This article provides a narrative overview of important developments in the study of child and adolescent life satisfaction, beginning with historical developments and concluding with directions for future research. Correlates are identified at all levels of Bronfenbrenner’s (1979) ecological systems framework. Theory, research methods, content, and intervention issues are addressed. The need for greater consideration of the extant research base in the development of intervention strategies is highlighted. Research on child and adolescent life satisfaction: Progress and opportunities.
Myeloid malignancies carrying somatic DNMT3A mutations (DNMT3Amut) are refractory to standard therapy. DNMT3Amut leukemia cells accumulate toxic DNA double-strand breaks (DSBs) and stalled replication forks, rendering them dependent on DNA damage response (DDR). We report here that DNA polymerase theta (Pol9), a key element in DSB repair by end-joining (Pol9-mediated end-joining [TMEJ]) and in fork restarting, promotes survival and proliferation of DNMT3Amut leukemia cells. Pol9 is overexpressed in DNMT3Amut leukemia cells due to abrogation of PARP1 PARylation-dependent UBE2O E3 ligase-mediated ubiquitination and proteasomal degradation of Pol9. In addition, PARP1-mediated recruitment of the SMARCAD1-MSH2/ MSH3 repressive complex to DSBs is diminished in DNMT3Amut leukemia cells, which facilitates association of Pol9 with DNA damage. Pol9 inhibitors enhance the anti-leukemic effects of standard drugs such as FLT3 kinase inhibitor quizartinib, cytarabine +/- doxorubicin, and etoposidein vitro and in mice with DNMT3Amut leukemia. Altogether, Pol9 is an attractive target in DNMT3Amut hematological malignancies.
Research Summary Organizations grant stakeholders who provide valuable resources insider status in governance, excluding less valuable outsiders. Firms thereby assemble a value-maximizing resource portfolio but face challenges when environmental shifts require adaptation that harms some insiders. We combine and extend new stakeholder and social movement theories, hypothesizing how various stakeholders influence such adaptation. Outsiders can enable adaptation depending on organizational governance and the array of insider stakeholders. For-profit firms are less open to outsider influence, but a wider array of insiders enables outsiders to align with certain groups to overcome the opposition of others who resist change. The nature of these alignments shapes whether adaptation involves transformative divestments or exploratory investments. We test our theory in the context of the Beyond Coal movement to divest coal plants.Managerial Summary To gain access to valuable resources, organizations commit to stakeholders who provide these resources. However, this creates problems when adapting to changes in the environment that undermine the value of these resources. How can managers balance their stakeholder commitments with the need to integrate the concerns of other stakeholders demanding adaptive changes? We find that organizational governance and the configuration of stakeholder interests can create openings for adaptation. Studying a period of rapid environmental change in the US electric utility industry, for-profit utilities were more likely to retire coal generators when activists aligned with consumer advocates, and more likely to invest in solar generators when activists aligned with prosumers.
RATIONALE:Opioid use disorders are marked by both drug use despite negative consequences and drug use to avoid negative physiological and psychological states. The dorsal raphe nucleus (DRN) serotonin (5-HT) system modulates reward- and stress-related responses, but its role in both male and female rats remains incompletely understood. OBJECTIVE:To investigate the role of the DRN 5-HT system in heroin-motivated behaviors in male and female rats, and, in parallel, to examine the impacts of stress-induced reinstatement of heroin seeking on DRN 5-HT cell electrophysiological profiles. METHODS:To probe DRN 5-HT contributions to basal, punished, and stress-driven heroin consumption, we performed chemogenetic manipulations in transgenic Tph2-iCre Sprague-Dawley rats. Twenty-two- and 50-kHz ultrasonic vocalizations (USVs), reflecting negative and positive affective state, respectively, were recorded during basal and punished heroin self-administration and a novel dual stressor-induced reinstatement model to delineate affective profiles. In a separate cohort of conventional Sprague-Dawley rats, ex vivo electrophysiology in DRN 5-HT cells examined the impact of stress-induced reinstatement of heroin seeking on spontaneous inhibitory postsynaptic currents (sIPSCs). RESULTS:Activation of the DRN 5-HT system increased heroin consumption under basal and punished conditions but did not alter stress-induced reinstatement or affective measures. Although females showed higher active lever pressing and consumption of heroin intake during acquisition of self-administration, responses to DRN 5-HT activation did not differ by sex. Ex vivo recordings revealed elevated sIPSCs in DRN 5-HT neurons from post-reinstatement females, but not males, indicating increased inhibitory drive. Notably, chemogenetic viral expression was densest in the dorsal DRN (DRD), associated with anxiety-related behavior, whereas electrophysiological recordings targeted ventrolateral/ventral DRN (DRVL/DRV) regions linked to anxiolysis. CONCLUSIONS:These findings demonstrate a role for the DRN 5-HT system in basal and punished heroin self-administration and a link between stress-induced heroin reinstatement and enhanced GABAergic inhibition of DRN 5-HT neurons in females. Serotonergic involvement in heroin consumption and sex differences in stress-driven heroin seeking patterns may reflect differential engagement of anatomically and functionally distinct DRN subdivisions.
Evidence suggests that modulation of cannabinoid signaling via CB2 receptors regulates neuroinflammation and confers neuroprotection, positioning these receptors as promising targets for age-related cognitive decline. However, there are limited studies that have directly explored the effects of acute CB2 receptor activation on cognitive domains impacted in aging. This study examined the impact of β-caryophyllene (BCP), a sesquiterpene with putative CB2 receptor agonist properties, on executive function and recognition memory in young and aged mice. Methods: Young (2 mo) and aged (15 mo) male and female C57BL/6J mice were trained in an operant go/no-go (GNG) visual discrimination task. Animals trained to criterion were injected with BCP (0, 25, 50, or 100 mg/kg; i.p.) using a within-subjects design. BCP effects were also tested in novel object recognition (NOR) and object location recognition (OLR) paradigms. Aged mice required more sessions than young mice to acquire GNG contingencies but performed equivalently post-acquisition. Acute BCP induced dose-dependent impairments in attentional control, with moderate-to-high doses (50 and 100 mg/kg) reducing go trial performance independent of age or sex, while inhibitory control (no-go trial performance) remained unaffected. In contrast, low-dose BCP (25 mg/kg) selectively enhanced inhibitory control in aged low-performing mice but not in young or high-performing aged mice. Low-dose BCP improved NOR but not OLR performance. Acute BCP produces domain- and dose-specific cognitive effects, with low doses enhancing inhibitory control in cognitively vulnerable aged mice. These rapid effects likely arise from neuromodulatory rather than delayed anti-inflammatory mechanisms, warranting further validation of CB2 receptor dependence.
