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Under chemically defined conditions, mouse pluripotent stem cells can be induced to closely resemble authentic totipotent stem cells that can differentiate to both embryonic and extraembryonic lineages.

Xu Tan, Yong Yang and colleagues identify patients with epidermolysis bullosa harboring mutations in KLHL24, which encodes a cullin 3–RBX1 ubiquitin ligase substrate receptor. They find that truncating mutations stabilize the protein by abolishing autoubiquitination, leading to enhanced ubiquitination and degradation of KRT14, the target substrate of KLHL24.

Tao et al. reported a series of cryo-EM structures of α-synuclein fibrils in complex with amyloid dyes and imaging tracers, and identified druggable pockets in the fibrils of multiple system atrophy.

Legumain is a protease found expressed in tumour cells and may be useful in the specific targeting of chemotherapeutics to tumour cells. Here, the authors design nanoparticles that are loaded with doxorubicin and contain a legumain cleavage site; once the nanoparticles enter tumour cells legumain activity results in the release of doxorubicin.

All-solid-state batteries are promising alternatives to Li-ion batteries. Here, the authors investigate the chemo-mechanical changes at the lithium metal/solid electrolyte interface via operando acoustic transmission and magnetic resonance imaging.

Seronegative healthcare workers with an innate signature of infection preferentially expand pre-existing T cells targeting the conserved replication transcription complex of SARS-CoV-2 in abortive infection.

During zygotic genome activation the embryo must re-wire the regulatory network that sustains totipotency earlier during development. Here they identify ZFP352 as an essential factor that targets retrotransposon families to facilitate dissolution of the totipotency network and enable ZGA.

A case–control study investigating the causes of recent cases of acute hepatitis of unknown aetiology in 32 children identifies an association between adeno-associated virus infection and host genetics in disease susceptibility.

Soybean is made resistant to Asian soybean rust using a gene cloned from pigeonpea, showing that legumes may contain a reservoir of disease-resistance genes.

Crystal sizes play a vital role in pushing up the efficiency of organometal halide perovskites based LEDs. Here Ban et al. incorporate a molecular additive to control the crystallite distribution and phase separation in the perovskite devices, resulting in high external quantum efficiency of 15.5%.

The structure of the D2 dopamine receptor in complex with its G protein reveals how dopamine receptors are activated and, importantly, how a G-protein-coupled receptor can interact with its G protein in a phospholipid membrane.

Non-coding RNAs are important regulators of several biological processes, including metabolic functions. Here Arcinas and colleagues demonstrate that circular RNAs, a class of non-coding RNAs, are widely expressed in adipose tissue and display dynamic regulation during adipogenesis and obesity.

Cells communicate with the outside world to maintain homeostasis. Here the authors design a synthetic biology DNA-based signalling system AMSsys that responds to the presence of ATP.

We develop a proton-exchange membrane system that reduces CO₂ to formic acid at a catalyst that is derived from waste lead–acid batteries and in which a lattice carbon activation mechanism contributes.

Heavy analogues of carbynes of the type R–\({{{\dot{\mathrm E:}}}}\), where E is a group 14 element, are difficult to isolate in the condensed phase due to their high reactivity. Now, a germylyne radical supported by a sterically hindered hydrindacene ligand has been prepared and structurally characterized. Theoretical calculations show that the spin density mainly resides at the germanium centre.

Cigarette smoke induces microRNA dysregulation in cancers. Here, the authors show that cigarette smoke promotes the maturation of oncogenic primary miR-25 due to METTL3 hypomethylation, and mature miR-25 suppresses PH ___domain leucine-rich repeat protein phosphatase 2, resulting in oncogenic AKT activation in pancreatic cancer.

Chiea Chuen Khor, Tin Aung, Francesca Pasutto, Janey Wiggs and colleagues report a global genome-wide association study of exfoliation syndrome and a fine-mapping analysis of a previously identified disease-associated locus, LOXL1. They identify a rare protective variant in LOXL1 exclusive to the Japanese population and five new common variant susceptibility loci.

Openshaw and colleagues find myeloid inflammation and complement activation signatures in patients with long COVID who were previously hospitalized.

Using cryo-electron microscopy, the authors report the structures of G-protein-coupled bile acid receptor–G_s complexes and reveal the structural basis of bile acid recognition.

