Search

Reactive carbanions are typically formed by deprotonating relatively acidic C–H bonds. Here, the authors demonstrate that combining sodium tris(pyrazolyl)borate with mesityllithium in the presence of a donor ligand generates a reactive organometallic mixture that deprotonates benzylic C–H bonds, enabling the isolation of cationic sodium benzyl species.

In this work, the authors probe the efficacy of BWC0977, a bacterial topoisomerase inhibitor, in pre-clinical animal models, also demonstrating that BWC0977 is safe and well tolerated in healthy human volunteers, in a phase 1 trial.

The M₅ muscarinic acetylcholine receptor represents a promising therapeutic target for neurological disorders. Here, the authors reveal a 2.1 Å cryo-EM structure of the M₅ bound to a selective positive allosteric modulator site that enables structure-based drug design.

MORC2, a chromatin remodeler involved in epigenetic silencing and DNA repair, is linked to cancer and neurological disorders when dysregulated. Here, the authors show that MORC2 binds DNA at multiple sites, clamps onto it, and induces compaction, a process regulated by its phosphorylation.

Many pathogens encode transporters that extract heme directly from host proteins. In this study, the authors demonstrate the utility of de novo-designed proteins in understanding the mechanism behind this process and how it can be inhibited in pathogenic E. coli.

The A3 adenosine receptor is a promising drug target for cancer, inflammation, and glaucoma. Here, authors determine atomic structures of the human A3 receptor, identifying a previously hidden binding pocket that will aid in the development of more effective A3 receptor-targeted medicines.

The synthesis of a tricoordinate antimony cation is reported by the removal of two chlorides from Tp^Me2SbCl₂, where Tp^Me2 is tris(3,5-dimethylpyrazolyl)borate. The multiple binding sites present in [Tp^Me2Sb]²⁺ bring an amine and an olefinic bond in proximity to enable an intermolecular hydroamination reaction.

Current SARS-CoV-2 vaccines require several injections for optimal immune protection. Here, the authors report an intranasal live-attenuated vaccine that induces long-term immunity following a single dose and protects from SARS-CoV-2 wildtype and variants in non-human primate and small animal models.

Synapse nanocolumns control neural transmission through precise alignment of neurotransmitter receptors and release sites. Here, the authors identify the Neurexin-LRRTM2 complex as a central organiser of excitatory synapse nanostructure and function.

National implementation of a computed tomographic angiography and AI-diagnostic tool, CT-derived fractional flow reserve (FFR-CT), did not provide significant benefits in reducing mortality but led to fewer invasive coronary angiograms and downstream cardiac tests.

Authors show that base editing can convert sickle hemoglobin (HbS) to the rare but naturally occurring variant G-Makassar (HbG). Purified HbG appears normal, but in a mouse model, HbGS red cells sickle under hypoxia, highlighting the importance of assessing red cell quality when evaluating novel gene editing strategies for hematologic disorders.

Here, Kropp et al. use cryo-electron microscopy and structural modeling to show that the enzyme [MoCu]-CO dehydrogenase interacts with its partner, the membrane-bound quinone-binding protein CoxG, to facilitate electron transfer from atmospheric CO oxidation to the respiratory chain. This interaction is conserved across diverse bacteria and archaea.

This study shows that plants can secrete vesicular and non-vesicular small RNAs outside cells to direct silencing of a virulence factor in an interacting bacterium. This antibacterial gene silencing phenomenon was found to dampen pathogenesis.

During myocardial infarction, cardiac macrophages expand, become activated and play an important role in cardiac repair and remodelling. Here the authors show that integrin α5 is upregulated in infarct macrophages and contributes to myocardial repair, triggering an angiogenic phenotype and protecting from adverse remodelling.

Plasmodium falciparum Snf2L is an ISWI-related ATPase that actively repositions P. falciparum nucleosomes in vivo.

The P2X1 receptor is a promising target for the development of a non-hormonal male contraceptive. Here, researchers determined the atomic structure of the P2X1 receptor, revealing opportunities for developing drugs to target this receptor.

