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The excitatory neuron diversity and specialized connectivity of complex, multilayered mammalian neocortex are driven by mammalian-specific cis-regulatory elements bound by ZBTB18, deletion of which disrupts gene expression and results in projection patterns resembling those of non-mammalian brains.

Age-related microbiome changes increase medium-chain fatty acid-producing bacteria, driving GPR84-mediated myeloid inflammation, impaired vagal signalling and hippocampal dysfunction; targeting this gut–brain pathway restores memory in aged mice.

Heparan sulfate proteoglycans facilitate the assembly of clusters of glycoRNAs and cell surface RNA-binding proteins, which negatively modulate VEGF-A signalling and angiogenesis.

Li and colleagues show that the transcription factor ZFP148 restrains the differentiation of antigen-specific CD8⁺ T cells toward cytolytic effector cells by repressing the expression of KLF2.

The contribution of ether lipid species in cancer cell fate has not been fully understood yet. Here the authors show that malignant cancer cells employ ether lipids to modulate membrane biophysical properties, enhancing iron endocytosis and ferroptosis susceptibility.

Massively parallel reporter assays across five cell types identify thousands of causal, noncoding regulatory variants among 220,000 loci, revealing diverse regulatory mechanisms shaping complex traits and disease.

A 3D soft electronic mesh allows high-resolution electrical recording and stimulation across the full surface of neural organoids, enabling long-term studies, drug testing and optogenetic control without compromising their viability owing to its porous design.

Sabatino and colleagues examine expanded CD8⁺ T cell clonotypes from a small cohort of multiple sclerosis patients. They identified several cognate peptide epitopes that derive from Epstein–Barr virus, suggesting EBV reactivation may drive pathogenesis in these patients.

The authors demonstrate that targeted protein degradation of the dengue virus capsid suppresses infection through capsid-dependent pathways rather than classical inhibition, revealing a new antiviral strategy effective against resistant viral variants.

TnpB endonucleases are engineered for improved genome editing.

This manuscript from Choquette and colleagues finds that sclerostin gene expression is up-regulated in bone by β3-adrenergic signaling via an adipose to bone relay and acts as an endocrine factor to inhibit adipose tissue beiging in mice.

Li, Cui, Yang, Lu, Jiang, Zhang and colleagues identify a lactate transport mechanism from tumour-associated macrophages that regulates DNA repair and immune cell infiltration, which could be targeted to enhance immunotherapy efficacy in glioblastoma models.

A generative modeling framework enables large-scale designed DNA synthesis, yielding candidate cell therapies.

Most patients with B-cell leukemia respond to chimeric antigen receptor T cell (CAR T) therapy, yet many relapse due to loss of CAR T function. Here, the authors show that the metabolism of CAR T from short- and long-term responders is different, which may explain why CAR T lose functionality.

Post-transcriptional regulation of mRNA translation was explored using Ribo-STAMP and single-cell RNA sequencing to reveal cell-type-specific and isoform-specific translation patterns across hippocampal neuronal and non-neuronal cell types, highlighting functional differences between CA1 and CA3.

The authors developed an LXR inverse agonist, TLC-2716, and show it is effective in reducing triglycerides and cholesterol in dysmetabolic preclinical models. Additionally, a phase 1 trial in healthy participants shows that TLC-2716 is well tolerated and reduces plasma triglycerides and postprandial remnant cholesterol, highlighting its potential for managing cardiovascular risk.

KRAS is an oncogene that switches between a GDP-bound inactive state and a GTP-bound active state. Recently developed KRAS G12C inhibitors are specific to the GDP-bound inactive state. Here, the authors develop a class of covalent KRAS G12C inhibitors capable of targeting both states for the treatment of KRAS-driven cancer.

A method termed ac⁴C-seq is introduced for the transcriptome-wide mapping of the RNA modification N⁴-acetylcytidine, revealing widespread temperature-dependent acetylation that facilitates thermoadaptation in hyperthermophilic archaea.

Chimeric antigen receptor T (CAR-T) cell therapy uses engineered donor T cells to recognize and eliminate cancer cells through cognate antigen-dependent activation. Here authors develop an alternative to bead-based or cancer-cell-induced CAR-T cell activation by presenting the antigen on the surface of engineered yeast cells, which allows precise regulation of antigen density.

Cas12a3 nucleases constitute a distinct clade of type V CRISPR–Cas bacterial immune systems that preferentially cleave the 3′ tails of tRNAs after recognition of target RNA to induce growth arrest and block phage dissemination.

Langstein-Skora, Schmid, Huth et al. propose that intrinsically disordered region functionality can be driven by the interplay between linear binding motifs and contextual chemical characteristics such as charge and hydrophobicity.

