive, Affective and Somatic Empathy Scales for Adults.

The Cognitive, Affective and Somatic Empathy Scales (CASES) assess three forms of empathy, each with subscales for positive and negative empathy. The present study extends this child instrument to adults and examines its factor structure and construct validity. A secondary aim is to investigate the under-researched area of positive empathy. Community samples totaling 2,604 adults completed the CASES for adults, together with scales assessing construct validity. Confirmatory factor analysis supported the three-factor cognitive-affective-somatic model and a two-factor positive-negative empathy model. Findings were replicated in a second independent sample. Internal reliabilities ranged from .80 to .92. Individuals with higher psychopathy and stimulation-seeking scores were less impaired in their empathic reactions to positive relative to negative valence events, suggesting that they are relatively capable of responding emotionally to rewarding events. Somatic empathy was most strongly associated with pleasure in affective touch and with female > male gender differences. While proactive aggression was associated with reduced cognitive and affective empathy, reactive aggression was associated with increased empathy. Findings provide initial support for the utility of CASES for assessing different forms of empathy and suggest that the balance between positive and negative empathy could provide new insights into psychological traits.

Effects of Chronic and State Loneliness on Heart Rate Variability in Women.

BACKGROUND: Loneliness, the subjective experience of social isolation, represents one of the largest risk factors for physical illness and early death in humans. However, the mechanisms by which loneliness leads to adverse health outcomes are not well understood. PURPOSE: In this study, we examined altered parasympathetic nervous system function as a potential pathway by which chronic loneliness and state loneliness may "get under the skin" to impact cardiovascular physiology. METHODS: In a controlled laboratory setting, vagally mediated resting heart rate variability (HRV), HRV reactivity to an induction of state loneliness, and HRV reactivity to a cognitive challenge task were assessed in a sample of 316 healthy women (18-28 years). RESULTS: Greater chronic loneliness in women predicted lower resting HRV, an independent risk factor for cardiovascular disease and all-cause mortality, after controlling for demographic, psychosocial, and health behavior covariates. Furthermore, women higher in chronic loneliness experienced significantly larger increases in HRV to state loneliness and reported significantly higher levels of negative affect immediately following state loneliness, compared with their less chronically lonely counterparts. Chronic loneliness also predicted blunted HRV reactivity-a maladaptive physiological response-to cognitive challenge. CONCLUSIONS: The current findings provide evidence that chronic loneliness is associated with altered parasympathetic function (both resting HRV and HRV reactivity) in women, and that the immediate experience of state loneliness is linked to a proximate increase in HRV among chronically lonely women. Results are discussed in terms of implications for cardiovascular health and the evolutionary functions of loneliness.

The cognitive, affective, and somatic empathy scales (CASES): Cross-cultural replication and specificity to different forms of aggression and victimization.

A psychometrically sound measure of empathy that captures its multifaceted nature is critical in furthering research on empathy. The only instrument that assesses three domains of empathy together with positive and negative valence empathy is the newly developed 30-item cognitive, affective, and somatic empathy scales (CASES). The current study examines the cross-culture generalizability of CASES in Hong Kong and explores links between empathy and different forms of aggression and peer victimization. A sample of 4,676 Hong Kong youth (62% male) completed CASES, alongside measures of reactive/proactive aggression and multidimensional peer victimization. A subsample of youth (n = 2,321-2,464) and their parents completed additional instruments for testing the validity of CASES. We replicated most of the concurrent, convergent, and discriminant validity findings in the original development of CASES. Proactive aggression was most strongly linked to affective empathy, whereas reactive aggression was most strongly linked to somatic empathy. Differential associations were revealed between subscales of CASES and forms of peer victimization. Findings provide cross-cultural generalizability for a brief self-report instrument that captures the multifaceted nature of empathy. The multifaceted nature of empathy is further supported by differential associations with forms of aggression and victimization.

The Scent of a Good Night's Sleep: Olfactory Cues of a Romantic Partner Improve Sleep Efficiency.

