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Identification of a hyperstable boronate enables automated lego-like synthesis to access a wider range of three-dimensionally complex small organic molecules rich in Csp³–C bonds. 

Annunziato, Quan and Donckele et al. identify G3BP2 (Ras–GAP SH3 domain-binding protein 2) as a molecular glue-induced neosubstrate of the CRL4^CRBN E3 ubiquitin ligase. The CRBN–glue neosurface uses a molecular surface mimicry mechanism to recruit and degrade G3BP2 in a compound-dependent manner.

Inteins can act as post-translational environmental sensors in vivo. Here the authors characterize two inteins present in the Mycobacterium smegmatis replicative helicase DnaB that display distinct splicing behaviors and are differentially sensitive to inhibition by biological stressors and propose that splicing inhibition could modulate DnaB levels to protect the cell against replication stress.

An investigation using various methods reports an association between adeno-associated virus 2 and paediatric hepatitis of unknown aetiology.

Macrocycles are molecular structures extensively used in the design of catalysts, therapeutics and supramolecular assemblies but synthesis procedures that can produce macrocycles in high yield under high reaction concentrations are rare. Here the authors report the use of dynamic hindered urea bond for the construction of urea macrocycles with high efficiency.

New agonists of the serotonin 5-HT_2A receptor (5-HT_2AR) confer high brain permeability and antidepressant activity and—in contrast to classic 5-HT_2AR agonists—lack psychedelic activity.

Enterococcus faecalis has been reported to inhibit Candida albicans virulence via secretion of the bacteriocin EntV. Here, the authors present the crystal structure and characterise the antifungal properties of this peptide in numerous in vitro and in vivo assays.

Direct coupling of aliphatic C–H nucleophiles to aryl electrophiles is described, through the combination of light-driven polyoxometalate hydrogen atom transfer and nickel catalysis.

The poor thermal conductance of interfaces is a significant bottleneck to the integration of nanoscale devices in a range of applications. Now, the thermal conductance at metal/dielectric heterointerfaces is significantly enhanced by the introduction of an organic nanomolecular monolayer.

Despite the importance of trifluoromethylated compounds, direct catalytic methods for the conversion of C(sp³)–H bonds into the corresponding C(sp³)–CF₃ analogues have remained elusive. This transformation has now been achieved by the merger of copper catalysis with decatungstate photocatalysis, enabling the C(sp³)–H trifluoromethylation of abundant feedstocks, natural products and pharmaceuticals.

Protein sequences from fossil tooth enamel of a rhinocerotid from Canada’s High Arctic are used to develop phylogenetic frameworks from a specimen too old to preserve ancient DNA.

Structural and functional analyses reveal how 9-O-acetyl sialic acid is recognized by the human coronavirus OC43 S glycoprotein and how this interaction promotes viral entry.

A highly potent and selective small-molecule catalytic inhibitor of the protein lysine methyltransferase NSD2 shows therapeutic efficacy in preclinical models of KRAS-driven pancreatic cancer and lung cancer.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

A new biosynthetic core-forming enzyme, arginine cyclodipeptide synthase (RCDPS), was found to produce cyclo-arginine-Xaa dipeptides via a tRNA-dependent mechanism, and further genome mining using RCDPS as a beacon uncovered new natural products.

Limited tumor cell delivery is a major challenge for the efficacious delivery of siRNAs to silence traditionally undruggable oncogenes. Here the authors optimize siRNAs for in situ binding to albumin through C18 lipid modifications and show the application of the lead conjugate structure for targeting MCL1 in orthotopic breast tumors in mice.

Human ubiquitin E3 ligase E6AP contains a Zn-binding AZUL domain. Here the authors identify and name RAZUL, a domain in proteasome substrate receptor hRpn10 that binds AZUL, recruiting E6AP to proteasomes, and they present the NMR structure of the RAZUL:AZUL complex, which forms an intermolecular 4-helix bundle.

Modifications enhancing degradation resistance and albumin affinity enabled the delivery of an siRNA conjugate silencing MMP13 to guinea pig and murine arthritic joints, improving therapeutic outcomes following intravenous administration.

Bond et al. show that inducible PolG mutation in muscle causes mtDNA damage and muscle wasting. This is driven by the integrated stress response (ISR) and reduction in folate intermediates, linking impaired folate metabolism with ISR/disease induction.

Dural-associated lymphoid tissues are lymphoid structures around vascular hubs in the dura mater that sample antigens and rapidly support humoral immune responses after local pathogen challenge.

Here, using clinical samples and autopsy tissues, the authors combine fast-colorimetric test (LAMP) for SARS-CoV-2 infection and large-scale shotgun metatranscriptomics for host, viral, and microbial profiling and provide a map of the viral genetic features of the New York City outbreak and associate specific host responses and gene expression perturbations with SARS-CoV-2 infection.

LeDNA is a low-cost, open access tool ready to be deployed around the globe to democratize education in genetics and CRISPR gene editing technology.

Itaconate is shown to non-covalently inhibit the antioxidant enzyme peroxiredoxin 5 in macrophages, thereby modulating the production of mitochondrial peroxide and enhancing the type I interferon production.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

A set of GFP fusions with as few as 12 residues appended to the C terminus is shown to assemble into filaments in E. coli. Crystal structures reveal a mechanism termed ‘runaway domain coupling’ and illustrate how protein filament formation can evolve.

