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An ‘intracrine’ signaling mechanism is proposed whereby a G-protein-coupled receptor (free fatty acid receptor 4) senses locally released fatty acids on intracellular membranes associated with lipid droplets to efficiently regulate lipolysis in adipocytes.

β-Adrenergic signaling is a core regulator of brown adipocyte function. Here, the authors provide unbiased insight into the transcriptional network controlled by lipolysis in brown adipocytes, showing that lipolysis is required for much of the thermogenic gene program activated by β-adrenergic signals.

Engineered aminoacyl-tRNA synthetase (aaRS) mutants have been developed that facilitate ultrafast bioorthogonal noncanonical amino acid tagging (BONCAT) of newly synthesized proteins in diverse bacteria, including ESKAPE pathogens. The substrate polyspecificity of the aaRS mutants enables pulse-chase BONCAT and differential tagging of temporally distinct nascent proteomes in cells.

The solute carrier transporter protein SLC25A44 regulates uptake of branched-chain amino acids in mitochondria of brown adipose tissue in which they are utilized for thermogenesis.

Although the trivalent actinides are similar to the lanthanide series in terms of chemistry and bonding, their structures and properties can diverge significantly. Here, the authors report a series of complexes of the trivalent actinides Np(III) through Cf(III) along with their lanthanide counterparts using a polarizable non-innocent, sulfur-donor ligand.

Histone deacetylase 3 (HDAC3) is required to activate brown adipose tissue enhancers to ensure thermogenic aptitude.

Self-organized criticality can occur in cellular systems, but its origins remain unclear. Now it is shown that cytoskeletal criticality is influenced by the F-actin architecture and myosin active stress.

Noel et al. show aberrant updating of expectations in three distinct mouse models of autism spectrum disorder. Brain-wide neurophysiology data suggest this stems from excess units encoding deviations from prior mean and a lack of sensory prediction errors in frontal areas.

The authors highlight inconsistencies and divergencies in the literature reporting data on indirect calorimetry for studies on whole-body energy homeostasis, and propose harmonization of standards to facilitate data comparison and interpretation across different datasets.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

Analyses of genome and exome sequencing data identify rare coding and structural variants associated with atrial fibrillation and highlight genetic links between atrial fibrillation and cardiomyopathies.

Genome-wide analyses identify 30 independent loci associated with obsessive–compulsive disorder, highlighting genetic overlap with other psychiatric disorders and implicating putative effector genes and cell types contributing to its etiology.

Extending the therapeutic window for acute viral infections could save lives. Here, the authors show that combination treatment with a human monoclonal antibody and remdesivir initiated at 6 days post infection with Marburg virus provides 80% protection in non-human primates.

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate targeting HER2 but paradoxically efficient even in breast cancers expressing HER2 at very low levels. Here authors show that invasive breast cancers, even if their HER2 expression is negligible, secrete extracellular proteases, such as cathepsin L, which cleave the specialized linker of T-DXd, releasing the drug in the tumour microenvironment, while in HER2 positive breast cancers, T-DXd engages Fcγ receptors to promote phagocytosis of HER2-expressing cells and triggers payload-induced immunogenic cell death.

Studies of the physiological effects of metabolites often rely on injections of metabolite salts. In this study, Lund et al. show that the hypertonicity of the injected solutions can drive the metabolic effects attributed to pharmacological administration of lactate. This work highlights the importance of taking treatment osmolarity and counterions into account in the experimental design.

Mouse models expressing liver apoE in the absence of brain apoE reveal detrimental effects of peripheral apoE4 associated with Alzheimer’s risk on cognition and amyloid pathology through compromising vascular integrity and function.

Rahbani et al. show that the α₁-adrenergic receptor potentiates thermogenesis in thermogenic adipocytes, acting via Gα_q signalling, creatine kinase B and tissue-non-specific alkaline phosphatase.

The underlying mechanism of electroconvulsive therapy remains not fully understood. Here, the authors use optical neuroimaging in mice and humans to show that electroconvulsive therapy elicits a second brain event after seizure—spreading depolarization—a previously hidden phenomenon that may help to understand and optimize this treatment.

During an ongoing Ebola virus outbreak, infection before onset of protective immunity from vaccination is a possible scenario. Here the authors show in non-human primates that vaccination shortly before treatment with a monoclonal antibody does not negatively affect effectiveness of the antibody therapy.

The authors present a characterization of complex X-linked lncRNA loci with sex- and allele-specific epigenetic signatures that serve as a platform for the largest chromatin structures in mammals, thereby elucidating diverse phenotypes and combinatorial effects on autosomes.

MultiSTAAR provides a general and flexible statistical framework for functionally informed multi-trait rare variant analysis of biobank-scale sequencing studies by jointly analyzing multiple traits and incorporating annotation information.