Almost nothing is known about whether exposure to the scent of loved ones influences sleep. In the current study, 155 participants spent 2 nights with their partner's scent and 2 nights with a control scent (in random order). Sleep was measured in two ways: sleep efficiency (via actigraphy) and perceived sleep quality (via self-report). Sleep efficiency was higher when participants were exposed to their partner's scent. This increase occurred regardless of participants' beliefs about the origin of the scent. Perceived sleep quality was higher when participants believed that they were smelling their partner's scent. Exposure to a partner's scent led sleep efficiency to increase by more than 2% on average, an improvement similar in magnitude to the effect of melatonin on sleep. The current work speaks to the critical role of olfaction in communication and reveals that social scents can impact sleep.

Oral contraceptive use in adolescence predicts lasting vulnerability to depression in adulthood.

BACKGROUND: Previous evidence suggests that use of oral contraceptives (OCs), especially during adolescence, may increase women's vulnerability to depression in the short term. Here, we investigate whether women who had first used OC in adolescence show an increased prevalence of depression in the long term. METHODS: We examined 1,236 women in the United States National Health and Nutrition Examination Survey for whom information on depression and age at first OC use was publicly available. We compared women who reported first use of OCs in adolescence to women who had never used OCs and women who had first used OCs in adulthood on 1-year prevalence of major depressive disorder (MDD) assessed by trained interviewers. RESULTS: Compared with women who had used OCs during adolescence, women who had never used OCs were less likely to meet the criteria for MDD within the past year in adulthood [odds ratio (OR) = 0.31, 95% CI = 0.16-0.60], and so were women who only started using OCs in adulthood (OR = 0.54, 95% CI = 0.30-0.95). Third factors that have previously been proposed to explain the relationship between OC use and depression risk such as age at sexual debut, and, importantly, current OC use, did not account for the results in propensity score analyses. CONCLUSIONS: We show a long-term association between adolescent OC use and depression risk in adulthood regardless of current OC use. Our findings suggest that adolescence may be a sensitive period during which OC use could increase women's risk for depression, years after first exposure.

Overestimating Self-Blame for Stressful Life Events and Adolescents' Latent Trait Cortisol: The Moderating Role of Parental Warmth.

Cognitive interpretations of stressful events impact their implications for physiological stress processes. However, whether such interpretations are related to trait cortisol-an indicator of individual differences in stress physiology-is unknown. In 112 early adolescent girls (M age = 12.39 years), this study examined the association between self-blame estimates for past year events and latent trait cortisol, and whether maternal warmth moderated effects. Overestimating self-blame (versus objective indices) for independent (uncontrollable) events was associated with lower latent trait cortisol, and maternal warmth moderated the effect of self-blame estimates on latent trait cortisol for each dependent (at least partially controllable) and interpersonal events. Implications for understanding the impact of cognitive and interpersonal factors on trait cortisol during early adolescence are discussed.

Early adversity and internalizing symptoms in adolescence: Mediation by individual differences in latent trait cortisol.

Research suggests that early adversity places individuals at risk for psychopathology across the life span. Guided by concepts of allostasis and allostatic load, the present study examined whether early adversity contributes to the development of subsequent internalizing symptoms through its association with traitlike individual differences in hypothalamic-pituitary-adrenal axis regulation. Early adolescent girls (n = 113; M age = 12.30 years) provided saliva samples at waking, 30 min postwaking, and bedtime over 3 days (later assayed for cortisol). Objective contextual stress interviews with adolescents and their mothers were used to assess the accumulation of nine types of early adversity within the family environment. Greater early adversity predicted subsequent increases in internalizing symptoms through lower levels of latent trait cortisol. Traitlike individual differences in hypothalamic-pituitary-adrenal axis activity may be among the mechanisms through which early adversity confers risk for the development of psychopathology.

Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma.

Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC proto-oncogene. Tumors from EGFR- and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity.

Evaluating a Web-Based Social Anxiety Intervention Among Community Users: Analysis of Real-World Data.

