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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.

Macrophages play an important role in repair and regeneration of damaged nerves in spinal cord injury (SCI). Here, Guo et al. investigate effects of endoplasmic reticulum-mitochondria crosstalk on macrophage phenotype and develop a targeted nanorobot inhibiting the Ero1α/MAMs/mtCa²⁺ axis, promoting M2 polarization and neural repair as a therapeutic strategy to treat SCI.

Endosomal sequestration of lipid-based nanoparticles is a barrier to delivery of nucleic acids. Here the authors test an array of cholesterol variants and perform in-depth investigation of nanoparticle shape, internal structure and intracellular trafficking.

A newly published report reviews the techniques available for evaluating national performance in basic research and applies these techniques to solid state physics and genetics.

SpbK protects Bacillus subtilis from phage infection by depleting NAD⁺. In this study, the authors uncover the molecular mechanisms underlying SpbK’s self association-dependent NADase activity and its activation by the SPβ phage portal protein YonE.

Single, self-amplifying RNA molecules condensed by an oppositely charged polyelectrolyte self-assemble into compact globular nanoparticles that can be used as vaccines to generate potent immunological responses at low doses.

JWST imaged three of the gas giants orbiting the star HR 8799 to study their atmospheres. The uniform enrichment of heavy elements, including sulfur, indicates that they formed like Jupiter and Saturn by accreting a lot of icy and rocky solids.

The spatial and temporal control of material properties at a distance have been so far achieved with light, heat, or sound. Here, the authors control chemical reactions and further polymerization of composites with an electric field via inverse piezo-effect resulting in multi-stiffness gels.

Leder et al. show that the chaperones PDIA6, Hsp70 BiP, ERdj3, PDIA1 and Hsp90 form co-condensates within the endoplasmic reticulum, enhancing folding and preventing misfolding of client proteins.

The ESCRT pathway is crucial for membrane remodelling in eukaryotes. Here, Hatano et al. explore the phylogeny, structure, and biochemistry of homologues of the ESCRT machinery and the associated ubiquitylation system in Asgard archaea, the closest living relatives of eukaryotes.

Many properties of polymers are dictated by topology. However, the topology of a macromolecule is typically a static feature after synthesis. Now, an approach to dynamic and transformable macromolecular architecture has been developed. When triggered by an external stimulus, macromolecular topology can be triggered to transform via thermodynamic control.

The pathogen Orientia tsutsugamushi is an obligate intracellular bacterium that depends on host cell machinery for intracellular movement. Here, Manigrasso et al. provide insights into the molecular mechanisms by which the bacteria hijack the host’s microtubule networks to navigate within cells.

In meiosis, BRCA2 associates to MEILB2 localising at DNA double-strand breaks (DSBs). Here, the authors identify BRCA2 and MEILB2- associating protein 1 termed BRME1 to work together in regulating meiotic recombination.

The Hsp70/Hsp40 system plays an important role in maintaining cellular proteostasis but so far it is not well understood how Hsp70 proteins are recruited to specific Hsp40 co-chaperones. Here, the authors combine biochemical and biophysical approaches to characterise the oligomeric mammalian Hsp40 DnaJB8. They identify an intra-oligomer DnaJB8 interaction between the N-terminal J-Domain and the C-terminal domain that occludes the J-Domain surface that binds Hsp70 and propose a model for DnaJB8-Hsp70 recruitment.

Durable agonism of NPR1 achieved with a novel investigational monoclonal antibody could mirror the positive hemodynamic changes in blood pressure and heart failure identified in humans with lifelong exposure to NPR1 coding variants.

LARGE1 glycosyltransferase synthesizes matriglycan (xylose-glucuronate)_n on dystroglycan, and short matriglycan can cause neuromuscular disorders. Authors show that LARGE1 processively polymerizes matriglycan of defined length on prodystroglycan.

A targeted design to stabilize the respiratory syncytial virus prefusion F trimer enables the generation of a foldon-free immunogen that elicits similar humoral responses to approved vaccines.

