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Background: Refugees' parenting behaviour is profoundly influenced by their mental health, which is, in turn, influenced by their situation of displacement. Our research presents the first systematic review on parenting and mental health in protracted refugee situations, where 78% of all refugees reside., Methods: We pre-registered our protocol and screened documents in 22 languages from 10 electronic databases, reports by 16 international humanitarian organisations and region-specific content from the top 100 websites for each of the 72 countries that 'host' protracted refugees. Our criteria were empirical papers reporting parenting and parental mental health data on refugees who are in a protracted refugee situation. Studies including only internally displaced or stateless persons were excluded., Results: A total of 18,125 documents were screened and 30 studies were included. We identified a universal pathway linking macro-level stressors in protracted refugee situations, such as movement restrictions and documentation issues, to symptoms of depression and anxiety, which, in turn, led to negative parenting practices. Addtionally, culture-specific pathways were observed in the way parental mental health and parenting were expressed. Situational (e.g., overcrowding) and relational factors (e.g., spousal dynamics) modulated both of these pathways. Biases in the research included the over-representation of specific protracted refugee situations, overreliance on self-reported data, and a heavy focus on mothers while neglecting fathers and other caregivers. Longitudinal research is needed to clarify the directionality and causality between specific macro-level stressors in a given protracted refugee situation and parental mental health and practices. Refugees were rarely consulted or involved in the design of research about their parenting and parental mental health., Conclusion: In recognising the existing links between protracted refugee situations, parental mental health, and parenting, our systematic review calls for a shift in thinking: from focusing solely on the micro aspects that affect 'refugee parenting' to understanding and tackling the broader macro-level stressors that drive them. We urge for larger and long-term research efforts that consider diverse protracted refugee situations, greater investment in science communication and diplomacy with governments, and stronger implementation of durable solutions by states to alleviate the roots of refugee parents' distress and negative parenting practices., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Enhancing resilience is one way to prevent future mental illnesses and encourage recovery in the face of adversity. To develop and test the acceptability and feasibility (A&F) of a combined family and individual resilience intervention in two rural/semi-rural low-income settings in India and Kenya. We developed a five-session intervention including Life Skills Education (LSE) and a model of family resiliency. Among adolescents aged 14-16 years and their families in India and Kenya, we collected socio-demographics and audio records of delivery and undertook a process evaluation. Due to COVID-19, we developed a hybrid intervention. The facilitators and participants preferred the in-person model. India: Of 17 families, 10 fully completed the intervention. They identified three critical components: 1) story-telling, 2) cooperation and working together and 3) expressing feelings. Kenya: All 15 families completed the intervention. Critical elements were 1) seeing social value in learning to make good decisions, 2) promoting an optimistic view of life, 3) hearing stories that resonated with their situation and 4) enhancing family performance through knowledge-building. We mapped the active ingredients, showing fidelity and acceptability. The intervention showed promising A&F parameters. Flexibility and local adaptation were important for delivery., Competing Interests: The authors report no conflict of interest., (© The Author(s) 2024.)

Objective: This study aims to identify the most recommended components of creative art therapy (CAT) to improve the mental health of refugee adolescents., Design: A three-round Delphi design is proposed. The first round will include semi-structured interviews with a panel of 12 CAT professionals worldwide and 12 refugee adolescents aged 10-24 in Jordan with a history of participating in creative arts interventions. The hybrid approach of coding and thematic analysis will be conducted to develop statements on recommended CAT components from the interview narratives. In the second round, the same and newly enrolled 24 professionals and 24 refugee adolescents will be asked to rate the statements according to their importance, propose new statements, and add comments. A similar procedure will be followed in the third round, where panellists will rate new and old statements after perusing the feedback from the second round., Main Outcome Measure: A statement will gain consensus and indicate essential components when rated 'essential' or 'very important' by > = 80% of panellists. Very important components are those with the same ratings by 60-79.9% of panellists., Results: A list of essential and very important components, perspectives and suggestions will be provided to guide practice and intervention development., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ramadan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Community-led, shared book reading programs may help improve refugee children's reading abilities and attitudes towards reading. We Love Reading (WLR)-a light-touch, community-led, shared book reading program-was evaluated in a pre-registered, wait-listed, randomised controlled trial (AEARCTR-0006523). 322 Syrian refugee mother-child dyads (children: 4-8-year-olds, 50.0% female) in Jordan were tested at two timepoints, 15 weeks apart. WLR did not significantly affect child literacy or child-reported child attitudes toward reading (ps > 0.05). Mothers did report improved child attitudes toward reading from WLR (p = 0.046, η 2  = 0.013). The intervention did not lead to improvements in family relationships (ps > 0.05). WLR may have promise in improving attitudes toward reading in forcibly displaced children but did not affect literacy or child-reported attitudes toward reading; these results provide insight into what changes are needed for effective shared book reading interventions in this population., (© 2024. The Author(s).)