BACKGROUND: Social anxiety is both harmful and prevalent. It also currently remains among the most undertreated major mental disorders, due, in part, to socially anxious individuals' concerns about the stigma and expense of seeking help. The privacy and affordability of computer-aided psychotherapy interventions may render them particularly helpful in addressing these concerns, and they are also highly scalable, but most tend to be only somewhat effective without therapist support. However, a recent evaluation of a new self-guided, 7-module internet-delivered cognitive behavioral therapy intervention called Overcome Social Anxiety found that it was highly effective. OBJECTIVE: The initial evaluation of Overcome Social Anxiety revealed that it led to significant reductions in symptom severity among university undergraduates. The aim of this study was to extend the results of the initial study and investigate their generalizability by directly evaluating the intervention's effectiveness among a general community sample. METHODS: While signing up for Overcome Social Anxiety, users consented to the usage of their anonymized outcome data for research purposes. Before and after completing the intervention, users completed the Fear of Negative Evaluation Scale (FNE), which we employed as the primary outcome measure. Secondary outcome measures included the Depression Anxiety Stress Scales (DASS) and 2 bespoke questionnaires measuring socially anxious thoughts (Thoughts Questionnaire) and avoidance behaviors (Avoidance Questionnaire). RESULTS: Participants who completed the intervention (102/369, 27.7%) experienced significant reductions in the severity of their symptoms on all measures employed, including FNE (P<.001; Cohen d=1.76), the depression subscale of DASS (P<.001; Cohen d=0.70), the anxiety subscale of DASS (P<.001; Cohen d=0.74), the stress subscale of DASS (P<.001; Cohen d=0.80), the Thoughts Questionnaire (P<.001; Cohen d=1.46), and the Avoidance Questionnaire (P<.001; Cohen d=1.42). CONCLUSIONS: Our results provide further evidence that Overcome Social Anxiety reduces the severity of social anxiety symptoms among those who complete it and suggest that its effectiveness extends to the general community. The completion rate is the highest documented for a fully automated intervention for anxiety, depression, or low mood in a real community sample. In addition, our results indicate that Overcome Social Anxiety reduces the severity of symptoms of depression, physiological symptoms of anxiety, and stress in addition to symptoms of social anxiety.

Vegetarian or meat? Food choice modeling of main dishes occurs outside of awareness.

It is well established that the amount eaten by other people affects how much we eat, but unanswered questions exist regarding how much the food choices of other people affect the types of food that we choose. Past research on food choice modeling has primarily been conducted in controlled laboratory situations and has focused on snack foods. The current research examines the extent to which food choice modeling of a main dish occurs in a real-life context and whether people are aware of being influenced by others. The lunch orders of café patrons were surreptitiously tracked and participants were recruited after they paid for their lunch. Participants were asked what they ordered, whether they were influenced by the prior order, and what their relationship was to the person ahead of them in line. We analyzed the data of participants who were not acquainted with the person ahead of them (N = 174). As hypothesized, participants' main-dish lunch orders matched the choice of the person ordering ahead of them in line at rates significantly higher than chance. A significant modeling effect was observed even among participants who reported that their order was not influenced by the prior order. This research provided evidence of main-dish choice modeling occurring in real-life eating situations and outside of conscious awareness - demonstrating a powerful social influence on eating behaviours.

The Cognitive, Affective, and Somatic Empathy Scales (CASES) for Children.

Although the assessment of empathy has moved from general empathy to differentiating between cognitive and affective empathy, no instruments have assessed somatic (motor) empathy, and none have separated positive from negative affect empathy. The main objective of this study was to develop a 30-item self-report cognitive, affective, and somatic empathy scale (CASES) with positive and negative affect components for use with children and adolescents. A community sample of 428 male and female 11-year-olds completed the CASES together with validity questionnaires and were assessed on IQ. Caregivers reported on callous-unemotional traits, behavior problems, social adversity, and paternal criminality. Confirmatory factor analysis provided support for a 3-factor cognitive-affective-somatic structure of CASES and support for a broader 6-factor model of empathy. Configural and metric factor invariance across genders was established. Good internal consistency was obtained for the main scales. Criterion validity was established by lower empathy in callous-unemotional children. Incremental and predictive validity was documented by empathy at baseline predicting 12 months later to callous-unemotional traits after controlling for baseline callous-unemotional traits. Discriminant validity was documented by empathy being unrelated to internalizing behavior problems and differentially related to proactive and reactive forms of aggression. Construct validity was documented by lower empathy being associated with lower IQ, being male, more externalizing behavior problems, and criminality in the biological parent. Results provide initial support for a brief but multidimensional empathy scale with good sampling and face validity that can be used with children and adolescents.