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Stratified medicine promises to tailor treatment for individual patients, however it remains a major challenge to leverage genetic risk data to aid patient stratification. Here the authors introduce an approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue-specific gene expression levels, and highlight its ability to identify biologically meaningful and clinically actionable patient subgroups, supporting the notion of different patient ‘biotypes’ characterized by partially distinct disease mechanisms.

The authors reveal an inherent trade-off between logarithmic average phonon frequency and the electron-phonon coupling constant in conventional BCS superconductors. The analysis suggests that achieving room-temperature conventional superconductivity at ambient pressure is extremely unlikely.

Zeiser and colleagues show that CAR T cell therapy results in upregulation of the TGFβ-activated kinase-1 (TAK1)–NF-κB–p38 MAPK pathway in microglia, causing neurocognitive defects, and find that TAK1 inhibition can reduce immune effector cell-associated neurotoxicity syndrome.

Intramolecular proton relays are proposed to enhance oxygen evolution for heterogeneous (hydro)oxide electrocatalysts, but molecular-level evidence remains limited. Now it has been shown, using an aza-fused microporous polymer with Ni–Fe sites, that adjacent Ni³⁺–OH sites relay protons from Fe⁴⁺=O, accelerating the water nucleophilic attack pathway and achieving high turnover frequencies with pH-tunable kinetics.

Gene correction in hematopoietic stem cells could be a powerful way to treat monogenic diseases of the blood and immune system. Here the authors develop a strategy using CRISPR-Cas9 and an aAdeno-Associated vVirus(AAV)-delivered IL2RG cDNA to correct X-linked sSevere Ccombined iImmunodeficiency (SCID-X1) with a high success rate.

Smale and colleagues explore evolutionary divergence in the NF-κB family. They show that intrinsic DNA-binding affinity rather than specificity led to neofunctionalization in mammals within this transcription factor family, supporting immunoregulatory rewiring in mammalian species.

Carbohydrate esterases alter polysaccharides by removing ester groups. Here, the authors resolved crystal structures of two CE20 enzymes and discovered a novel, water-mediated catalytic triad essential for activity, offering insights into enzyme function and mechanism.

This study reveals that females with isolated REM sleep behavior disorder show less neurodegeneration than males. The least affected regions in females are regions that overexpress estrogen-related genes, suggesting potential sex-specific neuroprotection.

NV center-based quantum sensors integrated into diamond anvil cells have enabled magnetic imaging under high pressure but are less suited for studying magnetic van der Waals materials. Here, the authors demonstrate magnetic imaging of micrometer-sized flakes of 1T-CrTe2 under high pressure using spin-centers in a thin hBN layer.

The brain can often continue to function despite lesions in many areas, but damage to particular locations may have serious effects. Here, the authors use the concept of Ollivier-Ricci curvature to investigate the robustness of brain networks.

The authors present an approach to collect and process solution NMR spectra based on steady-state free-precession acquisitions, which can provide higher sensitivity for small organic molecules than currently used Fourier-based counterparts.

CSF total tau (t-tau), often used as a marker of neuronal damage, is more strongly linked to synaptic degeneration. Here, the authors show that t-tau better reflects synaptic dysfunction than axonal or neuronal loss in Alzheimer’s disease.

Membrane-free complex coacervate microdroplets are compelling models for primitive compartmentalization, but it is unclear how molecular co-operativity influences physicochemical properties and activity of membrane-free compartments. Here, the authors use RNA/peptide coacervates as a model to reveal the relationship between coacervate properties and ribozyme activity.

The small heat-shock protein HSP27 occurs predominantly in oligomeric forms, which makes its structural characterisation challenging. Here the authors employ CPMG and high-pressure NMR with native mass spectrometry and biophysical assays to show that the active monomeric form of HSP27 is substantially disordered and highly chaperone-active.

Comparing single-cell RNA-seq and ATAC-seq data from multiple batches is challenging due to technical artifacts. Here, the authors propose a method that disentangles technical and biological effects, facilitating batch-confounded chromatin and gene expression state discovery and enhancing the analysis of perturbation effects on cell populations.

Many next-generation antibody therapeutics have enhanced potency but the risk of adverse events. Here the authors develop a conditionally activated, single-module CAR.

This study shows that neural representations of shape stimuli in human visual cortex are adaptively modulated when participants switch between different variants of a categorization task, becoming more separable across relevant decision boundaries.

Cells use clathrin-mediated endocytosis to internalize biomolecular cargo. The authors demonstrate that the Epsin1 protein ensures uptake of ubiquitylated cargo through ubiquitin-dependent regulation of the stability of endocytic protein networks.

The management of ulcerative colitis (UC) remains challenging due to the complexity of its etiology. Here, the authors establish that argininosuccinate synthetase 1 (ASS1) and its metabolite arginine are pivotal inducers of UC, through the triggering of mTOR and iNOS activation, and the induction of gut microbiota dysbiosis by metabolomics and proteomics. Inhibition of ASS1 by C-01 provides a viable strategy for the treatment of UC.

Zangari et al. show that d-cysteine targets NFS1, thus affecting Fe–S cluster biogenesis and impairing tumour growth.

Using the most recent Spatial Production Allocation Model 2020 crop data, agricultural green and blue water consumption is estimated. Water use increased by up to four-fifths for major crops in the past two decades.

