NF1 mutation-driven neuronal hyperexcitability sets a threshold for tumorigenesis and therapeutic targeting of murine optic glioma.

BACKGROUND: With the recognition that noncancerous cells function as critical regulators of brain tumor growth, we recently demonstrated that neurons drive low-grade glioma initiation and progression. Using mouse models of neurofibromatosis type 1 (NF1)-associated optic pathway glioma (OPG), we showed that Nf1 mutation induces neuronal hyperexcitability and midkine expression, which activates an immune axis to support tumor growth, such that high-dose lamotrigine treatment reduces Nf1-OPG proliferation. Herein, we execute a series of complementary experiments to address several key knowledge gaps relevant to future clinical translation. METHODS: We leverage a collection of Nf1-mutant mice that spontaneously develop OPGs to alter both germline and retinal neuron-specific midkine expression. Nf1-mutant mice harboring several different NF1 patient-derived germline mutations were employed to evaluate neuronal excitability and midkine expression. Two distinct Nf1-OPG preclinical mouse models were used to assess lamotrigine effects on tumor progression and growth in vivo. RESULTS: We establish that neuronal midkine is both necessary and sufficient for Nf1-OPG growth, demonstrating an obligate relationship between germline Nf1 mutation, neuronal excitability, midkine production, and Nf1-OPG proliferation. We show anti-epileptic drug (lamotrigine) specificity in suppressing neuronal midkine production. Relevant to clinical translation, lamotrigine prevents Nf1-OPG progression and suppresses the growth of existing tumors for months following drug cessation. Importantly, lamotrigine abrogates tumor growth in two Nf1-OPG strains using pediatric epilepsy clinical dosing. CONCLUSIONS: Together, these findings establish midkine and neuronal hyperexcitability as targetable drivers of Nf1-OPG growth and support the use of lamotrigine as a potential chemoprevention or chemotherapy agent for children with NF1-OPG.

Implementation of a standardised accept note to improve communication during inter-hospital transfer: a prospective cohort study.

IMPORTANCE: The transfer of patients between hospitals (interhospital transfer, IHT), exposes patients to communication errors and gaps in information exchange. OBJECTIVE: To design and implement a standardised accept note to improve communication during medical service transfers, and evaluate its impact on patient outcomes. DESIGN: Prospective interventional cohort study. SETTING: A 792-bed tertiary care hospital. PARTICIPANTS: All patient transfers from any acute care hospital to the general medicine, cardiology, oncology and intensive care unit (ICU) services between August 2020 and June 2022. INTERVENTIONS: A standardised accept note template was developed over a 9-month period with key stakeholder input and embedded in the electronic health record, completed by nurses within the hospital's Access Centre. MAIN OUTCOMES AND MEASURES: Primary outcome was clinician-reported medical errors collected via surveys of admitting clinicians within 72 hours after IHT patient admission. Secondary outcomes included clinician-reported failures in communication; presence and 'timeliness' of accept note documentation; patient length of stay (LOS) after transfer; rapid response or ICU transfer within 24 hours and in-hospital mortality. All outcomes were analysed postintervention versus preintervention, adjusting for patient demographics, diagnosis, comorbidity, illness severity, admitting service, time of year, hospital COVID census and census of admitting service and admitting team on date of admission. RESULTS: Of the 1004 and 654 IHT patients during preintervention and postintervention periods, surveys were collected on 735 (73.2%) and 462 (70.6%), respectively. Baseline characteristics were similar among patients in each time period and between survey responders and non-responders. Adjusted analyses demonstrated a 27% reduction in clinician-reported medical error rates postimplementation versus preimplementation (11.5 vs 15.8, adjusted OR (aOR) 0.73, 95% CI 0.53 to 0.99). Secondary outcomes demonstrated lower adjusted odds of clinician-reported failures in communication (aOR 0.88; 0.78 to 0.98) and rapid response/ICU transfer (aOR 0.57; 0.34 to 0.97), and improved presence (aOR 2.30; 1.75 to 3.02) and timeliness (-21.4 hours vs -8.7 hours, p<0.001) of accept note documentation. There were no significant differences in LOS or mortality. CONCLUSIONS AND RELEVANCE: Among 1658 medical patient transfers, implementing a standardised accept note was associated with improved presence and timeliness of accept note documentation, clinician-reported medical errors, failures in communication and clinical decline following transfer, suggesting that improving communication during IHT can improve patient outcomes.