Competing Interests: Competing interests: None declared.

Background: Meaningful involvement of adolescents in health research is their fundamental human right and has many benefits. A lack of awareness among researchers on how to meaningfully involve adolescents in health research has been linked to adolescent under involvement in health research. To address this barrier, studies have reported the need for more guidance. To inform the development of better guidelines on adolescent involvement, there is a need to first consolidate the currently available guidance on adolescent involvement in health research and to identify the gaps in these guidelines. This review aims to systematically identify all the currently available guidelines on adolescent involvement in health research and evaluate their scope, content, context, and quality., Methods: This rapid review was pre-registered with PROSPERO #CRD42021293586. It included documents that incorporated tangible recommendations on the involvement of adolescents in health research. We searched six databases for peer-reviewed literature: MEDLINE, CINAHL, Embase, Scopus, Web of Science, and ERIC. We conducted a grey literature search in Google Scholar, Google, websites of 472 relevant organisations and sought expert input. The quality of the guidelines was assessed using the Appraisal of Guidelines for REsearch & Evaluation (AGREE-II) Instrument. Data was analysed using descriptive analyses and narrative synthesis., Results: We found that the current guidelines on adolescent involvement in health research are often narrow in scope, targeting specific users and populations while focusing on limited research areas. The guidelines individually fail to provide comprehensive coverage of recommendations across all topics related to adolescent research involvement, that are collectively addressed across all included guidelines. Furthermore, these guidelines tend to be context-specific and are generally of low quality, often due to inadequate stakeholder involvement and a lack of rigorous development methods., Conclusion: This review provides a consolidated list of guidelines on adolescent involvement in health research along with their quality scores as a resource for researchers to select the guidelines suitable for their research topic, context, and scope for adolescent involvement. There is a need to develop a set of guidelines on adolescent involvement in research, which are comprehensive in scope, cover all key aspects of adolescent involvement in health research, can be adapted for different contexts, and which are based on rigorous and systematic methods., Patient and Public Involvement: Adolescent co-researchers D. B. and C. W. were involved at different stages of the review process. D. B. screened 25% of the peer-reviewed articles at the title and abstract screening stage and 10% at full-text screening stage. C. W. extracted data from 10% of the included guidelines. Both co-researchers reviewed and shared their feedback on the article and are co-authors on this paper. They will also be invited to contribute to further dissemination of the findings from this review., (© 2024 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Background: Less than 1% of studies on child and adolescent health report the involvement of adolescents in health research. This is attributed to barriers experienced by researchers and adolescents in the engagement process. To address this under-involvement of adolescents, we first need a better understanding of the factors that hinder adolescent involvement in health research., Objective: We conducted an umbrella review of reviews to consolidate the review-level evidence on the barriers to meaningful involvement of adolescents in health research., Methods: We preregistered this umbrella review of reviews with PROSPERO (CRD42021287467). We searched 11 databases; Google Scholar; and PROSPERO; supplemented by a hand search of the reference lists of eligible reviews, relevant journals, websites of 472 organisations, and input from experts. This resulted in the inclusion of 99 review articles exploring adolescent involvement in studies on adolescent physical or mental health, which were narratively synthesised. Adolescent coresearchers were engaged at all stages of the review., Results: We found that adolescent involvement in health research is impeded by several challenges experienced by