HpARI protein secreted by a helminth parasite suppresses interleukin-33

Infection by helminth parasites is associated with amelioration of allergic reactivity, but mechanistic insights into this association are lacking. Products secreted by the mouse parasite Heligmosomoides polygyrus suppress type 2 (allergic) immune responses through interference in the interleukin-33 (IL-33) pathway. Here, we identified H. polygyrus Alarmin Release Inhibitor (HpARI), an IL-33-suppressive 26-kDa protein, containing three predicted complement control protein (CCP) modules. In vivo, recombinant HpARI abrogated IL-33, group 2 innate lymphoid cell (ILC2) and eosinophilic responses to Alternaria allergen administration, and diminished eosinophilic responses to Nippostrongylus brasiliensis, increasing parasite burden. HpARI bound directly to both mouse and human IL-33 (in the cytokine's activated state) and also to nuclear DNA via its N-terminal CCP module pair (CCP1/2), tethering active IL-33 within necrotic cells, preventing its release, and forestalling initiation of type 2 allergic responses. Thus, HpARI employs a novel molecular strategy to suppress type 2 immunity in both infection and allergy. Osbourn et al identified HpARI, a protein secreted by a helminth parasite that is capable of suppressing allergic responses. HpARI binds to IL-33 (a critical inducer of allergy) and nuclear DNA, preventing the release of IL-33 from necrotic epithelial cells

Relapse prevention for addictive behaviors

The Relapse Prevention (RP) model has been a mainstay of addictions theory and treatment since its introduction three decades ago. This paper provides an overview and update of RP for addictive behaviors with a focus on developments over the last decade (2000-2010). Major treatment outcome studies and meta-analyses are summarized, as are selected empirical findings relevant to the tenets of the RP model. Notable advances in RP in the last decade include the introduction of a reformulated cognitive-behavioral model of relapse, the application of advanced statistical methods to model relapse in large randomized trials, and the development of mindfulness-based relapse prevention. We also review the emergent literature on genetic correlates of relapse following pharmacological and behavioral treatments. The continued influence of RP is evidenced by its integration in most cognitive-behavioral substance use interventions. However, the tendency to subsume RP within other treatment modalities has posed a barrier to systematic evaluation of the RP model. Overall, RP remains an influential cognitive-behavioral framework that can inform both theoretical and clinical approaches to understanding and facilitating behavior change

Subanaesthetic doses of ketamine reduce but do not eliminate predictive coding responses: implications for mechanisms of sensory disconnection

Background Sensory disconnection is a key feature of sleep and anaesthesia. We have proposed that predictive coding offers a framework for understanding the mechanisms of disconnection. Low doses of ketamine that do not induce disconnection should thus diminish predictive coding, but not abolish it. Methods Ketamine was administered to 14 participants up to a blood concentration of 0.3 μg ml−1 Participants were played a series of tones comprising a roving oddball sequence while electroencephalography evoked response potentials were recorded. We fit a Bayesian observer model to the tone sequence, correlating neural activity with the prediction errors generated by the model using linear mixed effects models and cluster-based statistics. Results Ketamine modulated prediction errors associated with the transition of one tone to the next (transitional probability), but not how often tones changed (environmental volatility), of the system. Transitional probability was reduced when blood concentrations of ketamine were increased to 0.2–0.3 μg ml−1 (96–208 ms, P=0.003); however, correlates of prediction error were still evident in the electroencephalogram (124–168 ms, P=0.003). Prediction errors related to environmental volatility were associated with electroencephalographic activity before ketamine (224–284 ms, P=0.028) and during 0.2–0.3 μg ml−1 ketamine (108–248 ms, P=0.003). At this subanaesthetic dose, ketamine did not exert a dose-dependent modulation of prediction error. Conclusions Subanaesthetic dosing of ketamine reduced correlates of predictive coding but did not eliminate them. Future studies should evaluate whether states of sensory disconnection, including anaesthetic doses of ketamine, are associated with a complete absence of predictive coding responses. Clinical trial registration NCT03284307

The Moderating Effect of Alcohol-Specific Parental Rule-Setting on the Relation between the Dopamine D2 Receptor Gene (DRD2), the Mu-Opioid Receptor Gene (OPRM1) and Alcohol Use in Young Adolescents

Contains fulltext : 102967.pdf (publisher's version ) (Closed access)Aims: The main aim of the study was to test the moderating effect of two genetic polymorphisms, one in the dopamine D2 receptor gene (DRD2) and one in the mu-opioid receptor gene (OPRM1), on the link between parental rule-setting and adolescent alcohol use. Methods: A total of 214 adolescents (M-age =13.7, 44.9% male) provided saliva samples and completed survey items describing alcohol use and parental rule-setting. Results: Findings indicated that alcohol-specific parental rule-setting was more robustly associated with alcohol use for adolescents with the DRD2 A1 risk allele and for those with the OPRM1 G-allele. Conclusion: This study replicates the interaction between parental rule-setting and the DRD2 risk allele on adolescent alcohol use and extends the literature by demonstrating the moderating effects of the OPRM1 risk allele on the link between parental rule-setting and adolescent alcohol use