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Despite the existence of many N–N-containing natural metabolites, little is known about the enzymatic mechanisms of N–N bond formation. Now, a catalytically relevant X-ray crystal structure of an N–N-bond-forming enzyme, PipS, is reported and detailed insights into its catalytic mechanism are provided.

C₂H₄ is one of the most important chemical raw materials. Here, the authors report that tuning of pore structure shifts the multi-component gas separation function, enabling one-step production of high-purity C₂H₄ in the quaternary mixture.

MK-7762 is a new oxazolidinone antitubercular agent that is structurally similar to linezolid, and demonstrated in vivo efficacy, lesion penetration and limited toxicity compared to linezolid, indicating it could be used in broad tuberculosis regimens.

CDK4/6 inhibitors are promising treatments for ER+ breast cancer, however resistance remains a challenge. Here, the authors analyse the NeoPalANA cohort and indicate that a 33 gene signature was predictive of response to neoadjuvant anastrozole and palbociclib.

Characterization of the heme-dependent enzyme KtzT reveals it to be the elusive enzyme responsible for nitrogen–nitrogen bond formation during the biosynthesis of piperazate, a building block for some nonribosomal peptide natural products.

Pyridoxal 5-phosphate (PLP) is an essential coenzyme involved in diverse amino acid transformations. The discovery that Ind4 catalyzes the PLP-dependent oxidation of an unactivated carbon of L-arginine, as a part of the indolmycin biosynthetic pathway, expands the scope of reactions facilitated by PLP-dependent enzymes.

An in-depth analysis of tissue biopsies from patients with multiple myeloma and CAR T cell therapy-associated immune-related adverse events (CirAEs) after treatment with commercial BCMA-targeted CAR T cell therapy shows that CD4⁺ CAR T cells mediate off-tumor toxicities and that high CD4:CD8 ratio at apheresis, robust early CAR T cell expansion, ICANS and ciltacabtagene autoleuce treatment are independently associated with the development of CirAEs.

A molecular glue induces CRBN homodimerization and degradation through degron mimicry, revealing a distinct glue mechanism and offering a tool to study CRBN biology.

H₂O, a primary proton donor, governs CO₂ reduction pathways and regulates selectivity, yet its coordination effects remain elusive. By exploiting the long-range structural order and porosity of crystalline coordination frameworks, this work uncovers how coordinated H₂O influences CO₂ reduction.

Engineering polymerases to synthesize alternative genetic polymers remains a challenging problem in synthetic biology. The current study offers insights into the structural and biochemical changes responsible for improving the fidelity and catalytic activity of a laboratory evolved TNA polymerase.

Vassy, Dornisch and colleagues developed a genomics-based prostate cancer risk model to support a randomized clinical trial of precision screening in a national healthcare system.

Negamycin is a decades-old antibiotic that can promote readthrough of premature stop codons and possesses a structure that contains an unusual N–N bond. Now, the long-mysterious negamycin gene cluster has been identified and characterized to reveal a heme-dependent enzyme that directly couples glycine and nitrite to form the N–N linkage.

Researchers studied the blood-based metabolome of over 23,000 people from ten ethnically diverse cohorts. They identified 235 metabolites associated with future risk of type 2 diabetes (T2D). By integrating genetic and modifiable lifestyle factors, their findings provide insights into T2D mechanisms and could improve risk prediction and inform precision prevention.

HTLV-1 type-C causes more severe disease than type-A, but the underlying reason is unclear. Here the authors show in a macaque model how type-C orf-I affects lung pathogenesis and the immune response to HTLV-1, providing a model to test viral targets for disease prevention.

The ferroptosis suppressor protein FSP1 has a critical role in ferroptosis protection of tumours across multiple in vivo models and is linked to worse prognosis in human lung adenocarcinoma, suggesting its potential as a therapeutic target in lung cancer.

Although biosynthetic pathways of selenium-containing macromolecules have been known for decades, pathways for specific incorporation of selenium into small molecules have only recently begun to be uncovered. Now the selenometabolome is expanded further through the discovery and biosynthetic elucidation of ovoselenol, a selenium-containing antioxidant found in marine microorganisms.

Results of an early-phase breast cancer prevention trial demonstrate the potential for breast cancer prevention in premenopausal women with anti-progestin therapy by inducing epithelial–stromal remodelling and suppression of luminal progenitors.

Alkynes found in natural products are typically assembled by metal-dependent enzymes. The enzyme BesB instead forms a terminal alkyne-containing amino acid using pyridoxal phosphate as a cofactor. Here, the authors use structural and mechanistic investigations to identify the key features of BesB that allow it to carry out its fascinating chemistry.

The BAM complex is assisted by periplasmic chaperones, such as SurA, in its folding and insertion of proteins into the bacterial outer membrane. Here, the authors use disulphide bond engineering to trap transient protein complexes and solve their cryoEM structures to shed light on the cycle of SurA arrival, OMP delivery, and handover to BAM.

 A method for topological automatic cell type classification across subcellular resolution spatial transcriptomic platforms is proposed, resolving cell type information and locating sparsely dispersed cells in human kidney and mouse kidney and brain.

Pan-expansion microscopy of tissue combines staining of proteins and lipids with immunolabeling.

The extent to which human bacterial pathogens broadly utilize ergothioneine as an antioxidant is unknown. Here, authors describe the discovery of a specific transporter for ergothioneine in a respiratory pathogen that is highly conserved among Firmicutes.