researchers and adolescents. Some challenges experienced by researchers were organisational issues which included limited resources, gatekeeping and paying adolescents. Some barriers were related to a lack of preparedness among researchers and included a lack of awareness of adolescent involvement, the need for training and guidance, and negative attitudes towards participatory research. There were also barriers around how adolescents can be involved, such as researchers finding it challenging to adapt to new methods, issues with recruitment and retention of adolescents, inclusiveness and accessibility. There were also challenges specific to adolescents, such as adolescents' skills and expertise, training, motivations and study goals. Finally, barriers related to the ethical involvement of adolescents included issues with power dynamics, confidentiality, safety and protection of adolescents. Some of the barriers reported by adolescents included tokenistic involvement, inaccessibility of adolescent involvement, and their competing demands., Conclusion: Researchers may find this review useful in understanding and planning for potential challenges of involving adolescents in research. Despite many identified barriers to adolescent engagement, few mitigation strategies were identified to address these barriers. There is a clear need to establish best practices for meaningful adolescent involvement in health research., Public and Patient Involvement in the Review: Adolescents were involved at multiple stages of this umbrella review of reviews. They reviewed the protocol, screened 25% of the articles at title and abstract screening stage, screened 10% of full-text articles, and worked on data analysis. They also helped plan and conduct a participatory workshop with an adolescent advisory group to discuss the challenges experienced by adolescents in health research., (© 2024 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Background: Refugee children are at high risk of mental health problems but face barriers to accessing mental health services, a problem exacerbated by a shortage of mental health professionals. Having trained lay counsellors deliver therapy via telephone could overcome these barriers. This is the first study to explore feasibility and acceptability of telephone-delivered therapy with refugee children in a humanitarian setting., Methods: An evidence-based intervention, Common Elements Treatment Approach, was adapted for telephone-delivery (t-CETA) and delivered by lay counsellors to Syrian refugee children in informal tented settlements in the Beqaa region of Lebanon. Following delivery of t-CETA, semi-structured interviews were conducted with counsellors (N = 3) and with children who received t-CETA (N = 11, 45% female, age 8-17 years) and their caregivers (N = 11, 100% female, age 29-56 years) (N = 25 interviews). Thematic content analysis was conducted separately for interviews with counsellors and interviews with families and results were synthesized., Results: Three themes emerged from interviews with counsellors and four themes from interviews with families, with substantial overlap between them. Synthesized themes were: counselling over the phone both solves and creates practical and logistical challenges; t-CETA is adapted to potential cultural blocks; the relationship between the counsellor and the child and caregiver is extremely important; the family's attitude to mental health influences their understanding of and engagement with counselling; and t-CETA works and is needed. Counselling over the phone overcame logistical barriers, such as poor transportation, and cultural barriers, such as stigma associated with attending mental health services. It provided a more flexible and accessible service and resulted in reductions in symptoms for many children. Challenges included access to phones and poor network coverage, finding an appropriate space, and communication challenges over the phone., Conclusions: Despite some challenges, telephone-delivered therapy for children shows promising evidence of feasibility and acceptability in a humanitarian context and has the potential to increase access to mental health services by hard-to-reach populations. Approaches to addressing challenges of telephone-delivered therapy are discussed. Trial Registration ClinicalTrials.gov ID: NCT03887312; registered 22nd March 2019., (© 2024. The Author(s).)