There is substantial interest in the development of base metal molecular catalysts for hydrogen generation. Here, the authors report a nitrosyl-containing diiron complex, and study its versatile electrochemical behaviour, which is due to the two unique iron sites and the redox active nitrosyl ligands.

Benzene is a genotoxic carcinogen with no safe level of exposure. Here, by creating and decorating a structural defect in a metal–organic framework to form MIL-125-Zn, a benzene uptake of 7.63 mmol g^–1 at 1.2 mbar is observed due to binding to Zn(II) sites.

Ribofuranose residues are installed on O-antigens of bacterial polysaccharides by a dual-activity enzyme that uses phosphoribosyl-5-phospho-d-ribosyl-α-1-diphosphate as a sugar donor and also catalyzes phosphate hydrolysis.

JNJ-9676—a small-molecule inhibitor targeting coronavirus M protein that shows excellent efficacy in Syrian golden hamster models—binds to and stabilizes the M protein dimer in an altered conformational state between its long and short forms, preventing the release of infectious virus.

There is a great need for inexpensive and sensitive tests to measure HIV viral load in patients’ samples. Here, Zhao et al. describe a cost-effective colorimetric method based on synthetic peptide nucleic acids that quantifies HIV RNA molecules from infected patients’ plasma.

Single-nucleus and single-cell RNA sequencing plus spatial profiling with four methods of core biopsies from 60 patients with metastatic breast cancer reveal patient-specific gene expression programs of breast cancer metastases that are maintained across time, site of metastasis and spatial profiling method, with spatial phenotypes correlating with microenvironmental features.

The cellular mechanisms underlying autophagy are conserved; however it is unclear how they evolved in higher organisms. Here the authors identify two oxidation-sensitive cysteine residues in the autophagy receptor SQSTM1/p62 in vertebrates which allow activation of pro-survival autophagy in stress conditions.

Directed evolution of the ribosome is challenging because the requirement of cell viability limits the mutations that can be made. Here the authors develop a platform for in vitro ribosome synthesis and evolution (RISE) to overcome these constraints.

The authors study (Bi,Sb)₂Te₃/FeTe bilayers, which feature emergent superconductivity at the interface with T_c ~ 12 K. Through angle-resolved photoemission spectroscopy and electrical transport measurements, they argue that the Dirac-fermion-mediated Ruderman-Kittel-Kasuya-Yosida-type interaction weakens antiferromagnetic order in FeTe layer, allowing for superconductivity.

In patients with DNA damage response-deficient solid tumors, the oral ATR kinase inhibitor camonsertib was well tolerated; a recommended phase 2 dose was identified; and encouraging anti-tumor activity was observed, with the highest response rate observed in patients with ovarian cancer.

An intra-articularly injected depot of nanoparticles targeting collagen and delivering small interfering RNA for matrix metalloproteinase 13 protects cartilage integrity and joint structure in mice with post-traumatic osteoarthritis.

The facile release of corrosive HCl gas and plasticizers from poly(vinyl chloride) (PVC) makes it a challenging material to recycle. Now, it has been shown that PVC waste can be directly used as a halogen source to synthesize chloroarenes. This paired electro(de)chlorination is mediated by a phthalate plasticizer already contained in PVC waste.

The electronic structures of photoactive proteins underlie many natural photoinduced processes. The authors, using UV liquid-microjet photoelectron spectroscopy and quantum chemistry calculations, determine electron detachment energies of the green fluorescent protein chromophore in aqueous solution, approaching conditions of the protein environment.

Osteoporosis and bone disease are common in patients with systemic mastocytosis. Here, the authors show that extracellular vesicles released by neoplastic mast cells of the patients block osteoblast differentiation and bone mineralization when injected into mice, via a mechanism involving suppression of osteogenic factors via miRNA-30a and miRNA-23a.

A study using a mouse solid tumour model suggests that adjusting the dosing frequency of the PI3Kδ inhibitor AMG319 in the treatment of human cancers could decrease tumour growth with fewer adverse effects.

How the 22q11.2 deletion predisposes to psychiatric disease is unclear. Here, the authors examine living human neuronal cells and show that 22q11.2 regulates the expression of genes linked to autism during early development, and genes linked to schizophrenia and synaptic biology in neurons.

A new study reveals the identity of proinflammatory and anti-inflammatory cytokines that influence beta cell stress and thus glucose tolerance.

Mineral weathering and microbial priming are two important processes that regulate soil formation and CO₂ emissions. Here the authors link weathering with primed organic matter decomposition, which plays a key role in controlling soil C dynamics.

Antibody discovery is bottlenecked by the individual expression and evaluation of antigen specific hits. Here, the authors build an antibody screening workflow leveraging cell-free protein synthesis that enables expression and evaluation of hundreds of antibody fragments in less than 24 h.

The immune synapse promotes cellular information exchange but the role of biophysical forces in synapse function is unclear. Here, the authors show that B cells exert two types of forces, a centripetal myosin II-driven force and a central actin protrusive force at the site of antigen extraction.

A bottom-up mathematical approach provides a framework for the design of mechanical networks of two- or three-dimensional frames composed of freely rotating rods and springs that achieve any desired coordinate motion.