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Non-steroidal anti-inflammatory drugs (NSAIDs) are known to alleviate pain by reducing inflammation. To the contrary, here, the authors show that selective inhibition of the prostaglandin E2 receptor (EP2) in Schwann cells eliminates pain without disrupting the protective and healing functions of inflammation.

Safely opening university campuses has been a major challenge during the COVID-19 pandemic. Here, the authors describe a program of public health measures employed at a university in the United States which, combined with other non-pharmaceutical interventions, allowed the university to stay open in fall 2020 with limited evidence of transmission.

This Review summarizes recent technical advancements in generative AI, outlines how new models might improve healthcare and discusses validation approaches—using lessons from recent successes and failures in the field.

A peripherally restricted CB1 agonist (VIP36) targeting a cryptic receptor pocket was developed, showing high efficacy in mouse pain models with minimal side effects and tolerance, potentially revolutionizing chronic pain treatment and GPCR drug design.

The authors present 7 cryo-EM structures of hallucinogenic and non-hallucinogenic compounds across multiple chemotypes bound to the 5-HT2A receptor, shedding light onto ligand specificity and signaling bias.

Some antiseizure medications including valporate are associated with neurodevelopmental conditions in children exposed in utero but evidence is less clear for other drugs. Here the authors investigate associations between antiseizure medication use in pregnancy and neurodevelopmental conditions using electronic health record data from the UK and Sweden.

Bitopic functionalized ligands based on fentanyl can target the sodium ion-binding site of the mu-opioid receptor and selectively modulate downstream signalling pathways, potentially leading to safer analgesics.

Soft mechanism driven robots, made via multi-material 3D printing, combine soft and rigid components for robust, adaptable locomotion. This framework balances flexibility and strength, enabling effective operation across varied terrains.

RNA-guided CRISPR-associated transposases (CAST) are natural systems with broad potential in biotechnology. Here, the authors report compact type V-K CAST discovered from genome-resolved metagenomics and demonstrate targeted integration of a large transgene to a safe-harbor site in the human genome.

The crystal structure of the mouse μ-opioid receptor bound to an antagonist is described, with possible implications for the future development of analgesics.

Biased signaling in κ-opiod receptors (KOR) offer an attractive strategy for pain management. Here the authors identify determinants of KOR signaling bias using structural methods in combination with molecular dynamics simulations.

AAV vectors are a promising gene delivery vehicle but have a limited DNA packaging capacity. Here, the authors identify cellular restriction factors whose temporary inhibition significantly enhances transduction efficiency of oversized transgenes split into dual AAV vectors.

The scourge of the hepatitis C virus in the United States is woefully underestimated. Brian R. Edlin reckons it's time the infection is given the priority it demands.

Policies for managing plastic debris are outdated and threaten the health of people and wildlife, say Chelsea M. Rochman, Mark Anthony Browne and colleagues.

Current inhibitors of platelet integrin αIIbβ3 cause excessive bleeding, which limited their clinical use in cardiac patients. Here the authors design pure orthosteric αIIbβ3 inhibitors that prevent platelet aggregation and thrombosis without causing bleeding in humanized mouse models of thrombosis

Here, using cryo-electron microscopy and solution NMR, the authors reveal the structural and dynamic mechanisms underlying the signaling versatility of a muscarinic receptor regulated by orthosteric and allosteric ligands.

The use of allosteric transcription factors (aTFs) as biosensors has been constrained by their limited natural ligand repertoire. Here, the authors report a method to screen large libraries of aTF variants to develop biosensors with altered specificities to non-native ligands.

Tirofiban is an inhibitor of platelet αIIbβ3 which may contribute to venous thrombosis. Here the authors developed a non-agonizing modified tirofiban, defined by its cryo-EM structure bound to platelet αIIbβ3 and elucidated the pathogenic role of αIIbβ3 in venous thrombogenesis.

Metabolic complications are common in patients suffering PCOS, including obesity, insulin resistance and type-2 diabetes. Here the authors show the efficacy of GLP1-based multi-agonists, and superiority of GLP1/E, for managing metabolic complications of PCOS in preclinical models, with improvement also of some reproductive traits.

Computational docking to the the μ-opioid-receptor identifies PZM21, a novel selective biased agonist that generates substantial affective analgesia in mice without altering respiration or inducing drug reinforcement.

Science education is being modernized to give students the skills they will need for jobs in the future.

The structural basis of integrin signaling in health and disease is not fully understood. Here, the authors determine the cryoEM structure of full-length platelet integrin αIIbβ3 in its apo and eptifibatide-bound conformations in a native membrane environment.

