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EGFR inhibitors are standard of care in patients with EGFR-mutant non-small cell lung cancer (NSCLC) but resistance often develops. Here the authors report that the evolution of EGFR inhibitor resistance in EGFR-mutant NSCLC results in a sensitivity to the compound, MCB-613, and investigate the underlying mechanism of action.

A bispecific non-coding RNA expressed by the IS110 family of mobile genetic elements forms the basis of a programmable genome-editing system that enables the insertion, excision or inversion of specific target DNA sequences.

Using cryo-electron microscopy, the structural mechanism by which non-coding bridge RNA confers target and donor DNA specificity to IS110 recombinases for programmable DNA recombination is explored.

A NOS bridge between cysteine and lysine residues serves as an allosteric redox switch in the transaldolase enzyme of Neisseria gonorrhoeae, demonstrating the existence of protein regulatory switches that contain covalent crosslinks other than disulfides.

The understanding of nucleation and growth of nanostructures plays a key role in complex materials design. Here, the authors illustrate how X-ray in situ studies link transformation at the molecular- and macro- length scales during the emergence of cobalt oxide assemblies.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

T-cell–mediated rejection (TCMR) remains a major cause of kidney transplant failure with incompletely understood mechanisms. Here the authors use single-nucleus RNA sequencing, spatial transcriptomics and immunofluorescence to show that injured kidney epithelial cell states associate with poor transplant outcomes after T-cell–mediated rejection.

Coupling live-cell imaging, machine learning and genomic sequencing, the MAGIC platform enables investigation of the cellular context, mutation rates and triggers of spontaneous chromosomal abnormality formation, shedding light on fundamental determinants of chromosomal instability.

Citizen science data are increasingly used in biodiversity monitoring. This study applies a digital twin approach to biodiversity monitoring using a large citizen science dataset on birds from Finland, demonstrating its potential for ecological forecasting.

The crystal structure of the yeast RNA Pol II elongation complex bound to the inhibitor α-amanitin is solved, revealing that two functional elements, the trigger loop and the bridge helix, are trapped in a position different from their pre- and post-translocation states. This is proposed to be a translocation intermediate, lending support to a Brownian ratchet mechanism for RNA Pol II translocation during elongation.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

Integrative structural biology combining quantitative live imaging, cryo-correlative microscopy, subtomogram averaging and molecular modelling enables in situ determination of the structure of the endoplasmic reticulum–mitochondria encounter complex in yeast.

TRPC3 regulates neuronal excitability via its constitutive activity. Using MD simulations and patch clamp techniques, Clarke et al. show that PIP2 controls TRPC3 via a salt bridge formed between the TRP helix and the S4-S5 linker, affecting both stimulated and constitutive TRPC3 activities.

DNA double-strand breaks endanger genome stability. Here, the authors present cryo-EM structures showing how Ku70/80 and DNA-PK bind DNA ends on nucleosomes, offering a mechanistic model for break recognition within chromatin.

Scientists disagree about area-based conservation’s role in addressing biodiversity loss. This Perspective examines how conservation scientists, land systems scientists and political ecologists approach these debates differently and argues that environmental data justice frameworks can bridge epistemic divides, helping researchers to develop more effective and equitable conservation interventions.

Cryo-EM elucidation of a fully reconstituted Pol II–DSF–PAF1–SPT6 elongation complex defines the position of PAF1 subunit RTF1 and reveals contacts with the Pol II bridge helix that may allosterically stimulate transcription elongation.

The repressive states of peroxisome proliferator-activated receptor γ (PPARγ) are ill-defined, despite nuclear receptors being a major drug target. Here authors demonstrate multiple structurally distinct repressive states, providing a structural rationale for ligand bias in a nuclear receptor.

The main protease, a key enzyme of SARS-CoV-2, can protect itself from oxidative damage. Here, Reinke, Schubert, and colleagues used XFEL radiation to image the enzyme, revealing the disulfide and NOS/SONOS bonds that form in response to oxygen.

