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The crystal structure of a methyltransferase domain embedded within an interrupted adenylation domain provides insight into how a nonribosomal peptide synthetase N-methylates amino acid precursors for their incorporation into the peptide product.

piggyBac transposons carrying reprogramming factors are used to reprogram mouse embryonic fibroblasts, with efficiencies equivalent to retroviral transduction, and then removed from the induced pluripotent state cell genome without a trace.

Using more than 100 independent iPSC lines derived from patients with Alzheimer’s disease, the authors discovered loci associated with the neuronal production of amyloid β and confirmed their influence using RNA interference.

The Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) aims to better understand population genetics of the African diaspora. Here, it uses deeply sequenced whole-genomes to describe the impact of admixture and potential disease burden of deleterious variants.

The Cancer Genome Atlas Research Network report integrated genomic and molecular analyses of 164 squamous cell carcinomas and adenocarcinomas of the oesophagus; they find genomic and molecular features that differentiate squamous and adenocarcinomas of the oesophagus, and strong similarities between oesophageal adenocarcinomas and the chromosomally unstable variant of gastric adenocarcinoma, suggesting that gastroesophageal adenocarcinoma is a single disease entity.

African swine fever virus type II DNA topoisomerase (AsfvTop2) is known to change DNA topology by employing a complex catalytic cycle and is involved in the early stages of viral gene replication, however, the structural and regulatory functions of AsfvTop2 remain underexplored. Here, the authors use cryo-EM to demonstrate six conformers of apo-AsfvTop2 as well as the structures of AsfvTop2-DNA-inhibitor complexes, revealing experimental evidence of their substrate binding mechanism that also shed light to other enzymes.

Exome-wide genetic analysis on >300,000 individuals identifies associations with plasma lipid traits. Loci significantly associated with cholesterol and triglycerides are examined together to determine the effects of alleles on type 2 diabetes and coronary artery disease risk.

Subtypes of cancer associated fibroblasts can both promote and suppress tumorigenesis. Here, the authors investigate how p53 status in pancreatic cancer cells affects their interaction with cancer associated fibroblasts, and report perlecan as a mediator of the pro-metastatic environment.

Treatment of prostate cancer, especially in its advanced stage, is still challenging; therefore, strategies to prevent metastatic dissemination are of great interest. Here the authors reveal a crucial role for liver X receptors in suppressing prostate carcinogenesis and metastatic progression in PTEN-null tumors.

SRPK1, a kinase involved in splicing regulation, is a potential therapeutic target for AML patients. Here, the authors show that SRPK1 inhibition changes isoform levels of key epigenetic regulators, including BRD4, and it has anti-tumor effects specifically against MLL-rearranged AML cells.

The common ABCG2 variant Q141K contributes to hyperuricemia and gout risk. Here, using a human interventional study and a new orthologous mouse model, the authors report a tissue specific pathobiology of the Q141K variant, and support a significant role for ABCG2 in urate excretion in both the kidney and intestine.

Bladder cancer is a complex genetic disease and a common cause of death due to malignancy. Here, the authors carry out whole-genome sequencing of 14 bladder cancers to characterize the genomic landscape of the disease and show that mutational burden is associated with tumour progression in these samples.

Imputation uses genotype information from SNP arrays to infer the genotypes of missing markers. Here, the authors show that an imputation reference panel derived from whole-genome sequencing of 3,781 samples from the UK10K project improves the imputation accuracy and coverage of low frequency variants compared to existing methods.

Heterosis can rapidly boost yield in crop species but development of hybrid-breeding systems for bread wheat remains a challenge. Here, Tucker et al. describe the molecular identification of the wheat Ms1 gene and discuss its potential for large-scale hybrid seed production in wheat.

Size and shape of the brain are, among others, influenced by the dimensions of the skull. Here, the authors report genome-wide association studies for head circumference and intracranial volume in children and adults and the identification of nine common or low-frequency variants associated with these traits.

