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Computational and machine-learning approaches that integrate genomic and transcriptomic variation from paired primary and metastatic non-small cell lung cancer samples from the TRACERx cohort reveal the role of transcriptional events in tumour evolution.

Reis e Sousa et al. show that cDC2As and cDC2Bs are derived from distinct subsets of bone marrow pre-cDC2s, suggesting that the two lineages are ontogenetically determined.

The k-turn is a widespread RNA element that adopts a kinked structure that mediates tertiary contacts and frequently binds specific proteins. Here, McPhee et al. show that the ability of a given k-turn to fold in the presence of metal ions alone—or to otherwise require protein binding—is attributable to a specific base pair.

Combination of epidemiology, preclinical models and ultradeep DNA profiling of clinical cohorts unpicks the inflammatory mechanism by which air pollution promotes lung cancer

Uncertainty associated with solution-based electron-transfer studies of DNA–metal-complex systems has now been overcome by combining X-ray and time-resolved infrared data obtained for ruthenium polypyridyl–DNA crystals. Using these methods both the geometry of the reaction site and the kinetics of the reversible photo-induced one-electron oxidation of guanine have been determined.

Rapid intestinal regeneration after injury is critical to maintain barrier integrity and homeostasis, but must be tightly controlled to prevent tumorigenesis. Here they show that the aryl hydrocarbon receptor is required to terminate the regenerative response after wound healing.

Third-generation sequencing can reveal information beyond the simple sequence of bases, but fulfilling this potential requires complex reference sets for training. Here, the authors present an approach to generate these reference sets and present various use cases for such multidimensional sequencing.

Immune lymphocyte estimation from nucleotide sequencing (ImmuneLENS) infers B cell and T cell fractions from whole-genome sequencing data. Applied to the 100,000 Genomes Project datasets, circulating T cell fraction provides sex-dependent and prognostic insights in patients.

Stress granules function at sites of intracellular membrane damage by forming on and stabilizing the ruptured membrane and promoting membrane repair.

Walport & coworkers report cell-active, potent and selective cyclic peptide modulators for the enzyme peptidylarginine deiminase PADI4/PAD4, including an inhibitor, an activator and an affinity molecule, revealing insights into PADI4 regulation.

Red blood cells, which do not possess a nucleus, have circadian redox rhythms with incompletely understood regulatory mechanisms. Here the authors show that glucose metabolism plays a crucial role in regulating circadian redox status of human red blood cells.

D-cycloserine (DCS) has been used for decades to treat Mycobacterium tuberculosis (Mtb) but resistance is rarely observed in clinical isolates. Here, the authors report ultra-low rate of emergence of resistance mutations as the underlying mechanism of DCS resistance evasion in Mtb.

The HIV Tat protein recruits a host elongation factor from the cellular 7SK complex to the viral TAR RNA to ensure transcriptional elongation. Here, Pham et al. solve the structures of both 7SK and TAR RNAs in complex with Tat’s RNA binding domain and gain mechanistic insights into the process.

Analyses of the TRACERx study unveil the relationship between tissue morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk of lung adenocarcinomas.

Hyperinflammation and immune dysfunction are key drivers of immunopathology in sepsis. Here the authors show microbial exploitation of phagocytic receptors is linked to triggering of sepsis and the immune cell mediated reduction in neutrophil life span.

Respiratory infections occur throughout life but how this shapes the lung immune system through time is unclear. Wack and colleagues show that a previous influenza infection recruits monocytes to the lung, which then assume an alveolar macrophage-like phenotype and mediate long-term antibacterial protection.

The signals regulating the establishment and maintenance of the pluripotent epiblast in human embryos are unclear. Here, the authors use a bioinformatics approach to identify the role of IGF1 in human embryo development, and from this, propose a culture medium with IGF1 together with Activin to sustain hESCs in the absence of FGF.

