Inhibition of Wnt/beta-Catenin Signaling by p38 MAP Kinase Inhibitors Is Explained by Cross-Reactivity with Casein Kinase I delta/epsilon

SummaryWnt/β-catenin signaling plays essential roles in embryonic development, adult stem cell maintenance, and disease. Screening of a small molecule compound library with a β-galactosidase fragment complementation assay measuring β-catenin nuclear entry revealed TAK-715 and AMG-548 as inhibitors of Wnt-3a-stimulated β-catenin signaling. TAK-715 and AMG-548 are inhibitors of p38 mitogen-activated protein kinase, which has been suggested to regulate activation of Wnt/β-catenin signaling. However, two highly selective and equally potent p38 inhibitors, VX-745 and Scio-469, did not inhibit Wnt-3a-stimulated β-catenin signaling. Profiling of TAK-715 and AMG-548 against a panel of over 200 kinases revealed cross-reactivity with casein kinase Iδ and ɛ, which are known activators of Wnt/β-catenin signaling. Our data demonstrate that this cross-reactivity accounts for the inhibition of β-catenin signaling by TAK-715 and AMG-548 and argue against a role of p38 in Wnt/β-catenin signaling

Early life adversity and serotonin transporter gene variation interact at the level of the adrenal gland to affect the adult hypothalamo-pituitary-adrenal axis

The short allelic variant of the serotonin transporter (5-HTT) promoter-linked polymorphic region (5-HTTLPR) has been associated with the etiology of major depression by interaction with early life stress (ELS). Furthermore, 5-HTTLPR has been associated with abnormal functioning of the stress-responsive hypothalamo-pituitary-adrenal (HPA) axis. Here, we examined if, and at what level, the HPA-axis is affected in an animal model for ELS × 5-HTTLPR interactions. Heterozygous and homozygous 5-HTT knockout rats and their wild-type littermates were exposed daily at postnatal days 2–14 to 3 h of maternal separation. When grown to adulthood, plasma levels of adrenocorticotropic hormone (ACTH), and the major rat glucocorticoid, corticosterone (CORT), were measured. Furthermore, the gene expression of key HPA-axis players at the level of the hypothalamus, pituitary and adrenal glands was assessed. No 5-HTT genotype × ELS interaction effects on gene expression were observed at the level of the hypothalamus or pituitary. However, we found significant 5-HTT genotype × ELS interaction effects for plasma CORT levels and adrenal mRNA levels of the ACTH receptor, such that 5-HTT deficiency was associated under control conditions with increased, but after ELS with decreased basal HPA-axis activity. With the use of an in vitro adrenal assay, naïve 5-HTT knockout rats were furthermore shown to display increased adrenal ACTH sensitivity. Therefore, we conclude that basal HPA-axis activity is affected by the interaction of 5- HTT genotype and ELS, and is programmed, within the axis itself, predominantly at the level of the adrenal gland. This study therefore emphasizes the importance of the adrenal gland for HPA-related psychiatric disorders

Alternative treatments for autism : prevalence and predictors

Autism is a heterogeneous neurodevelopmental disorder for which a large variety of treatments are offered, including alternative treatments. Vaccine-related treatments (treatments falsely claiming to cure autism by addressing its alleged cause: routine childhood vaccines such as MMR) continue to be offered worldwide, despite widespread evidence against the effectiveness and even possible harm related to these treatments. We analysed the use of alternative treatments in two studies: a survey study (N = 1989, autistic adults and parents/legal representatives of individuals with autism) and a clinical care study (N = 4520, patient files from a treatment center for autism). Both studies found a relatively high frequency of alternative treatments (23.0–30.7%) – in children even 46.4% -, mostly in combination with mainstream treatment. In the survey study vaccine-related treatments were used by 3.2% of all individuals with autism (and 6.7% of autistic children), and alternative treatment use was predicted by co-occurring diagnoses, younger age of diagnosis and mainstream treatment use. In the clinical care study, patients who had received treatment from a homeo-/osteopath more often had highly educated parents from Dutch/Western background and were more often enrolled in special education. Alternative treatments are widely used and should be included in treatment guidelines. Parents, practitioners and individuals with autism should be both advised and warned about the benefits and risks of these treatments. More research is needed to better understand the choice for and effect of alternative treatments for autism, and mainstream care should be improved

The effects of COVID-19 on child mental health:Biannual assessments up to April 2022 in a clinical and two general population samples

BACKGROUND: The COVID-19 pandemic has had an acute impact on child mental and social health, but long-term effects are still unclear. We examined how child mental health has developed since the start of the COVID-19 pandemic up to 2 years into the pandemic (April 2022).METHODS: We included children (age 8-18) from two general population samples (N = 222-1333 per measurement and N = 2401-13,362 for pre-covid data) and one clinical sample receiving psychiatric care (N = 334-748). Behavioral questionnaire data were assessed five times from April 2020 till April 2022 and pre-pandemic data were available for both general population samples. We collected parent-reported data on internalizing and externalizing problems with the Brief Problem Monitor and self-reported data on Anxiety, Depressive symptoms, Sleep-related impairments, Anger, Global health, and Peer relations with the Patient-Reported Outcomes Measurement Information System (PROMIS®).RESULTS: In all samples, parents reported overall increased internalizing problems, but no increases in externalizing problems, in their children. Children from the general population self-reported increased mental health problems from before to during the pandemic on all six PROMIS domains, with generally worst scores in April 2021, and scores improving toward April 2022 but not to pre-pandemic norms. Children from the clinical sample reported increased mental health problems throughout the pandemic, with generally worst scores in April 2021 or April 2022 and no improvement. We found evidence of minor age effects and no sex effects.CONCLUSIONS: Child mental health in the general population has deteriorated during the first phase of the COVID-19 pandemic, has improved since April 2021, but has not yet returned to pre-pandemic levels. Children in psychiatric care show worsening of mental health problems during the pandemic, which has not improved since. Changes in child mental health should be monitored comprehensively to inform health care and policy.</p

