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A technique using barcoded beads for DNA sequencing within tissue sections enables spatial resolution of tumour clonal heterogeneity and can be multiplexed with other analytical techniques for analysis of complex cellular phenotypes.

Cooperative species of extrachromosomal DNAs are coordinately inherited through mitotic co-segregation.

Macrophages are pleiotropic and can have different functions and phenotypes. Here the authors show that a population of macrophages, previously described as pro-fibrotic, can be induced through Notch2 blockade and that in a mouse lung injury and fibrosis model this macrophage population does not promote inflammation or fibrosis.

A rapidly growing black hole in a very active phase has been observed with JWST ~1.5 billion years after the Big Bang. Bright in X-rays, it is accreting at a rate 4,000% in excess of the Eddington limit, offering insights into early black hole growth.

During the early development of an organism, some cells are fated to grow while other seemingly healthy cells die. Experiments and theory now reveal that a hydraulic instability is the key to this decision.

An approach that combines deep mutational scanning with neural network-based thermodynamic modelling is used to provide comprehensive maps of the energetic and allosteric effects of mutations in two common protein domains.

Truncation of exon 18 of FGFR2 (FGFR2^ΔE18) is a potent driver mutation in mice and humans, and FGFR-targeted therapy should be considered for patients with cancer expressing stable FGFR2^ΔE18 variants.

Here the authors probe the cleavage and gate opening of single-stranded DNA by the human topoisomerase TRR using a unique single-molecule strategy to reveal structural plasticity in response to both double-stranded DNA and the helicase BLM.

Analysis of whole-genome sequencing data across 2,658 tumors spanning 38 cancer types shows that chromothripsis is pervasive, with a frequency of more than 50% in several cancer types, contributing to oncogene amplification, gene inactivation and cancer genome evolution.

Cryo-electron microscopy and tomography studies reveal the structures, conformations and distributions of spike protein trimers on intact severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virions and provide a basis for understanding the interactions of the spike protein with neutralizing antibodies.

A 2.2 Å cryo-electron microscopy structure of an actively translating 80S ribosome from tobacco reveals bound tRNA and mRNA, the nascent peptide and numerous cofactors, providing a basis for understanding the molecular mechanism of protein synthesis in plants.

Combining expansion microscopy with super-resolution radial fluctuations captures the morphology of single proteins.

Covalent organic frameworks (COFs) can be synthesized through a wide range of reactions but phosphonate-COFs remained elusive. Here the authors report a polyphosphonate-COFs constructed via P-O-P linkages with good water and exceptional electrochemical stability.

The molecular characteristics and therapeutic vulnerabilities of TFCP2-rearranged rhabdomyosarcomas (RMS) require further exploration. Here, the authors use multi-omics analyses and functional and mechanistic investigations to characterize TFCP2-rearranged RMS – including cases with FUS/EWSR1-TFCP2 fusions – across two precision oncology programs.

Enhanced light–molecule interactions in high-finesse fibre-based Fabry–Pérot microcavities are used to detect and profile individual unlabelled solution-phase biomolecules, leading to potential applications in the life and chemical sciences.

The eukaryotic RNA Polymerase III transcribes tRNAs, some ribosomal and spliceosomal RNAs. Here, the authors resolve a cryo-EM structure of human RNA Polymerase III in its apo form and complemented it with crystal structures and SAXS analysis of RPC5, revealing insights into the molecular mechanisms of Pol III transcription.

Structures of the assembled matrix protein 1 of influenza A virus in intact virus particles and of oligomers of this protein reconstituted in vitro reveal mechanisms of assembly and disassembly of influenza virus.

Here, the authors demonstrate that cortical microstructure in young adults shows marked sex bias, which is most pronounced in paralimbic areas. The effects are put into context with variations in sex hormones and local cytoarchitecture.

Integration of postmortem molecular and dendritic spine morphological measurements enables the detection of microscale molecules associated with person-to-person variability in macroscale brain connectivity estimated from antemortem neuroimaging.

Polymerase Bcs3, which allows the fermentation-free synthesis of Haemophilus influenzae type b capsule for vaccine development, adopts a basket-like shape with all six active sites facing the interior, creating a protected environment for catalysis.

In yeast, the heterodimeric ribosome-associated complex (RAC) acts in concert with the Hsp70 protein Ssb, forming a unique chaperone triad. Here the authors use structural and biochemical approaches to shed light on how translation and folding are coupled in eukaryotes.

Bacterial resistance is propagated in part by metallo-β-lactamases, which hydrolyze and inactivate β-lactam antibiotics. An unusual cysteine residue in the active site is now shown to be critical for retaining the second metal ion, and thus enzyme activity, at low zinc concentrations.

Promoter recognition is a critical step in the initiation of transcription of DNA to RNA. Here, the authors describe a novel mechanism by which a phage-encoded RNA polymerase recognizes viral promoters containing deoxyuridines instead of thymidines.

