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RNAi therapy has huge potential but effective delivery to target location is a major issue. Here, the authors report on the delivery of RNAi to tumors using self-agglomerating nanohydrogels that can overcome the different delivery barriers and supply multiple RNAi payloads.

In mice, a SPOCD1–TPR-dependent ‘nowhere-to-hide’ mechanism is required for complete non-stochastic piRNA-directed LINE1 DNA methylation by preventing transposons from escaping surveillance within heterochromatin.

DNA damage threatens genome stability, but its dynamics in living systems remain difficult to track. Here, the authors engineer MCPH1-based protein probes that specifically recognize γH2AX, enabling real-time visualization and mapping of DNA damage across diverse cellular and organismal contexts.

The authors show that RALF22 has a dual role in cell wall assembly in root hairs: as a structural component organizing cell wall architecture and as a feedback signalling molecule that regulates this process depending on its interaction partners.

While neutrophils are the first line of defence against infections and inflammation, their unrestricted recruitment and constant activation might result in prolonged inflammation and sharpening of specific pathological conditions. Here the authors develop a strategy to specifically target activated, pro-inflammatory neutrophils and neutrophil–platelet complexes to deliver therapeutics in the context of a murine model of venous thrombosis.

Pcm1 bridges centrosome asymmetry and polarized endosome trafficking to regulate radial glia progenitor fate decisions, balancing self-renewal and differentiation in zebrafish and human cortical organoids.

The actin cytoskeleton is built from actin monomers encoded by seven almost identical genes. Here, the authors show that individual actin isoforms cannot substitute for each other and make specialized contributions to cell division.

Multiplexable barcodes for electron microscopy are applied to brain imaging.

Evidence exists that the typically antiviral signaling mediator STING is, counterintuitively, needed for optimal human rhinovirus infection. Here the authors confirm this finding and show how human rhinovirus can reduce stored Ca2⁺ levels to drive this effect.

Membrane trafficking is essential for organelle biogenesis. Here, the authors discover an alternative assembly of the Commander trafficking complex and show its role in melanosome biogenesis and in a subtype of albinism.

Chiu et al. show that hypo-osmotic conditions, which induce glycerol efflux, and glycerol levels regulate the conformation and localization of the golgin Imh1, adding a layer of regulation by which glycerol affects Golgi integrity.

Death-inducer obliterator 3 (DIDO3) and PHD finger protein 3 (PHF3) are paralogue proteins that regulate transcription elongation by docking onto phosphorylated serine-2 in the C-terminal domain (CTD) of Pol II through their SPOC domains. Here the authors characterize the interplay of these proteins and show that they coregulate neuronal target genes.

Fluorescence-quenched substrates, which accurately report on glycoside hydrolase activity, provide real-time activity measurements on α-GALA and α-NAGAL, including in fibroblasts from patients with linked lysosomal storage diseases.

Integrative anatomical, molecular, behavioral, and modeling evidence suggests that higher dopamine D1 receptor expression in prefrontal cortical parvalbumin neurons in marmosets likely contributes to their higher distractibility relative to macaques.

MICU1 is a regulatory subunit of mitochondrial Ca²⁺ channels that shields mitochondria from Ca²⁺ overload. Here the authors show that MICU1 methylation by PRMT1 reduces Ca²⁺ sensitivity, which is normalized by UCP2/3, re-establishing mitochondrial Ca²⁺uptake activity.

Migrating cancer cells are round or elongated, and it is thought that the differently shaped cells invade surrounding tissue using different mechanisms. Here, Orgaz et al. show that the round cells secrete matrix metalloproteinases, which allow them to degrade surrounding connective tissue more effectively than elongated cells.

Fougère, Grison et al. show that the ER–Golgi intermediate compartment (ERGIC) in plants is a tubulo-vesicular network marked by MEMBRIN proteins that is largely Golgi-independent. The plant ERGIC matures into Golgi cisternae, in a process that depends on sphingolipids.

Myosin motors perform many fundamental functions in eukaryotic cells by providing force generation, transport or tethering capacity. Here, the authors show that a single phosphorylation event can modulate actin-activated ATPase activity and change the mechanical properties of myosin-VI.

FUT10 and FUT11, originally annotated as α1,3-fucosyltransferases, are actually protein O-fucosyltransferases participating in a non-canonical ER quality control pathway for EMI domain-containing protein secretion.

Accurate repair of DNA damage is crucial for genome stability and preventing disease. Here, the authors adapt single-cell omics technologies to map the location of repair proteins across the human genome, showing formation of multi-way chromatin hubs in response to damage.

CD103⁺ T cells are associated with control over tumors but how this is mediated is unclear. Here the authors show that CD61 colocalizes and functionally combines with CD103 in the T cell synaptic response to promote antitumor T cell responses.

Fernandes, Angelidaki et al. provide evidence supporting the spatial separation of mTORC1 activation and signalling. Differentially localized mTORC1 complexes phosphorylate distinct substrates in response to different amino acid supplies.