The preservation of the world's biodiversity for future generations has been a global objective for many years, with the establishment of the International Union for Conservation of Nature (IUCN) Red List of Threatened Species in 1964. However, the conservation of parasites is a more recent development and, due to the difficulty in obtaining data and studying some of the parasitic species, comes its own series of challenges. Using parasites of cyprinid hosts (one critically endangered, one endangered and three near threatened) collected from South Africa's Cape Fold freshwater ecoregion (CF) as a case study, this paper discusses the challenges and possible solutions for implementing a fish parasite conservation project. Novel data on the fish parasites (1819 metazoan parasite individuals, representing the Acanthocephala, Cestoda, Copepoda, Digenea, Monogenea and Nematoda) of the CF are provided from the five endemic hosts, Cheilobarbus serra (Peters, 1864), Labeobarbus seeberi (Gilchrist et Thompson, 1913), Pseudobarbus phlegethon (Barnard, 1938), Sedercypris calidus (Barnard, 1938), and Sedercypris erubescens (Skelton, 1974). Conservation statuses for selected parasite taxa are also proposed based on the conservation statuses of the fish hosts, according to the Conservation Assessment Methodology for Animal Parasites (CAMAP)., (© 2023 The Author(s).)

Introduction: A lack of awareness on how to engage adolescents in research has been reported as one of the barriers to meaningful youth involvement in health research. Currently, available guidelines on youth involvement are limited in terms of the scope (e.g., focused on limited health research areas), content (e.g., include broad principles) and context (e.g., most guidelines are from high-income countries) for which the guidelines are applicable. To address this, we will develop a set of comprehensive guidelines based on consolidated evidence on youth involvement in health research. To inform these guidelines, we are first conducting an umbrella review to (1) summarise and synthesise findings from reviews on involving adolescents in health research, (2) consolidate the challenges experienced in youth involvement and the recommendations to mitigate these challenges, (3) identify best practices and (4) identify gaps and methodological weaknesses in the extant literature on involving adolescents in health research., Methods and Analysis: We will include review articles exploring adolescents' involvement in studies aiming to improve their physical or mental health. Databases to be searched include Cochrane Database of Systematic Reviews, Medical Literature Analysis and Retrieval System Online (MEDLINE), Scopus, Embase, PsycINFO, PsycArticles, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Epistemonikos and Health Systems Evidence. A grey literature search will be conducted in Web of Science, ProQuest, Google Scholar and PROSPERO, supplemented by a handsearch of the reference lists of eligible reviews, relevant journals, websites of related organisations and input from experts. Data will be analysed using narrative synthesis., Ethics and Dissemination: Ethical approval is not required as we are not collecting participant data as part of this review. The findings of this umbrella review will be disseminated through peer-reviewed publications, participatory workshops and academic conferences., Prospero Registration Number: CRD42021287467., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The perinatal period is often characterized by specific fear, worry, and anxiety concerning the pregnancy and its outcomes, referred to as pregnancy-related anxiety. Pregnancy-related anxiety is uniquely associated with negative maternal and child health outcomes during pregnancy, at birth, and early childhood; as such, it is increasingly studied. We examined how pregnancy-related anxiety is measured, where measures were developed and validated, and where pregnancy-related anxiety has been assessed. We will use these factors to identify potential issues in measurement of pregnancy-related anxiety and the geographic gaps in this area of research., Methods: We searched the Africa-Wide, CINAHL, MEDLINE, PsycARTICLES, PsycINFO; PubMed, Scopus, Web of Science Core Collection, SciELO Citation Index, and ERIC databases for studies published at any point up to 01 August 2020 that assessed pregnancy-related anxiety. Search terms included pregnancy-related anxiety, pregnancy-related worry, prenatal anxiety, anxiety during pregnancy, and pregnancy-specific anxiety, among others. Inclusion criteria included: empirical research, published in English, and the inclusion of any assessment of pregnancy-related anxiety in a sample of pregnant women. This review is registered on PROSPERO (CRD42020189938)., Results: The search identified 2904 records; after screening, we retained 352 full-text articles for consideration, ultimately including 269 studies in the review based on the inclusion and exclusion criteria. In total, 39 measures of pregnancy-related anxiety were used in these 269 papers, with 18 used in two or more studies. Less than 20% of the included studies (n = 44) reported research conducted in low- and middle-income country contexts. With one exception, all measures of pregnancy-related anxiety used in more than one study were developed in high-income country contexts. Only 13.8% validated the measures for use with a low- or middle-income country population., Conclusions: Together, these results suggest that pregnancy-related anxiety is being assessed frequently among pregnant people and in many countries, but often using tools that were developed in a context dissimilar to the participants' context and which have not been validated for the target population. Culturally relevant measures of pregnancy-related anxiety which are developed and validated in low-income countries are urgently needed., (© 2022. The Author(s).)

Responses to early life adversity differ greatly across individuals. Elucidating which factors underlie this variation can help us better understand how to improve health trajectories. Here we used a case:control study of refugee and non-refugee youth, differentially exposed to war-related trauma, to investigate the effects of genetics and psychosocial environment on response to trauma. We investigated genetic variants in two genes (serotonin transporter, 5-HTT, and catechol-O-methyltransferase, COMT) that have been implicated in response to trauma. We collected buccal samples and survey data from 417 Syrian refugee and 306 Jordanian non-refugee youth who were enrolled in a randomized controlled trial to evaluate a mental health-focused intervention. Measures of lifetime trauma exposure, resilience, and six mental health and psychosocial stress outcomes were collected at three time points: baseline, ~13 weeks, and ~48 weeks. We used multilevel models to identify gene x environment (GxE) interactions and direct effects of the genetic variants in association with the six outcome measures over time. We did not identify any interactions with trauma exposure, but we did identify GxE interactions with both genes and resilience; 1) individuals with high expression (HE) variants of 5-HTTLPR and high levels of resilience had the lowest levels of perceived stress and 2) individuals homozygous for the Val variant of COMT with high levels of resilience showed stable levels of post-traumatic stress symptoms. We also identified a direct protective effect of 5-HTTLPR HE homozygotes on perceived insecurity. Our results point to novel interactions between the protective effects of genetic variants and resilience, lending support to ideas of differential susceptibility and altered stress reactivity in a cohort of war-affected adolescents., Competing Interests: The authors have declared that no competing interests exist.

