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Transport protein particle (TRAPP; also known as trafficking protein particle) complexes activate the GTPase Ypt1 or RAB1 to regulate membrane traffic in yeast and mammals, respectively. Two different TRAPP complexes tether coated vesicles during endoplasmic reticulum–Golgi and intra-Golgi traffic, respectively, and a third complex functions in autophagy. The TRAPP complexes thereby connect GTPase activation to unique membrane-tethering events.

Here the authors reveal unique structural organization of the mammalian TRAPPII complex, which is critical in regulating membrane trafficking. They find that TRAPPII serves as a guanine nucleotide exchange factor for unexpected Rab GTPases such as Rab43 and Rab19.

Here, the authors generate a single-cell DNA methylation and transcriptome dataset from mouse peripheral blood samples, spanning a broad range of ages. They next develop scEpiAge, a single-cell DNA methylation age predictor.

At single-cell resolution, Tarkhov et al. delineate stochastic and co-regulated components of epigenetic aging, revealing a simultaneous loss of regulation at the epigenetic and transcriptional levels in aging.

Persisting symptoms after concussion (PSaC) present a complex neuropsychiatric challenge with limited treatment options due to inconsistent neuroimaging findings. Here the authors employ a multi-analytic approach to identify the salience network as a core dysfunction hub in PSaC, proposing specific cortical regions as potential targets for personalized neuromodulation therapies.

DNA methylation (DNAm) is a key biomarker of aging, with age-related DNAm changes being well-characterized. Here, the authors show that low-methylated regions (LMRs) bound by PRC2 in embryonic stem cells gain methylation with age in somatic cells, proposing the “PRC2-AgeIndex” as a universal biomarker of cellular aging.

Quiescent populations are a likely key source of treatment resistance in glioblastoma. Here, the authors characterize KAT5 as a critical mediator of quiescence and adoption of progenitor-like states.

Recent structural, biochemical and single-molecule biophysical studies have elucidated the molecular mechanisms underlying the control of SNARE (solubleN-ethylmaleimide-sensitive factor attachment protein receptor) complex assembly and disassembly by chaperones.

Heterochronic parabiosis ameliorates age-related diseases in mice, but how it affects epigenetic aging and long-term health was not known. Here, the authors show that in mice exposure to young circulation leads to reduced epigenetic aging, an effect that persists for several months after removing the youthful circulation.

A subset of intracellular transmembrane proteins such as acid-hydrolase receptors, as well as extracellular toxins such as Shiga toxin, undergoes retrograde transport from endosomes to thetrans-Golgi network. Recent studies have begun to provide insights into the molecular machinery involved.

A series of fluorescent probes is designed that act as dual agonists on both GLP1 and GIP receptors, and are used to image receptor binding activities in tissues and animals.

Eukaryotic Arf family proteins involved in endomembrane organelle dynamics arose from the Asgard archaeal ArfR GTPases, indicating this capability likely originated in the archaeal ancestor of eukaryotes.

Pooled and single-cell CRISPR screens provide a detailed map of human cytomegalovirus infection.

The mechanisms underlying the ability to remyelinate in aging and disease are unclear. Here, the authors show that DOR-mediated activation of α-ketoglutarate in mature oligodendrocytes can promote myelin production in mice during demyelination and aging.

The isolation and propagation of oligodendroglial cells from postnatal animals can be impractical for functional genetic studies. This study highlights the potential of a new approach to rapidly generate oligodendrocytes and their progenitors from mouse embryonic and induced pluripotent stem cells, independent of mouse strain or mutational status.

The first effective cancer vaccine targeted Marek's disease, a virus-induced neoplastic disease in domestic chickens. Here, Osterrieder and colleagues discuss recent progress in research on the causative agent, Marek's disease virus (MDV), and how MDV could be a useful model system of virus-induced lymphoma.

Protein interactions are essential for neural signaling and often perturbed in brain conditions. Here, the authors developed a CRISPR-based chemical-genetic approach to identify endogenous proximity proteomes that inform mechanism and phenotypic rescue strategies in mouse models of autism.

GLP-1 is an incretin hormone and neuromodulator produced by gut enterocytes and CNS neurons. Brierley et al. find that GLP-1 from peripheral and central sources acts independently through distinct gut–brain circuits to suppress eating.

Autophagosome biogenesis starts at the isolation membrane (also called the phagophore). Our understanding of the molecular processes that initiate the isolation membrane, the membrane sources from which this membrane originates and how it is expanded to the autophagosome membrane by autophagy-related (ATG) proteins and the vesicular trafficking machinery, is increasing.

The failure of metabolic tissues to respond to insulin is an early marker of type 2 diabetes. Here, the authors show, using global phosphoproteomics, that insulin resistance is caused by a marked rewiring of both canonical and non-canonical insulin signalling, and includes dysregulated GSK3 activity.

Samelson et al. report that BRD2 inhibition suppresses SARS-CoV-2 infection in epithelial cells and Syrian hamsters via reducing the transcription of host cell surface receptor ACE2.

Bruton’s tyrosine kinase (BTK) is expressed in immune cells and microglia, where its role remains poorly understood. Here, the authors show that BTK modulates microglial neuroinflammatory pathways relevant to multiple sclerosis (MS) and report robust effects of BTK inhibition in human in vitro models and animal models of MS.

The regulation of energy homeostasis by centrally-produced GLP-1 is not yet fully understood. Here, authors show that GLP-1 neuronal circuitry in the olfactory bulb reduces food intake and enhances insulin secretion in obese mice. The increase in insulin secretion is mediated by a GABA-dependent relay in the paraventricular hypothalamus and decreased sympathetic nerve activity.

Genome-wide ancient DNA data from individuals from the Middle Bronze Age to Iron Age documents large-scale movement of people from the European continent between 1300 and 800 bc that was probably responsible for spreading early Celtic languages to Britain.

Identifying driver genes in unstable, heterogenous tumour types can be challenging. Here, Mourikis, Benedetti, Foxall and colleagues present a machine learning algorithm to tackle this problem in esophageal adenocarcinoma.

Here, Li et al. perform a genome-wide CRISPR screen to identify host dependency factors for influenza A virus infection and show that the host mRNA cap methyltransferase CMTR1 is important for viral cap snatching and that it affects expression of antiviral genes.

Here the authors show that the patterning signals WNT, BMP, and FGF control chromosome segregation fidelity during early lineage specification and neurogenesis, which could provide a rationale for the spatio-temporal distribution of genomic mosaicism during human development.

In the developing cerebral cortex, early generated neurons, called Cajal-Retzius (CR) cells, migrate from their place of origin to the cortical surface. Here the authors show that the secreted axon guidance cue Semaphorin-3E and its receptor PlexinD1 regulate CR migration in mouse embryos.

Mutations in proteins that localize to primary cilia cause devastating diseases, yet the primary cilium is a poorly understood organelle. Here the authors use interaction proteomics to identify a network of human ciliary proteins that provides new insights into several biological processes and diseases.

The planar cell polarity (PCP) effector Fuz had not been studied in mice. Due to disrupted ciliogenesis, Fuz mutant mice show neural tube and skeletal defects. Fuz regulates trafficking of membrane cargoes to cilia through its interaction with a GTPase of the Rab family.

There are no new oligodendrocytes in potentially remyelinated multiple sclerosis shadow plaques, although oligodendrocyte generation is increased in the normal appearing white matter of patients with aggressive disease, informing the development of new therapies.