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Lithium plating is governed by microscale transport heterogeneity, yet conventional macroscale battery models resolve only spatially-averaged quantities. In this work, we extend the dual-continuum (DC) and Doyle-Fuller-Newman (DFN) frameworks to predict local lithium-plating onset within negative-electrode microstructures while retaining the computational efficiency of upscaled approaches. A closure problem for electrolyte transport is introduced to link averaged electrolyte variables to underlying geometric features, permitting reconstruction of local lithium-plating overpotential fields from an upscaled solution. Comparison with direct numerical simulations (DNS) demonstrates that the method accurately identifies regions of highest plating risk. Beyond pinpointing where lithium plating is most likely, the closure is further used to propose a correction to the DC and DFN models, improving predictions of when plating first becomes thermodynamically favourable. We envisage two primary applications for this framework: (i) in electrode design, to efficiently evaluate candidate microstructures without resorting to computationally intensive DNS; (ii) to improve upscaled models, by enhancing their estimation of when lithium plating becomes favourable. This framework is readily extendable to study other degradation mechanisms driven by microscale transport heterogeneity. Finally, the closure problem opens a pathway to understanding the geometrical features that drive lithium-plating risk.

While observational studies and small pilot trials suggest that vitamin D, omega-3 and exercise may slow biological aging, larger clinical trials testing these treatments individually or in combination are lacking. Here, we report the results of a post hoc analysis among 777 participants of the DO-HEALTH trial on the effect of vitamin D (2,000 IU per day) and/or omega-3 (1 g per day) and/or a home exercise program on four next-generation DNA methylation (DNAm) measures of biological aging (PhenoAge, GrimAge, GrimAge2 and DunedinPACE) over 3 years. Omega-3 alone slowed the DNAm clocks PhenoAge, GrimAge2 and DunedinPACE, and all three treatments had additive benefits on PhenoAge. Overall, from baseline to year 3, standardized effects ranged from 0.16 to 0.32 units (2.9–3.8 months). In summary, our trial indicates a small protective effect of omega-3 treatment on slowing biological aging over 3 years across several clocks, with an additive protective effect of omega-3, vitamin D and exercise based on PhenoAge. Applying epigenetic clocks to samples from the DO-HEALTH trial, Bischoff-Ferrari et al. report a small protective effect of omega-3 supplementation over 3 years on several clocks and an additive protective effect of omega-3, vitamin D and exercise using PhenoAge.

The metabotropic glutamate receptors (mGlus) are class C G protein-coupled receptors (GPCR) that form obligate dimers activated by the major excitatory neurotransmitter L-glutamate. The architecture of mGlu receptor comprises an extracellular Venus-Fly Trap domain (VFT) connected to the transmembrane domain (7TM) through a Cysteine-Rich Domain (CRD). The binding of L-glutamate in the VFTs and subsequent conformational change results in the signal being transmitted to the 7TM inducing G protein binding and activation. The mGlu receptors signal transduction can be allosterically potentiated by positive allosteric modulators (PAMs) binding to the 7TMs, which are of therapeutic interest in various neurological disorders. Here, we report the cryoEM structures of metabotropic glutamate receptor 5 (mGlu5) purified with three chemically and pharmacologically distinct PAMs. We find that the PAMs modulate the receptor equilibrium through their different binding modes, revealing how their interactions in the 7TMs impact the mGlu5 receptor conformational landscape and function. In addition, we identified a PAM-free but agonist-bound intermediate state that also reveals interactions mediated by intracellular loop 2. The activation of mGlu5 receptor is a multi-step process in which the binding of the PAMs in the 7TM modulates the equilibrium towards the active state. 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.

Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB), results in more human mortality than any other single pathogen, in part because of the lack of an effective vaccine. Although T cells are essential for immunity to TB, the mechanisms that provide protective immunity are poorly understood. In this Review, we describe current gaps in our knowledge about T cell-mediated immune responses to M. tuberculosis and discuss how recent technologies, including multiphoton intravital microscopy, spatial multiomics and high-resolution in vivo analyses of cell–cell interactions, may be used to gain insights that can inform the design of T cell-targeted TB vaccines. T cells have an essential role in immune responses to Mycobacterium tuberculosis, but the mechanisms by which they may provide protective immunity remain poorly understood. This Review explores the knowns and unknowns of T cell immunity in tuberculosis and how recent technologies may inform the design of T cell-targeted TB vaccines.