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Plants synthesize numerous alkaloids that mimic animal neurotransmitters 1 . The diversity of alkaloid structures is achieved through the generation and tailoring of unique carbon scaffolds 2,3 , yet many neuroactive alkaloids belong to a scaffold class for which no biosynthetic route or enzyme catalyst is known. By studying highly coordinated, tissue-specific gene expression in plants that produce neuroactive Lycopodium alkaloids 4 , we identified an unexpected enzyme class for alkaloid biosynthesis: neofunctionalized α-carbonic anhydrases (CAHs). We show that three CAH-like (CAL) proteins are required in the biosynthetic route to a key precursor of the Lycopodium alkaloids by catalysing a stereospecific Mannich-like condensation and subsequent bicyclic scaffold generation. Also, we describe a series of scaffold tailoring steps that generate the optimized acetylcholinesterase inhibition activity of huperzine A 5 . Our findings suggest a broader involvement of CAH-like enzymes in specialized metabolism and demonstrate how successive scaffold tailoring can drive potency against a neurological protein target., (© 2023. The Author(s).)

Aims: Efficacy of aspirin in primary prevention of cardiovascular disease (CVD) may be influenced by a common allele in guanylate cyclase GUCY1A3, which has been shown to modify platelet function and increase CVD risk., Methods and Results: We investigated whether homozygotes of the GUCY1A3 rs7692387 risk (G) allele benefited from aspirin in two long-term, randomized placebo-controlled trials of aspirin in primary CVD prevention: the Women's Genome Health Study (WGHS, N = 23 294) and a myocardial infarction (MI, N = 550) and stroke (N = 382) case-control set from the Physician's Health Study (PHS, N = 22 071). Bleeding risk was evaluated in the WGHS. In the placebo group of the WGHS, the GUCY1A3 risk (G) allele was confirmed to increase CVD risk [hazard ratio 1.38; 95% confidence interval (CI) 1.08-1.78; P = 0.01]. Random-effects meta-analysis of the WGHS and PHS revealed that aspirin reduced CVD events among risk allele homozygotes [G/G: odds ratio (OR) 0.79; 95% CI 0.65-0.97; P = 0.03] but increased CVD events among non-risk allele carriers (e.g. G/A: OR 1.39; 95% CI 1.03-1.87; P = 0.03) thus implying an interaction between genotype stratum and aspirin intake (Pinteraction = 0.01). Bleeding associated with aspirin increased in all genotype groups, with higher risks in heterozygotes., Conclusion: In two randomized placebo-controlled trials in the setting of primary prevention, aspirin reduced the incidence of CVD events in individuals homozygous for the GUCY1A3 risk (G) allele, whereas heterozygote individuals had more events when taking aspirin., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

The placebo effect is a phenomenon in which patients who are given an inactive treatment (e.g., inert pill) show a perceived or actual improvement in a medical condition. Placebo effects in clinical trials have been investigated for many years especially because placebo treatments often serve as the control arm of randomized clinical trial designs. Recent observations suggest that placebo effects may be modified by genetics. This observation has given rise to the term "placebome," which refers to a group of genome-related mediators that affect an individual's response to placebo treatments. In this study, we conduct a network analysis of the placebome and identify a placebome module in the comprehensive human interactome using a seed-connector algorithm. The placebome module is significantly enriched with neurotransmitter signaling pathways and brain-specific proteins. We validate the placebome module using a large cohort of the Women's Genome Health Study (WGHS) trial and demonstrate that the placebome module is significantly enriched with genes whose SNPs modify the outcome in the placebo arm of the trial. To gain insights into placebo effects in different diseases and drug treatments, we use a network proximity measure to examine the closeness of the placebome module to different disease modules and drug target modules. The results demonstrate that the network proximity of the placebome module to disease modules in the interactome significantly correlates with the strength of the placebo effect in the corresponding diseases. The proximity of the placebome module to molecular pathways affected by certain drug classes indicates the existence of placebo-drug interactions. This study is helpful for understanding the molecular mechanisms mediating the placebo response, and sets the stage for minimizing its effects in clinical trials and for developing therapeutic strategies that intentionally engage it.

