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Impaired liver metabolic function is related to mortality in severely malnourished children. Here the authors report a role for the tryptophan-NAD + pathway in reduced hepatic mitochondrial function and liver steatosis in a mouse model of severe malnutrition.

AMPA receptors associated with TARP subunits enable the development of selective AMPA receptor drugs. Here, the authors provide cryo-EM structures of receptors bound to three TARP-γ8 selective drugs, and reveal bifunctionality of one ligand.

Current long acting HIV therapies face challenges like prolonged pharmacokinetic tails, which increase resistance risk. The authors develop dimeric bictegravir prodrug nanosuspensions that sustain therapeutic levels for six months with a short PK tail, supporting safer ultra-long-acting HIV treatment.

A newly discovered negative allosteric modulator of the µ-opioid receptor works together with naloxone to potently block opioid agonist signalling with reduced adverse effects.

Skeletal muscle contractions are regulated by a process known as excitation–contraction coupling (ECC), defects in which can cause myopathies. Here Horstick et al.show that the protein STAC3 is a component of the ECC machinery and identify mutations in STAC3 as the cause of Native American Myopathy.

Levels of the metabolic coenzyme NAD⁺ decline during aging, which is linked to many age-related diseases. Zhang et al. review recent clinical and translational evidence testing NAD⁺ supplementation in age-related diseases, highlighting therapeutic challenges and opportunities.

Genomic and phenomic screens of 827 wheat landraces from the A. E. Watkins collection provide insight into the wheat population genetic background, unlocking many agronomic traits and revealing haplotypes that could potentially be used to improve modern wheat cultivars.

By increasing NAD⁺ consumption in various organelles, mitochondria are revealed to act as buffers that help maintain subcellular NAD⁺ levels. At the same time, cells are found to be particularly sensitive to a decline in NAD⁺ levels originating from mitochondria themselves.

Activators of K_Ca2.2 channels constitute potential novel treatments for neurologic disorders. Here, authors report cryo-EM structures of activator-bound channels, providing a framework for structure-based drug design targeting K_Ca2.2 channels.

Oral nicotinamide riboside (NR) at a dose of 3000 mg daily for 30 days is safe and associated with a pronounced systemic augmentation of the NAD metabolome, but no methyl donor depletion.

How Indigenous populations in the southern tip of South America have changed over time has been unclear. Here the authors generate genome-wide data for 20 ancient individuals and examine how past migrations and admixture events correlate to geography and shifts in the archaeological record.

Allosteric control of metabotropic glutamate receptor is of therapeutic value in the treatment of neurological disorders. Here, using cryoEM, the authors describe the diversity of positive allosteric modulation on the metabotropic glutamate receptor, mGlu₅.

An NNMT inhibitor reduces tumour burden and metastasis in multiple mouse cancer models and restores immune checkpoint blockade efficacy by decreasing cancer-associated-fibroblast-mediated recruitment of myeloid-derived suppressor cells and reinvigorating CD8⁺ T cell activation.

In an arm of an ongoing multicenter phase 2 trial testing different therapies in patients with genetically profiled grade 2 or 3 meningiomas, treatment with an oral CDK4/6 inhibitor met the primary endpoint for progression-free survival at 6 months in patients with CDK or NF2 alterations.

Systematic analysis from the Global Burden of Disease study reported that, despite global improvements from 1990 to 2021, dietary iron deficiency-associated disease burden remains high in women, children and residents in low socio-demographic index countries.

PGC1α protects against kidney injury by upregulating enzymes that enhance nicotinamide adenine dinucleotide (NAD) and driving local accumulation of the fatty acid breakdown product β-hydroxybutyrate, which leads to increased production of the renoprotective prostaglandin E₂.

Nucleic acid aptamers have emerged as promising alternatives to antibodies. Here, we show that incorporating unnatural bases enhances binding affinity by stabilizing the aptamer conformation and enabling specific engagement with hydrophobic pockets— acting like both armor and sword.

Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

A negative allosteric modulator of the G-protein-coupled receptor β₂-adrenergic receptor binds to a membrane-facing surface adjacent to a molecular switch for receptor activation, and its binding disrupts a water-mediated polar network stabilizing an inactive switch conformation.

Chronic care manages long-term, progressive conditions, while acute care handles short-term ones. Here, authors show chronic conditions account for most of the global health burden, with 68% of DALYs and 93% of YLDs attributed to chronic care needs.

Doan et al. show that loss of cardiac NAD⁺ is sufficient to drive metabolic derangements, hypertrophic remodeling and lethal arrhythmias in adult mouse hearts, despite maintenance of ejection fraction and bioenergetics.

