Here we present a program aimed at free-energy calculations in molecular systems. It consists of a series of routines that can be interfaced with the most popular classical molecular dynamics (MD) codes through a simple patching procedure. This leaves the possibility for the user to exploit many different MD engines depending on the system simulated and on the computational resources available. Free-energy calculations can be performed as a function of many collective variables, with a particular focus on biological problems, and using state-of-the-art methods such as metadynamics, umbrella sampling and Jarzynski-equation based steered MD. The present software, written in ANSI-C language, can be easily interfaced with both fortran and C/C++ codes.

The PLUMED consortium (2019). Promoting transparency and reproducibility in enhanced molecular simulations. Nature Methods, 16(8), 670-673. https://doi.

Aims To explore the usefulness of data derived from observational studies on adverse drug reactions (ADRs) in de®ning and preventing the risk of pharmacological interventions in children in different health care settings. Methods A systematic review of studies on ADRs in hospitalized children, in outpatient children, and on ADRs causing paediatric hospital admissions was performed. Studies were identi®ed through a search of the MEDLINE and EMBASE databases. The inclusion criteria required that the population was not selected for particular conditions or drug exposure and prospective monitoring was used for identifying ADRs. Data were analysed by a random-effects model. Results Seventeen prospective studies were included. In hospitalized children, the overall incidence of ADRs was 9.53% (95% con®dence interval [CI], 6.81,12.26); severe reactions accounted for 12.29% (95%CI, 8.43,16.17) of the total. The overall rate of paediatric hospital admissions due to ADRs was 2.09% (95%CI, 1.02,3.77); 39.3% (95%CI, 30.7,47.9) of the ADRs causing hospital admissions were life threatening reactions. For outpatient children the overall incidence of ADRs was 1.46% (95%CI, 0.7,3.03).Conclusions The results show that ADRs in children are a signi®cant public health issue. The completeness and accuracy of prescription reporting as well as clinical information from studies was a rarity, making it dif®cult for health practitioners to implement evidence based preventive strategies. Further, methodologically sound drug surveillance studies are necessary for an effective promotion of a safer use of drugs in children.

SUMMARY G protein-coupled receptors form hetero-dimers and higher order hetero-oligomers, yet the significance of receptor heteromerization in cellular and behavioral responses is poorly understood. Atypical antipsychotic drugs, such as clozapine and risperidone all have in common a high affinity for the serotonin 5-HT2A receptor (2AR). However, closely related nonantipsychotic drugs, such as ritanserin and methysergide, while blocking 2AR function, lack comparable neuropsychological effects. Why some but not all drugs that inhibit 2AR-dependent signaling exhibit antipsychotic properties remains unresolved. We found that a heteromeric complex formed between the metabotropic glutamate 2 receptor (mGluR2) and the 2AR critically integrates the action of drugs affecting signaling and behavioral outcomes. Acting through the mGluR2/2AR heterocomplex, both glutamatergic and serotonergic drugs achieve a balance between Gi- and Gq-dependent signaling that predicts their psychoactive behavioral effects. These observations provide a novel mechanistic insight into antipsychotic action that may advance therapeutic strategies for schizophrenia.

The platelet integrin ␣ IIb ␤ 3 is essential for hemostasis and thrombosis through its binding of adhesive plasma proteins. We have determined crystal structures of the