Background: Whilst there is little uncertainty about the deleterious impact of pollution on human and planetary health, pollution's impact on adolescent mental health is less well understood. This is particularly true for young people in underdeveloped and developing world contexts, about whom research is generally lacking. Furthermore, although adolescent resilience continues to be a research priority, little attention has been paid to adolescent pathways of resilience in the face or aftermath of pollution exposure. The objective of this study will be to examine the associations between pollution and mental health in 10- to 24-year-olds (i.e. adolescents)., Methods: We designed and registered a study protocol for a systematic review of studies which link pollution and mental health in adolescents. We will include observational studies (e.g. cohort, case-control, time series analyses) that assess the associations between exposure to any form of pollution and the mental health of 10- to 24-year-olds. The primary outcome will be symptoms associated with neurodevelopmental disorders; disruptive, impulse-control, and conduct disorders; depressive disorders; anxiety disorders; substance disorders; and schizophrenia. No secondary outcomes will be considered. Literature searches will be conducted in multiple electronic databases (from inception onwards), including PubMed, MEDLINE, SCOPUS, Web of Science, CINAHL, PsycINFO, SciELO, ERIC, and Africa-Wide. Two investigators will independently screen all citations, full-text articles, and abstract data. The methodological quality (or bias) of included studies will be appraised using appropriate tools. We will provide a narrative synthesis of the evidence., Discussion: This systematic review will evaluate the evidence on the associations between pollution and the mental health of 10- to 24-year-olds. Our findings will be of potential interest to multiple audiences (including adolescent patients/clients, their families, caregivers, healthcare professionals, scientists, and policy makers) and could be used to develop prevention and intervention strategies as well as focus future research. Results will be published in a peer-reviewed journal., Systematic Review Registration: PROSPERO CRD42020176664.

Early adversity and trauma can have profound effects on children's affective development and mental health outcomes. Interventions that improve mental health and socioemotional development are essential to mitigate these effects. We conducted a pilot study examining whether a reading-based program ( We Love Reading ) improves emotion recognition and mental health through socialization in Syrian refugee ( n = 49) and Jordanian non-refugee children ( n = 45) aged 7-12 years old ( M = 8.9, 57% girls) living in Jordan. To measure emotion recognition, children classified the expression in faces morphed between two emotions (happy-sad and fear-anger), while mental health was assessed using survey measures of optimism, depression, anxiety, distress, and insecurity. Prior to the intervention, both groups of children were significantly biased to interpret ambiguous facial expressions as sad, while there was no clear bias on the fear-anger spectrum. Following the intervention, we found changes in Syrian refugee children's bias in emotion recognition away from sad facial expressions, although this returned to pre-intervention levels 2 months after the end of the program. This shift in the bias away from sad facial expressions was not associated with changes in self-reported mental health symptoms. These results suggest a potential positive role of the reading intervention on affective development, but further research is required to determine the longer-term impacts of the program., Competing Interests: RD is the Director of WLR. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Michalek, Lisi, Awad, Hadfield, Mareschal and Dajani.)

Background: Evidence of 'what works' in humanitarian programming is important for addressing the disruptive consequences of conflict and forced displacement. However, collecting robust scientific evidence, and ensuring contextual relevance, is challenging. We measured the biological, psychosocial, and cognitive impacts of a structured psychosocial intervention, implemented by Mercy Corps with Syrian refugees and Jordanian host-community youth. In this paper, we present a case analysis of this evaluation study and reflect on the scientific contributions of the work, the challenges experienced in its delivery, and the strategies deployed to address them., Discussion: We identified challenges with respect to study design, methods, and dissemination: these included the logistics and acceptability of implementing a randomized controlled trial in a humanitarian context, the selection and refinement of culturally-relevant research tools and community-based practices, and the dissemination of results to multiple stakeholders. We demonstrated beneficial and sustained impacts on self-reports of insecurity, stress, and mental health; developed a reliable and culturally-relevant measure of resilience; experimentally tested cognitive skills; and showed that levels of cortisol, a biomarker of chronic stress, reduced by one third in response to intervention. Using stress biomarkers offered proof-of-concept evidence, beyond self-reported data: interventions targeting mental health and psychosocial wellbeing can regulate physiological stress in the body as well as improve self-reported mental health and wellbeing. We built constructive dialogue between local communities, scholars, humanitarian practitioners, and policy-makers., Conclusions: Our work shows the value of rigorous research in humanitarian settings, emphasizing relevance for local communities and meaningful ways to build research ownership. Findings encourage the adoption of cognitive measures and stress biomarkers alongside self-report surveys in evaluating programme impacts. High-quality scientific research with youth can be feasible, useful, and ethical in humanitarian settings., Competing Interests: Competing interestsNone., (© The Author(s) 2020.)

