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A potent and selective inhibitor of KRAS^G12D, the most common mutant form of the KRAS oncoprotein, has anti-tumor efficacy in multiple pre-clinical cancer models, opening the possibility to therapeutically target this highly prevalent oncogenic driver.

Exome-wide analysis identifies rare and low-frequency coding variants associated with body mass index. Gene-based meta-analysis and functional studies implicate 13 genes, eight of which are novel, and neuronal pathways as factors in human obesity.

Data from over 700,000 individuals reveal the identity of 83 sequence variants that affect human height, implicating new candidate genes and pathways as being involved in growth.

The inability of the heart to efficiently relax as it beats, termed diastolic dysfunction, is a major underlying cause of heart disease. As a new strategy for treating diastolic dysfunction, Joseph Metzger and his colleagues engineered directed substitutions in the calcium-binding protein Parvalbumin to optimize its ability to promote cardiac myocyte relaxation. Gene transfer of this Parvalbumin variant promoted cardiac myocyte relaxation of rabbit and canine heart failure models in vitro and corrected heart function in two in vivo mouse models of diastolic dysfunction.

Dark streaks that appear on the surface of Mars during warm seasons have been observed at the mid-latitudes and tentatively attributed to the flow of briny water. Imagery from the Mars Reconnaissance Orbiter over multiple Mars years suggests that these seasonally active features are also present in equatorial regions, where liquid surface water is not expected.

Patricia Munroe, Joanna Howson and colleagues genotype ∼350,000 individuals and identify 30 new blood pressure– or hypertension-associated risk loci. Their analyses provide insights into the pathophysiology of hypertension and highlight new potential targets for clinical intervention.

Genome-wide association meta-analysis of AAA identifies 121 independent risk loci and highlights potential therapeutic targets such as proprotein convertase, subtilisin/kexin-type 9 (PCSK9).

A genome-wide-association meta-analysis of 18,381 austim spectrum disorder (ASD) cases and 27,969 controls identifies five risk loci. The authors find quantitative and qualitative polygenic heterogeneity across ASD subtypes.

Analysis of plastic debris found in surface waters shows that lakes and reservoirs in densely populated and urbanized regions, as well as those with elevated deposition areas, are particularly vulnerable to plastic contamination.

Sequencing data from two large-scale studies show that most of the genetic variation influencing the risk of type 2 diabetes involves common alleles and is found in regions previously identified by genome-wide association studies, clarifying the genetic architecture of this disease.

Observations from the Lucy spacecraft of the small main-belt asteroid (152830) Dinkinesh reveals unexpected complexity, with a longitudinal trough and equatorial ridge, as well as the discovery of the first contact binary satellite.

Integration of GWAS and single-cell transcriptomic data from the entire nervous system systematically identifies cell types underlying brain complex traits and provides insights into the etiology of Parkinson’s disease.

Oligonucleotides targeting mRNA are promising therapeutic agents but suffer from poor bioavailability. Here, the authors develop reduced-charge oligonucleotides with artificial LNA-amide linkages with improved cell uptake and minimal structural deviation to the DNA:RNA duplex.

CRISPR/Cas9-mediated forward genetic screens and gene-trap mutagenesis screens in haploid cells are both powerful techniques to examine gene function. Here, the authors show the two approaches have high concordance and identify an uncharacterized gene, TXNDC11, which is involved in endoplasmic reticulum-associated degradation.

In maize, a comprehensive set of approaches enabled the authors to analyse the biosynthetic pathway of the zealexin group of terpenoids and characterize the role of these antibiotic compounds in disease resistance.

Multiple molecular profiling methods are required to study urothelial non-muscle-invasive bladder cancer (NMIBC) due to its heterogeneity. Here the authors integrate multi-omics data of 834 NMIBC patients, identifying a molecular subgroup associated with multiple alterations and worse outcomes.

The mechanisms underlying the activity of non-receptor tyrosine kinase, TNK1, in cancers are unclear. Here the authors show that MARK mediates 14-3-3 and TNK1 interaction which restrains TNK1 activity, while the release of TNK1 from 14-3-3 leads to TNK1 activation through its interaction with ubiquitin and thus results in TNK1-mediated tumor growth in vivo

Contrary to the view that urbanization is a major driver of the global rise in obesity, the global increase in body-mass index is shown to be mostly due to increases in the body-mass indexes of rural populations.

The mouse neocortex supports sensory performance through transient increases in sensory coding redundancy, neural codes that are robust to cellular variability, and inter-area fluctuation modes that transmit sensory data and task responses in non-interfering channels.

Environmental influences during prenatal development may have implications for health and disease later in life. Here, Czamara et al. assess DNA methylation in cord blood from new-born under various models including environmental and genetic effects individually and their additive or interaction effects.

Pulmonary function is influenced by environmental factors, lifestyle, and genetics. Here, in a multiethnic GWAS meta-analysis for pulmonary function traits, the authors identify over 50 additional genetic loci, a subset of which are specific for European, African, Asian, or Hispanic/Latino ancestry.

Genome-wide association studies have only revealed a handful of genetic loci for longevity. Here, in a case–control design based on phenotype definitions of individuals surviving at or beyond the age corresponding to the 90th and 99th survival percentile, the authors report two additional loci located in the APOE locus and near GPR78.

Depression is correlated with many brain-related traits. Here, Shen et al. perform phenome-wide association studies of a depression polygenic risk score (PRS) and find associations with 51 behavioural and 26 neuroimaging traits which are further followed up on using Mendelian randomization and mediation analyses.

Photoinduced non-adiabatic intramolecular processes have important applications but their mechanisms are challenging to explore. Here the authors detect and assign vibrational wavepacket dynamics in a Fe carbene complex by ultrafast X-ray emission spectroscopy and X-ray scattering, resolving nuclear and electronic motion.

β-tryptases are responsible for most of the proteolytic activity during mast cell activation. Here, the authors develop β-tryptase-inhibiting antibodies and provide structural and biochemical evidence that the bivalency of the antibodies is a prerequisite for their inhibitory activity.

Exome-wide genetic analysis on >300,000 individuals identifies associations with plasma lipid traits. Loci significantly associated with cholesterol and triglycerides are examined together to determine the effects of alleles on type 2 diabetes and coronary artery disease risk.