Epistasis effects among amino acids at distal sites within binding pockets can have important impacts on protein fitness landscapes. Here the authors present BRIDGE, which matches non-overlapping sequence reads with their cognate DNA templates.

The molecular basis for the enrollment of X family DNA polymerases in non-homologous end joining (NHEJ) is unclear. Here the authors elucidate the structure of Pol λ within the DNA-PK long-range complex and Pol μ in association with Ku70/80 and characterize the interaction between the BRCT domains of Pol λ and μ with Ku70/80.

Estrogen receptor α is a primary driver of ER+ breast cancer and reproductive development. Here, the structure of the apo state is reported, providing a revised model for ligand-dependent and -independent regulation of receptor function.

Cagrilintide is a long-acting agonist of amylin and calcitonin receptors in late phase trials for obesity. Here, authors present structures of cagilintide with each target receptor, revealing the molecular basis for its non-selective action.

Photoswitching of phytochromes is based on the isomerization of the tetrapyrrole chromophore, and eventually leads to the (de)activation of an enzymatic output module. Now it has been shown that both the structural changes associated with photoswitching and the thermal decay of the light-activated state are coupled to proton translocations in the chromophore pocket.

Ionizing radiation from cosmic rays has been identified as a source of correlated errors in superconducting qubits, but a direct demonstration of this link has been lacking. Here the authors measure the coincidence between correlated errors and incident cosmic rays in a chip with 10 transmon qubits.

Engineered DNA recombinases efficiently and specifically insert genetic cargos without the use of landing pads.

The NeoRHEA trial showed that treatment with palbociclib and endocrine therapy decreases T cell proliferation and the presence of tissue-resident memory T cells. These results are important for the development of CDK4 selective inhibitors.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

Antimicrobial resistance (AMR) is a global challenge. In this Perspective, authors highlight the unique role of early-career researchers (ECRs) in the transdisciplinary progress in AMR research.

Eukaryotic RNA polymerase I (Pol I) is responsible for the transcription of rRNA genes. Here the authors determine the cryo-EM structure of the Pol I-Rrn3 complex, providing insight into how Rrn3 stabilizes the monomeric initiation competent Pol I to drive pre-initiation complex formation.

RNA polymerase I is the central enzyme that synthesizes ribosomal RNA in eukaryotic cells, and its regulation underlies cell growth. Here the authors present a high-resolution cryo-EM structure of the Pol I-Rrn3 complex that explains how Rrn3 specifically recognizes Pol I to form an initiation competent complex.

Luchini et al., correct for time-varying tests to quantify week-to-week acceleration in COVID-19 infection and mortality from May 2020 to December 2021 in WHO regions. Africa exhibits infection-acceleration episodes whose magnitude and frequency match those in other regions, and that are followed by mortality accelerations about ten weeks later.

Single-cell RNA sequencing reveals molecular determinants of the developmental programs that orchestrate the intermingling of neuronal subtypes in the hypothalamus.

The authors report single-pixel infrared imaging thermometry via diagonally aggregated encoding masks and non-iterative reconstruction for passive, non-contact, accurate mapping of inner canthi temperature variations linked to physiology and habits.

Phytochromes are photoreceptors that are present in plants, bacteria and fungi. Here the authors present crystal structures of the phytochrome Agp2 from Agrobacterium fabrum in the parent Pfr state as well as a functional Meta-F intermediate and discuss mechanistic implications for photoconversion.

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 crystal structure of the complete 14-subunit RNA polymerase (Pol) I from yeast is determined, providing insights into its unique architecture and the possible functional roles of its components.

Graphene systems exhibit flavor order transitions driven by tuning parameters. Here, the authors demonstrate an optical technique for detecting flavor textures in graphene via the exciton response of a proximal transition metal dichalcogenide layer.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

The cryo-electron microscopy structure of the human adenosine A₁ receptor in complex with adenosine and heterotrimeric G_i2 protein provides molecular insights into receptor and G-protein selectivity.