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The authors identify a single main-chain hydrogen bond required to keep GABA_A receptors closed in the absence of neurotransmitter. Electrophysiology and molecular dynamics simulations suggest disruption of this bond is a key component of channel opening during inhibitory synaptic signaling in the brain.

The high-plasticity cell state (HPCS) is a critical hub that enables reciprocal transitions between cancer cell states, and targeting the HPCS may suppress cancer progression and eradicate treatment resistance.

C−H bond functionalization methodologies usually rely on substrate-controlled directing-group chemistries to facilitate regioselective activation. Now, chemobiocatalytic cascades are reported that enable catalyst-controlled regioselective access to aryl nitriles, primary amides and carboxylic acids.

Soil microbial populations bloom and then die-off in ecosystems with seasonal snowpack. This study showed that distinct taxa utilize different N sources for growth or energy during the microbial bloom and alter the fate of N after snowmelt.

Proteins, other metabolites and many valuable synthetic products contain amide bonds and there is a need for more sustainable amide synthesis routes. Here the authors show an integrated next generation multi-catalytic system, merging nitrile hydratase enzymes with a Cu-catalysed N-arylation reaction in a single reaction vessel, for the construction of ubiquitous amide bonds.

Although mechanistic understanding can drive new reactivity development, the key bond-forming and -breaking steps in catalytic cycles are often sufficiently fast to elude observation. Here, the authors photochemically produce a key intermediate in Mn-catalysed C–H functionalization, and follow the subsequent steps—spanning processes occurring over seven orders of magnitude in time—using time-resolved infrared spectroscopy.

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.

Hydrogen evolution and oxidation on platinum surfaces are central reactions in electrochemical devices. Sun et al. show that they can be promoted by introduction of the organic molecules, N-methylimidazoles, and explore the underlying phenomena at play through in situ spectroscopy and computation.

The Suzuki-Miyaura cross coupling is widely used in industrial and academic settings for the formation of carbon-carbon bonds. Here, the authors report a procedure whereby a molecule with multiple reactive carbon-boron bonds can undergo sequential, selective Suzuki-Miyaura reactions without the need for protecting groups.

Epstein–Barr virus (EBV) is a widespread herpesvirus linked to cancer and autoimmune disease. The authors in this work design and characterize a stabilized prefusion form of gB, an essential viral fusion protein, advancing EBV vaccine and therapeutic development.

Here the authors describe a stabilization technology that engineers crosslinks between tyrosine sidechains into a natively folded vaccine immunogen and show that immunogenicity is improved in small animal models by locking the most potently neutralizing epitopes.

Fast inactivation is characteristic of voltage-gated sodium channels. In this work, the authors show that this process occurs in two distinct, consecutive steps and propose a lock and key model for fast inactivation.

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.

Uranium oxo groups are very inert, in contrast with many transition metal oxo compounds that can carry out reactions that are difficult to achieve with other reagents. Now, the controlled lithiation of a ‘Pacman’ complex is shown to activate the uranium oxo group towards functionalization and single electron transfer.

RFdiffusion2, an extension of the RFdiffusion framework, builds de novo enzyme active sites using atom-level functional group constraints.

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.

A generative artificial intelligence-powered method enables de novo design of highly active enzymes based on information about the geometry of residues in the active site, without requiring protein backbone or sequence information.

DNA in many bacteriophages contains unusual chemical modifications. Here, the authors discover that carboxymethylcytosine is a natural DNA base and reveal its role as an intermediate enabling further DNA hypermodification.

iGluSnFR4f and iGluSnFR4s are the latest generation of genetically encoded glutamate sensors. They are advantageous for detecting rapid dynamics and large population activity, respectively, as demonstrated in a variety of applications in the mouse brain.

Therapeutic gene editing in vivo is an ongoing challenge. Here, authors demonstrate Cas9 nickase guided DNA ligation as a nonviral method for installing permanent genomic corrections with favorable on target edit profiles in model animal cell types and adult mice.

An inverse design strategy is reported for the organization of nanoscale matter using DNA-programmable bonds and the fabrication of hierarchically ordered 3D assemblies.

Torrens-Spence et al. reveal how plants in the cabbage family uniquely accelerate production of salicylic acid, a key defense hormone, through evolution of a specialized enzyme called EPS1. This finding could help enhance disease resistance in other crops.

In a randomized phase 2 trial in patients with acute coronary syndrome and high levels of the inflammation biomarker C-reactive protein, treatment with low-dose interleukin-2 increased the numbers of regulatory T cells and reduced arterial inflammation, compared to placebo.

Use of immobilized enzymes in bioremediation has potential in water treatment, but limited enzymatic activity and stability can cause issues. Here, the authors report the development of a strategy to immobilize enzymes within a hydrogel while maintaining good activity against a range of pollutants.

Liu, Liu, Wu and Yao et al. developed a peptide inhibitor that selectively blocks the Ada-two-A-containing histone complex by targeting the YEATS2 YEATS domain and suppresses tumor growth in non-small cell lung cancer.

A combination of high-resolution spatial imaging, spatial proteomics and transcriptional data reveals sparse and heterogeneous bacterial signals in gliomas and brain metastases.

Baird et al. present the phase 2 PIONEER trial findings on the antitumor activity of combining aromatase inhibitor letrozole with megestrol in postmenopausal women with operable estrogen-receptor-positive human epidermal-growth-factor-receptor-2-negative breast cancer.