Identifying jets originating from heavy quarks plays a fundamental role in hadronic collider experiments. In this work, the ATLAS Collaboration describes and tests a transformer-based neural network architecture for jet flavour tagging based on low-level input and physics-inspired constraints.

The integrated stress response (ISR) is the focus of numerous investigations and drug development programs. Here, the authors show that ATP-competitive inhibitors of ISR kinases PERK, PKR and GCN2 inhibit their targets but activate the ISR by directly binding to and activating a sister ISR kinase.

A novel antiviral targeting the SARS-CoV-2 PLpro protease shows strong efficacy in a mouse model, preventing lung pathology and reducing brain dysfunction. The study provides proof-of-principle that PLpro inhibition may be a viable strategy for preventing and treating long COVID.

Battery electrode binders are hard to image but strongly affect battery performance. Here, authors use silver and bromine staining to reveal common cellulose- and rubber-based binders in graphite and Si negative electrodes and identify processing that reduces electrode resistance.

Remote tumours cause liver dysfunction by releasing extracellular vesicles and particles containing palmitic acid, which induces TNF signalling in Kupffer cells, resulting in inflammation, fatty deposits and metabolic dysregulation, thus both reducing the efficacy and increasing the toxicity of chemotherapies.

High-resolution cryo-EM structures of a small heat shock protein reveal how client-induced scaffold destabilization promotes polydispersed higher-order assembly and cooperative sequestration, revealing insight into the structural basis of sHSP chaperone function under cell stress.

The CELSRs are cell-surface receptors with large extracellular regions (ECRs) essential for development. Here, the authors determine the structure of the CELSR ECR and define elements of the ECR important for CELSR-mediated cell adhesion.

The transmembrane export apparatus regulates protein secretion through bacterial type III secretion systems. New structural data indicate that MxiA, a major component of the apparatus, assembles in a nonameric ring. This and additional structural information provide a framework for understanding how protein secretion is controlled.

The molecular mechanism between each progesterone receptor (PR) isoform and oncogenic co-regulators SRC3 and p300 is poorly understood. Here, the authors report PR isoform-specific interactions with these co-regulators and antagonist-driven protein interactions, challenging the classical model of nuclear receptor activation.

The authors report an efficacious vaccine for human metapneumovirus based on a prefusion-stabilized fusion protein trimer that does not require a trimerization domain, designed using an AI convolutional classifier trained to predict optimized complex polar interactions.

The combination of a covalent electrophile with a peptide or protein-based scaffold enables the targeting of shallow protein surfaces, but the approaches to convert native peptide sequences into covalent binders are missing. Here, the authors report the design of protein-based thiomethacrylate ester electrophiles that can be installed on unprotected peptides and proteins via cysteine side chains and react efficiently and selectively with cysteine and lysine side chains on the target.

Human chromatin remodeller SMARCAD1 exhibits a substrate preference for subnucleosomal particles over the canonical nucleosome.

Here the authors uncover how a floppy tail in a protein acts as a remote switch, flipping activity on or off by tweaking internal motion, which reveals a powerful new way proteins regulate themselves without direct contact.

There is a lack of vaccines for prevention of human respirovirus 3 (RV3) infection. Bakkers et al. report the design of a stabilized RV3 preF protein vaccine candidate that induces strong neutralizing antibodies and protective responses in small animal models.

DNAJC12 variants cause parkinsonism. Here, the authors show that DNAJC12 stabilizes tyrosine hydroxylase, a crucial enzyme in dopamine synthesis, and identify key structural motifs for this interaction, explaining the pathogenesis of truncated variants.

PUF proteins, conserved stem cell regulators, maintain germline stem cells with partner proteins in nematodes. Here, authors discover a complex of two FBF-2 PUF proteins and partner LST-1 that represses target mRNA via adjacent regulatory elements.