Here, Parzych et al describe the development of a DNA-delivered SARS-CoV-2 mAb cocktail displaying synergistic RBD binding that confers broad neutralizing activity against variants of concern and prophylactic efficacy in multiple small animal models.

Protein citrullination regulates the physiological function of proteins and is linked to various autoimmune disorders. Here, the authors report on the allosteric targeting of PAD1-4 leading to broad inhibition of protein citrullination in neutrophils.

Engineered polyketide synthases historically have little to no activity. Here, the authors use updated modules from the pikromycin synthase to make 155 synthases, showing that the updated module has a higher success rate, but that ketosynthase gatekeeping and module skipping can prevent function.

Using structural, biochemical, and functional assays, the authors demonstrate that the E3 ligase KLHDC2, via newly developed small-molecule ligands, can be co-opted to target critical targets for degradation.

Current proteolysis-targeting chimeras can promote the ubiquitination and subsequent degradation of both target and off-target proteins by inducing their respective proximity with the cereblon ubiquitin ligase. Now, by developing and deploying an off-target profiling platform, ‘bumped proteolysis-targeting chimeras’ can maintain on-target degradation efficacy with reduced off-targets.

An einsteinium coordination complex is synthesized and spectroscopically characterized using less than 200 nanograms of einsteinium, enabling examination of its structure and measurement of an einsteinium bond distance.

Understanding how materials respond to impacts at extreme strain rates is crucial, yet current approaches present significant challenges. Here, the authors report the use of a mechanophore-functionalized block copolymer to encode and report energy dissipation mechanisms in response to impacts.

Spin-polarized defects in 2D materials are attracting attention for future quantum technology applications, but their controlled fabrication is still challenging. Here, the authors report the creation and characterization of effective spin 1/2 defects via the atomically-precise generation of magnetic carbon radical ions in 2D WS₂.

Here the authors demonstrate that the assembly of mitochondrial respiratory supercomplex (III₂–IV) from Toxoplasma gondii is critical for parasite fitness. They reveal the basis for cytochrome b inhibition by atovaquone and improved ELQ inhibitors.

Structural studies of the itch receptors MRGPRX2 and MRGPRX4 in complex with endogenous and synthetic ligands provide a basis for the development of therapeutic compounds for pain, itch and mast cell-mediated hypersensitivity.

Staphylococcus epidermidis induces a potent, durable and specific antibody response that is conserved in humans and non-human primates, and which could be redirected against pathogens as a new form of topical vaccination.

Biochemical and structural analysis, combined with metadynamics simulations, illustrate how a single amino acid substitution switches a β-glycosidase from a double S_N2 mechanism to a front-face S_Ni-like mechanism.

How the necroptosis executioner, MLKL, converts to a killer form has been mysterious. Here, authors show RIPK3-mediated phosphorylation of human MLKL is the cue for pseudokinase domain dimerization before assembly of pro-necroptotic MLKL tetramers.

Authors show that water trapped between 2D MXene sheets forms amorphous ice clusters at low temperatures, which cause a hysteresis of electrical conductivity. This structural rearrangement of water is affected by the presence of solvated cations, allowing reversible switching of the electronic properties of MXene films.

A combination of elicitor screening to induce expression of silent biosynthetic gene clusters with imaging mass spectrometry to visualize the resulting metabolome enables the discovery of nine cryptic natural products.

Hu et al. discovered that the truncated form of human epidermal growth factor receptor 2 (HER2), called p95HER2, drives tumor progression and resistance to the antibody–drug conjugate trastuzumab deruxtecan in HER2⁺ breast cancer. Blocking p95HER2 restores antitumor immunity.

The catalytic power of DNA polymerases for artificial genetic polymer (XNA) synthesis remains underdeveloped. Now, the evolution and structure of an α-l-threofuranosyl nucleic acid polymerase is described that achieves XNA synthesis with ∼1 nt s⁻¹ and >99% template-copying fidelity.

Broadening activation energy distributions and increasing radiocarbon ages reveal the global importance of mineral protection in promoting organic carbon preservation.

A modular anti-albumin nanobody conjugated to a STING agonist enhances antitumour immunity by improving pharmacokinetics, tumour accumulation and immune responses, inhibiting murine tumour growth and enhancing cancer immunotherapies.

Soldier beetles use a polyacetylenic fatty acid to repel avian predators and protect their eggs. Haritoset al. find that three genes in soldier beetles convert oleic acid to a precursor of 8Z-dihydromatricaria acid—the first eukaryotic genes reported to produce conjugated polyacetylenic fatty acids.

The immune response to the spike protein of SARS-CoV-2 has been relatively well studied, but less is known about other viral proteins. Here, the authors identify immunopeptides from seven structural and non-structural SARS-CoV-2 proteins presented to the immune system by HLA molecules and confirm T-cell responses against some of them in convalescent individuals.

Four crystal structures of the human serotonin receptor 5-HT_2BR in complex with chemically and pharmacologically diverse drugs elucidate the structural bases for receptor activation, agonist-mediated biased signaling and β-arrestin2 translocation.

Induced proximity by molecular glues is a strategy that leverages the recruitment of proteins to facilitate their modification or degradation. Here the authors present unbiased quantitative proteomic, biochemical and computational workflows that uncover hundreds of CRBN molecular glue targets using recombinant protein and cell lysate.