Lee et al. show that DMXL1, a regulator of V-ATPase assembly, is recruited to lysosomes upon TRPML1 activation in a manner dependent on conjugation of ATG8 proteins on lysosomal membranes (CASM) and promotes lysosomal function.

The ubiquitin E3 ligase CUL2–APPBP2 determines PRDM16 protein stability by catalysing PRDM16 polyubiquitination in beige fat.

How signaling pathways recruit SWI/SNF chromatin remodeling complexes is not known. Here the authors suggest a ubiquitin directed mechanism targeting SWI/SNF for Wnt pathway dependent transcription, important for development and cancer.

Unlike carbon, boron is unable to form graphene-type structures, although variants with hexagonal holes have been suggested. Here the authors provide experimental evidence for the viability of such atom-thin boron sheets on the basis of a hexagonal vacancy discovered in a 36-atom planar boron cluster.

Enhancer of zeste homolog 2 (EZH2) has been implicated as a driver of disease progression and resistance to hormonal therapies. Here, the authors focus on EZH2 in two subtypes of advanced prostate cancer and report how it modulates the bivalent genes thereby leading to forward differentiation after being targeted in neuroendocrine prostate cancer.

The mouse develops a developmentally and functionally distinct, non-canonical beige fat cell type as an adaptation to cold ambient temperature.

Main-group analogues to fullerene-C₆₀ have been predicted theoretically many times. Now, B₄₀⁻ has been observed using photoelectron spectroscopy and, with its neutral analogue, B40, confirmed computationally. In contrast to fullerene-C₆₀, the all-boron fullerene (or borospherene) features triangles, hexagons and heptagons, bonded uniformly by delocalized σ and π bonds over the cage surface.

Factors controlling cancer and neoplasia prevalence across species are unclear. Here, the authors investigate the impact of diet and plasma glucose levels across 273 vertebrate species, finding no association between glucose levels and cancer within birds, mammals, or reptiles.

In mouse and nonhuman primate models, treatment with selective, long-acting neurokinin 2 receptor agonists aids weight loss by suppressing appetite and increasing energy expenditure, as well as by increasing insulin sensitivity.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

Pulmonary hypertension and congestive right heart failure afflict some cattle living at high altitude in an autosomal dominant pattern, yet no responsible genes have been identified. Here Newman et al.use whole-exome sequencing to identify variants in the hypoxia inducible factor gene, EPAS1.

Dysregulated CD4 T cells that recognize gut commensal antigens are able to infiltrate the central nervous systems and are re-stimulated by host proteins, resulting in neuroinflammation.

Castaño et al. show that primary breast tumours drive an IL-1β -mediated inflammatory response that inhibits cellular plasticity and metastatic colonization of metastasis-initiating cells.

Thermostable antibodies called SPEARs enable rapid immunostaining with improved tissue penetration.

Samples of different body regions from hundreds of human donors are used to study how genetic variation influences gene expression levels in 44 disease-relevant tissues.

Mutations of CCR5 have been linked to improved outcome to HIV infection. Here the authors use CRISPR-Cas9 genome editing of CCR5 in mobilized hematopoietic stem progenitor cells and show protection in a murine xenograft HIV infection model.

Here, the authors leverage whole-genome sequencing from >88,000 diverse individuals to uncover 18 BMI-related genetic signals, including novel variants in participants of African genetic ancestry, highlighting the value of diversity in genetic discovery.

Currently, gold recovery from waste materials requires inorganic cyanides and more environmentally benign methods are required. Here, the authors report that host–guest interactions between α-cyclodextrin and gold lead to the precipitation of one-dimensional superstructures, offering a selective and green alternative.

This study reports the preparation of degradable poly(β-amino ester) microparticles as a promising replacement for nondegradable microplastics in cleansing products and food fortification, demonstrating effective cleansing, toxic element removal and robust nutrient protection with efficient release.

The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

Double-strand breaks (DSBs) in DNA are challenging to repair. Here, the authors show that transcript RNAs impact the DSB repair outcomes in human and yeast cells by promoting NHEJ or MMEJ in a sequence-specific manner, suggesting a direct role for RNA in modulating genome stability and evolution.

Wang et al. present T cell receptor sequencing of serial tumor and blood samples from TIL-treated patients with non-small cell lung cancer, identifying tumor-reactive clonotypes expressing dysfunctional programs in patients lacking clinical benefit.

Mutational signature analysis of Pseudomonas aeruginosa identifies hypermutator clinical strains and prognostically predicts multidrug resistance acquisiton, potentially serving as a tool to guide effective personalized treatment.

Complete sequences of chromosomes telomere-to-telomere from chimpanzee, bonobo, gorilla, Bornean orangutan, Sumatran orangutan and siamang provide a comprehensive and valuable resource for future evolutionary comparisons.