Emerging Adult and Caregiver Psychosocial Experiences with Severe Hypoglycemic Events and the Perceived Impact of Nasal Glucagon: A Cross-Sectional Study.

INTRODUCTION: Severe hypoglycemic events are distressing. Although past studies have shown that young adulthood is a potentially distressing time, few studies have explored distress about severe hypoglycemia in this age group. The real-world psychosocial experiences of potential severe hypoglycemic events and the perceived impact of glucagon treatments like nasal glucagon are currently unknown. We explored perceptions of severe hypoglycemic events and impact of nasal glucagon on psychosocial experiences with these events in emerging adults with type 1 diabetes and caregivers of emerging adults and children/teens. Further, we compared perceptions of preparedness and protection in handling severe hypoglycemic events with nasal glucagon versus the emergency glucagon kit that requires reconstitution (e-kit). METHODS: This observational, cross-sectional study enrolled emerging adults (aged 18-26; N = 364) with type 1 diabetes, caregivers of emerging adults (aged 18-26; N = 138) with type 1 diabetes, and caregivers of children/teens (aged 4-17; N = 315) with type 1 diabetes. Participants completed an online survey about their experiences with severe hypoglycemia, perceptions of nasal glucagon impact on psychosocial experiences, and perceptions of feeling prepared and protected with nasal glucagon and the e-kit. RESULTS: Many emerging adults (63.7%) agreed that the experience of severe hypoglycemic events was distressing; 33.3% and 46.7% of caregivers of emerging adults and children/teens, respectively, reported distress. Participants reported positive perceptions of nasal glucagon impact, particularly improved confidence in other people's ability to help during severe hypoglycemic events: emerging adults, 81.4%; caregivers of emerging adults, 77.6%; caregivers of children/teens, 75.5%. Participants demonstrated higher perceptions of preparedness and protection for nasal glucagon than for the e-kit (p < 0.001). CONCLUSIONS: Participants reported improved confidence in other people's ability to help during severe hypoglycemic events since having nasal glucagon available. This suggests that nasal glucagon may help broaden the support network for young people with type 1 diabetes and their caregivers.

Daily experiences of type 1 diabetes stress across adulthood.

AIMS: Daily diabetes stressful events take a toll on individuals with type 1 diabetes, and these experiences may look different across adulthood. The aims of the current study were to understand the nature of daily diabetes stress across adulthood and explore whether these experiences differed by age. METHODS: In this qualitative study, adults with T1D (N = 199, Mage  = 46.81 years) described the most stressful event related to their diabetes each evening as part of a 14-day diary. Using a grounded theory approach, diabetes stressful events were coded for where they occurred, the source of stress (i.e. interpersonal or not), and content (e.g. sleep; blood glucose checking; frustration). RESULTS: Participants reported having a diabetes-related stressful event on 58% (M = 0.58, SD = (0.25)) of days. Daily stressful events included issues of diabetes management, diabetes-related interference to or from other areas of life, and negative impact on psychological well-being, but rarely included a social component. Older adults were less likely to report having a diabetes-related stressful event, but were more likely to report that stressful events occurred at home, compared to younger adults. CONCLUSION: The lived experience of diabetes-related stress appears similar across ages, with individuals continuing to experience generally the same types of diabetes-related events in similar frequencies. Interventions to help improve diabetes outcomes or well-being may benefit from targeting the most commonly experienced areas of stress, which includes reducing the interference of daily activities to and by diabetes management.

Daily stress spillover and crossover in couples coping with type 1 diabetes.