In a mouse model of the leukodystrophy Pelizaeus–Merzbacher disease, myelination, motor performance, respiratory function and lifespan are improved by suppressing proteolipid protein expression, suggesting PLP1 as a therapeutic target for human patients with this disease and, more broadly, antisense oligonucleotides as a pharmaceutical modality for treatment of myelin disorders.

DNA methylation in the context of epigenetics occurs on the 5' position of cytosine, which can be further oxidized by enzymes from the Ten-eleven translocation (Tet) family, resulting in 5-hydroxymethylcytosine (5-hmC). In the context of embryonic stem cells, Tet and 5-hmC DNA act in an alternate epigenetic state that regulates epigenetic programming and stem cell differentiation. Here, the authors describe the epigenomic profiling of 5-hmC in mouse and human brain across different time periods during development and aging.

Brown and colleagues generated an atlas of miRNA expression profiles from primary mouse immune cell populations and connected these signatures with ATAC–seq, ChIP–seq and nascent RNA profiles to establish a map of miRNA promoter and enhancer usage in immune cells.

Understanding tumor metastasis is crucial to developing more effective cancer therapies. Here McCreery et al. analyzed the mutational profile of metastases from chemically induced skin tumors in mice and found that parallel evolution of synchronously disseminated tumor cells underlies most metastasis.

Phytase is a high molecular weight acid phosphatase. The structure has an α/β-domain similar to that of rat acid phosphatase and an α-domain with a new fold.

Antibody-barcode eCLIP (ABC) uses proximity ligation to couple DNA-barcoded antibodies to RNA-binding protein (RBP)-protected RNA fragments for multiplexed eCLIP. ABC can be used to interrogate several RBPs in a single tube with results on par with eCLIP.

Pharmacological inhibition of GFRAL–RET signaling in preclinical tumor models supports the therapeutic potential for reversing GDF15-dependent cachexia in people with cancer.

Millions of primary IgG-secreting cells from mouse and human are characterized for activity and antibody sequence at the single-cell level.

DNA damage response signalling pathways are often altered in tumours, which can affect their response to chemotherapy and targeted therapies. This Review discusses the mechanisms by which altered DNA damage responses elicit such therapy resistance.

Multi-ancestry genome-wide association analyses for birth weight in 153,781 individuals identified 60 genomic loci in which birth weight and fetal genotype were associated and found an inverse genetic correlation between birth weight and cardiometabolic risk.

John Maris, Matthew Meyerson, Marco Marra and colleagues report results of a large-scale sequencing study of neuroblastoma. They observe a low median exonic mutation frequency and strikingly few recurrently mutated genes in these tumors, highlighting challenges for developing targeted therapeutic strategies based on frequently mutated oncogenic drivers.

Translation termination, once thought to be the least complex of the steps in protein synthesis, is emerging as a process subject to considerable regulation. The prevalent mode for this regulation seems to be eRF-tweaking, the modulation of release factor activity by proteins involved in other gene expression pathways.

Rachel Freathy and colleagues report results of a large-scale genome-wide association study of birth weight. They identify four loci newly associated with this trait and find overlap between birth weight–associated loci and those influencing adult height and metabolism.

Power exhaust is one of the biggest challenges stopping fusion energy. This article shows experimental evidence for strategically shaping the power exhaust region as a solution to this challenge, utilising physics understanding to strike a balance between engineering complexity and power exhaust benefits, consistent with reduced models and simulations.

The identity of the transduction molecules underlying cold sensation has long been a mystery in sensory physiology. Now, using a combination of electrophysiological recording, calcium imaging and behavioural analysis, TRPM8 is shown to have a major role in normal cold transduction in mice.

An association mapping study of type-2-diabetes-related quantitative traits in the Greenlandic population identified a common variant in TBC1D4 that increases plasma glucose levels and serum insulin levels after an oral glucose load and type 2 diabetes risk, with effect sizes several times larger than any previous findings of large-scale genome-wide association studies for these traits.

RING finger proteins constitute the largest class of ubiquitin protein ligases (E3s). These function to specifically ubiquitylate target proteins. As discussed in this Review, many RING finger proteins are deregulated in cancer.