Resilience is a dynamic process of positive adaptation to significant adversity. While there has been substantial focus on risks and negative outcomes associated with youth migrancy, there is limited evidence of the relationship between the adversity of migration, and resilience, wellbeing, and positive mental health in adolescents. This international study aimed to explore the differences in resilience, wellbeing, and mental health behaviors in migrant and non-migrant adolescents tested across six countries (Australia, New Zealand, UK, China, South Africa, and Canada) with varying levels of trauma exposure. The study was a cross-sectional survey design with a convenience sample of 194 10-17 year old migrants and non-migrants. The migrant sample included both "internal" migrants (change of residence within a country) and "external" migrants (change of residence across national borders) for comparison. Across the sites, migrants reported a higher mean number of traumatic events for the past year than non-migrants, with internal migrants reporting more events than external migrants overall. South African adolescents reported a higher mean number of traumatic events for the past year than all other sites. External migrants reported higher resilience scores yet reduced prosocial behaviors relative to internal migrants and non-migrants, whereas both internal and external migrants reported higher peer problems than non-migrants. When considering the interacting effects of trauma, the presence or absence of trauma did not appear to impact migrant scores in terms of resilience, wellbeing, or conduct problems. In comparison, trauma-exposed non-migrants showed detriments relative to trauma-exposed migrant peers for all of these measures. In conclusion, the survey tool was found to be reliable and acceptable for use in international studies of different samples of adolescent migrants. Overall, migrant adolescents showed greater resilience resources than non-migrants and, although the migrants experienced more traumatic events, the impact of trauma on mental health outcomes was greater in the non-migrants. There is a need for further research with larger prospective sample sizes to investigate how levels of resilience and wellbeing vary over time and across countries, and the ways resilience can be promoted in adolescents exposed to trauma, regardless of migrancy status., (Copyright © 2020 Gatt, Alexander, Emond, Foster, Hadfield, Mason-Jones, Reid, Theron, Ungar, Wouldes and Wu.)

Early childhood trauma can have profound and lifelong effects on adult mental health and psychosocial wellbeing. Nevertheless, responses to trauma are highly variable. Genetic variants may help explain variation in responses to trauma by identifying alleles that associate with changes in mental health measures. Protective factors, such as resilience, likely also play an important role in responses to trauma. The effects of genetic variants, in combination with protective factors, on psychosocial health are not well understood, particularly in non-Western contexts. In this study, we test the relative influence of genetic variants of monoamine oxidase A (MAOA, a gene proposed to influence the impact of childhood trauma on adult violence and antisocial behavior), levels of resilience, and exposure to traumatic events on psychosocial stress and mental health trajectories over time. We use data from a cohort of 12-18-year-old Syrian refugees who were forcibly displaced to neighboring Jordan (n = 399). DNA samples and survey data on trauma exposure, resilience (CYRM-12), and psychosocial stress were collected at three time points: baseline, ~13 weeks, and ~48 weeks. Using multilevel models, we identified an association of MAOA variant, in males only, with symptom scores of psychosocial stress on the Perceived Stress Scale (PSS) over time (p = 8.1 x 10-4). We also found that resilience is strongly associated with PSS (p = 7.9 x 10-9), underscoring the importance of protective factors in influencing levels of psychosocial stress. Furthermore, there was an additive effect wherein the sharpest reductions in perceived psychosocial stress are seen in low-activity MAOA males with low trauma exposure or high resilience levels. Our results highlight the value of studies that integrate genetic and psychosocial factors to better understand complex phenotypes, such as responses to trauma in contexts of high trauma exposure., Competing Interests: The authors have declared that no competing interests exist.

The BH3-only protein, Bim, exists as three splice variants (Bim(S), Bim(L), and Bim(EL)) of differing pro-apoptotic potency. Bim(EL), the least effective killer, is degraded by the proteasome in response to phosphorylation by extracellular signal-regulated kinases 1 and 2 (ERK1/2). ERK1/2-dependent phosphorylation correlates with the presence of a domain unique to the Bim(EL) splice variant that includes the major ERK1/2 phosphorylation site Ser(65). However, efficient phosphorylation by ERK1/2, c-Jun N-terminal kinase, or p38 requires the presence in the substrate of a discrete kinase-docking domain as well as the phosphoacceptor site. Here we show that the region unique to Bim(EL) (amino acids 41-97) harbors two potential DEF-type ERK1/2 kinase-docking domains, DEF1 and DEF2. Peptide competition assays revealed that the DEF2 peptide could act autonomously to bind active ERK1/2, whereas the DEF1 peptide did not. Truncation analysis identified a minimal region, residues 80-97, containing the DEF2 motif as sufficient for ERK1/2 binding. Mutation of key residues in the DEF2 motif abolished the interaction of ERK1/2 and Bim(EL) and also abolished ERK1/2-dependent phosphorylation of Bim(EL) in vivo, thereby stabilizing the protein and enhancing cytotoxicity. Our results identify a new physiologically relevant functional motif in Bim(EL) that may account for the distinct biological properties of this splice variant.