This paper provides an overview of premenstrual dysphoric disorder (PMDD) and its clinical relevance in differentiation to premenstrual syndrome (PMS). Regarding recent research on epidemiology, aetiology, symptoms and therapy, PMDD is a discrete disorder and has a good prognosis in cases of appropriate diagnosis and therapy. The information provided in this review will help to better integrate PMDD into the psychiatric diagnostic process; options for diagnosis and treatment are also presented., (© Georg Thieme Verlag KG Stuttgart · New York.)

In Germany, preventive detention can be imposed if a repeat offender shows a proclivity to commit further significant criminal acts. The courts require expert opinion to provide information about personality traits relevant for this disposition. However, currently, consensus about this topic is lacking. On the basis of a standardized examination, the relevance of Hare's concept of "psychopathy" for expert opinion is discussed in the context of preventive detention.

In the last decade, preventive detention-especially that relating to sexual offenders- has gained relevance for the German legal system. However, data are lacking concerning the inmates and the modus operandi of the psychiatric experts. Court orders and psychiatric statements of 114 offenders with orders of preventive detention were examined, 57 of whom were incarcerated because of sexual offences. Sexual offenders mostly show antisocial personality traits or even disorders, with a history of poly-trophic delinquency. In only four cases, the diagnosis of a sexual disorder was given. The analysis showed a high rate of psychiatric expert testimonies' lacking basic information, with incomplete assessment of sexual history. None of the experts used standardized prognostic instruments, meaning that most of the risk factors included in the Sexual Violence Risk-20 and the Static-99 were not considered. Further work needs to be done to improve the quality of psychiatric statements concerning sexual offenders.

Expert testimonies and judges of 224 lawsuits of the years 1991 to 2001, who lead to the order of Preventive Detention in the German federal states of Bavaria, Brandenburg, Northrhine Westfalia and Saxony were analysed. Offenders with the order of Preventive Detention have mostly committed violent and/or sexual offences. Nearly two third of the inmates show personality traits with relevance for psychiatry or even personality disorders. Thus the discrimination between forensic psychiatric measurements and preventive detention is difficult. The quality of forensic psychiatric reports does not reflect the complexity of this task. They show diagnostic and prognostic weaknesses.

Objective: To investigate the growth of children from pregnancies with gestational diabetes mellitus (GDM) and its association with antenatal maternal, fetal, and recent anthropometric parameters of mother and father., Research Design and Methods: In 324 pregnancies of Caucasian women with GDM, BMI before pregnancy, maternal glycemic values, and measurements of the fetal abdominal circumference were recorded. The weight and height of infants were measured at birth and at follow-up at 5.4 years (range 2.5-8.5). In addition, somatic data from routine examinations at 6, 12, and 24 months and the BMI of parents at follow-up were obtained. BMI standard deviation scores (SDSs) were calculated based on age-correspondent data., Results: At all time points, BMI was significantly above average (+0.82 SDS at birth; +0.56 at 6, +0.35 at 12, and +0.32 at 24 months; and +0.66 at follow-up; P < 0.001). BMI at birth was related to BMI at follow-up (r = 0.27, P < 0.001). The rate of overweight at follow-up was 37% in children with birth BMI > or =90th percentile and 25% in those with normal BMI at birth (P < 0.05). Abdominal circumference of third trimester and postprandial glucose values were related to BMI at follow-up (r = 0.22 and r = 0.18, P < 0.01). Recent maternal, paternal, and birth BMI were independent predictors of BMI at follow-up (r = 0.42, P < 0.001). Sixty-nine percent of children of parents with BMI > or =30 kg/m(2) were overweight at follow-up compared with 20% of those with parental BMI <30 kg/m(2) (P < 0.001)., Conclusions: Children of mothers with GDM have a high rate of overweight that is associated both with intrauterine growth and parental obesity.