The GntR superfamily is one of the largest families of transcription factors in prokaryotes. Here the authors combine biophysical analysis and structural biology to dissect the mechanism by which NanR — a GntR-family regulator — binds to its promoter to repress the transcription of genes necessary for sialic acid metabolism.

Here the authors show that a gene-inactivating protein complex packs inactive genes into a dynamic and accessible structure. The study challenges the traditional views that restricted accessibility and low dynamics cause gene repression.

Structural and biochemical studies of the Mycobacterium smegmatis hydrogenase Huc provides insights into how [NiFe] hydrogenases oxidize trace amounts of atmospheric hydrogen and transfer the electrons liberated via quinone transport.

Peesh et al. show that ischemic stroke reduces microbiota-derived and increases host-derived aryl (AHR) hydrocarbon ligands. Post-stroke treatment with indole-based AHR ligands improved microglia-mediated antigen processing and co-stimulatory immune functions.

Venous tumour thrombus can occur within renal cell carcinoma, and can require complex additional surgery and treatment. Here, the authors analyse multiparametric data from patients treated with axitinib and develop a machine learning model to predict neoadjuvant treatment response.

Kim and colleagues perform a phase 2 clinical trial (ELM-2) of odronextamab monotherapy in patients with relapsed/refractory diffuse large B cell lymphoma and report on the primary analyses of the efficacy and safety profile.

Functional CRISPR screens in patient-matched pre-treatment and post-treatment glioblastoma models identify the PTP4A–ROBO1 axis as a driver of tumorigenicity and enriched ROBO1 expression in recurrent glioblastoma that can be targeted with CAR T cell therapy.

Cryo-electron microscopy structures of the human lysosomal transmembrane protein LYCHOS show that it comprises a transporter-like domain fused to a G-protein-coupled receptor, and that the transporter domain is similar to the plant PIN family.

The study reveals the Acinetobacter baumannii T6SS Rhs effector, Tse15, uses its clade domain as an internal chaperone to facilitate toxin delivery and the Rhs cage is not secreted.

Understanding virus assembly could identify potential drug targets. Here the authors use a safe and efficient method to solve pathogenic flavivirus structures, revealing two lipid-like ligands within highly conserved pockets of the stem region of envelope protein that are important for virus maturation.

Macrophage-expressed gene 1 (MPEG1) functions within the phagolysosome to damage engulfed microbes, presumably via forming pores in target membranes. In order to provide insights into the mechanism of MPEG1 function and membrane binding, the authors present structures of hexadecameric MPEG1 prepores both in solution and in complex with liposomes.

The ability to edit large stretches of mRNA transcripts remains a significant challenge. Here, the authors demonstrate that CRISPR-Cas13 systems can be repurposed to assist trans-splicing of exogenous RNA fragments into an endogenous pre-mRNA transcript, a method termed CRISPR Assisted mRNA Fragment Trans-splicing (CRAFT).

Cryogenic electron microscopy determines the structure of a fully assembled, MR1-reactive, human Vγ8Vδ3 TCR–CD3δγε₂ζ₂ complex bound by anti-CD3ε antibody Fab fragments.

Porcupine (PORCN) is an endoplasmic reticulum-resident membrane-bound O-acyltransferase that plays a crucial role in Wnt signalling and is as a therapeutic target for Wnt-driven cancers. Here, the authors use cryo-electron microscopy to elucidate the structures of human PORCN with inhibitors, uncovering key interactions mediating inhibitor binding and catalysis.

Antarctic ice core records provide insights into past environmental conditions. Here, an abrupt, synchronous increase in dust from ice cores in Antarctica is identified that suggests a sudden equatorward shift of westerly winds and coincides with a reduction in atmospheric CO2.

Cost-optimal European energy transition with CO₂ and methane neutrality objective is studied. While renewables are the key drivers of climate neutrality, the continuous role of natural gas requires high levels of both CO₂ and methane abatement.

MIPS521, a positive allosteric modulator of the adenosine A₁ receptor, has analgesic properties in a rat model of neuropathic pain through a mechanism by which MIPS521 stabilizes the complex between adenosine, receptor and G protein.