Bim, a "BH3-only" protein, is expressed de novo following withdrawal of serum survival factors and promotes cell death. We have shown previously that activation of the ERK1/2 pathway promotes phosphorylation of Bim(EL), targeting it for degradation via the proteasome. However, the nature of the kinase responsible for Bim(EL) phosphorylation remained unclear. We now show that Bim(EL) is phosphorylated on at least three sites in response to activation of the ERK1/2 pathway. By using the peptidylprolyl isomerase, Pin1, as a probe for proline-directed phosphorylation, we show that ERK1/2-dependent phosphorylation of Bim(EL) occurs at (S/T)P motifs. ERK1/2 phosphorylates Bim(EL), but not Bim(S) or Bim(L), in vitro, and mutation of Ser(65) to alanine blocks the phosphorylation of Bim(EL) by ERK1/2 in vitro and in vivo and prevents the degradation of the protein following activation of the ERK1/2 pathway. We also find that ERK1/2, but not JNK, can physically associate with GST-Bim(EL), but not GST-Bim(L) or GST-Bim(S), in vitro. ERK1/2 also binds to full-length Bim(EL) in vivo, and we have localized a potential ERK1/2 "docking domain" lying within a 27-amino acid stretch of the Bim(EL) protein. Our findings provide new insights into the post-translational regulation of Bim(EL) and the role of the ERK1/2 pathway in cell survival signaling.

To investigate the role of thrombin in regulating apoptosis, we have used CCl39 cells, a fibroblast cell line in which thrombin-induced cell proliferation has been extensively studied. Withdrawal of serum from CCl39 cells resulted in a rapid apoptotic response that was completely prevented by the inclusion of thrombin. The protective effect of thrombin was reversed by pertussis toxin, suggesting that cell-survival signalling pathways are activated via a G(i) or G(o) heterotrimeric GTPase. Serum-withdrawal-induced death required de novo gene expression and was preceded by the rapid de novo expression of the pro-apoptotic 'BH3-only' protein Bim (Bcl-2-interacting mediator of cell death). Thrombin strongly inhibited the up-regulation of both Bim protein and Bim mRNA. The ability of thrombin to repress Bim expression, and to protect cells from apoptosis, was reversed by U0126, a MEK1/2 [MAPK (mitogen-activated protein kinase) or ERK (extracellular-signal-regulated kinase) 1/2] inhibitor, or LY294002, a phosphoinositide 3'-kinase (PI3K) inhibitor, suggesting that both the Raf-->MEK-->ERK1/2 and PI3K pathways co-operate to repress Bim and promote cell survival. A PAR1p (protease-activated receptor 1 agonist peptide) was also able to protect cells from serum-withdrawal-induced apoptosis, suggesting that thrombin acts via PAR1 to prevent apoptosis.

Both the ERK and phosphatidylinositol 3'-kinase (PI3K) signaling pathways can protect cells from apoptosis following withdrawal of survival factors. We have previously shown that the ERK1/2 pathway acts independently of PI3K to block expression of the BH3-only protein, BimEL, and prevent serum withdrawal-induced cell death, although the precise mechanism by which ERK reduced BimEL levels was unclear. By comparing Bim mRNA and Bim protein, expression we now show that the rapid expression of BimEL following serum withdrawal cannot be accounted for simply by increases in mRNA following inhibition of PI3K. In cells maintained in serum BimEL is a phosphoprotein. We show that activation of the ERK1/2 pathway is both necessary and sufficient to promote BimEL phosphorylation and that this leads to a substantial increase in turnover of the BimEL protein. ERK1/2-dependent degradation of BimEL proceeds via the proteasome pathway because it is blocked by proteasome inhibitors and is defective at the restrictive temperature in cells with a temperature-sensitive mutation in the E1 component of the ubiquitin-conjugating system. Finally, co-transfection of BimEL and FLAG-ubiquitin causes the accumulation of polyubiquitinated forms of Bim, and this requires the ERK1/2 pathway. Our findings provide new insights into the regulation of Bim and the role of the ERK pathway in cell survival.