In the context of a chronic illness such as Type 1 diabetes (T1D), managing general stressors may be linked to diabetes-specific stressors for persons with T1D, an intraindividual contagion phenomenon (i.e., spillover). Among those with romantic partners, stress may also be associated with the partner's stress (i.e., crossover). These intraindividual and interpersonal processes may be further strengthened or weakened in the presence of individual (e.g., sleep satisfaction) and interpersonal (e.g., relationship satisfaction) factors. This study examined spillover and crossover effects between daily general and diabetes-specific stressors and whether sleep satisfaction and relationship satisfaction moderated spillover and crossover effects among couples in which one person had T1D. Persons with T1D (n = 199; Mage = 46.82, 52.3% female) and their romantic partners (n = 199; Mage = 46.41, 47.2% female) reported general stressors and sleep satisfaction, and persons with T1D reported diabetes-specific stressors on 14 consecutive days. Both couple members completed a survey that assessed relationship satisfaction. Multilevel models revealed significant within-person and between-person stress spillover and crossover effects. When examining the moderating role of sleep satisfaction, however, persons with T1D with better sleep satisfaction did not experience spillover between one domain and the other. Furthermore, partners with higher relationship satisfaction did not experience crossover between the persons with T1D-specific stressors and their general stressors. These findings support the conceptualization of the link between general and diabetes-specific stressors as both an intraindividual and a dyadic process among couples coping with T1D. In addition, better sleep satisfaction can prevent spillover effects, and relationship satisfaction can prevent stress crossover effects. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Close relationships and diabetes management across the lifespan: The good, the bad, and autonomy.

Relationships are linked with positive and negative self-management and illness outcomes for individuals with type 1 diabetes. Explanations for these mixed associations have remained separated in psychosocial research in type 1 diabetes by relationship type (e.g. parent vs spouse) and individual's age (e.g. adolescence vs older adulthood). In this conceptual review, we present a novel perspective that close relationships across the lifespan may be beneficial for illness self-management when they support individuals' sense of autonomy, defined from a Basic Psychological Needs perspective. Processes of autonomy support are crucial for promoting illness management across all ages and relationship types.

Shared illness appraisal and self-efficacy among adults with type 1 diabetes.

We examined the interaction between shared illness appraisal and self-efficacy among couples in which one partner was diagnosed with type 1 diabetes (n = 199). We hypothesized that the relation between self-efficacy and health would be weakened under conditions of shared rather than individual appraisal. Multiple regression analyses demonstrated that partner shared illness appraisal interacted with the self-efficacy of the person with type 1 diabetes to predict overall psychological distress and daily diabetes stressors in the predicted direction. Plots of the interactions suggest that partner appraisal of diabetes as shared buffers individuals with lower levels of self-efficacy from poorer health.

Age differences in reactivity to daily general and Type 1 diabetes stressors.

Older adults often report less exposure to and less affective reactions to daily stressors. However, older adults with a chronic illness such as Type 1 diabetes may experience more daily stressors due to the complications of diabetes and may be more affected by those stressors. The study examined (a) age differences in reported exposure to general and diabetes stressors, (b) whether daily general and diabetes stressors relate to daily positive and negative affect, self-care, and blood glucose, and (c) whether these daily associations are moderated by age and comorbidity. Individuals with Type 1 diabetes (n = 199; 52.3% female, average age 46.81 years) completed a checklist for 14 days reporting general and diabetes stressors. General diabetes distress was assessed with the Diabetes Distress Scale. Daily positive and negative affect and daily self-care behaviors were rated each day. Blood glucose was assessed via glucometers. Older adults reported fewer daily general and diabetes stressors and less diabetes distress compared to younger adults. Multilevel models indicated that both daily general and diabetes stressors (between- and within-person) were associated with lower positive and higher negative affect. Fewer diabetes stressors were associated with better self-care and lower (better) mean blood glucose. Neither age nor comorbidity interacted with general or diabetes stressors to predict any outcome (except one effect for comorbidity), indicating that older adults and those experiencing more comorbid conditions were similarly affected by stressors. Results suggest that older adults experience fewer stressors than younger adults but are similarly affected when stressors do occur. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Daily illness appraisal and collaboration in couples with type 1 diabetes.

