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Analyses of genome and exome sequencing data identify rare coding and structural variants associated with atrial fibrillation and highlight genetic links between atrial fibrillation and cardiomyopathies.

Genome-wide analyses identify variants associated with sinus node dysfunction, distal conduction disease and pacemaker implantation, implicating ion channel function, cardiac developmental programs and sarcomeric structure in bradyarrhythmia susceptibility.

In response to water shortage, plants produce abscisic acid (ABA), which improves water consumption and stress tolerance; now, a strategy for controlling water use by activating engineered ABA receptors using an existing agrochemical, mandipropamid, is described.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Using data from a single time point, passenger-approximated clonal expansion rate (PACER) estimates the fitness of common driver mutations that lead to clonal haematopoiesis and identifies TCL1A activation as a mediator of clonal expansion.

Genome-wide association meta-analyses identify more than 350 loci associated with atrial fibrillation. A polygenic score derived from these results improves atrial fibrillation risk prediction compared to published clinical and polygenic scores.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

Federated ML (FL) provides an alternative to train accurate and generalizable ML models, by only sharing numerical model updates. Here, the authors present the largest FL study to-date to generate an automatic tumor boundary detector for glioblastoma.

Park et al. redesigned the abscisic acid-induced dimerization module to respond to diverse ligands and function orthogonally to the natural modules, enabling synthetic biological circuit design in plants and yeast.

Abscisic acid (ABA) dynamically balances plant water use and availability. It is synthesized during water deficit and quickly catabolized into breakdown products previously thought to be largely inactive. New work demonstrates that phaseic acid, a major ABA catabolite, is a weak ABA receptor agonist with its own auxiliary role in water relations.

A genome-wide association study of critically ill patients with COVID-19 identifies genetic signals that relate to important host antiviral defence mechanisms and mediators of inflammatory organ damage that may be targeted by repurposing drug treatments.

The synthetic ABA agonist pyrabactin helped identify the PYR/PYL family of ABA receptors. Now the selectivity of pyrabactin toward specific members of this family is explained using genetic, chemical and structural approaches. Subtle differences in the binding pockets of the receptors lead to productive or nonproductive conformations upon pyrabactin binding.

Biosensors are developed from malleable hormone receptors.

Whole-genome sequencing analysis of individuals with primary immunodeficiency identifies new candidate disease-associated genes and shows how the interplay between genetic variants can explain the variable penetrance and complexity of the disease.

Whole-genome sequencing and phenotype data sharing are introduced in a national health system to streamline diagnosis and to discover coding and non-coding variants that cause rare diseases.

Caenorhabditis elegans has the potential to be used to discover new, biologically active small molecules in a high-throughput fashion and also to identify the protein targets of those small molecules.

A metabolically bioactivated selective imidazothiazole nematicide shows comparable effectiveness at controlling plant root infection by Meloidogyne incognita to commercial nematicides, which are traditionally nonselective and toxic.

The Impact of Genomic Variation on Function Consortium is combining single-cell mapping, genomic perturbations and predictive modelling to investigate relationships between human genomic variation, genome function and phenotypes and will provide an open resource to the community.

The plant hormone abscisic acid (ABA) has, among other things, a central role in coordinating the adaptive response in situations of decreased water availability. A family of intracellular ABA receptors, named PYR/PYL/RCAR, has recently been identified. Here, the crystal structure of Arabidopsis thaliana PYR1, which consists of a dimer in which one of the subunits is bound to ABA, is presented.

ABACUS2 Förster resonance energy transfer biosensors allow an unparalleled view of abscisic acid accumulations and depletions in living plants. Well-watered roots accumulate abscisic acid in growing cells upon shoot dehydration and this is essential to maintain root growth under low humidity.

Whole-exome sequencing in a large autism study identifies over 100 autosomal genes that are likely to affect risk for the disorder; these genes, which show unusual evolutionary constraint against mutations, carry de novo loss-of-function mutations in over 5% of autistic subjects and many function in synaptic, transcriptional and chromatin-remodelling pathways.

Systematic phenotyping of 58,101 mutants of the model eukaryotic alga Chlamydomonas reinhardtii under 121 environmental and chemical stress conditions provides a large resource for characterizing gene function.

Screening for new anthelmintic compounds that are active against parasitic nematodes is costly and labour intensive. Here, the authors use the non-parasitic nematode Caenorhabditis elegansto identify 30 anthelmintic lead compounds in an effective and cost-efficient manner.

Abscisic acid (ABA), a small-molecule hormone that regulates stress responses in plants, initiates signaling by nucleating ABA receptor–PP2C interactions. A structure-guided approach has produced a class of 3′-S-alkylated ABA derivatives that prevent PP2C binding to ABA receptors by blocking a solvent-exposed channel.

The fourteen members of the PYR/PYL family are receptors for the plant hormone abscisic acid (ABA). Now structural and functional work using the synthetic ligand pyrabactin, which inhibits seed germination, reveal that the PYL/PYR receptors respond differently to pyrabactin, elucidate the mechanisms for selective activation or inhibition of ABA receptors and allow the design of novel agonists.

The plant hormone abscisic acid (ABA) is a regulator of plant growth, development and responses to environmental stresses. Recently, the PYR/PYL/RCAR family of START proteins was found to bind ABA and mediate inactivation of downstream effectors. The crystal structures of apo and ABA-bound receptors as well as a ternary PYL2–ABA–PP2C complex is now reported and analysed, revealing a gate–latch–lock mechanism underlying ABA signalling.

Chemical screening in C. elegans is limited by the relatively poor target accessibility of small molecules. A systematic survey of drug-like small molecule accumulation and metabolism in C. elegans was used to create a computational tool for preselecting compounds likely to effectively perturb worms.

Vaccination is effective in protecting from COVID-19. Here the authors report immune responses and breakthrough infections in twice-vaccinated patients receiving anti-TNF treatments for inflammatory bowel disease, and find dampened vaccine responses that implicate the need of adapted vaccination schedules for these patients.

In polyploid wheat, overexpression of abscisic acid receptor pyrabactin resistance 1-like 4 increases water-use efficiency just like in model plants, confirming the biotechnological potential of this strategy in crops.

The plant hormone abscisic acid (ABA) is a regulator of plant growth, development and responses to environmental stresses. Although several proteins have been reported to function as ABA receptors and many more are known to be involved in ABA signalling, the identities of ABA receptors remain controversial and the mechanism of signalling unclear. ABA-mediated signalling is now reconstituted in vitro, defining a minimal set of core components of the pathway.

A C. elegans-based screening approach identifies nementin as a nematode-selective nematicide that can be used synergistically with acetylcholinesterase inhibitors

At the recent Artificial Intelligence Applications in Biopharma Summit in Boston, USA, a panel of scientists from industry who work at the interface of machine learning and pharma discussed the diverging opinions on the past, present and future role of AI for ADME/Tox in drug discovery and development.