Deltex E3s modify ADP-ribosylated targets with ubiquitin, creating a hybrid modification whose readers remains unknown. Here, the authors synthesise a non-hydrolysable probe that mimics the modification and identify RNF114 as an interactor. RNF114 binds tightly to this modification and further elongates it with a K11-linked ubiquitin chain.

BamA carries out the essential process of folding outer membrane β-barrels in Gram-negative bacteria and is a potential antibiotic target. Here, the authors discover macrocyclic peptide inhibitors that trap BamA in distinct structural conformations.

Structural, biochemical and cellular analyses show that bacterial antigens can mimic gliadin epitopes involved in celiac disease being presented by HLA-DQ2.5 and recognized by T cells derived from patients.

Replicative sliding clamp loading is critical for DNA replication and repair. Here, authors report structures of major clamp loading intermediates in a bacterial system, revealing how the clamp is opened and loaded onto DNA.

Xenotransplantation in humans using pig organs could improve the transplant organ supply. Here the authors transplant pig kidneys into a brain-dead recipient and monitor the human immune cell response early after transplantation using spatial and single cell transcriptomics and show early myeloid cell infiltration.

Proteins smaller than about 50 kDa are currently too small to be imaged at high resolution by cryo‐electron microscopy (cryo‐EM). Here authors design a protein scaffold that binds 12 copies of a small 26 kDa protein (GFP), which allowed visualizing GFP at a resolution of 3.8Å by cryo‐EM.

Cellular senescence drives aging, with the p53–FOXO4 axis sustaining senescent cell viability. This study reveals structural insights into p53 binding to FOXO4/FOXO4-DRI, informing the development of p53-targeted senolytics for age related diseases.

Chapman, Klaourakis and colleagues reveal that a lymphatic vasculature with poor clearance capacity in perinatal, regeneration-competent mouse hearts is required to retain pro-reparative macrophages and allow cardiac regeneration.

tRNA modifications are vital for their function in protein synthesis, one of the most central processes in all living cells. Here the authors show how KEOPS, a multi-subunit tRNA modifying complex, engages and acts on a substrate tRNA.

Percolation is a tool used to investigate a network’s response as random links are removed. Here the author presents a generic analytic theory to describe how percolation properties are affected in coloured networks, where the colour can represent a network feature such as multiplexity or the belonging to a community.

Certain specific antigens have been shown to activate T cells in an MHC independent manner. Here the authors show a phycoerythrin reactive mouse TCR which recognises native protein and characterise the molecular nature of this interaction and that this specific TCR can be selected in the thymus.

The recently proposed Twin Field QKD protocol allows to beat the linear scaling of the key rate with the channel losses. Here, the authors extend it including a full security proof in the finite block size regime, allowing for practically-relevant secure key rates.

Human RIF1 protein protects cells from DNA replication stress, through mechanisms that remain uncertain. Here the authors demonstrate that the RIF1-Long isoform interacts with BRCA1 upon extended replication stress, enabling RAD51-dependent repair of broken replication forks.

A large-scale multi-omics analysis reports oncogenic alterations that drive medulloblastoma progression, rather than initiation, and the findings show how single-cell technologies can be used for early detection and diagnosis of medulloblastoma.

The products and dynamics in mutual neutralisation of \({{{{\rm{O}}}}_{2}}^{+}\) with O⁻ occurring in atmospheric sprites are unknown. Here, the authors reveal a dissociative two-step mechanism via intermediate Rydberg states and a dependence on the \({{{{\rm{O}}}}_{2}}^{+}\) vibrational state.

Germanium (based) lasers are a promising route towards a fully CMOS-compatible light source, key to the further development of silicon photonics. Here, the authors realize lasing from strained germanium microbridges up to 100 K, finding a quantum efficiency close to 100%.

R-loops formed by RNA hybridization to DNA template strand during transcription influence HIV-1 integration into the CD4⁺ T cell genome. The unwinding of R-loops by splicing helicase Aquarius facilitates integration into speckle-associated domains.

Nuclear import receptors (NIRs) regulate self-association of RNA-binding proteins as phase modifiers, while C9orf72-derived arginine-rich polydipeptides lead to aberrant phase transitions. Here the authors show in molecular basis how arginine-rich poly-dipeptides impede the ability of NIRs, particularly Kapβ2.

In this Review, Grapsa and colleagues provide an overview of the imaging modalities used in the diagnosis and management of tricuspid regurgitation, describe the valve repair and replacement strategies undergoing clinical testing, and highlight the technological innovations that aim to optimize diagnosis, patient selection and the device development process.

T cell receptors co-recognizing both MHC and antigenic peptide for a tri-party specific interaction has been a central dogma of T cell-mediated responses. Here the authors use X-ray crystallography to identify a TCR that contacts only the MHC beta chain of HLA-DQ2, with this specificity potentially enforced by Leucine-55 of HLA-DQ2.5 to exclude interaction with other MHCs.

Many volatile elements are depleted in the bulk silicate Earth. Here, the authors found that these volatile elements tend to react with Fe under pressure and may be sequestered within Earth’s core by forming substitutional Fe alloys.

Large-scale combination drug screens in cancer are extremely challenging because of the immense number of possible combinations. Here, the authors develop BATCHIE, a Bayesian active learning platform to design scalable and maximally informative drug combination screening assays; this is validated in retrospective and prospective cancer studies.