Here the authors combine a deep generative model with structure-based drug design and prospectively validate functionally active, nanomolar, A_2A adenosine receptor ligands and solve their crystal structures to close the Artificial Intelligence Structure-Based Drug Design loop.

Water has a role to play in the future of cooling but is currently limited by the lack of meaningful control methods. Here, authors demonstrate the ability of electrostatic fields to act as a catalyst for water-based evaporative cooling, paving the way for widescale adoption of evaporative cooling.

DNA interstrand crosslinks induced by acetaldehyde are repaired by both the Fanconi anaemia pathway and by a second, excision-independent repair mechanism.

Enzyme-catalyzed biodegradation is an emerging green strategy for environmental remediation, although challenged by high cost and poor robustness. Here, the authors report a cellulose derived hydrogel with immobilized laccase for water remediation.

The location of EGFR exon 20 loop insertions (EGFRex20ins) has been shown to alter sensitivity to lung cancer therapy. Here, the authors report the results of the ZENITH20 clinical trial investigating poziotinib (EGFR TKI) in lung cancer patients and, combining with a similar trial, investigate how structural differences due to location of EGGFRex20ins alters sensitivity to EGFR TKI.

Therapeutic options for patients with renal medullary carcinoma (RMC) are limited. Here the authors report the results of a phase II clinical trial of anti-PD1 nivolumab plus anti-CTLA4 ipilimumab in RMC, associating the activation of a myeloid mimicry program in tumor cells to the rapid disease progression and hyper-progression observed in treated patients.

Ribosomes convert chemical energy to mechanical work. Here, the authors monitor ribosome binding to the GTPase EF-G and the ensuing mechanical work on mRNA in real time, uncovering a major energetic contribution from EF-G binding, rather than GTP hydrolysis, to the mechanical work.

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 study reveals the structure of ArnC, a membrane glycosyltransferase that modifies undecaprenyl phosphate with aminoarabinose (L-Ara4N), leading to polymyxin resistance. The structure of ArnC in two states and MD simulations provide insights regarding the catalytic cycle of the enzyme.

The opening mechanism of the SARS-CoV-2 spike protein has been studied by integrating computational and experimental data. Combining weighted ensemble molecular dynamics simulations, biolayer interferometry and ManifoldEM analysis of cryo-EM data revealed that the glycan at N343 plays a gating role in the opening mechanism of the SARS-CoV-2 spike protein.

This study reports on biologically sourced polymuconate polymers with weakened C–C backbone bonds, designed for closed-loop chemical recycling to monomers. Synthesized via free-radical polymerization, these materials achieve tunable mechanical properties comparable to those of commercial plastics. A techno-economic analysis shows that recycling significantly reduces costs and environmental impacts, enhancing the competitiveness of these polymers in the sustainable plastics market.

Microbial decomposition of plant litter initially increases the molecular diversity of dissolved organic matter, but prolonged microbial recycling diminishes this diversity, highlighting how microbial metabolism influences soil carbon turnover.

Polymorphism, the presence of different crystal structures of the same molecular system, provides an opportunity to discover new phenomena and properties. Here, the authors crystallize coronene in the presence of a magnetic field, forming a different polymorph, which remains stable under ambient conditions.

A common mechanism by which cancer cells acquire resistance to chemotherapeutics is through the overexpression of efflux pumps, but platinum anticancer agents that crosslink DNA and interact with proteins are poor efflux pump substrates. Here, the authors design dual warhead drug conjugates by tethering a platinum pharmacophore to the doxorubicin backbone, which exhibit the activity of both parent anticancer compounds and can overcome drug efflux effectively due to covalent binding to intracellular biomolecules.

The local X-ray-induced dynamics that occur in protein crystals during serial femtosecond crystallography (SFX) measurements at XFELs are not well understood. Here the authors performed a time-resolved X-ray pump X-ray probe SFX experiment, and they observe distinct structural changes in the disulfide bridges and peptide backbone of proteins; complementing theoretical approaches allow them to further characterize the details of the X-ray induced ionization and local structural dynamics.

Bioplastics are desirable materials for the replacement of petrochemical-derived plastics, but achieving the desired properties can be challenging. Here, the authors report a bioplastic formed from a combination of polysaccharide sources and DNA from living organism waste, with biodegradability and recyclability.

The antiepileptic drug retigabine potentiates neuronal KCNQ potassium channels. Here, the authors use a combination of unnatural amino acid mutagenesis and electrophysiology to show that retigabine acts by hydrogen bonding with a tryptophan indole nitrogen in the channel pore.

Terminal Co^IV-oxo species are key intermediates in various cobalt-mediated oxidation reactions, but little is known about their chemical properties. Here the authors generate and isolate a mononuclear non-haem Co^IV-O complex and analyse its structure and reactivity towards a range of catalytic transformations.

Readily accessible enantioenriched sulfonylhydrazides and low loadings of an inexpensive achiral Ni catalyst can be used to control the stereochemical outcome of radical cross-coupling.

This study demonstrates GHz-speed electro-optic modulation using ferroelectric nematic liquid crystals, offering dual-phase shifting, poling-free operation, low loss, and CMOS compatibility-enabling scalable hybrid silicon-organic photonics.

Total in vitro biosynthesis can reveal unusual pathways evolved by nature to produce natural products. Here the authors report on enzymatic cascades, comprising a cryptic methylation sequence, efficiently delivering β-lactone-containing peptide proteasome inhibitors with promising anticancer activity.