CC139 fibroblasts are one of several model systems in which the Raf --> MEK --> ERK1/2 pathway can inhibit apoptosis independently of the PI3K pathway; however, the precise mechanism for this protective effect is not known. Serum withdrawal from CC139 fibroblasts resulted in the rapid onset of apoptosis, which was prevented by actinomycin D or cycloheximide. Serum withdrawal promoted the rapid, de novo accumulation of Bim(EL), a proapoptotic 'BH3-only' member of the Bcl-2 protein family. Bim(EL) expression was an early event, occurring several hours prior to caspase activation. In contrast to studies in neurons, activation of the JNK --> c-Jun pathway was neither necessary nor sufficient to induce Bim(EL) expression. Selective inhibition of either the ERK pathway (with U0126) or the PI3K pathway (with LY294002) caused an increase in the expression of Bim(EL). Furthermore, selective activation of the ERK1/2 pathway by deltaRaf-1:ER* substantially reduced Bim(EL) expression, abolished conformational changes in Bax and blocked the appearance of apoptotic cells. The ability of deltaRaf-1:ER* to repress Bim(EL) expression required the ERK pathway but was independent of the PI3K --> PDK --> PKB pathway. Thus, serum withdrawal-induced expression of Bim(EL) occurs independently of the JNK --> c-Jun pathway and can be repressed by the ERK pathway independently of the PI3K pathway. This may contribute to Raf- and Ras-induced cell survival at low serum concentrations.

Peptide growth factors can promote the cell migration and proliferation that is needed to repair epithelia after mechanical or chemical injury. We report here that scrape-wounding rat intestinal epithelial (RIE-1) cell monolayers caused a rapid increase in levels of heparin-binding epidermal-growth-factor-like growth factor (HB-EGF) mRNA, with a maximal response at approx. 1 h. Hybridization in situ showed that transcript induction occurred primarily in cells at or near wound borders. The increase in HB-EGF mRNA was preceded by activation of the p42 mitogen-activated protein kinase (MAPK) in the wounded cell cultures. Moreover, the induction of HB-EGF mRNA was blocked by PD098059 and U0126, inhibitors that prevent the activation of p42/p44 MAPKs and extracellular signal-regulated protein kinase 5 (ERK5). Both p42 MAPK activation and HB-EGF mRNA induction were inhibited by genistein, indicating a requirement for an upstream tyrosine kinase activity. In contrast, neither response was affected by inhibition of phosphoinositide 3-kinase activity, down-regulation of protein kinase C, or disruption of the actin cytoskeleton with cytochalasin B. We conclude that scrape-wounding epithelial cell monolayers induces HB-EGF mRNA expression by a mechanism that most probably requires p42/p44 MAPK activation, although we cannot exclude a role for ERK5. Our results suggest a physiological role for locally synthesized HB-EGF in promoting epithelial repair after injury.

The senescence of plant organs associated with reproductive development has been studied extensively during the past century, and it has long been recognized that this type of death is internally programmed. The regulation of organ senescence as well as its biochemical and genetic determinants has been an historically rich area of research. Certain plant hormones have been implicated as regulators or modulators of organ senescence and many of the biochemical pathways associated with the senescence syndrome have been elucidated. The genetic basis of organ senescence has also been well established by the identification of mutations that impair the senescence program and recently, transgenic plants have been used to critically determine the role of specific enzymes and hormonal signals in mediating programmed senescence of plant organs. Here, we review the current understanding of the processes that regulate leaf, flower and fruit senescence, emphasizing the role that programmed organ senescence plays in the adaptive fitness of plants.

Ascidians exhibit two different modes of development. A tadpole larva is formed during urodele development, whereas the larval phase is modified or absent during anural development. Anural development is restricted to a small number of species in one or possibly two ascidian families and is probably derived from ancestors with urodele development. Anural and urodele ascidians constitute a model system in which to study the evolution of development, but the phylogeny of anural development has not been resolved. Classification based on larval characters suggests that anural species are monophyletic, whereas classification according to adult morphology suggests they are polyphyletic. In the present study, we have inferred the origin of anural development using rDNA sequences. The central region of 18S rDNA and the hypervariable D2 loop of 28S rDNA were amplified from the genomic DNA of anural and urodele ascidian species by the polymerase chain reaction and sequenced. Phylogenetic trees inferred from 18S rDNA sequences of 21 species placed anural developers into two discrete groups corresponding to the Styelidae and Molgulidae, suggesting that anural development evolved independently in these families. Furthermore, the 18S rDNA trees inferred at least four independent origins of anural development in the family Molgulidae. Phylogenetic trees inferred from the D2 loop sequences of 13 molgulid species confirmed the 18S rDNA phylogeny. Anural development appears to have evolved rapidly because some anural species are placed as closely related sister groups to urodele species. The phylogeny inferred from rDNA sequences is consistent with molgulid systematics according to adult morphology and supports the polyphyletic origin of anural development in ascidians.