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Exo-selective Diels–Alderases with a broad substrate scope for synthetically valuable reactions are lacking. Now, a highly exo-selective Diels–Alderase compatible with a wide range of diene and dienophile substrates is discovered, its X-ray structure solved and the catalytic mechanism defined.

Epithelial cells that line the gut secrete complex glycoproteins that form a mucus layer to protect the gut wall from enteric pathogens. Here, the authors provide a comprehensive characterisation of endo-acting glycoside hydrolases expressed by mucin-degrading members of the microbiome that are able to cleave the O-glycan chains of a range of different animal and human mucins.

Enzymatic Diels–Alder reactions are of high synthetic interest, but mechanistic insights remain scarce. Now, a structure of the Diels–Alderase CghA in complex with its product is reported, a catalytic mechanism proposed and the enzyme is engineered to form the energetically disfavoured exo adduct.

Three-body low-energy s-wave states play an important role in few-body physics and associated universal phenomena, yet their experimental observation in nuclear system has been elusive. Here, the authors identify the three-body s-wave properties in neutron-rich ¹⁰He nuclei with improved statistics and sensitivities.

Natural products populate areas of chemical space not occupied by average synthetic molecules. Here, an analysis of more than 180,000 natural product structures results in a library of 2,000 natural-product-derived fragments, which resemble the properties of the natural products themselves and give access to novel inhibitor chemotypes.

Lysosome positioning is essential for cell metabolism and stress responses. Here, the authors show that the TMEM55B-associated protein TBC1D9B controls lysosome positioning, autophagy, and starvation-induced degradation by serving as a GTPase activating protein of ARL8B

Endocannabinoids are involved in regulating neural progenitor cell proliferation, as well as neuronal and glial differentiation. In this Review, Maccarrone, Harkany and colleagues discuss mechanisms of endocannabinoid signalling, the action of plant cannabinoids in the foetal brain, and their exploitation to modulate diseases associated with defective cell cycle control, particularly cancer.

Cycloaddition reactions are among the most useful reactions in chemical synthesis, but biosynthetic enzymes with 2 + 2 cyclase activity have yet to be observed. Now it is shown that a β-barrel-fold protein catalyses competitive 2 + 2 and 4 + 2 cycloaddition reactions. This protein can be engineered to preferentially produce the exo-2 + 2, exo-4 + 2 or endo-4 + 2 product.

Dynamic S–S bonds have been leveraged in a variety of applications. Now trisulfides have been found to undergo rapid and spontaneous S–S metathesis in polar aprotic solvents. A mechanistic investigation of this unusual reaction enabled applications in natural product modification, dynamic combinatorial library synthesis and chemically recyclable polymers.

CD1a presents a broad repertoire of lipid-based antigens. Rossjohn and colleagues show that the TCR docks over CD1a in a manner that precludes contact with permissive antigens, while nonpermissive antigens disrupt the TCR-CD1a contact.

The [1,2]-Wittig rearrangement of allylic ethers is traditionally considered to proceed via formation and recombination of radical pairs. Now it has been shown that an alternative reaction cascade, involving initial enantioselective [2,3]-rearrangement followed by base-promoted anionic fragmentation–recombination that proceeds with high enantiospecificity, allows a catalytic enantioselective [1,2]-Wittig process.

Stratified medicine promises to tailor treatment for individual patients, however it remains a major challenge to leverage genetic risk data to aid patient stratification. Here the authors introduce an approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue-specific gene expression levels, and highlight its ability to identify biologically meaningful and clinically actionable patient subgroups, supporting the notion of different patient ‘biotypes’ characterized by partially distinct disease mechanisms.

Biological sex affects all aspects of animal physiology. Using the model C. elegans, the authors show that metabolomes are highly sex-specific and include a vast space of yet unidentified metabolites that may control development and lifespan.

Ndeh et al. show that a genetic locus in the human gut bacterium, Bacteroides thetaiotaomicron, encodes a combination of glycosidases, a glycoprotease and a kinase enabling it to process and metabolise O-glycoproteins and the core mucin O-glycan sugar N-acetylgalactosamine.

Here, the authors show that 2’-O-methylated RNA fragments from ribosomal RNA naturally block TLR7 and TLR8, helping to avoid avoid harmful self-RNA detection and autoimmunity.

Metastatic clear cell renal cell carcinoma has a poor prognosis. Here, the authors use single cell RNA-seq to show a distinct gene expression signature in the primary tumour of metastatic patients, and highlights immune cell receptor interactions as potential therapeutic targets.

Hegazy and colleagues demonstrate that epithelial oncostatin M receptor expression drives gut inflammation and tumor formation.

This study presents a living systematic review and open-data meta-analytic database from 15 randomized controlled trials examining the effects of psilocybin treatment on depressive symptoms. Existing evidence suggests that psilocybin treatment alleviates depressive symptoms.

Stereoselective carbon-carbon bond formation via palladium-catalyzed asymmetric allylic alkylation is important to access chiral natural products but commonly used catalyst systems often require high loadings or specific preactivation protocols. Here, the authors report several chiral single-component Pd(0) precatalysts that are active at low loadings for a variety of asymmetric allylic alkylation reactions.

Preliminary clinical trials suggest that ibogaine and its active metabolite noribogaine have powerful anti-addictive properties, Now, a strategy for the scalable, asymmetric total synthesis of ibogaine has been developed that also provides access to iboga analogues. Biological testing identified a psychoplastogenic iboga analogue that is a potent modulator of the serotonin transporter.