Inherited mitochondrial DNA mutations can result in diverse clinical phenotypes. Here, the authors characterise a heteroplasmic tRNA^Ala mutation (m.5019A>G) in mice and demonstrate that macrophages carrying this mutation display altered function and metabolism in vitro, along with increased type I IFN release following LPS challenge in vivo.

Cell surface receptors perceive immunogenic elicitors, triggering downstream signalling via receptor-like cytoplasmic kinases such as BIK1. Here the authors define and use the phosphorylation motif of BIK1 to find novel substrate candidates.

Lin, Geng and colleagues identify a non-canonical AHR pathway that is activated by canonical AHR inhibitors, promoting the proliferation of quiescent endothelial cells with potential applications in cell therapy.

Elyaman and colleagues performed comparative single-cell transcriptomic and TCR repertoire analyses on T cells obtained from human cadaver brain and leptomeningeal tissues from individuals diagnosed with neurodegenerative disease.

Here the authors identify the granin hormone SCG2 as a ligand for the inhibitory receptor LILRB4. They show that SCG2 released from tumors can suppress antitumor immune responses via this interaction, indicating possible therapeutic strategies.

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.

The specifics of the pediatric immune response that gives rise to antibodies capable of neutralising diverse HIV-1 strains is not fully understood. Here the authors characterise the immune environment of Simian-HIV infected paediatric macaques and link to antibody neutralisation induction.

EGF-induced recruitment of UPF1 adjacent to HNRNPC induces splicing surveillance of cell proliferation mRNAs.

Lipid nanoparticle based mRNA vaccines are known to induce robust CD4 + T cell responses. Here the authors establish a role of endogenously derived antigen processing in the optimal priming of CD4 + T cell responses to mRNA lipid nanoparticle vaccines.

Neuropathic pain is commonly treated with opioids due to limited alternatives. Here, authors determine cryo-EM structures of the neuronal glycine transporter GlyT2 and develop a reversible inhibitor that provides analgesia in vivo without side effects.

Turley and colleagues find that Gremlin1-expressing lymph node fibroblastic reticular cells support dendritic cell homeostasis via provision of FLT3L.

Dietary restriction promotes the expansion of effector T cells via ketone bodies, which enhances anti-tumour immunity and synergizes with immunotherapy in mice.

A detailed spatiotemporal roadmap of the human female and male reproductive tracts during key periods of sexual differentiation provides new cellular and molecular insights into how early axial gradients lead to specific cell lineages and tissue structures.

A web tool enables the rapid design of prime-editing guide RNAs from reference and edited DNA sequences, for diverse prime-editing applications.

An approach combining BONCAT, stable isotope probing and metaproteomics showcases the hidden metabolic interconnectivity of microorganisms within an anaerobic digestion community.

Excised signal circles are circular DNA by-products of V(D)J recombination that form a complex with the V(D)J recombinase, and when increased in abundance, result in increased mutagenesis, causing adverse outcomes in cancer.

N-glycans on glycoRNAs prevent innate immune sensing of endogenous small RNAs, and the natural mechanism they use demonstrates how glycoRNAs exist on the cell surface and in the endosomal network without inducing autoinflammatory responses.

Achieving tight Cas9 regulation without sacrificing activity remains difficult. Here, the authors design multi-level circuits combining anti-CRISPRs, splice sites, chemical induction, and degron control to enable ultra-high dynamic range and precise, on-demand genome editing across contexts.

H5N1 avian influenza viruses caused an outbreak in dairy cattle. We show that the potential for avian viruses to replicate in cow cells varies across H5N1 evolution, suggesting that the risk of spillover into mammals differs between variants.

Gao, Nowak-Imialek, Chen et al. generate porcine and human stem cells that possess expanded developmental potency for both embryonic and extra-embryonic cell lineages.

The authors previously pinpointed OLAH (oleoyl-ACP-hydrolase) as a driver of life-threatening viral diseases. Here, the authors identify increased IL-18Rα expression on CD8⁺ T cells, which acquire a reduced cytotoxic signature, correlates with severe respiratory viral infection of influenza A virus, RSV and COVID-19.

Chen et al. present EMRAge, a biological age measure built using electronic medical records, and OMICmAge, a multi-omic signal superimposed on DNA methylation. Both measures show strong associations with disease and mortality in validation cohorts.

This study presents a splice-based selection method that enriches actively editing cells in base editing screening at target loci, reducing the number of unedited cells from over 40% to less than 10%.

Chronic alcohol use in humans and mice downregulates small intestinal mAChR4 and reduces goblet-cell-associated antigen passage formation, disrupting antimicrobial immunity.