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Macrocyclic peptides can be genetically encoded and synthesized in cells; however, the programmable diversity is limited. Now, macrocycles containing two non-canonical amino acids have been genetically encoded and synthesized in codon-reassigned Syn61Δ3 cells. Incorporating diverse hydroxy acids in Syn61Δ3 cells enables the synthesis of non-natural depsipeptides containing either one or two ester bonds.

The third variable (V3) loop on the HIV-1 Env glycoprotein is required for viral entry. Here, the authors applied DARPin technology to produce broadly neutralizing inhibitors targeting a region of V3 that becomes accessible after binding to the CD4 receptor.

Gorman et al. designed a Lassa virus prefusion-stabilized soluble glycoprotein complex trimer (GPC), with which they identified a Lassa virus-neutralizing nanobody that bound the GPC apex and elicited neutralizing antibody responses in guinea pigs.

Iridium oxide is the state-of-the-art catalyst for water oxidation in an acidic electrolyte. Now amorphous and crystalline iridium oxides are studied using operando time-resolved optical spectroscopy, together with other techniques, to reveal the nature and density of active centres and the role of adsorbate–adsorbate interactions.

Boronic acids are promising catalysts for the direct functionalization of alcohols without requiring precious metals. Here, the authors report an easily synthesized class of cyclic hemiboronic acid catalysts which are applicable in both nucleophilic and electrophilic modes of alcohol activation.

Measurements of the conformations adopted by isolated proteins at low temperatures show remarkable plasticity including substantial cold induced restructuring and complex frozen conformational landscapes for disordered proteins in the absence of solvent.

The upsurge of mpox has stimulated the development of new vaccines and therapeutics. Here, the authors describe a VLP vaccine comprised of modified MPXV proteins M1, A35, and B6 and demonstrate induction of protective antibodies in mice and non-human primates.

The nature of SEL1L-HRD1 ERAD substrates remains unclear. Here, the authors identified ~100 endogenous substrates, and showed that SEL1L-HRD1 ERAD is indispensable for the activity of GPI transamidase complex and the biogenesis of GPI-anchored proteins.

A lead-optimization strategy combining porin permeation properties and biochemical potency leads to development of a new class of antibiotic based on broad inhibition of penicillin-binding proteins from Gram-negative bacteria.

Here the authors describe a functional screening platform in human stem cells to identify and optimize protein-based gene editing additives that increase homologous directed recombination and have potential to improve gene therapy workflows.

The crystal structure of V1/V2, the only unresolved portion of the HIV-1 gp120 envelope glycoprotein, is reported in complex with human antibody PG9 and reveals a paradigm of antibody recognition with implications for vaccine development.

Chemotherapy resistance in recurrent gliomas is a large hurdle for successful therapy. Here, the authors show that some recurrent gliomas harbour O-6-methylguanine-DNA methyltransferase (MGMT) genomic rearrangements, and in vitro and in vivo these contribute to temozolomide resistance.

The conductance of single-molecule junctions is affected by the structure of the molecule and how it is bound to the electrodes, which may be examined using Raman spectroscopy. Liuet al. have developed 'fishing-mode' tip-enhanced Raman spectroscopy, which allows the simultaneous determination of conductance and Raman spectra.

Additions to alkenes and alkynes are useful routes for generating highly functionalized products. Here the authors report the 1,1-difunctionalization of alkynes through a CuH-catalysed asymmetric hydroboration/hydroamination cascade.

Nucleic acid superstructures are required to package genomes into the nucleus of cells. In this study, the superstructure of an RNA supercoil species is reported and is shown to be dependent on an RNA-binding protein that induces a higher level of organization compared with DNA superstructures.

The proteasome complexes, composed of 20S core particles and one or two regulatory particles (proteasome activators), degrade most eukaryotic proteins. Here, the authors identify a sequence motif and resolve its interactions mediating the activation of the human 20S proteasome.

The SARS-CoV-2 spike glycoprotein is flexible, and its receptor-binding domain (RBD) fluctuates between open and closed conformations. Disulfide bonds are engineered into the spike ectodomain to lock the RBD in the closed state, leading to a construct with high thermostability.

Seo et al. present an approach to regulate the formation and optoelectronic quality of the SnO₂ electrodes, improving electroluminescence and efficiency in perovskite solar cells.

Salt bridges between positively charged residues within the S4 transmembrane segment of the voltage-sensing potassium channel, Shaker, and acidic residues in S2 and S3 segments are not necessary during channel gating; rather, two of the acidic residues may occupy a hydrophilic water-filled vestibule that creates an energetically favorable environment for S4 movement during channel gating.

Net-zero bioplastics are possible when combined with high recycling rates. This study presents a mixed polyester recycling process integrated with monomer separation and purification for both fossil- and bio-based plastics. Techno-economic and life cycle analyses confirm its environmental and commercial advantages, advancing the path toward circular, low-emission polyester plastics.

Acetic acid efficiently depolymerizes aliphatic and aromatic epoxy-amine thermosets used in carbon fibre-reinforced polymers (CFRPs) to yield recoverable monomers and pristine carbon fibres, which, based on process modelling, techno-economic analysis and life cycle assessment, could enable industrial recycling of CFRPs.

Patients with classic Hodgkin lymphoma (cHL) respond well to PD-1 blockade, but the underlying cellular insights are still lacking. Here, the authors use single-cell transcriptome and spatial analyses to identify distinct circulating and tumor-infiltrating CD4⁺ T cell, B cell and IL1β⁺ monocyte/macrophage features associated with response to PD-1 blockade in cHL.

HORNET, a method that uses unsupervised machine learning and deep neural networks to analyse atomic force microscopy data enables structural determination of RNA molecules in multiple conformations.

