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Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

Understanding conserved functional genomic properties between human and mouse provides important context for mouse model studies. Here, the authors present a genome-wide conservation score integrating epigenomic, transcription factor binding, and transcriptomic data from mouse and human genomes.

Different functional variants in ADH1B (and elsewhere) in Europeans and Africans strongly affect risk for alcohol dependence. Dependence only partly genetically correlates with consumption, with strong correlations to other psychiatric disorders.

The assembly of the genome of the koala provides insights into its adaptive biology and identifies gene expansions that contribute to its ability to detoxify eucalyptus-derived compounds and perceive plant secondary metabolites.

Sun et al. report human lifespan changes in the brain’s functional connectome in 33,250 individuals, which highlights critical growth milestones and distinct maturation patterns and offers a normative reference for development, aging and diseases.

Swanton and colleagues present a clonal expression signature, ORACLE, which, in combination with clinicopathological and molecular risk factors, can predict survival of patients with lung adenocarcinoma, and they prospectively validate its prognostic value.

Comprehensive genomic and transcriptomics analyses of more than 1,300 cases of childhood T-lineage acute lymphoblastic leukaemia identify 15 distinct subtypes that are associated with specific outcomes.

Sexual interactions with males shorten the lifespan of the opposite sex in several species, including Caenorhabditis elegans, but the mechanisms are not fully understood. Here the authors use transcriptomic profiling in C. elegans to systematically identify the genetic pathways involved in male-induced demise, which include upregulation of a conserved ion channel that regulates fat metabolism.

Ribonucleotide reductase (RNR) catalyzes the conversion of ribonucleotides to deoxyribonucleotides, which is an essential step in DNA synthesis. Here the authors use small-angle X-ray scattering, X-ray crystallography, and cryo-electron microscopy to capture active and inactive forms of the Bacillus subtilis RNR and provide mechanistic insights into a convergent form of allosteric regulation.

In a non-prespecified interim analysis of a phase 1 trial, autologous PRAME-directed TCR T cell therapy was safe and elicited durable responses in patients with recurrent and/or treatment-refractory PRAME⁺ advanced solid tumors, including melanoma and synovial sarcoma.

By studying cortical activity patterns during prey capture and spontaneous behavior in marmosets, the authors identify distinct subnetworks defined by reliable spike timing correlations. These subnetworks emerge during prey capture, with each potentially playing different roles in controlling reaching movements.

Patient-derived xenografts provide a resource for basic and translational cancer research. Here, the authors generate multiple pediatric high-grade glioma xenografts, use omics technologies to show that they are representative of primary tumours and use them to assess therapeutic response.

The blooming alga Emiliania huxleyi and its viruses are a model for density-dependent virulent dynamics. However, Knowles et al. show that this host–virus system exhibits temperate dynamics at natural host densities, in a manner dependent on host physiology.

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.

Mutation of the C-terminal extension of 5′-aminolevulinate synthase 2 (ALAS2) is the molecular cause for X-linked protoporphyria, but the underlying mechanism is unclear. Based on crystal structures and MD simulations of ALAS2, the authors here show how the C-terminal extension regulates ALAS2 activity.

A combination of hardware developments has increased the achievable spatial resolution in 7 Tesla human neuroimaging to about 0.4 mm.

The effects of pesticides on individual species could propagate into additional community-wide and ecosystem-level effects. Here the authors use a mesocosm experiment to test how a diverse array of herbicides and insecticides disrupt aquatic community structure and ecosystem function.

In individuals diagnosed with age-related macular degeneration in one eye, a deep learning model can predict progression to the ‘wet’, sight-threatening form of the disease in the second eye within a 6-month time frame.

Patients with classic Hodgkin lymphoma (cHL) respond well to PD-1 blockade, but the underlying cellular insights are still lacking. Here, the authors use single-cell transcriptome and spatial analyses to identify distinct circulating and tumor-infiltrating CD4⁺ T cell, B cell and IL1β⁺ monocyte/macrophage features associated with response to PD-1 blockade in cHL.

The photoreceptor cilium contains an exclusive group of proteins responsible for capturing light and eliciting a visual response. Here, the authors show that the tectonic complex plays a role in the barrier that prevents unsolicited protein entry into the cilium.

Previous studies on astrocyte development have led to controversial results due to a lack of pertinent tools. Here, authors analyze large numbers of astrocyte clones generated by nearby cortical progenitors using the MAGIC Markers strategy and ChroMS 3D imaging, and show that clonally-related astrocytes organize in a non-stereotyped manner and that cortical astrocyte subtypes are not intrinsically specified.

It remains unclear how rapid antibiotic switching affects the evolution of antibiotic resistance in individual patients. Here, Chung et al. combine short- and long-read sequencing and resistance phenotyping of 420 serial isolates of Pseudomonas aeruginosa collected from the onset of respiratory infection, and show that rare resistance mutations can increase by nearly 40-fold over 5–12 days in response to antibiotic changes, while mutations conferring resistance to antibiotics not administered diminish and even go to extinction.

Hydroxysteroid 17-beta-dehydrogenase 13 (HSD17B13) is a hepatic lipid droplet-associated enzyme that is upregulated in patients with non-alcoholic fatty liver disease. Here, the authors report crystal structures of HSD17B13 and its complexes with two series of inhibitors.