In response to amino acid and growth factor removal the TSC1/2 complex translocates to the lysosome to inactivate mTOR and inhibit cell growth. Here, the authors have shown that other cellular stresses also trigger this translocation to the lysosome suggesting that this is a universal mechanism in the stress response.

In the CNS, glutamatergic neurons directly control functional hyperemia via synaptic-like transmission onto arteriolar smooth muscle cells. Inhibiting this process reduces brain atrophy following cerebral ischemia.

Long-lived molecular collision complexes — or ‘resonances’ — are difficult to identify experimentally. Now crossed-beam experiments and quantum calculations are reported for rotationally inelastic CO−He collisions at energies corresponding to temperatures as low as 4 K. Quantum dynamical resonances that are predicted by theory were detected and fully characterized.

Savan and colleagues show that distinct isoforms of the RNA-binding protein ZAP function as an antiviral restriction factor or as an interferon-resolution factor, based on differences in their intracellular localization.

In this manuscript the authors show that Filopodia switch between bundles of fascin-crosslinked actin and cofilin-decorated filaments, which exclude fascin binding due to altered structure and packing, as well as affect filopodial searching dynamics.

Castellani, Zhang and colleagues found that centromeres and (epi)genetic features influence local crossover positions during meiotic recombination in a plant with diffused centromeres, whereas chromosome synapsis dynamics seems key to broad-scale crossover patterning.

Reliable intracellular delivery of antibodies is one of the grand challenges in biomedical research, with the potential to address unmet clinical needs or to enable basic research. Now, it has been shown that tricyclic peptide complexes can transport functional antibodies into the cytoplasm and nucleus of cells to specifically target intracellular proteins.

Nicastro, Brohée et al. find that the fatty acid synthesis intermediate malonyl-CoA inhibits mTORC1, showing mTORC1 senses the capacity of a cell to synthesise fatty acids and linking fatty acid generation with the overall biosynthetic output through mTORC1.

Self-derived DNA may trigger interferon-driven autoinflammation mediated by the cGAS-STING axis. Here, the authors find that mutations in the GTPase ARF1 cause an interferonopathy by promoting aberrant mitochondrial DNA release and impairing STING recycling.

Calcium signals initiated by IP3 receptors in ER membranes regulate most cellular activities. Here, the authors show that KRas-induced actininteracting protein (KRAP) tethers a small subset of IP3 receptors to actin and licenses them to evoke cytosolic calcium signals.

Claudin family proteins are important for regulating epithelial barrier function. Here the authors show that claudin-23 controls paracellular flux by combining with other claudins to alter tight junction architecture and permeability.

In this work, the authors investigated the cellular mode of prion propagation. The report that proteopathic seeds of abnormal PrP are N-terminally truncated and detected within minutes after infection. These seeds reach the plasma membrane by regulated secretory pathways where phenotypically distinct fibril-like PrP aggregates are formed with a lag of 24 h after infection.

Release of glutamate at high frequency involves a distinct subset of synaptic vesicles made by adaptor protein AP-3. Sorting of the phospholipid flippase ATP8A1 by AP-3 confers release at high frequency by recruiting synapsin to synaptic vesicles.

Daly, Danson and colleagues employ a multi-omic approach in neuroglioma cells to characterise endolysosomal dysfunction caused by perturbation of the evolutionarily conserved Retromer complex, highlighting Retromer’s neuroprotective function.

Here the authors establish the SPOC domain as a universal reader of the RNA Pol II CTD code and a versatile reader of phosphoserine marks found in co- and post-transcriptional regulators such as m6A writer and reader proteins.

Plasmodium falciparum is known to secrete an aspartic protease called plasmepsin X. Here, Triglia et al present a characterisation of plasmepsin X function in the context of erythrocyte invasion and its regulation of PCRCR, a complex that anchors the leading vaccine candidate PfRh5 to the parasite surface.

Endocytosis and degradation of plasma membrane proteins in the axon initial segment, together with the diffusion-barrier mechanism, maintain a polarized distribution of plasma membrane proteins in Caenorhabditis elegans, mouse, rat and human neurons.

Cell clusters mechanically reorganize viscoelastic collagen networks, resulting in transient gradients in collagen density, alignment and stiffness that promote spontaneous persistent migration.

Dick and colleagues identify human LT-HSC subsets with distinct quiescent states. They link these differences to INKA1-mediated downregulation of the transmembrane protein CD112 and its interaction with the protein deacetylase SIRT1. INKA1 is inversely correlated with the histone H4K16Ac mark, which then distinguishes ‘latent’ CD112^lo LT-HSCs from CD112^hi LT-HSCs that are more readily activated in response to hematopoietic stress.

Lanna and colleagues discover extracellular vesicle-mediated transfer of telomeres from antigen-presenting cells to T cells, which enables elongation of chromosomes, protection against replicative senescence and long-term immune defence.

Several proteomic approaches allow the analysis of covalent protein SUMOylation, but it remains challenging to systematically study the consequences of a substrate being modified. Here, the authors combine proximity biotinylation and protein-fragment complementation to identify SUMO-dependent protein interactors.