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In this work, fragments identified by 19F-NMR are optimized into submicromolar binders of the MITF transcription factor. These results support direct targeting of bHLH-LZ DNA binding domains and provide a foundation for the development of new melanoma therapies.

Rare mutations in the high requirement temperature protein A1 (HTRA1) cause cerebral vasculopathy. Here, authors establish mechanistically distinct protein repair approaches to reverse the deleterious effects of pathogenic mutations interfering with the assembly and protease function of HTRA1.

Systemically administered modified siRNAs can be used in monkeys to achieve long-lasting silencing of a gene — previously, this had been established only in mice.

Epicardial engineered heart muscle allografts from induced pluripotent stem cell-derived cardiomyocytes can safely and effectively remuscularize chronically failing hearts in rhesus macaques, leading to improved cardiac function and paving the way for human clinical trials.

Diffraction-before-destruction of ultrashort X-ray pulses can visualize non-equilibrium processes at the nanoscale with sub-femtosecond precision. Here, the authors demonstrate how the brightness and the spatial resolution of such snapshots can be substantially increased despite ionization.

Nitroxoline is a bacteriostatic quinoline antibiotic, known to form complexes with metals, with few clinical applications. Here, Cacace et al. show that the compound displays a broad activity spectrum, with species-specific bactericidal activity, and acts as a metallophore inducing copper and zinc intoxication in bacterial cells.

Using well-calibrated statistical methods the authors jointly analyze Undiagnosed Diseases Network genomes, identifying known and novel disease genes. Software is publicly available to support future cross-cohort rare disease discovery efforts.

Hofer et al. show that fasting promotes the synthesis of spermidine, which stimulates eIF5A hypusination to induce autophagy and increase lifespan in various species in a conserved manner.

Climatic variables are useful but often weak predictors of plant functional trait variation across ecosystems. Here the authors investigate how assigning plant communities to a habitat hierarchy improves the explanatory power of climate-trait relationships at the continental scale.

Lateral opening of the LptDE transporter in the outer membrane of Gram-negative bacteria is necessary for insertion of lipopolysaccharides. Here, Botte et al. report a cryo-EM structure of a partially opened LptDE transporter, in complex with rigid chaperones derived from nanobodies.

Although ageing is the most important risk factor for chronic ailments, effective interventions remain rare. Here, the authors identify the flavonoid 4,4’-dimethoxychalcone and demonstrate that it extends lifespan and promotes health in multiple organisms by inducing autophagy.

Biotransformation of xenobiotics by gut microbiota can impact bioactivity and toxicity. A new study shows how hydrogen sulfide generated by gut microbes reduces azo compounds extracellularly and non-enzymatically.

A disturbed microbial network characterizes relapsing refractory Crohn’s disease and antedates disease recurrence after surgical removal of the active disease segment.

Glucocorticoids reprogram the mitochondrial metabolism of macrophages, resulting in increased and sustained production of the anti-inflammatory metabolite itaconate and, as a consequence, inhibition of the inflammatory response.

Coronary revascularization has a prominent role in the management of chronic, stable coronary artery disease, but decision-making guided by angiography alone for identifying haemodynamically relevant lesions can be challenging. The DEFER study now demonstrates favourable 15-year outcomes after deferral of revascularization in angiographically relevant, but functionally nonsignificant, coronary lesions.

KRAS is one of the most frequently mutated oncogenes and a major target in anticancer drug discovery, but small molecule modulators that work in the clinic have been elusive; here a new approach to target KRAS is described, based on interfering with its binding to the prenyl-binding protein PDEδ.

Genome-wide association studies (GWAS) have become a key tool to discover genetic markers for complex traits; however, environmental factors that interact with genes are rarely considered. Here, the authors conduct a GWAS of obesity traits, and find that smoking may alter genetic susceptibilities.

Iron coordination complexes can be used to gain insight on biologically relevant iron-oxygen compounds generated in iron metalloenzymes. Here, the authors characterise a μ-1,2-hydroperoxo Fe^IIIFe^III and a μ-1,2-peroxo Fe^IVFe^III, and study their reactivity in C-H activation.

Adult forms of inflammatory bowel disease (IBD) are of a polygenic nature, but paediatric and very early onset (VEO) IBD also occur as monogenic forms. Here, using whole exome sequencing, the authors explore both the monogenic and polygenic contribution to VEO-IBD and characterize a rare somatic mosaic VEO-IBD patient.

Myotonic dystrophy type 2 is characterized by large CCUG repeats in the CNBP gene that result in myopathy. Here, the authors show that recognition of aberrant protein translation derived from these repeats leads to ER stress and mitochondrial DNA release, leading to cGAS/STING activation and type-I IFN responses.

Schad et al. find that, during Pavlovian conditioning, model-free striatal reward prediction errors are present in a group of sign-tracking humans, while goal-tracking humans show learning signals from a model-based system instead.

The functional role of intestinal secretory IgA for host–microbiota interactions is investigated, showing that intestinal bacterial exposure leads to selection of diverse plasma cells that secrete antigen-specific IgA, which predominantly targets bacterial membranes.

Noise-induced hearing loss (NIHL) is a prevalent problem in the industrialized world. Now, Lukas Rüttiger and colleagues show that the phosphodiesterase inhibitor vardenafil can prevent NIHL in rats and mice.

Spermidine, a naturally occurring polyamine, extends the lifespan of mice and is cardioprotective in both aged mice and hypertensive rats. In humans, high dietary spermidine intake is associated with reduced blood pressure and a lower incidence of cardiovascular disease.

Although the precipitating mechanisms of atrial fibrillation are not fully understood, atrial fibrosis is thought to set the stage for arrhythmia. Volker Rudolph et al. now show that the enzyme myeloperoxidase, released by inflammatory cells, is a key inducer of atrial fibrosis and arrhythmia in a mouse model of atrial fibrillation, and that myeloperoxidase levels are associated with atrial fibrillation in humans.

cAMP is a second messenger that acts in distinct intracellular locations regulating diverse cellular functions. Here the authors design a FRET-based cAMP biosensor and use it to measure in vivodynamics of cAMP concentration changes in the sarcoplasmatic reticulum of mouse cardiomyocytes in health and disease.

The eukaryotic ribosome-associated complex (RAC) chaperone is poorly understood. Structural analyses now provide insight into the catalytic inactivity and possible functions of the Ssz1 subunit and reveal that RAC interacts with the ribosome via the Zuo1 subunit. RAC crouches over the ribosomal exit tunnel, where its conformation may be controlled by the ribosomal expansion segment ES27.

A global grassland study reveals soil moisture, not local treatments, drives microbial and detritivore activity, highlighting the potential influence of climate change and human interventions on grassland ecosystems.

CD98hc in macrophages attenuates the severity of colitis. This change in the macrophage development is associated with increased expression of apoptotic genes, suggesting that CD98hc maintains the gut homeostasis by ensuring the development of gut macrophages.

Magnetic resonance imaging of hyperpolarized contrast agents has enabled unprecedented imaging capabilities in a biomedical setting, but its widespread application is hindered by the time and costs associated with preparing hyperpolarized carbon-13 samples. Here, the authors demonstrate virtually-continuous production of batches of highly-hyperpolarized carbon-13 contrast agents every 15 s within an MRI system without a stand-alone polarizer.