Analysis of polymorphisms of canine Cytochrome P 450-CYP2D15

Cytochrome P450 (CYP) proteins constitute a large ancient family of oxidative enzymes essential for the efficient elimination of a wide variety of clinically used drugs. Polymorphic variants of human CYP2D6 are associated with the conversion rate and efficacy of several drugs such as antidepressants. Polymorphisms of the canine orthologue CYP2D15 are of interest because these antidepressants are also used in dogs with behavioral problems and the outcome of the treatment is variable. However, the annotated CYP2D15 gene is incomplete and inaccurately assembled in CanFam3.1, hampering DNA sequence analysis of the gene in individual dogs. We elucidated the complete exon-intron structure of CYP2D15 to enable comprehensive genotyping of the gene using genomic DNA. We surveyed variations of the gene in four diverse dog breeds and identified novel polymorphisms in exon 2 in border collies. Further investigation to establish the impact of these canine CYP2D15 polymorphisms on interindividual variability in expression and function of this metabolizing enzyme is now feasible. Further knowledge of CYP pharmacogenetics will help individualize therapy and thereby increase therapeutic efficacy, especially in the use of antidepressants in veterinary behavioral medicine

A strategy for human factors/ergonomics: developing the discipline and profession

Human factors/ergonomics (HFE) has great potential to contribute to the design of all kinds of systems with people (work systems, product/service systems), but faces challenges in the readiness of its market and in the supply of high-quality applications. HFE has a unique combination of three fundamental characteristics: (1) it takes a systems approach (2) it is design driven and (3) it focuses on two closely related outcomes: performance and well-being. In order to contribute to future system design, HFE must demonstrate its value more successfully to the main stakeholders of system design. HFE already has a strong value proposition (mainly well-being) and interactivity with the stakeholder group of &apos;system actors&apos; (employees and product/service users). However, the value proposition (mainly performance) and relationships with the stakeholder groups of &apos;system experts&apos; (experts from technical and social sciences involved in system design), and &apos;system decision makers&apos; (managers and other decision makers involved in system design, purchase, implementation and use), who have a strong power to influence system design, need to be developed. Therefore, the first main strategic direction is to strengthen the demand for high-quality HFE by increasing awareness among powerful stakeholders of the value of high-quality HFE by communicating with stakeholders, by building partnerships and by educating stakeholders. The second main strategic direction is to strengthen the application of high-quality HFE by promoting the education of HFE specialists, by ensuring high-quality standards of HFE applications and HFE specialists, and by promoting HFE research excellence at universities and other organisations. This strategy requires cooperation between the HFE community at large, consisting of the International Ergonomics Association (IEA), local (national and regional) HFE societies, and HFE specialists. We propose a joint world-wide HFE development plan, in which the IEA takes a leadership role. Practitioner Summary: Human factors/ergonomics (HFE) has much to offer by addressing major business and societal challenges regarding work and product/ service systems. HFE potential, however, is underexploited. This paper presents a strategy for the HFE community to strengthen demand and application of *Corresponding author. Email: [email protected] high-quality HFE, emphasising its key elements: systems approach, design driven, and performance and well-being goals

How age, sex and genotype shape the stress response

Exposure to chronic stress is a leading pre-disposing factor for several neuropsychiatric disorders as it often leads to maladaptive responses. The response to stressful events is heterogeneous, underpinning a wide spectrum of distinct changes amongst stress-exposed individuals'. Several factors can underlie a different perception to stressors and the setting of distinct coping strategies that will lead to individual differences on the susceptibility/resistance to stress. Beyond the factors related to the stressor itself, such as intensity, duration or predictability, there are factors intrinsic to the individuals that are relevant to shape the stress response, such as age, sex and genetics. In this review, we examine the contribution of such intrinsic factors to the modulation of the stress response based on experimental rodent models of response to stress and discuss to what extent that knowledge can be potentially translated to humans.FEDER through the Operational Programme Competitiveness Factors - COMPETE and National Funds through FCT - Foundation for Science and Technology under the project POCI-01-0145-FEDER-007038; and by the project NORTE-01-0145-FEDER-000013, supported by Norte Portugal Regional Operational Programme (NORTE, 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). We acknowledge the Portuguese Foundation for Science and Technology (FCT) for providing a post-doctoral fellowship to SR (SFRH/BPD/72710/2010), a doctoral fellowship to SM (SFRH/BD/69311/2010) and a fellowship to AN (ANR/NEU-OSD/0258/2012)info:eu-repo/semantics/publishedVersio