OBJECTIVE: Dyadic coping theories posit that spousal involvement may benefit illness management through collaborative and supportive (C&S) strategies and shared illness appraisals. Illness appraisals have only been examined as individual differences rather than fluctuating daily as individuals manage the difficult Type 1 diabetes regimen. The study examined how daily illness appraisals of individuals with Type 1 diabetes and their spouses were linked to spouses' daily C&S strategies and whether C&S strategies were most beneficial for daily diabetes outcomes when they occurred in the context of shared illness appraisals. METHOD: Couples (N = 199) in which one person had Type 1 diabetes (M age patients = 46.81; 52.3% female; spouses = 46.40, 47.5% female) completed a 14-day diary assessing illness appraisals (ranging from nonshared through shared) and spouses' C&S strategies. Patients reported daily self-regulation failures, self-care behaviors, and perceived coping effectiveness. Daily blood glucose was gathered from glucometers. RESULTS: Multilevel models indicated both within-person and between-person effects of patients' and spouses' illness appraisals on C&S strategies with higher shared illness appraisals associated with greater C&S strategies. Greater shared illness appraisals were associated with fewer self-regulation failures and better self-care. C&S strategies were associated with lower self-care and higher blood glucose levels. Appraisal interacted with C&S strategies such that C&S strategies were associated with more self-regulation failures, lower self-care, and lower perceived coping effectiveness when patients reported lower shared appraisals. CONCLUSIONS: Results suggest that C&S strategies may be more detrimental for diabetes management when individuals view diabetes as less shared. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

The separation in coordination between social- and self-regulation for emerging adults with type 1 diabetes.

To examine how self-regulation and social-regulation surrounding type 1 diabetes (T1D) management are coordinated during early emerging adulthood and whether classes of coordination relate to HbA1c and executive functioning (EF). Emerging adult participants (N = 212) with T1D (M age = 18.8 years, SD = .40) completed a 14-day diary to capture components of self-regulation and social-regulation. A mixture multi-level latent coordination model first determined the separate but coordinated factor structure of self- and social-regulation, then determined the number of distinct classes of coordination and how those classes linked to HbA1c and EF. The best-fitting model included three coordinative factors (self, mother, and father) of regulation and two distinct classes. The class with lower HbA1c and higher EF had more stable self- and social-regulation, more connections between self- and social-regulation and reflected more adaptive patterns, consistent with medical management goals. Social connection with parents may aid in regulation during this at-risk transitional time of emerging adulthood.

Yours, Mine, and Ours: A Qualitative Analysis of the Impact of Type 1 Diabetes Management in Older Adult Married Couples.

OBJECTIVE: The purpose of this study was to understand perceptions of diabetes management responsibilities and the impact of diabetes on day-to-day activities in older adulthood for individuals with type 1 diabetes and their spouses. DESIGN AND METHODS: This qualitative content analysis used a constant-compare approach to analyze individual interviews conducted with older adults and their spouses. People with type 1 diabetes (PWD) and their spouses were interviewed regarding how they coped or dealt with diabetes, what activities they carried out or avoided because of diabetes, and how they appraised diabetes as an individual or shared problem. RESULTS: Participants (n = 52) included 26 older adults with diabetes (mean age 69 years, SD 2.56 years; 38.5% female) and their spouses (mean age 68 years, SD 5.11 years; 61.5% female). Half of the PWD (50%) and the majority of spouses (76.9%) appraised diabetes as a shared issue. Five themes emerged from the interview data: 1) Perceptions pf PWD of spouse involvement in diabetes care, 2) PWD underestimated the impact of diabetes on their spouse's daily lives, 3) gendered nature of spouses supporting diabetes management, 4) evolution of diabetes and the relationship across developmental time, and 5) differences in diabetes management among couples. CONCLUSION: Older adults with type 1 diabetes and their spouses have different perspectives regarding diabetes support and responsibility and may not always realize what support is being provided or needed to optimize effective diabetes management. Advancing age with or without diabetes complications may necessitate that spouses provide diabetes support. Diabetes management training for spouses would likely be helpful.