Non-covalent and covalent chemistry can be controlled by using synthetic tools, such as templates. However, selective multicomponent self-assembly remains challenging because of the many kinetic intermediates with trap-state abilities, hampering access to desired products. Now exo-templating via pseudorotaxane formation has been shown to reduce pathway complexity in the multicomponent self-assembly of M₁₂L₂₄ nanospheres.

In Bacteroidetes, SusCD complexes mediate uptake of large nutrients across the outer membrane. SusCD structures in the apo state and in complex with β2,6 fructo-oligosaccharides reveal several substrate molecules in the binding cavity and suggest details of the pedal bin mechanism employed in glycan import.

Meta-analyses of genome-wide association studies for endometriosis identify 49 distinct association signals. Fine-mapping of causal variants explores functional effects across various tissues. Genetic correlations between endometriosis and other pain conditions are also highlighted.

Red blood cells (RBCs) are phagocytosed in the spleen in sickle cell disease and malaria. Here, Cao et al. show that high mannose N-glycans, exposed on diseased or oxidized RBC surfaces, bind mannose receptor CD206 on host cells, mediating phagocytosis.

The human gut microbiota helps us to degrade complex dietary carbohydrates such as xylan and, in turn, the carbohydrate breakdown products control the structure of the microbiota. Here the authors characterize the xylan-degrading apparatus of a key member of the gut microbiota, Bacteroides ovatus.

A de novo designed zinc-binding protein has been converted into a highly active, stereoselective catalyst for a hetero-Diels–Alder reaction. Design and directed evolution were used to effectively harness Lewis acid catalysis and create an enzyme more proficient than other reported Diels–Alderases.

The gut microbiota member Bacteroides thetaiotaomicron can utilize various complex N-glycans, including those from immunoglobulins, via a complex and diverse set of enzymes encoded by multiple non-adjacent loci.

Potential toxicity from cationic moieties and limited organ tropism are two challenges faced by current mRNA delivery vehicles. Here, authors develop non-cationic, highly biocompatible metal–organic nanoparticles that enable robust mRNA expression in vivo with tunable organ tropism.

CRISPR base editing enables the precise introduction of single-nucleotide mutations in the genome. Here, authors generated new adenine/cytosine base editor dataset and proposed a deep-learning model CRISPRon-BE for base editor efficiency prediction, thereby enhancing base editing applications.

Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

LepI is an S-adenosylmethionine-dependent pericyclase that catalyses the dehydration, hetero-Diels–Alder reaction and retro-Claisen rearrangement reactions that occur in the formation of the 2-pyridone natural product leporin C. Now, the mechanistic details that underpin this range of catalytic reactions have been uncovered from the crystal structures of LepI and LepI in complex with ligands.

[10]annulene derivatives are typically non-planar and non-aromatic, with aromatic planar variants suffering from kinetic instability. Now, the synthesis of a planar and aromatic dehydro[10]annulene featuring a fused cyclopropane and an internal alkyne is reported. The resulting hydrocarbon is bench stable and can be stored for extended periods of time.

During development of eutherian females, one of the X-chromosomes is silenced. Here, authors show that alleles on the inactive X-chromosome are dynamically expressed along neural differentiation enhancing resilience of female neural tissue.

Periselective catalytic asymmetric cross-Diels–Alder reactions between two different conjugated dienes remain underdeveloped. Now, the selectivity challenges are overcome in such a reaction of electron-poor 2-pyrones and unactivated conjugated dienes, and an ambimodal transition state is identified.

Chemoenzymatic synthesis of glycopeptides enables the identification of glycan specificity of two broadly neutralizing antibodies against HIV-1.

Fatty acid desaturation is central to metazoan lipid metabolism. Here, using C. elegans as a model, the authors show that both endogenous and microbiota-dependent small molecule signals converge to promote lipid desaturation via the nuclear receptor NHR-49/PPARα.

Alkenes are essential functional groups in organic chemistry, featuring well-defined geometries and bond orders of 2. In this study, cubene and 1,7-quadricyclene are calculated to possess unusual hyperpyramidalized geometries and low alkene bond orders near 1.5. Their resultant high reactivities ultimately permit access to intricate scaffolds and new chemical space.

This study demonstrates the capability of deep learning protein design models in generating functionally validated β-strand pairing interfaces, expanding the structural diversity of de novo binding proteins and accessible target surfaces.

The cytosolic ubiquitin ligase Nedd4-1 is known to promote autophagy. Here, the authors characterize a primate-specific splice isoform, Nedd4-1(NE), that is localized to late endosomes in the presence of amino acids, where it inhibits autophagy.

Rossi and colleagues assemble an in vitro enzymatic pipeline using enzymes from distinct domains of life to recapitulate eukaryotic N-glycosylation. This work advances the synthesis of bespoke glycopeptides with biomedical and biotechnological applications.

Human gut bacteria can degrade arabinoxylans, polysaccharides found in dietary fiber. Here, Pereira et al. identify a bacterial gene cluster encoding esterases for degradation of complex arabinoxylans. The action of these enzymes results in accumulation of ferulic acid, a phenolic compound with antioxidative and immunomodulatory properties.

The variability in clinical outcomes of SARS-CoV-2 infection is partly due to deficiencies in production or response to type I interferons (IFN). Here, the authors describe a FIP200-dependent lysosomal degradation pathway, independent of canonical autophagy and type I IFN, that restricts SARS-CoV-2 replication, offering insights into critical COVID-19 pneumonia mechanisms.