Nsp15 is a uridine specific endoribonuclease present in all coronaviruses. Here, the authors determine the cryo-EM structures of SARS-CoV-2 Nsp15 in the apo and UTP-bound states, which together with biochemical experiments, mass spectrometry and molecular dynamics simulations provide insights into the catalytic mechanism of Nsp15 and its conformational dynamics.

The transcription factors TCF1 and LEF1 promote self-renewal and regulatory functions in B-1a cells.

The degree to which the conformation of the human metapneumovirus fusion (F) protein affects immunogenicity has been debated. Here, Hsieh et al. engineer prefusion-stabilized F variants with enhanced thermostability that elicit higher neutralizing antibody titers in mice than postfusion F.

Analysis of two homologous groups of fungal pericyclases demonstrates how they can catalyse either an Alder-ene reaction—which has not previously been found in nature—or a hetero-Diels–Alder reaction.

AKT inhibitors synergize with agents that suppress the histone methyltransferase EZH2 and promote robust tumour regression in multiple triple-negative breast cancer models in vivo by triggering an involution-like process.

A deep-learning-based strategy is used to design artificial luciferases that catalyse the oxidative chemiluminescence of diphenylterazine with high substrate specificity and catalytic efficiency.

Type IIA topoisomerases (topo2As) create transient double-strand DNA breaks. Here, the authors report structures showing how QPT-1 binds in the DNA/topo2A complex at the same site as the fluoroquinolone moxifloxacin, and discuss the potential for developing new classes of antibiotics.

The raptorial appendages of stomatopods are known to inflict large impact forces at high speeds, while exhibiting large damage tolerance. Here, the authors study the structure, distribution and nanomechanical properties of mineral phases in stomatopod's clubs, finding that calcium sulphate is co-localized with crystalline fluorapatite.

Understanding the pathology in the lungs of patients with COVID-19 might provide clues as to the susceptibility of patients and how the SARS-CoV-2 virus can be fatal. Here the authors analyze cadaveric pulmonary tissue and show one group with high viral load, early death, inflammation and inflammatory damage, and another with low viral load, longer duration of disease, and more M2-like polarization and fibrotic lung damage.

Knowledge on how antibody responses have evolved is critical for the induction of protective immunity. Here the authors analyse, using high-throughput sequencing of both exon and intron regions, the mutation and lineage development of an HIV-neutralizing antibody to find an unexpected early emergence of broadly neutralizing species.

The crystal structure of the full-length ileS T-box–tRNA complex from Mycobacterium tuberculosis provides a complete high-resolution explanation of tRNA decoding and aminoacylation sensing by this riboregulator.

Despite the development of inhibitors targeting active GTP-bound (ON) KRAS(G12C) for the treatment of KRAS G12C-driven non-small cell lung cancer (NSCLC), resistance remains an issue. Here, the authors show that despite inhibition of KRAS G12C ON, there is residual mTOR activity driving resistance, which was successfully targeted by combining with a selective mTOR inhibitor.

Bacterial symbionts of animals may contain antibiotics that are particularly suitable for development into therapeutics; one such compound, darobactin, is active against important Gram-negative pathogens both in vitro and in animal models of infection.

Tertiary lymphoid structures play important roles during homeostatic but also immunopathological conditions including autoimmune disorders. Here the authors integrate single cell sequencing with spatial proteomics and transcriptomics to define a cellular and spatial map of tertiary lymphoid structures in salivary glands of patients with Sjogren’s syndrome.

In this study, Flickinger et al. uncover the essential role of cytosolic NADK and why the relative importance of this role further depends on folate availability.

Despite growing interest in environmental metabolomics, we lack conceptual frameworks for considering how metabolites vary across space and time in ecological systems. Here, the authors apply (species) community assembly concepts to metabolomics data, offering a way forward in understanding the assembly of metabolite assemblages.

Probing the chemistry of transuranic elements is notoriously challenging. Now, three neptunium(III) organometallic sandwich complexes have been prepared using a flexible macrocycle as ligand, and their molecular and electronic structures characterized, adding to our understanding of the behaviour of f-elements and suggesting that the lower oxidation state Np(II) may be chemically accessible.

DNA Ligase IV (LigIV) catalyzes nick sealing of DNA double-strand break substrates during non-homologous end-joining. Here the authors present the crystal structures of two human LigIV DNA-bound catalytic states, which provide insights into its catalytic mechanism and the molecular basis of LIG4 syndrome causing disease mutations.

Ultrasound neuromodulation overcomes limitations of electrode-based stimulation through improved

targeting and long-term stability for treating neurological disorders. Here, authors present a hair-thin, implantable piezoelectric stimulator that selectively modulates neurons in the deep brain.

The structure of the bacterial toxin BinAB, which is used to combat mosquito-borne diseases, reveals pH-sensitive switches and carbohydrate-binding modules that may contribute to the larvicidal function of the toxin.

Ancestral sequence inference, directed evolution, structural analysis, NMR, and molecular dynamics simulations illuminate how enantioselective activity arises during the evolutionary trajectory of chalcone isomerase from a noncatalytic ancestor.

Streamlined data-driven drug discovery remains challenging, especially in resource-limited settings. Here, the authors present ZairaChem, an AI/ML tool that streamlines QSAR/QSPR modelling, implemented for the first time at the H3D Centre in South Africa.

Using RFdiffusion, a general method for targeting intrinsically disordered proteins and regions for protein design has been developed.

Hagenbeek et al. identify a small-molecule pan-TEAD inhibitor that blocks the interaction between YAP/TAZ and TEAD proteins. They demonstrate that treatment with the inhibitor leads to antitumor activity and can synergize with KRAS G12C inhibition.