Keeping parents connected in early emerging adulthood: Diabetes-related disclosure and solicitation.

Emerging adults with Type 1 diabetes benefit when parents remain knowledgeable of their self-management. Yet how early emerging adults remain connected with parents while they experience normative declines in involvement and move out of the parental home is unclear. The present study examined how disclosure to, and solicitation from, parents may (a) be a way that emerging adults and parents remain connected, (b) occur with different methods of contact (i.e., face-to-face; non-face-to-face), and (c) associate with diabetes management differently for those living in versus outside of the parental home. Early emerging adults with Type 1 diabetes (N = 202; Mage = 18.81 years; 66% female) completed measures of their methods of contact with parents; diabetes-related disclosure to, and solicitation from, parents; and diabetes management as part of a 14-day daily diary. General linear models found that face-to-face contact was associated with greater disclosure to parents, for both those living in and out of the parental home. Individuals who lived outside the parental home used more non-face-to-face contact (e.g., texting) than those in the parental home. Multilevel models revealed that higher disclosure to mothers on a daily basis (within-persons) and to mothers and fathers overall (between-persons) was associated with better diabetes management similarly for those living in versus out of the parental home. Results suggest that face-to-face contact may be most effective for keeping parents "in the know" about diabetes management. Moreover, disclosure and solicitation continue to support diabetes management even as individuals move out of the parental home. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Parental Involvement and Executive Function in Emerging Adults with Type 1 Diabetes.

OBJECTIVE: To examine (a) changes in parental involvement across early emerging adulthood, (b) whether yearly fluctuations in parental involvement were associated with adherence and glycated hemoglobin (HbA1c) over time, and (c) whether higher involvement was more beneficial for those with poorer executive function (EF). METHODS: A total of 228 high school seniors (M age = 17.76) with type 1 diabetes reported on mothers' and fathers' acceptance, knowledge of diabetes activities, disclosure to mothers and fathers regarding diabetes, and adherence at four yearly time points. At baseline, participants completed performance-based measures of EF. HbA1c was collected from assay kits. RESULTS: Growth curve models revealed significant declines in disclosure to fathers and mothers' and fathers' knowledge of diabetes activities; no changes were found in mothers' or fathers' acceptance nor disclosure to mothers. Multilevel models indicated significant between-person effects for nearly all aspects of parental involvement with more acceptance, knowledge, and disclosure associated with better HbA1c and adherence. Within-person effects for disclosure to fathers, and mothers' and fathers' knowledge indicated that in years when emerging adults perceived higher amounts of these types of involvement (compared with their own average), HbA1c was lower. Within-person effects were found for acceptance to mothers, disclosure to mothers and fathers, and mothers' diabetes knowledge for adherence. Disclosure to fathers and mothers' knowledge of diabetes activities were especially beneficial for HbA1c for those with poorer EF performance. CONCLUSIONS: Parental involvement in diabetes management remains important during the high-risk time of emerging adulthood, especially for those with poorer EF.

Structural model of patient-centered communication and diabetes management in early emerging adults at the transfer to adult care.

Early emerging adulthood (ages 18-25) is a time of risk for type 1 diabetes (T1D) when relationships with parents and providers are changing. We examined whether individuals' high-quality relationships with mothers are associated with greater perceptions of patient-centered communication (PCC) with their doctor and whether PCC is associated with better adherence and glycemic control through diabetes-related self-efficacy. Additionally, we tested whether associations of PCC with self-efficacy and diabetes outcomes are stronger among those who had transferred to adult care. One-year post-high school, 217 individuals with T1D (60% women, 53% in adult care) reported perceptions of maternal relationship quality, PCC, self-efficacy, and adherence. Glycemic control was measured via HbA1c assay kits. Structural equation modeling indicated good model fit and revealed indirect paths linking higher maternal relationship quality to better adherence through higher PCC, and higher PCC to better HbA1c through adherence. Transfer status moderated the link between PCC and self-efficacy, suggesting PCC may be especially important when emerging adults transfer to adult care.

Patient and partner illness appraisals and health among adults with type 1 diabetes.