Polo-like kinase 1 (Plk1) regulates multiple processes that are important for cell proliferation, and it is a promising anticancer drug target. Efforts to inhibit Plk1 function by disrupting interactions that are essential for its proper localization identify a high-affinity alkylated phosphopeptide ligand specific for Plk1.

Phenylketonuria (PKU) is characterized by increased levels of phenylalanine in the blood and progressive mental retardation. Now, phenylalanine is shown to form toxic amyloid fibrils at high concentrations, which accumulate in the brains of PKU patients and mouse models.

Using a multi-omics approach, Wang et al. explored sex-specific and region-specific patterns of intestinal aging in non-human primates, identifying regulators with conserved functions in Caenorhabditis elegans intestinal aging, in colitis in mice and in patient colorectal cancer samples.

Chen et al. report that the immune modulatory metabolite itaconic acid selectively inhibits the activity of TET DNA dioxygenases to repress the inflammatory responses.

Guccione and colleagues identify and characterize a sorafenib derivative, WNTinib, with therapeutic efficacy in β-catenin-mutated hepatocellular carcinoma and identify EZH2 as important for the activity of the inhibitor.

Developing new click chemistry reactions for robust molecular assembly remains challenging. Here the authors report a light-induced primary amines and o-nitrobenzyl alcohols photoclick cyclization for rapid and modular functionalization of small molecules and native biomolecules, in vitro and in living systems.

Reliable detection of mutations below 0.5% variant allele frequency remains a key challenge for circulating tumor DNA sequencing assays.

Combined use of microcrystal electron diffraction and genome mining for biosynthetic gene clusters enables the rapid structural elucidation of natural products, including a newly discovered 2-pyridone compound and a revised structure of fischerin.

The transcriptional regulator PRDM15 is expressed at low levels in normal tissues but overexpressed in B-cell lymphomas. Here, the authors show that PRDM15 depletion does not affect adult somatic cell homeostasis but leads to a metabolic crisis which impairs B-cell lymphomagenesis.

A massive star at a redshift of 6.2, corresponding to 900 million years after the Big Bang, is magnified greatly by lensing of the foreground galaxy cluster WH0137–08.

Analysis of mitochondrial genomes (mtDNA) by using whole-genome sequencing data from 2,658 cancer samples across 38 cancer types identifies hypermutated mtDNA cases, frequent somatic nuclear transfer of mtDNA and high variability of mtDNA copy number in many cancers.

An antibody-discovery pipeline integrating single-cell mRNA-sequence analysis, bioinformatics, synthetic biology and high-throughput functional analyses enables the rapid discovery of potent human monoclonal antibodies against viral pathogens.

Using the GTEx data and others, a comprehensive analysis of adenosine-to-inosine RNA editing in mammals is presented; targets of the various ADAR enzymes are identified, as are several potential regulators of editing, such as AIMP2.

The underlying mechanisms by which Smad4 loss-of-function accelerates lung cancer metastasis is unclear. Here, the authors show PAK3 as a downstream effector of Smad4 promoting metastatic signalling and suggest Smad4-PAK3 regulation as a point of potential therapy in metastatic lung cancer.

Human antigen R (HuR) is an RNA binding protein that promotes mRNA stability. Here the authors show that HuR represses adipogenesis in white and brown adipose tissue by stabilizing Insig1 and other targets.

The millimetre image of the Centaurus A nucleus by the Event Horizon Telescope reveals a highly collimated, asymmetrically edge-brightened jet. The source’s event horizon shadow should be visible at terahertz frequencies, consistent with the universal scale invariance of black holes.

There are distinct hypermethylation patterns in gene promoters in hepatocellular carcinomas (HCCs). Here, the authors show that the enhancer of C/EBPβ is recurrently hypomethylated in human HCCs, recapitulating this in a transgenic murine model and linking aberrant enhancer hypomethylation to hepatocarcinogenesis.

The identification of cross-linked peptides at a proteome scale for interactome analyses represents a complex challenge. Here the authors report an efficient and reliable search engine pLink 2 for proteome-scale cross-linking mass spectrometry analyses, and demonstrate how to systematically evaluate the credibility of search engines.

Kucha is a rare variety of tea tree that produces the non-stimulatory theacrine instead of caffeine. Here the authors show that theacrine synthase from Kucha has N9-methyltransferase activity resulting from amino acid substitutions that explain substrate specificity and could potentially guide production of caffeine-free tea.

CRISPR–CasX represents a distinct RNA-guided platform that is functionally separate from Cas9 and Cas12a and is active for bacterial and human genome modification.