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Base editing of the pathogenic trinucleotide repeat expansions underlying Huntington’s disease and Friedreich’s ataxia introduces repeat interruptions that reduce somatic expansion in patient cells and mice.

The hearing-loss phenotype can be corrected via the injection, into the inner ear, of a base editor packaged in an adeno-associated virus, as shown in mice harbouring a mutation homozygous to human OTOF and in humanized mice with the human mutation.

Nme2Cas9 has been well established as a genome editing platform. Here the authors engineer Nme2Cas9 to further increase the activity and targeting scope of compact Nme2Cas9 base editors and validate ___domain-inlaid Nme2-ABEs for single-AAV delivery in vivo.

Zhou et al. show that palmitoylation of GPX4 via ZDHHC8 sustains ferroptosis resistance in melanoma and other cancer cells and propose targeting ZDHHC8 with a small molecule to boost CD8⁺ T cell-induced ferroptosis, thereby improving immunotherapy.

DNA base editors can display off-target effects on DNA and RNA. Here the authors embed the base editing enzymes in the middle of nCas9 to reduce these without impacting on-target editing.

Atherosclerosis is associated with the dysregulation of lipid metabolism in vascular endothelial cells. Here, the authors show that the accumulation of lipid droplets in vascular endothelial cells disrupts endothelial ciliation and contributes to atherosclerosis by reducing cytosolic palmitic acid.

Off-target mutations that occur at a frequency below 0.5% can be difficult to detect. Here the authors use predicted off-target amplification to increase detection sensitivity.

Although compact Un1Cas12f1 has improved, low gene editing activity was observed in some target genes. Here, authors developed eCas12f1, which exhibits similar cleavage activity to SpCas9 and can be effectively applied in targeted therapy, demonstrating its potential as a powerful gene editing tool.

Determining the causal variants at GWAS loci is crucial for understanding genetic disease mechanisms. Here, the authors apply MPRA to perform non-small cell lung cancer (NSCLC) variant-to-function mapping at scale and propose distinct genetic architectures underlying NSCLC susceptibility.

OmiCLIP is a visual–omics foundation model that integrates histology and spatial transcriptomics. The associated Loki platform offers accurate and robust tools for alignment, annotation, cell-type decomposition and spatial gene expression prediction.

Analyses of multiple phylogenetic marker datasets of Asgard archaea provide insight into the transition from prokaryotes to eukaryotes, specifically placing eukaryotes within Asgard archaea and as a sister lineage to Hodarchaeales.

A base editor for precise adenine transversions is demonstrated in mouse embryos.

Noncoding variants in a TTTG microsatellite on 15q26.1 are identified in Japanese patients with childhood and adult-onset thyroid abnormalities. Functional analyses suggest that these variants affect the role of the microsatellite as a potential regulator of thyroid cell growth.

Melanocortin-1 receptor is a palmitoylated protein and variants of the receptor are associated with red hair colour and susceptibility to melanoma. Here, the authors describe a method to enhance the palmitoylation of the receptor, which can inhibit melanomagenesis in mice.

The protein modification palmitoylation increases the ability of variant forms of the melanocortin-1 receptor (MC1R) to induce pigmentation, and this is linked to reduced development of melanomas.

Analysis of the blood DNA virome in patients with COVID-19 and autoimmune disease associates endogenous HHV-6 (eHHV-6) and high anellovirus load with increased disease risk, most notably for systemic lupus erythematosus. eHHV-6 carriers show a distinct immune response.

Genetic mechanisms influencing COVID-19 susceptibility are not well understood. Here, the authors analyzed whole blood RNA-seq data of 465 Japanese individuals with COVID-19, highlighting thousands of fine-mapped variants affecting expression and splicing of genes, as well as the presence of COVID-19 severity-interaction eQTLs.

A genome-wide association study highlights a variant in DOCK2, which is common in East Asian populations but rare in Europeans, as a host genetic risk factor for severe COVID-19.