In a study of 199 couples in which one person had type 1 diabetes, we examined how patient appraisal of the diabetes as shared versus individual was associated with collaborative, supportive and unsupportive behavior and whether patient shared illness appraisal was most beneficial for health when it occurred in the context of supportive behavior. We assessed illness appraisal among patients with type 1 diabetes and their partners and had patients complete relationship and health measures. Results showed partners were more likely than patients to hold shared illness appraisals. Patients' shared appraisals were associated with more collaborative and instrumental support, more emotional support, less protective buffering, and more overprotective behavior. When patients and partners were consistent in their shared appraisals, support was highest. Regression analysis showed collaborative and instrumental support, as well as emotional support, was related to better psychological and physical health when patients held shared compared to individual illness appraisals.

Daily sleep quality and daily stressors in couples coping with type 1 diabetes.

OBJECTIVE: To examine the influence of daily sleep quality in patients with Type 1 diabetes (T1D) on that of their spouses and to investigate the influence of couples' sleep quality on patients' diabetes-specific stressors and couples' general stressors the following day. METHODS: 199 patients with Type 1 diabetes (Mage = 46.82) and their spouses (Mage = 46.41) completed a 14-day diary where they reported on their own sleep quality, and the presence of general stressors. Patients reported the presence of diabetes-specific stressors. Multilevel modeling examined the effects of daily variability in (within-person effects) and average levels of (between-person effects) sleep quality on the number of next-day diabetes-specific stressors (controlling for prior day stressors). Furthermore, the actor-partner interdependence model was used to examine the effect of sleep quality on general stressors. RESULTS: Greater patients' daily sleep quality was related to their spouses' greater sleep quality. Increases in the patients' own daily- and average sleep quality were uniquely associated with fewer next day diabetes-specific stressors. Better own daily- and average sleep quality were associated with fewer general stressors for both partners. Spouses' increased daily sleep quality was associated with fewer general stressors of patients. CONCLUSIONS: The results support that sleep quality is a dyadic phenomenon among couples and suggest that better sleep quality may buffer diabetes specific and general stress in couples coping with T1D. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Host Plant Suitability in a Specialist Herbivore, Euphydryas anicia (Nymphalidae): Preference, Performance and Sequestration.

The checkerspot butterfly, Euphydryas anicia (Nymphalidae), specializes on plants containing iridoid glycosides and has the ability to sequester these compounds from its host plants. This study investigated larval preference, performance, and sequestration of iridoid glycosides in a population of E. anicia at Crescent Meadows, Colorado, USA. Although previous studies showed that other populations in Colorado use the host plant, Castilleja integra (Orobanchaceae), we found no evidence for E. anicia ovipositing or feeding on C. integra at Crescent Meadows. Though C. integra and another host plant, Penstemon glaber (Plantaginaceae), occur at Crescent Meadows, the primary host plant used was P. glaber. To determine why C. integra was not being used at the Crescent Meadows site, we first examined the host plant preference of naïve larvae between P. glaber and C. integra. Then we assessed the growth and survivorship of larvae reared on each plant species. Finally, we quantified the iridoid glycoside concentrations of the two plant species and diapausing caterpillars reared on each host plant. Our results showed that E. anicia larvae prefer P. glaber. Also, larvae survive and grow better when reared on P. glaber than on C. integra. Castilleja integra was found to contain two primary iridoid glycosides, macfadienoside and catalpol, and larvae reared on this plant sequestered both compounds; whereas P. glaber contained only catalpol and larvae reared on this species sequestered catalpol. Thus, although larvae are able to use C. integra in the laboratory, the drivers behind the lack of use at the Crescent Meadows site remain unclear.

Hope, help, and healing: Culturally embedded approaches to suicide prevention, intervention and postvention services with native Hawaiian youth.

