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Here the authors combine a deep generative model with structure-based drug design and prospectively validate functionally active, nanomolar, A_2A adenosine receptor ligands and solve their crystal structures to close the Artificial Intelligence Structure-Based Drug Design loop.

Atmospheric methane-oxidizing bacteria constitute the sole biological sink for atmospheric methane. Here, Schmider et al. assess the ability and strategies of seven methanotrophic species to grow with air as sole energy, carbon, and nitrogen source, showing that these bacteria can grow on the trace concentrations of methane, carbon monoxide, and hydrogen present in air.

In magnetoelectric materials, the magnetization can be controlled by the application of an electric field, making it comparatively easy to switch magnetization, which is attractive for data storage and other proposed devices. Unfortunately, the effect in single-phase materials is typically fairly weak. Here Fogh et al. demonstrate a two orders of magnitude enhancement of the magnetoelectric coupling in LiNi_0.8Fe_0.2PO₄ compared to the parent compounds.

The SCOOP signalling peptide family expands to 50 members, whose activities are strictly dependent upon the receptor kinase MIK2. Two subtilase classes process PROSCOOPs, generating bioactive SCOOP peptides. A subtilase mutant phenocopies the mik2 receptor mutant.

The precise relationship between neurobehavioural effects and neurotransmitter effects of psychiatric drugs are not always understood. Here the authors develop a database documenting the neurotransmitter response in rats to 258 different neuropsychiatric drugs, and conclude that this neurotransmitter response does not, in general, reflect the current categorisation of those drugs.

Breakdown of vascular barriers is a major complication of inflammatory diseases. However, the mechanisms underlying platelet recruitment to inflammatory micro-environments remains unclear. Here, the authors identify haptotaxis as a key effector function of immune-responsive platelets

Analyses of genomes from 914 children, adolescents, and young adults provide a comprehensive resource of genomic alterations across a spectrum of common childhood cancers.

A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.

Single Nucleotide Polymorphisms (SNPs) affect cellular regulatory networks, and SNP co-occurrences contribute to disease pathogenesis in ulcerative colitis (UC). Here the authors introduce iSNP, a precision medicine pipeline that combines genomics and network biology approaches to uncover patient specific pathways affected in complex diseases.

The subset of chronic lymphocytic leukemia (CLL) expressing the IGLV3- 21R110 BCR light chain often shows an aggressive clinical course. Here the authors report the development and characterization of IGLV3-21R110- targeted CAR T cells, showing selective targeting and eradication of IGLV3- 21R110 expressing CLL cells.

Medulloblastoma is the most common brain tumour in children; using whole-genome sequencing of tumour samples the authors show that the clinically challenging Group 3 and 4 tumours can be tetraploid, and reveal the expression of the first medulloblastoma fusion genes identified.

Future groundwater levels in Germany are expected to decrease considerably under the influence of changing climate, exacerbating the trends and patterns already occurring. Simulations also show substantially reduced effects under stringent mitigation scenarios.

Working memory requires the brain to switch between cognitive states and activity patterns. Here, the authors show that the steering of these neural network dynamics is influenced by dopamine D1- and D2-receptor function and altered in schizophrenia.

The order of DNA methylation and histone modifications during transcription remained unclear. Here the authors show that HMGA2 induces DNA nicks at TGFB1-responsive genes, promoting nucleosome incorporation containing γ-H2AX, which is required for repair-mediated DNA demethylation and transcription.

Idiopathic pulmonary fibrosis (IPF) is a lethal disease with insufficient treatment strategies. Here the authors show that reduction of the microRNA MIRLET7D and hyperactivation of EP300 contribute to impaired epigenetic silencing by the MiCEE complex in pulmonary fibroblasts of IPF patients, and demonstrate the benefit of inhibiting EP300 for the treatment of IPF.

Resistance to first line treatment is a major hurdle in cancer treatment, that can be overcome with drug combinations. Here, the authors provide a large drug combination screen across cancer cell lines to benchmark crowdsourced methods and to computationally predict drug synergies.

This Review synthesizes the literature from over 10 years of Cell Painting for image-based profiling and highlights how advances in this technology enable new biological discovery of cellular phenotypes and cell responses to perturbations.

Stefan Pfister and the ICGC PedBrain Tumor Project report whole-genome sequencing of 96 pilocytic astrocytomas. They identify recurrent activating mutations in FGFR1 and PTPN11 and novel NTRK2 fusion genes.

Whole-genome sequencing identified recurrent fusions involving the MET oncogene, and MET inhibitors suppressed tumor growth in mouse models and in a human patient.

Here, the authors summarize the current state of multi-parameter profiling technologies and how phenotypic profiling of small molecules provides important insights into their mechanisms of action, as well as a systems level understanding of biological pathways and their responses to drug treatments.

The Innovative Medicines Initiative Consortium RESOLUTE has started to develop tools and produce data sets to de-orphanize transporters in the solute carrier protein (SLC) superfamily, thereby lowering the barrier for the scientific community to explore SLCs as an attractive drug target class.

Structure-based docking screens of compound libraries are common in early drug and probe discovery. This protocol outlines best practices and control calculations to evaluate docking parameters prior to undertaking a large-scale prospective screen.

This Perspective reviews tools developed over the past five years in the macromolecular modeling, docking and design software Rosetta.

The development of a nanoparticle RNA vaccine is reported that preferentially targets dendritic cells after systemic administration, and is shown to provide durable interferon-α-dependent antigen-specific immunity in mouse tumour models; initial results in advanced melanoma patients indicate potential efficacy in humans.

Studies employing machine-learning (ML) tools in the chemical sciences often report their evaluations in a heterogeneous way. The evaluation guidelines provided in this Perspective should enable more rigorous ML reporting.

Animal studies have shown that oxytocin (OXT) and arginine vasopressin (AVP) are crucial regulators of social behaviour. In this Review, Meyer-Lindenberg and colleagues consider behavioural, genetic and neuroimaging studies that show that these peptides also influence social behaviour and cognition in humans, and suggest that the OXT and AVP systems could be targets for the treatment of mental disorders characterized by social dysfunction.

A community of researchers report the lessons learned from applying 44 algorithms to predict drug sensitivity in cancer cell lines using genomic, epigenetic and proteomic datasets

A community computational challenge generates algorithms to predict activity of drug combinations.

Cell Painting, gene expression, and chemical structural data are used to examine the differences between mitochondrial toxicants and non-toxicants and enhance the detection of mitotoxic compounds for future drug discovery.

Sachs et al. examine the effects of different ex vivo anticoagulants on the biomechanical and functional properties of single platelets using high-throughput real-time fluorescence and deformability cytometry (RT-FDC). Their results demonstrate that the choice of ex vivo anticoagulant may strongly impact the outcomes of mechanophenotyping.