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Germline DDX41 mutations are linked to myeloid neoplasms, but their roles in the disease is unclear. Here, the authors show that DDX41 resolves G-quadruplex structures to maintain erythroid genome stability and prevent cGAS-mediated cell death. These functions are lost in disease-associated variants.

Time-resolved electron microscopy reveals that intersectin-1 and endophilin A1 condensates hold replacement synaptic vesicles close to release sites. Without this, replacement vesicles are unavailable for immediate use, causing synaptic depression in response to stimulation trains.

Cancer mutations in histone H3 cause genome instability, but the mechanisms remain to be elucidated. Here, the authors show in a plant model that the oncohistone H3.1K27M disrupts the TSK/TONSL-H3.1 DNA repair pathway.

Coccolith-associated polysaccharides (CAPs) are central for the biomineralization of marine algae. Here, Leeet al. show that CAPs can be isolated from extant and fossil samples and that their uronic acid content can be used as a palaeoclimate proxy.

The discovery that DNA methylation of different CpG sites can serve as digital barcodes of clonal identity led to the development of EPI-Clone, an algorithm that enables single-cell lineage tracing through cellular differentiation at scale.

X-ray, cryo-EM and kinetic studies of the circadian oscillator KaiBC from the photosynthetic bacterium Rhodobacter sphaeroides shed light on the evolution of self-regulating oscillators.

In response to phage infection, the Toll/interleukin-1 receptor (TIR) domain protein ThsB of the type II Thoeris defence system produces histidine conjugated to ADP-ribose, which stimulates bacterial defence by interacting with the Macro domain of the ThsA membrane effector protein.

Axons have always been assumed to be cylindrical. Using in silico modeling and cryopreservation of tissues, Griswold et al. demonstrate that unmyelinated axons of the mammalian central nervous system exhibit pearls-on-a-string morphology through their entire length.

The role of IgG glycosylation in the immune response has been studied, but less is known about IgM glycosylation. Here the authors characterize glycosylation of SARS-CoV-2 spike specific IgM and show that it correlates with COVID-19 severity and affects complement deposition.

The molecular mechanisms that maintain thymic epithelial cell (TEC) identity throughout life are incompletely understood. Here, the authors demonstrate that the transcription factor, Ovol2, maintains post-natal TECs by preventing their epithelial-to-mesenchymal transition.

The PI3K–PANK4 axis regulates coenzyme A synthesis, the abundance of acetyl-CoA, and CoA-dependent processes such as lipid metabolism, and these regulatory mechanisms coordinate cellular CoA supplies with the demands of hormone and growth-factor-driven or oncogene-driven metabolism and growth.

Renee Reijo Pera, Vittorio Sebastiano and colleagues identify three human pluripotency-associated transcripts (HPATs) that function in preimplantation development. They find that these three HPATs are also required for efficient nuclear reprogramming and that one, HPAT5, interacts with let-7 to modulate gene expression during reprogramming and differentiation.

This paper shows that the yeast ubiquitin-like protein Urm1p is a sulphur carrier that modifies tRNA. It identifies a pathway whereby Urm1p is first adenylated by Uba4p, then is subsequently thiolated by Uba4p, after which the sulphur moiety is transferred from the thiolated Urm1p onto U₃₄ of a cytoplasmic adenylated tRNA.

New optical methods for investigating the activity of small molecules in cells may facilitate development of anticancer therapeutics. Here, the authors use a super-resolution optical platform and single molecule tracking to gain insight into WRN regulation in cancer.

Here it is shown that the NAD-dependent deacetylase SIRT2 is an essential component of necrosis, and that mouse hearts that do not contain SIRT2 or that are treated with a pharmacological inhibitor of SIRT2 are largely protected from ischaemic injury.

A DNA nanostructure can be used to create a multi-enzyme complex in which an artificial swinging arm facilitates hydride transfer between two coupled dehydrogenases.

Data from over 700,000 individuals reveal the identity of 83 sequence variants that affect human height, implicating new candidate genes and pathways as being involved in growth.

A genome-wide association study meta-analysis combined with multiomics data of osteoarthritis identifies 700 effector genes as well as biological processes with a convergent involvement of multiple effector genes; 10% of these genes express the target of approved drugs.

A deep learning model detects low frequency mosaic variants with improved accuracy.

Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.

This protocol from Fu et al. describes the use of self-assembled DNA nanostructures as assembly scaffolds to spatially arrange multienzyme complexes and probe their interactions.

Single-molecule optimization leads to a cartwheeling DNA walker with a more than tenfold improved stepping rate.

Mathieson et al. carried out a genome-wide association study of reproductive success (number of children born) in humans, revealing the importance of diverse neuro-endocrine and behavioural factors.

Antibody drug conjugates (ADCs) with pyrrolobenzodiazepine (PBD) payloads are promising cancer therapeutics but are limited by toxicity. Here, the authors develop a HER2-targeted ADC (DHES0815A) with a reduced potency PBD payload that demonstrated promising preclinical efficacy and nonhuman primate tolerability, but culminated in a phase I clinical trial in patients with metastatic breast cancer which was terminated due to toxicity.

Here, Xiao et al. isolate a large panel of antibodies against human metapneumovirus fusion protein from human B cells, and characterize their epitopes, neutralization activities, and antigen binding specificity, providing a useful framework for understanding the immune response against hMPV.

An analysis of the evolutionary distribution of predicted structures for the metamorphic protein KaiB using AF-Cluster reveals that both conformations of KaiB were distributed in clusters across the KaiB family.

Self-renewal and pluripotency of human embryonic stem cells (hESCs) depends upon the function of the transcription factor OCT4. Here, the authors identified proteins associated with the OCT4 enhancer, notably ZNF207 that maintains both pluripotency and differentiation towards ectoderm through isoform switching.

The source of biological toluene production in diverse anoxic microbial communities is a glycyl radical enzyme that catalyzes phenylacetate decarboxylation (PhdB), and its cognate activating radical S-adenosylmethionine enzyme (PhdA).

Dendritic cells are critical for initiation of immune responses and for induction of tolerance. Here the authors show that deletion of survival factor c-flip in CD11c-expressing cells subset perturbs CD8a⁺dendritic cell, NK and macrophage pools, and leads to development of autoimmune arthritis.

An inhibitor of the deubiquitinase (DUB) USP10 regulates the degradation of oncogenic FLT3, thus defining USP10 as a DUB for FLT3 and providing a therapeutic approach for human acute myeloid leukemia in which FLT3 activation is dysregulated.

Glycogen Storage Disease 1a (Gsd1a) is an inherited disorder caused by glucose 6-phosphatase (G6Pase-α) deficiency and characterized by hypoglycaemia and high risk of liver cancer. Here the authors develop a mRNA-based G6Pase-α delivery therapy that is efficacious and safe in a mouse model of GSD1a.