The local delivery of a calcium channel blocker and a Rho-kinase inhibitor, determined by screening for small molecules that cause ureteral relaxation, significantly reduce ureteral contraction in pigs.

Thrombospondin-1 (TSP-1) activates latent TGF-β in the extracellular matrix. Here the authors show that inappropriate activation of latent TGF-β in murine, bovine and human lung by monocyte-produced TSP-1 causes pulmonary hypertension, and that interference with the activation process prevents disease development.

Studies on the µ-opioid receptor using fluorescent labelling of intracellular residues and energy transfer experiments in the presence of different ligands with or without G-protein binding reveals conformational changes that correlate to ligand efficacy.

The use of chimeric antigen receptor modified immune cell therapeutics has improved the treatment of a range of tumours. Here the authors explore a dual-target iPSC-derived NK cell product as a potential therapeutic for the treatment of multiple myeloma.

Here the authors describe a functional screening platform in human stem cells to identify and optimize protein-based gene editing additives that increase homologous directed recombination and have potential to improve gene therapy workflows.

Exposure to volatile chemical products happens during or in the vicinity of product use and through ambient air; the latter pathway is neglected in exposure estimates. This study shows that both pathways should be considered in efforts to develop safer and more sustainable products and to achieve cleaner air.

If the activity of genetically specified neurons is silenced in a temporally precise fashion, the roles of different cell classes in neural processes can be studied. Members of the class of light-driven outward proton pumps are now shown to mediate powerful, safe, multiple-colour silencing of neural activity. The gene archaerhodopsin-3 (Arch) enables near 100% silencing of neurons in the awake brain when virally expressed in the mouse cortex and illuminated with yellow light.

Screening a large barcoded library of unique CD19-specific chimaeric antigen receptors with diverse intracellular domains allows for the discovery of receptors that elicit enhanced antitumoural functions.

Chimeric antigen receptor T cells in the clinic currently target cell-type-specific extracellular antigens on malignant cells. Here, authors engineer tumor-specific chimeric antigen receptor T cells that target human leukocyte antigen-presented neoantigens derived from mutant intracellular proteins.

Computational and biochemical studies have revealed the mechanisms by which arrestin proteins are activated by G-protein-coupled receptors — potentially opening up broad avenues for drug discovery.

Here, the authors develop an AAV-CRISPR mediated somatic knock-in. They apply this system to restore hemostasis in neonatal hemophilia B mice and show liver-specificity of the knock-in and low serum antibody production.

MYC amplification is an independent prognostic factor for the most aggressive subgroup (Group 3) of pediatric medulloblastoma (G3 MB). Here, the authors highlight the role of the RNA-binding protein, Musashi-1 (MSI1) in G3 MB and identify MSI1-bound targets sharing MYC associated pathways.

Technologies for in situ capture and storage of intermittent solar energy are an important research goal. Here the authors report a solar rechargeable flow cell based on a dual-silicon photoelectrochemical cell and a quinone/bromine redox flow battery for in situsolar energy conversion and storage.

Markovic et al. demonstrate in rodents that anhedonia-like states in inflammatory pain are mediated through increased inhibitory control and subsequent diminished activity of mesolimbic dopamine neurons.

A challenge with the use of metal anodes in batteries is their inability to sustain structural stability, especially at high currents. Here the authors examine electrochemomechanical properties of metal anodes and demonstrate an effective semi-solid electrode approach at practically relevant conditions.

Bacillus thuringiensis israelensis (Bti) produces the naturally-crystalline proteinaceous toxin Cyt1Aa that is toxic to mosquito larvae. Here the authors grow recombinant nanocrystals of the Cyt1Aa protoxin in vivo and use serial femtosecond crystallography to determine its structure at different redox and pH conditions and by combining their structural data with further biochemical, toxicological and biophysical analyses provide mechanistic insights into the Cyt1Aa bioactivation cascade.

Integrins are promising targets in the treatment of conditions that range from cancer to acute coronary syndromes. However, the partial agonism exhibited by RGD ligand–based drugs can result in life-threatening complications. A new study provides the structural basis for pure antagonism by a high-affinity integrin ligand and suggests a path to the design of safer integrin inhibitors.

A large-scale computational effort is used to predict the activity of 656 drugs against 73 protein targets that have been associated with adverse drug reactions; the abdominal pain side effect of the synthetic oestrogen chlorotrianisene is shown to be mediated through its inhibition of cyclooxygenase-1.