Neutrophils actively induce tumour necrosis, driving vascular occlusion, pleomorphic necrosis and metastasis.

Several persistent challenges limit the efficacy and applicability of adoptive T cell therapies for cancer, including suboptimal function and/or persistence in vivo, a narrow range of targetable antigens and complex manufacturing processes. This Review discusses the potential of ‘CRISPR 2.0’ precision gene-editing platforms, such as base editing and prime editing to address all of these challenges, and describes the progress made towards clinical translation of these technologies.

Here, the authors show that histone H3 through H3K56 acetylation, is essential for chromatin remodelling in nascent chromatin post-DNA replication. Subsequent H3K56 deacetylation during G2/M signals chromatin maturation, ensures both genome and epigenome integrity.

X-ray crystal structures of a tRNA synthetase bound to wild-type and mutant alanine tRNAs reveal the structural basis for selectivity.

A longitudinal evolutionary analysis of 126 lung cancer patients with metastatic disease reveals the timing of metastatic divergence, modes of dissemination and the genomic events subject to selection during the metastatic transition.

Analyses of multiregional tumour samples from 421 patients with non-small cell lung cancer prospectively enrolled to the TRACERx study reveal determinants of tumour evolution and relationships between intratumour heterogeneity and clinical outcome.

Post-translational modifications of tRNAs can alter their decoding specificity. A molecular basis for altered codon specificity is now provided by the crystal structure of the archaeal tRNA₂^Ile modified with agmatidine at the wobble cytidine residue in complex with the AUA codon on the ribosome.

The authors present a molecular approach and a software suite for high-throughput sequencing and characterization of microbial tRNA transcripts, which provide unique physiological insights into complex environmental microbes.

The transcription factor c-Maf controls IL-10 production in T cells. O’Garra and colleagues use systems and in vivo functional analysis of T cell subsets to reveal distinct context-specific roles for c-Maf.

Here, we report the mutation rate of SARS-CoV-2, the virus responsible for COVID-19. We find that the secondary structure of the RNA-encoded viral genome is crucial to modulating the mutation rate and evolves under strong selective constraints.

Which combination of current genome sequencing and assembly approaches results in high-quality, complete diploid genome assemblies is determined.

The BMP inhibitor GREM1 is a key regulator of cellular heterogeneity in pancreatic cancer in human and mouse.

Jung-Garcia et al. dissect the contributions of isoforms of the inner nuclear membrane protein LAP1 to nuclear envelope blebbing, constrained migration and invasion in melanoma cells.

We show the evolution of a case of EGFR mutant lung cancer treated with a combination of erlotinib, osimertinib, radiotherapy and a personalized neopeptide vaccine targeting somatic mutations, including EGFR exon 19 deletion.

A methyltransferase ribozyme, along with the small-molecule cofactor O⁶-methylguanine, is shown to catalyse the site-specific installation of 1-methyladenosine in various RNAs, providing insights into the catalytic abilities of RNA.

Designing high performance RNA molecules is a unifying challenge across many areas of biotechnology research. Here, authors develop GARDN and SANDSTORM, a data-efficient generative AI framework for designing a diverse set of RNA molecules. These tools represent a promising addition to the sequence design toolkit that could be used in many domains.

PBK is a mitotic kinase implicated in cancer. This study reveals how PBK evicts key C2H2-zinc finger transcription factors such as Ikaros, Aiolos and CTCF from DNA as cells divide, regulating mitotic chromatin accessibility and chromosome compaction.

Despite growing interest in environmental metabolomics, we lack conceptual frameworks for considering how metabolites vary across space and time in ecological systems. Here, the authors apply (species) community assembly concepts to metabolomics data, offering a way forward in understanding the assembly of metabolite assemblages.

Crystallographic and cryo-EM analyses using short synthetic single-stranded RNAs unveil the structural basis for recognition of bacterial 23S rRNA and vesicular stomatitis virus by Toll-like receptor 13, which triggers an immune response.