Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family and is involved in cytokine signalling. In vitro analyses suggest that TYK2 also has kinase-independent, i.e., non-canonical, functions. We have generated gene-targeted mice harbouring a mutation in the ATP-binding pocket of the kinase domain. The Tyk2 kinase-inactive ( Tyk2 K923E ) mice are viable and show no gross abnormalities. We show that kinase-active TYK2 is required for full-fledged type I interferon- (IFN) induced activation of the transcription factors STAT1-4 and for the in vivo antiviral defence against viruses primarily controlled through type I IFN actions. In addition, TYK2 kinase activity was found to be required for the protein’s stability. An inhibitory function was only observed upon over-expression of TYK2 K923E in vitro. Tyk2 K923E mice represent the first model for studying the kinase-independent function of a JAK in vivo and for assessing the consequences of side effects of JAK inhibitors.

Testosterone is associated with status-seeking behaviors such as competition, which may depend on whether one wins or loses status, but also on the stability of one's status. We examined (1) to what extent testosterone administration affects competition behavior in repeated social contests in men with high or low rank, and (2), whether this relationship is moderated by hierarchy stability, as predicted by the status instability hypothesis. Using a real effort-based design in healthy male participants (N = 173 males), we first found that testosterone (vs. placebo) increased motivation to compete for status, but only in individuals with a low unstable status. A second part of the experiment, tailored to directly compare stable with unstable hierarchies, indicated that exogenous testosterone again increased competitive motivation in individuals with a low unstable status, but decreased competition behavior in men with low stable status. Additionally, exogenous testosterone increased motivation in those with a stable high status. Further analysis suggested that these effects were moderated by individuals' trait dominance, and genetic differences assessed by the androgen receptor (CAG-repeat) and dopamine transporter (DAT1) polymorphisms. Our study provides evidence that testosterone specifically boosts status-related motivation when there is an opportunity to improve one's social status. The findings contribute to our understanding of testosterone's causal role in status-seeking motivation in competition behavior, and indicate that testosterone adaptively increases our drive for high status in a context-dependent manner. We discuss potential neurobiological pathways through which testosterone may attain these effects on behavior.

No abstract

Human behaviour requires flexible arbitration between actions we do out of habit and actions that are directed towards a specific goal. Drugs that target opioid and dopamine receptors are notorious for inducing maladaptive habitual drug consumption; yet, how the opioidergic and dopaminergic neurotransmitter systems contribute to the arbitration between habitual and goal-directed behaviour is poorly understood. By combining pharmacological challenges with a well-established decision-making task and a novel computational model, we show that the administration of the dopamine D2/3 receptor antagonist amisulpride led to an increase in goal-directed or ‘model-based’ relative to habitual or ‘model-free’ behaviour, whereas the non-selective opioid receptor antagonist naltrexone had no appreciable effect. The effect of amisulpride on model-based/model-free behaviour did not scale with drug serum levels in the blood. Furthermore, participants with higher amisulpride serum levels showed higher explorative behaviour. These findings highlight the distinct functional contributions of dopamine and opioid receptors to goal-directed and habitual behaviour and support the notion that even small doses of amisulpride promote flexible application of cognitive control.

Intoxications with yew (Taxus spp.) pose a challenge to forensic toxicology because a variety of Taxus ingredients have been associated with its toxic effects. To provide preliminary evidence in cases where plant material is available, we introduce a novel direct PCR assay for the detection of DNA traces from Taxus spp. This assay has been successfully applied to a forensic case of suicidal poisoning via ingestion of Taxus leaves. PCR primers were designed to target a sequence located in the internal transcribed spacer 1 (ITS1) of nuclear ribosomal DNA, which is well conserved among species of the genus Taxus and can, therefore, be exploited to discriminate between Taxus and other conifers. Because ITS1 exists as a multicopy sequence within the plant genome, the assay provides enough sensitivity to work with trace amounts that are below the DNA content of a single cell. Specificity of the assay was tested with DNA extracts from Taxaceae and selected representatives from other related plant families (Cephalotaxaceae, Cupressaceae and Pinaceae). When combined with the commercial Phire® Plant Direct PCR Kit (Finnzymes), the primers allowed application of a two-step cycling protocol (without the annealing step), and because direct PCR requires only little sample pre-treatment, results from PCR could be obtained within 1.5 h after analysis had begun. Direct PCR was performed with diluted gastric content from the forensic case. Amplification products of the expected size were purified and sequenced. Sequence data were subjected to Basic Local Alignment Search Tool analysis and affiliated with ITS1 from Taxus spp.

BackgroundOctamer-binding factor 6 (Oct-6, Pou3f1, SCIP, Tst-1) is a transcription factor of the Pit-Oct-Unc (POU) family. POU proteins regulate key developmental processes and have been identified from a diverse range of species. Oct-6 expression is described to be confined to the developing brain, Schwann cells, oligodendrocyte precursors, testes, and skin. Its function is primarily characterised in Schwann cells, where it is required for correctly timed transition to the myelinating state. In the present study, we report that Oct-6 is an interferon (IFN)-inducible protein and show for the first time expression in murine fibroblasts and macrophages.ResultsOct-6 was induced by type I and type II IFN, but not by interleukin-6. Induction of Oct-6 after IFNβ treatment was mainly dependent on signal transducer and activator of transcription 1 (Stat1) and partially on tyrosine kinase 2 (Tyk2). Chromatin immunopreciptitation experiments revealed binding of Stat1 to the Oct-6 promoter in a region around 500 bp upstream of the transcription start site, a region different from the downstream regulatory element involved in Schwann cell-specific Oct-6 expression. Oct-6 was also induced by dsRNA treatment and during viral infections, in both cases via autocrine/paracrine actions of IFNα/β. Using microarray and RT-qPCR, we furthermore show that Oct-6 is involved in the regulation of transcriptional responses to dsRNA, in particular in the gene regulation of serine/threonine protein kinase 40 (Stk40) and U7 snRNA-associated Sm-like protein Lsm10 (Lsm10).ConclusionOur data show that Oct-6 expression is not as restricted as previously assumed. Induction of Oct-6 by IFNs and viruses in at least two different cell types, and involvement of Oct-6 in gene regulation after dsRNA treatment, suggest novel functions of Oct-6 in innate immune responses.

No abstract

Testosterone is associated with status-seeking behaviors such as competition, which may depend on whether one wins or loses status, but also on the stability of one’s status. We examined (1) to what extent testosterone administration affects competition behavior in repeated social contests in men with high or low rank, and (2), whether this relationship is moderated by hierarchy stability, as predicted by the status instability hypothesis. Using a real effort-based design in healthy male participants (N = 173 males), we first found that testosterone (vs. placebo) increased motivation to compete for status, but only in individuals with a low unstable status. A second part of the experiment, tailored to directly compare stable with unstable hierarchies, indicated that exogenous testosterone again increased competitive motivation in individuals with a low unstable status, but decreased competition behavior in men with low stable status. Additionally, exogenous testosterone increased motivation in those with a stable high status. Further analysis suggested that these effects were moderated by individuals’ trait dominance, and genetic differences assessed by the androgen receptor (CAG-repeat) and dopamine transporter (DAT1) polymorphisms. Our study provides evidence that testosterone specifically boosts status-related motivation when there is an opportunity to improve one’s social status. The findings contribute to our understanding of testosterone’s causal role in status-seeking motivation in competition behavior, and indicate that testosterone adaptively increases our drive for high status in a context-dependent manner. We discuss potential neurobiological pathways through which testosterone may attain these effects on behavior.