This study reveals how two splice inserts alter the conformation and dimeric arrangement of the teneurin-3 extracellular region. These insights elucidate the role of teneurin isoforms in neuronal recognition and circuit wiring.

Here, the authors describe a tubular module connecting oxidoreductases to the membrane. This system, found in many microorganisms, reveals a distinct mode of membrane anchoring and an electron transfer mechanism involved in energy conservation.

The bacterium Brucella abortus is an intracellular pathogen that modulates autophagy in host cells. Here, the authors identify two B. abortus effectors that interact with host protease SENP3, thus promoting cytoplasmic accumulation of nucleolar proteins associated with ribosomal biogenesis and facilitating intracellular replication of the pathogen

Mutations in PCDH15 cause deafness and blindness in Usher syndrome 1 F, but gene therapy is difficult because the PCDH15 sequence is too large for AAV vectors. Here, the authors engineered a miniPCDH15 that fits in AAV and rescues hearing in mouse Usher syndrome 1F models.

N-terminal acetylation is a common eukaryotic protein modification that is primarily catalysed by the N-acetyl transferase complex A (NatA). Here, the authors present the crystal structure of NatA bound to Huntingtin yeast two-hybrid protein K (HypK) and show that HypK is a negative regulator of NatA.

High-throughput chemical ligand discovery is challenged by false positives. Here, authors introduce a scalable enantioselective affinity-selection mass spectrometry approach for proteome-wide ligand discovery with high sensitivity and selectivity

A polymer gel composite self-strengthens in response to mechanical vibrations due to activation of mechanically sensitive ZnO crosslinking agents in its matrix, in a process that resembles bone remodelling observed in animals.

Severe COVID-19 is associated with epithelial and endothelial barrier dysfunction, however, the molecular pathways resulting in endothelial barrier dysfunction and vascular leakage are only sparsely understood. Here, Biering et al. show that SARS-CoV-2 spike protein is sufficient to induce barrier dysfunction and vascular leak. They show a role for integrins, TGF-beta, ECM remodeling enzymes, and glycosaminoglycans in this S-mediated barrier dysfunction.

This study shows how the yeast Ctf4 protein couples the DNA helicase, Cdc45–MCM–GINS, to DNA polymerase α — the GINS subunit of the helicase and the polymerase use a similar interaction to bind Ctf4, suggesting that, as Ctf4 is a trimer, two polymerases could be simultaneously coupled to a single helicase during lagging-strand synthesis.

Stabilized, native-like trimers of the HIV envelope protein, such as SOSIP trimers, are potential antigens for an HIV vaccine. Here, the authors generate a SOSIP trimer based on the consensus sequence of group M isolates, determine its structure and exposure of common epitopes, and show immunogenicity in rabbits and non-human primates.

Interleukin (IL-)11 is a signaling protein that plays key roles in several human diseases. Here the authors describe structures of IL-11 in complex with its receptors and determine the molecular mechanisms through which a variant of IL-11 inhibits signalling, opening avenues for therapeutic development.

Amyloid-like proteins are central to age-related diseases, such as Alzheimer’s and Parkinson’s. Here, the authors show that transcription errors can produce mutant proteins with enhanced amyloid- and prion-like properties in human cells.

Antibody diversification relies on the intentional mutagenesis of immunoglobulin genes for adaptive immune responses. Here, the authors identified a CTLH E3 ubiquitin ligase complex that co-opts FAM72A to recruit and degrade the UNG2 base excision repair factor to permit mutagenesis.

The blood circulation time is important to the biomedical application of nanomaterials. Here, the authors explore the effect of protein corona formation on the blood residency of nanomaterials and show circulation times are governed by the dynamic remodelling of protein opsonins in vivo.

Cellular nuisance compounds are a burden in chemical biology and drug screening. Here the authors profile prototypical cytotoxic and nuisance compounds using the cell painting assay to systematically characterise cellular morphologies associated with compound-dependent cellular injury and nuisance activity.