Healthy adults were tracked before, during and after high doses of psilocybin and methylphenidate to assess how psychedelics can change human brain networks, and psilocybin was found to massively disrupt functional connectivity in cortex and subcortex with some changes persisting for weeks.

This protocol describes how to achieve high spatial resolution imaging of biological tissues using nanospray desorption electrospray ionization mass spectrometry

Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.

Generative models show promise in drug discovery by enabling the design of molecules with desired properties, yet often face challenges related to target engagement, synthetic accessibility, and generalization. To address these, the authors developed a workflow combining a variational autoencoder with active learning cycles, generating diverse, drug-like molecules with synthetic feasibility and high predicted affinity for CDK2 and KRAS.

Import of proteins into peroxisomes depends on PEX5, PEX13 and PEX14. Here the authors obtain crystal structures and NMR data to show the recognition of diaromatic peptide motifs on a noncanonical surface of the PEX13 SH3 domain, revealing a dynamic network which modulates peroxisomal matrix import.

New biomarkers are required to improve the assessment of aortic wall integrity and risk of rupture. Here the authors report the development of an imaging probe for ADAMTS4, which they test in an abdominal aortic aneurysm mouse model and show in vivo prediction of aneurysm and rupture.

Super-resolution quantal imaging relates transmission at excitatory synapses to presynaptic molecular composition. The authors find that evoked transmission varies greatly between synapses and is uncorrelated and physically separate from spontaneous transmission, and identify responsible presynaptic proteins.

Oligosaccharyltransferase (OST), the central enzyme in N-glycosylation, modifies acceptor proteins by attaching a complex glycan. Cryo-EM structures of OST in distinct states, reveal the molecular basis of substrate recognition and catalysis.

Epstein–Barr Virus (EBV) nuclear antigen 1 is shown to induce breakage of a fragile site on chromosome 11 by binding to a cluster of EBV-like imperfect palindromic repeats.

Motile and non-motile cilia have distinct functions and protein complexes associated with them. Here, the authors show the conserved protein CFAP20 is important for both motile and non-motile cilia and is distinct from other ciliopathy-associated domains or macromolecular complexes.

Evidence from large longitudinal neuroimaging cohorts, which include genetic and behavioral data, suggest a common neural basis for symptoms seen across multiple psychiatric disorders.

Severe febrile illnesses in children may be various in presentation and aetiology but involve immune dysfunction amenable to immunomodulation. Here, the authors identify shared neutrophil and T cell dysfunction and a distinct interferon signature in critically ill children with severe febrile illness.

Digenic inheritance of deleterious variants in serine/arginine protein kinase 3 (SRPK3) and titin (TTN) leads to a progressive early onset skeletal muscle myopathy. Zebrafish double mutants exhibit a similar myopathy phenotype accompanied by myofibrillar disorganization.

Climate science and national emissions reporting communities have historically used different definitions and methods for anthropogenic land-based carbon removals. As the mitigation agenda accelerates, reconciling these differences for comparability and moving towards integration is crucial for enhancing confidence in land-use emission estimates.

FAM111A is a serine protease important for DNA replication and antiviral defense. Here, the authors report that the FAM111A dimerization is crucial for its proteolytic activity and for promoting DNA replication at trapped topoisomerase I.

A deep-learning-based approach enables automatic identification of synaptically connected neurons in electron microscopy datasets of the fly brain.

A series of cryo-EM structures examining transcription initiation by vaccinia poxvirus RNA polymerase reveal how viral transcription factors identify and melt a promoter and how a polymerase-associated helicase mediates promoter escape.

The authors show that the N-acetyltransferase PamZ acts as a self-resistance factor disabling the antibacterial paenilamicin that is produced by the honey bee larvae pathogen Paenibacillus larvae.

Loading of osmolytes into the phloem drives a pressure-flow transport mechanism. A maize sucrose transporter1 loss-of-function mutant has much reduced export of carbon from leaves, but increased potassium concentrations maintain phloem pressure.

The regulatory role of calcitonin in bone homeostasis is well studied, yet its molecular activity is poorly understood. The authors show that calcitonin regulates bone cells function by inhibiting the osteoclast secretion of sphingosine 1-phosphate, a lipid mediator of osteoclast–osteoblast crosstalk.

Macrophages coordinate the disposal of apoptotic cells. Ajay Chawla and his colleagues show that PPAR-δ, a sensor of fatty acids, is involved in this process. Ingestion of apoptotic cells by macrophages prompts the upregulation of PPAR-δ, which then responds by enhancing the expression of opsonins. Lack of PPAR-δ reduces apoptotic cell clearance and predisposes to autoimmunity (pages 1246–1248).

The shuttling of AMPA receptors to and from the synaptic membrane determines the strength of synaptic transmission. This study shows that ephrinB2 is part of the mechanism that stabilizes AMPA receptors at the synaptic surface. EphrinB2 and AMPA receptors are linked by two PDZ domains in the intracellular adaptor protein GRIP.