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The scales of Arapaima gigas, a fresh water fish found in the Amazon Basin, act as effective armour against predators. Here, Zimmermann et al. elucidate the deformation mechanisms that allow for this resistance, concluding that lamellae in the scales reorient under an applied load, preventing fracture.

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.

In this work, Beyer and colleagues have utilized display screening technologies to comprehensively chart RAS proteins “druggability” and in doing so unravel a targetable ligand-induced pocket in RAS opening unprecedented anti-RAS targeted opportunities.

MetaGraph enables scalable indexing of large sets of DNA, RNA or protein sequences using annotated de Bruijn graphs.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

Pathology-oriented multiplexing (PathoPlex) represents a framework for widespread access to multiplexed imaging and computational image analysis of clinical specimens at a relatively high throughput and subcellular resolution.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

HistoPlexer, a deep learning model, generates multiplexed protein expression maps from H&E images, capturing tumour–immune cell interactions. It outperforms baselines, enhances immune subtyping and survival prediction and offers a cost-effective tool for precision oncology.

An analysis of 2,173 individuals from the MetaCardis cohort quantifies the individual and combinatorial effects of a range of drugs on host health, metabolome and gut microbiome in cardiometabolic disease.

In the Tumor Profiler proof-of-concept observational study, a multiomics approach for profiling tumors from patients with melanoma was feasible, returning data within 4 weeks and informing treatment recommendations in 75% of cases.

Alternative stable states in forests have implications for the biosphere. Here, the authors combine forest biodiversity observations and simulations revealing that leaf types across temperate regions of the NH follow a bimodal distribution suggesting signatures of alternative forest states.

Ecosystem responses to prehistoric sea-ice loss are poorly known. Using marine sedimentary ancient DNA form the Bering Sea covering the last ~20,000 years, this study reveals a transition from a sea ice-adapted ecosystem, characterized by diatoms, copepods and codfish, to an ice-free Holocene with cyanobacteria, salmon and herring.

Predicting disease progression is an important medical problem, but it can be challenging for end-to-end machine learning approaches. Han and colleagues demonstrate that generative models can work together with medical experts to jointly predict the progression of a disease, osteoarthritis.

By studying individuals along a spectrum of cardiometabolic disease and adjusting for effects of lifestyle and medication, this investigation identifies alterations of the metabolome and microbiome from dysmetabolic conditions, such as obesity and type 2 diabetes, to ischemic heart disease.

Measurements on a chiral magnet show that non-symmorphic symmetries enforce topological crossings exactly at the Fermi level in certain materials; these crossings can be controlled by an applied magnetic field.

Jean-Pierre Bourquin, Martin Stanulla and colleagues report whole genome, whole exome and transcriptome sequencing of TCF3-HLF fusion–positive acute lymphoblastic leukemia. Drug response profiling in patient-derived xenografts identified sensitivity to the BCL2-specific inhibitor ABT-199 (venetoclax) as a new option for treating this fatal disease.

The mycobacterial ABC transporter IrtAB functions as a siderophore importer despite exhibiting an exporter fold in its structure, and contains a siderophore interaction domain capable of siderophore reduction and iron release inside the cell.

European forests are threatened by climate change with impacts on the distribution of tree species. Previous discussions on the consequences of biome shifts have concentrated only on ecological issues; however, research now shows that under forecasted changes in temperature and precipitation there could be a decline of economically valuable species, which would lead to a loss in the value of European forest land.

Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease with a complex underlying genetic etiology. Here, the authors identify a series of rare variants in DSP and PPL in multiplex families with EoE and uncover a pathogenic role for desmosomal dysfunction in EoE.

The molecular mechanisms underlying drug resistance in relapsed or refractory (rr) acute myeloid leukemia (AML) remain to be explored. Here, the use of bulk and single cell multi-omics and ex vivo drug profiling for 21 rrAML patients reveals mechanisms of resistance to the Bcl-2 inhibitor venetoclax and treatment vulnerabilities.

HRO761 is a potent, selective, allosteric WRN inhibitor that binds at the interface of the D1 and D2 helicase domains, locking WRN in an inactive conformation.

A machine-learning algorithm based on an array of demographic, physiological and clinical information is able to predict, hours in advance, circulatory failure of patients in the intensive-care unit.

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

Diffraction imaging studies of free individual nanoparticles have so far been restricted to XUV and X-ray free - electron laser facilities. Here the authors demonstrate the possibility of using table-top XUV laser sources to image prolate shapes of superfluid helium droplets.

Increased metabolic activity promotes HIV-1 infection in CD4 T lymphocytes, but the contribution of different metabolic pathways is unclear. Here the authors show that carbon entry into the citric acid cycle is required to support the early stages of HIV-1 infection.

Long-read single-cell RNA sequencing is capable of detecting isoform-level gene expression and genomic alterations such as mutations and gene fusions, thereby providing cell-specific genotype-phenotype information. Here, the authors use long-read scRNA-seq on metastatic ovarian cancer samples and detect cell-type specific isoforms and gene fusions that may otherwise be misclassified in short-read data.

Defects in non-canonical Wnt/planar cell polarity signalling have recently been linked to breast cancer aggressiveness. Puvirajesinghe et al. identify VANGL2, p62/SQSTM1 and JNK as important players in this pathway which may be amenable to therapeutic intervention in breast cancer.

Femtosecond crystallography with an X-ray free-electron laser is used to analyse micrometre-sized protein crystals, generating a high-resolution structure of the protein without previous knowledge of what it looks like.

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.

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.

Data from millions of trees in thousands of locations are used to show that certain key traits affect competitive ability in predictable ways, and that there are trade-offs between traits that favour growth with and without competition.

Complex clinical samples can be imaged with 25 nm resolution using a light-emitting-diode-based wide-field microscope.