Gutierrez and Tyler investigate the limits of replicative lifespan in yeast. The authors show that nucleolar expansion during aging is a mortality timer. Enlargement of nucleoli beyond a defined size alters their biophysical properties; normally excluded DNA repair protein enter, causing aberrant rDNA recombination, genome instability and death.

This study assessed the durability of immunity in humans after vaccination with an MVA-based MERS vaccine. The data show that antibodies and T cells persist for at least two years, with the antibodies capable of cross-neutralizing MERS-CoV variants.

In a prospective, double-blind, randomized, placebo-controlled trial, supplementation with a combination of conventional and gut-targeted nicotinamide was safe and effective in ameliorating COVID-19 symptoms.

Barnes et al. report a dynamic and reciprocal crosstalk between tissue tension and glycocalyx bulkiness that promotes a mesenchymal, stem-like phenotype in GBM.

Reducing the risk of maladaptation is critical to successful climate adaptation, yet such dichotomy hampers nuanced assessments of adaptation outcomes. The authors provide a framework to assess relevant dimensions of adaptation outcomes on a continuum and apply it to various adaptation options.

Long-read chromatin assay reveals (1) a novel class of accessible chromatin regions, (2) accessibility within individual LTR retrotransposons and (3) the relationship between diffuse accessibility, gene body methylation and hAT transposon insertion.

The activation mechanism of metabotropic glutamate receptor subtype 5, a member of the family C G-protein-coupled receptors, is characterized by a combination of cryo-electron microscopy, crystallography and signalling studies.

Water has remarkable dynamic properties; a transition from a fragile to a strong liquid has been proposed to explain how they change on cooling. Experiments now show evidence for such a transition in bulk supercooled water at around 233 K.

Animal models provide insights that alternative approaches can’t. A heated debate about which method is better is distracting researchers from doing good science.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

Cryo-electron microscopy structures show that metabotropic glutamate receptor 2 forms a dimer to which only one G protein is coupled, revealing the basis for asymmetric signal transduction.

Meta-analyses in up to 1.3 million individuals identify 87 rare-variant associations with blood pressure traits. On average, rare variants exhibit effects ~8 times larger than the mean effects of common variants and implicate candidate causal genes at associated regions.

Pseudomonas aeruginosa infections are increasingly difficult to treat due to the development of antimicrobial resistance. Here, the authors describe the synthesis, characterisation and efficacy of a quorum sensing inhibitor.

We propose a model for a sequential, multistep activation mechanism of metabotropic glutamate receptor subtype 5, including a series of structures in lipid nanodiscs, from inactive to fully active, with agonist-bound intermediate states.

Hefzi et al. engineer cells to nearly eliminate lactate production and increase mitochondrial use of pyruvate by deleting both lactate dehydrogenases and pyruvate dehydrogenase kinases with the goal of circumventing pH and osmolarity issues that arise in bioreactor-based production of biopharmaceuticals.

SAMHD1 has a dNTPase-independent resection function in genome maintenance. Here the authors show that SAMHD1 is deacetylated at conserved K354 by SIRT1 to facilitate direct binding with ssDNA to promote DNA end resection and homologous recombination.

The very low water contents of minerals in achondrite meteorites from the early Solar System show that substantial amounts of water could only have been delivered to Earth by means of unmelted material.

Molecular dynamics (MD) simulations are widely used for understanding atomic motion but require substantial computational time. In new research by Nam et al., a generative artificial intelligence framework is developed to accelerate the MD simulations for crystalline materials, by reframing the task as conditional generation of atomic displacement.

GPCR dynamics are critical for signal transmission into the cell. Here, the authors probe receptor plasticity using molecular dynamics simulations, enabling the detection of allosteric sites and drug entry gateways for a broad range of GPCR types.

G protein-coupled receptors (GPCRs) are highly successful drug targets, particularly for central nervous system (CNS) disorders. Compared to traditional drugs that target the orthosteric ligand-binding site of GPCRs, allosteric modulators have the potential to achieve greater subtype selectivity and allow the normal function of endogenous ligands to be preserved. Conn and colleagues reflect on the key principles for successful optimization of GPCR allosteric modulators.

The bioavailability of NAD is vital for muscle health. Here, the authors unveil a pathway from glucose sensing to muscle NAD modulation via the TAS1R2 receptor, suggesting TAS1R2 as a therapeutic target for muscle health preservation.

Trigonelline is identified as a human metabolite that can be used for NAD⁺ synthesis and is shown to improve muscle function in aged worms and mice.