Suicide rates have reached their highest documented levels in the United States with the greatest increases among indigenous youth, including Native Hawaiians. Culturally informed, effective prevention and treatment services are needed now more than ever for Native communities to heal and flourish. Multicomponent prevention and service strategies rooted in indigenous values and approaches show the most promise. Native Hawaiian communities are united around a common goal of suicide prevention, intervention and postvention, linking cultural meanings to improve understanding and guide local efforts. This paper highlights important cultural values to consider when developing and implementing suicide prevention, intervention and postvention. Strategies build upon the strengths of Native Hawaiian youth and their respective communities. Native Hawaiian sayings anchor each level and serve to organize a set of culturally informed and culturally embedded programs and approaches along the continuum of prevention, intervention and postvention. Application of indigenization to suicide prevention enhances connections to people and place, inspiring hope among Native Hawaiian youth, their families and their communities. (PsycINFO Database Record

Host plant iridoid glycosides mediate herbivore interactions with natural enemies.

Many insect herbivores are dietary specialists capable of sequestering the secondary metabolites produced by their host plants. These defensive compounds have important but complex implications for tritrophic interactions between plants, herbivores, and natural enemies. The sequestration of host plant secondary metabolites defends herbivores from attack by generalist predators, but may also compromise the immune response, making insect herbivores more vulnerable to parasitism. Here, we investigate the role of plant secondary metabolites in mediating interactions between a specialist herbivore and its natural enemies. The host plants are two Penstemon species, Penstemon glaber and Penstemon virgatus, which are chemically defended by iridoid glycosides (IGs). First, we examined how Penstemon iridoid glycoside content influences the sequestration of IGs by a specialist herbivore, Euphydryas anicia. Then, we performed ant bioassays to assess how host plant species influences larval susceptibility to predators and phenoloxidase assays to assess the immunocompetence and potential vulnerability to parasitoids and pathogens. We found that the concentration of IGs sequestered by E. anicia larvae varied with host plant diet. Larvae reared on P. glaber sequestered more IGs than larvae reared on P. virgatus. Yet, ant predators found larvae unpalatable regardless of host plant diet and were also repelled by sugar solutions containing isolated IGs. However, E. anicia larvae reared on P. glaber showed higher levels of phenoloxidase activity than larvae reared on P. virgatus. Our results suggest that the sequestration of some secondary metabolites can effectively protect herbivores from predation, yet may also increase vulnerability to parasitism via decreased immunocompetence.

Pharmacological Inhibition of ERK Signaling Rescues Pathophysiology and Behavioral Phenotype Associated with 16p11.2 Chromosomal Deletion in Mice.

The human 16p11.2 microdeletion is one of the most common gene copy number variations linked to autism, but the pathophysiology associated with this chromosomal abnormality is largely unknown. The 593 kb deletion contains the ERK1 gene and other genes that converge onto the ERK/MAP kinase pathway. Perturbations in ERK signaling are linked to a group of related neurodevelopmental disorders hallmarked by intellectual disability, including autism. We report that mice harboring the 16p11.2 deletion exhibit a paradoxical elevation of ERK activity, cortical cytoarchitecture abnormalities and behavioral deficits. Importantly, we show that treatment with a novel ERK pathway inhibitor during a critical period of brain development rescues the molecular, anatomical and behavioral deficits in the 16p11.2 deletion mice. The ERK inhibitor treatment administered to adult mice ameliorates a subset of these behavioral deficits. Our findings provide evidence for potential targeted therapeutic intervention in 16p11.2 deletion carriers.SIGNIFICANCE STATEMENT The ERK/MAPK pathway is genetically linked to autism spectrum disorders and other syndromes typified by intellectual disability. We provide direct evidence connecting the ERK/MAP kinases to the developmental abnormalities in neurogenesis and cortical cytoarchitecture associated with the 16p11.2 chromosomal deletion. Most importantly, we demonstrate that treatment with a novel ERK-specific inhibitor during development rescues aberrant cortical cytoarchitecture and restores normal levels of cell-cycle regulators during cortical neurogenesis. These treatments partially reverse the behavioral deficits observed in the 16p11.2del mouse model, including hyperactivity, memory as well as olfaction, and maternal behavior. We also report a rescue of a subset of these deficits upon treatment of adult 16p11.2del mice. These data provide a strong rationale for therapeutic approaches to this disorder.