Fibrodysplasia ossificans progressiva is an ultra-rare genetic disorder with progressive heterotopic ossification. Yang et al develop different gene therapy approaches and show their efficacy in mouse models and in human induced pluripotent stem cells.

Analyses of genome and exome sequencing data identify rare coding and structural variants associated with atrial fibrillation and highlight genetic links between atrial fibrillation and cardiomyopathies.

N₂ reduction to ammonia typically requires transition metal catalysts, proceeding via a strong metal–nitrogen interaction. Now a Ba–Si orthosilicate oxynitride–hydride has been shown to function as a transition-metal-free catalyst for ammonia synthesis through an anion-vacancy-mediated mechanism, where electrons at the vacancy sites facilitate N₂ activation.

Synaptic vesicles are held in a fusion-competent state prior to their rapid release, which is thought to depend upon formation of trans-SNARE complexes. Takahashi et al. directly image this primed state using FLIM/FRET, and demonstrate differences in basal SNARE organization between neurons and β cells.

Solid organ transplant recipients are at increased risk of infectious disease and have unique molecular pathophysiology. Here the authors use host-microbe profiling to assess SARS-CoV-2 infection and immunity in solid organ transplant recipients, showing enhanced viral abundance, impaired clearance, and increased expression of innate immunity genes.

The authors identify V-161, a compound that inhibits enterococcal Na⁺-V-ATPase and reduces VRE colonization in mice. The high-resolution structure of V-161 reveals its action on the Na+ transport pathway, offering new therapeutic insights.

Dual-atom catalysts are promising for CO₂ reduction reactions; however, sluggish kinetics limit practical applications. Now, a Ni dual-atom catalyst has been synthesized, realizing efficient electrocatalytic CO₂ reduction with a CO partial current density of ~1 A cm² at >99% Faradaic efficiency.

This study identifies TTTCA- and TTTTA-repeat expansions in benign adult familial myoclonic epilepsy. Cortical neurons from affected people exhibit RNA foci containing these expanded repeats, suggesting RNA toxicity as the mechanism underlying disease pathogenesis.

Voltage-gated Na+ channel β-subunits are concentrated in the nodes of Ranvier and axon initial segments of myelinated axons and have a variety of functions. Here the authors show, using genetically modified mice, that this subunit is present in unmyelinated fibres in the striatum and is required for generation of resurgent Na+ current in striatal neurons.

Splicing of transcripts containing micro and small exons requires specific factors. This study shows that GRP20 regulates micro- and small-exon retention of transcripts including floral homeotic genes, whose splicing is crucial for flower development.

The role of immune-tumor cell interactions in lung adenocarcinoma (LUAD) development remains to be explored. Here, spatial transcriptomics and in situ RNA profiling of samples from 30 LUAD patients reveals changes in the phenotypic properties of tumors cells associated with changes in immune cell features.

Peripheral blood mononuclear cells from 73 Japanese patients with coronavirus disease 2019 (COVID-19) and 75 healthy controls were analyzed using single-cell transcriptomics. Combining these data with genotyping data highlights the interplay between host genetics and the immune response in modulating disease severity.

A mechanism of mechanosensation and transduction in the presynaptic boutons is identified, in which sensing of fine pressure leads to enhanced neurotransmitter release.

Orexin signaling is provided by diffusely distributed fibers and involved in different brain circuits that orchestrate sleep and wakefulness states. Here, the authors show that a proportion of orexin neurons project to the sublaterodorsal tegmental nucleus and exhibit rapid eye movement (REM) sleep-related actions.

Here, the authors develop a PMO-based heteroduplex oligonucleotide technology that enhances PMO delivery to tissues and normalizes motor/cardiac function and CNS symptoms in a mouse model of Duchenne muscular dystrophy.

Epithelial cells can use an immune-like mechanism to extrude neighboring precancerous cells; however, the recognition and control mechanisms of this process are unclear. Maruyama and colleagues demonstrate that LILRB3 on normal epithelial cells recognizes elevated MHC class I on transformed cells and triggers the extrusion process.