Methyl transfer in psilocybin biosynthesis.

Psilocybin, the natural hallucinogen produced by Psilocybe ("magic") mushrooms, holds great promise for the treatment of depression and several other mental health conditions. The final step in the psilocybin biosynthetic pathway, dimethylation of the tryptophan-derived intermediate norbaeocystin, is catalysed by PsiM. Here we present atomic resolution (0.9 Å) crystal structures of PsiM trapped at various stages of its reaction cycle, providing detailed insight into the SAM-dependent methylation mechanism. Structural and phylogenetic analyses suggest that PsiM derives from epitranscriptomic N6-methyladenosine writers of the METTL16 family, which is further supported by the observation that bound substrates physicochemically mimic RNA. Inherent limitations of the ancestral monomethyltransferase scaffold hamper the efficiency of psilocybin assembly and leave PsiM incapable of catalysing trimethylation to aeruginascin. The results of our study will support bioengineering efforts aiming to create novel variants of psilocybin with improved therapeutic properties.

Genetic Survey of Psilocybe Natural Products.

Psilocybe magic mushrooms are best known for their main natural product, psilocybin, and its dephosphorylated congener, the psychedelic metabolite psilocin. Beyond tryptamines, the secondary metabolome of these fungi is poorly understood. The genomes of five species (P. azurescens, P. cubensis, P. cyanescens, P. mexicana, and P. serbica) were browsed to understand more profoundly common and species-specific metabolic capacities. The genomic analyses revealed a much greater and yet unexplored metabolic diversity than evident from parallel chemical analyses. P. cyanescens and P. mexicana were identified as aeruginascin producers. Lumichrome and verpacamide A were also detected as Psilocybe metabolites. The observations concerning the potential secondary metabolome of this fungal genus support pharmacological and toxicological efforts to find a rational basis for yet elusive phenomena, such as paralytic effects, attributed to consumption of some magic mushrooms.

Ethik First - extracurricular support for medical students and young physicians facing moral dilemmas in hospital routine.

Introduction: Moral value conflicts play an increasingly central role in everyday hospital life. Clinical ethics, however, is only marginally represented in the compulsory curriculum for human medicine and the additional education regulations. The aim of the Ethik First project at the University Medical Center Schleswig-Holstein, Campus Kiel is to close this gap with an extracurricular offer and to support medical students from the fifth clinical semester onward and during their practical year as well as assistant doctors in dealing with moral dilemmas in everyday hospital life. The project has taken the concomitant learning objectives from the national competency-based learning objective catalog for medicine. According to the target group, the address in particular, showed higher taxonomy levels. Project description: The multimodal concept is based on three pillars: In monthly principle-based case conferences, participants practice ethical reflection and moral judgment primarily on the basis of concrete cases introduced by them using the methods of problem-based learning and consideration-based deliberation. If participants do not bring forth a case, they discuss ethical aspects of current political relevance. Moreover, there is an annual public speaker event. Results: Since the project began in 2017, ~20 students and interns have taken part in Ethik First one or more times. In a web-based interim evaluation (N=13), all respondents fully agreed that they considered the format helpful for dealing with ethical questions at the clinic. They rated the relevance for their later profession as high. There is evidence for support in moral dilemma situations. Discussion: The first evaluation results of the voluntary extracurricular offer show the acceptance of the selected format, which goes beyond pure teaching in its conception in that it addresses moral stress as well and strengthens the participants' individual resilience. Conclusion: Ethik First reinforces the role of ethical aspects in the training of (prospective) doctors and focuses on reflecting on cases they have experienced firsthand. We formulate a desideratum for appropriate advanced training concepts both in medical studies and in advanced medical training such that the training and development of comparable projects at medical faculties and at medical associations with student participation can be discussed.