A CRISPR knock-in strategy that uses endogenous gene regulatory mechanisms can engineer ‘armoured’ CAR T cells that secrete proinflammatory cytokines directly within a tumour without causing toxicity, leading to prolonged survival in mice.

Yang et al. show that transcription–replication collisions lead to large tandem duplications, which are frequent in female-enriched, upper gastrointestinal tract and prostate cancers and are associated with poor survival and mutations in specific genes, such as CDK12.

Fine-tuning the RoseTTAFold structure prediction network on protein structure denoising tasks yields a generative model for protein design that achieves outstanding performance on a wide range of protein structure and function design challenges.

Some anesthetics despite being generally associated with sedation, can also increase brain activity—a phenomenon called paradoxical excitation. The authors identified dozens of compounds that generally decrease neuronal activity, but increase activity in the caudal hindbrain of zebrafish.

KDM4C regulates cathepsin L-mediated histone H3 N-terminal tail clipping through grainyhead-like 2 (GRHL2) methylation in breast cancer. This link between the cellular redox state and chromatin remodeling might represent a therapeutic target in KDM4C-amplified tumors.

It is unknown how cortical stimulation identifies brain regions critical to speech and language when they depend upon broader brain networks. Here the authors show that these critical areas function as connectors between modules in the language network.

RNA-guided CRISPR-associated transposases (CAST) are natural systems with broad potential in biotechnology. Here, the authors report compact type V-K CAST discovered from genome-resolved metagenomics and demonstrate targeted integration of a large transgene to a safe-harbor site in the human genome.

Comparison of paired primary and recurrent glioblastomas at the single-cell transcriptomic level describes molecular and cellular trajectories associated with tumor recurrence, highlighting extensive heterogeneity and microenvironmental co-evolution.

A framework combining combinatorial CRISPR knockout in breast, lung and oropharyngeal cancer in vitro models with public data identifies synthetic lethal interactions, such as perturbed KDM5C sensitizing cells to PARP7 inhibition.

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.

Cristinziano et al. report the use of bacteriophages and dual beta lactam antibiotics to treat a patient with a Mycobacterium abscessus sternal wound infection. One of the phages was epigenetically modified for specificity to the M. abscessus strain.

Many pathogens manipulate ubiquitin-mediated signaling to evade host cell defense. Here, the authors characterize the structure and enzymatic activity of a deubiquitylase domain from the causative pathogen of scrub typhus, providing evidence for a distinct mechanism of ubiquitin chain selectivity.

Spatial molecular imaging analysis of human pancreatic adenocarcinomas describes multicellular neighborhoods in the tumor microenvironment. Ligand–receptor analysis using optimal transport-based SCOTIA identifies interleukin-6 as a mediator of chemoresistance.

Tissue-resident effector memory T cells respond rapidly after reencountering antigen. Masopust and colleagues show that memory CD8⁺ T cells also induce the release of chemokines, then recruit more memory cells to the site of infection.

Paediatric therapy-related myeloid neoplasms (tMN) have a dismal prognosis and have not been comprehensively profiled. Here the authors characterise the molecular landscape of 84 paediatric tMN patients, and find that, unlike adult tMNs, these do not emerge from pre-existing clones and that MECOM dysregulation is frequent.

A bulky residue in the stem domain of the influenza virus H2 hemagglutinin appears pivotal in eliciting broadly cross-reactive antibodies capable of recognizing diverse group 1 influenza subtypes and is informative for universal influenza vaccine development.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) is a rare but life-threatening severe cutaneous drug reaction mediated by CD8⁺ T cells. Here the authors characterise the immune response in skin samples at the site of tissue damage from patients affected with SJS/TEN and compare this to healthy skin or blister fluid and find populations of CD8⁺ T cell clonotypes expressing cytotoxic mediator molecules.

DNA Ligase IV (LigIV) catalyzes nick sealing of DNA double-strand break substrates during non-homologous end-joining. Here the authors present the crystal structures of two human LigIV DNA-bound catalytic states, which provide insights into its catalytic mechanism and the molecular basis of LIG4 syndrome causing disease mutations.

Mapping of multi-omic molecular quantitative trait loci associated with tandem repeat size variation in up to 4,412 human brain samples from 1,597 donors offers insights into how these variants affect gene regulation and mediate disease risk.

Cas12i is a genome editing platform with compact size that fits in AAV vector with short 43-mer gRNA, absence of tracrRNA, ability to process pre-crRNA, and high specificity. Here the authors present an unbiased mutational scanning approach to engineer Cas12i, which shows low activity in mammalian cells, and identify single substitutions that significantly improve indel activity.

A population-scale map of gene expression in primary human microglia provides a systematic exploration of microglia diversity and how age, sex, pathology, cortical anatomy and common germline genetic variation influence the microglia transcriptome.

Cryo-EM structures of the human mitochondrial chaperone Hsp60 reveal alternating apical domain conformations that enable simultaneous client and co-chaperone interactions. These results provide a structural mechanism for efficient client capture and chaperone cycling.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

A fluorescence-based sensor of PKA activity has increased brightness, dynamic range and signal-to-noise ratio over related sensors and is useful for visualizing kinase activity in HeLa cells, primary neurons and the cortex of awake mice.