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Broadly applicable genetically encoded probes and peptide-based compounds specifically inhibit Gα_s, the prototypical signal transducer of G-protein-coupled receptors, providing new mechanistic insights into signaling at the subcellular scale.

Mountaintop facility in Azores can track pollution from North America.

Despite frequent AKT/mTOR pathway activation in patient’s rhabdomyosarcoma (RMS), success of AKT inhibitors in the clinical has been limited. Here, using RMS patient-derived models, the authors demonstrate that the efficacy of the AKT inhibitor, ipatasertib, is in part due to its off-target effects on PRKG1, identifying PRKG1 as a potential biomarker for ipatasertib response.

Hi-C methods for studying 3D genome structure typically require millions of cells and struggle with repetitive regions. Here, authors develop CiFi, combining 3C with PacBio HiFi sequencing, enabling chromatin analysis from as few as 60,000 cells and chromosome-scale assembly from small samples.

Dietary n-6 PUFAs enhance adipose tissue expandability through the PPARγ–LPCAT3 membrane remodelling axis.

The molecular features of paediatric central nervous system (CNS) tumours are not fully understood, posing a challenge for targeted therapies. Here, the authors characterise paediatric CNS tumours using single-nucleus RNA-seq; they identify cell type populations associated with specific tumour types and with response to therapy.

Iacobucci et al. present the single-cell transcriptomic profile of patients with B cell acute lymphoblastic leukemia, report enriched multipotency and develop a multipotency score that is associated with worse survival in pediatric patients.

The physical organization of the genome in non-bilaterian animals and their closest unicellular relatives is characterized; comparative analysis shows chromatin looping is a conserved feature of genome architecture and spatial genome regulation emerged early in animal evolution.

The binding of small molecules to the double stranded DNA may significantly alter its stability and functionality, which is the basis for many therapeutic and sensing applications. Here, the authors report that DNA binders can be used to program reaction pathways of a dynamic DNA reaction, where DNA strand displacement can be tuned quantitatively according to the affinity, charge, and concentrations of a given DNA binder.

PBK is a mitotic kinase implicated in cancer. This study reveals how PBK evicts key C2H2-zinc finger transcription factors such as Ikaros, Aiolos and CTCF from DNA as cells divide, regulating mitotic chromatin accessibility and chromosome compaction.

Renner et al. show that HIV-1 concentrates the metabolite IP6 into its virions to catalyze assembly of its iconic conical capsid. Disabling this enrichment mechanism prevents assembly and renders HIV-1 non-infectious.

Here the authors show that a gene-inactivating protein complex packs inactive genes into a dynamic and accessible structure. The study challenges the traditional views that restricted accessibility and low dynamics cause gene repression.

Glycosylation is an abundant form of post-translational modification. Here the authors present a generalizable workflow for the selection of indole-modified aptamers that can recognize protein glycoforms with high specificity.

Zaman, Yang and Huang et al. demonstrate MDK’s suppressive effect on amyloid-β and its impact on amyloid burden and microglial activation in Alzheimer disease mice, highlighting its protective role in pathogenesis.

Here, the authors present a method to rapidly isolate actively translating ribosomes in a time- and cost-effective manner using poly-lysine. The method is compatible with a wide variety of cell and tissue types and can be used for mass spectrometry, cryoEM, and in vitro translation assays.

Clonal hematopoiesis is associated with an increased risk of hematologic and a range of inflammation-related diseases. Here, Yang et al. demonstrate a critical role for aberrant thrombopoietin receptor signaling in TET2-mutation driven clonal hematopoiesis.

Teplizumab is clinically approved for delaying the onset of type 1 diabetes, with the responses affected by EBV serology status. Here the authors pursue immune profiling of EBV⁺ or EBV^- participants before and after teplizumab treatment to find more pronounced immune modulation in treated EBV⁺ individuals to hint a cellular mechanism for this EBV effect.

Many clock proteins contain intrinsically disordered regions, but how these regions mediate protein interactions is poorly understood. Here, the authors identify charge blocks within a disordered clock protein that regulate circadian timing.

Dendritic cells play pivotal roles in the immune response to viral infection but are targeted by flaviviruses resulting in evasion of the host response. Here the authors show Zika but not Dengue virus limits the NF-κB response in monocyte derived dendritic cells diminishing their ability to activate T cells.

A survey of the cellular RNA-binding proteins (RBPs) that interact with dengue virus and Zika virus genomic RNA identifies ribosome-binding protein 1 and vigilin as bona fide RBPs able to promote viral RNA translation, replication and stability.

Concentrative nucleoside transporters (CNTs) are cellular nucleoside influx systems, but their in vivo roles are poorly defined. By generating CNT1 knockout (KO) mice, here the authors show a role of CNT1 in the renal reabsorption of endogenous and synthetic nucleosides.

Here the authors analyse the impact of space on haemoglobin gene regulation using data from NASA, JAXA and SpaceX i4 missions. They find that globin gene down-regulation leads to space anaemia with post-flight recovery, and reveal an adult-to-foetal globin switch activation.

Androgen response elements (AREs) regulation produce opposite effects in normal and cancer prostate cells. Here, authors engineer a modifier of ARE-containing chromatin (MACC) to define the elements responsible for a normal growth-suppressive program, which can be reengaged in prostate cancer cells.

Chiou et al. provide a multiregion bulk (N = 527 samples) and single-nucleus (N = 24 samples) brain transcriptional dataset encompassing 15 brain regions and both sexes in a unique population of free-ranging, behaviorally phenotyped rhesus macaques.

Vitamin B12 is an essential nutritional co-factor for the folate and methionine cycles, which together constitute one-carbon metabolism. The authors find that Vitamin B12 influences various cell fates by modulating RAS/MAPK signaling in C. elegans. Mammalian cells expressing hyperactive RAS respond similarly.

Photoreceptor outer segment abnormalities cause retinitis pigmentosa, a form of blindness. Here, authors show that the disease-associated gene RPGR regulates actin-mediated outer segment turnover through its interaction with the actin severer, cofilin.

Variant-to-gene-to-program is a new approach to building maps of genome function to link risk variants to disease genes and to convergent signalling pathways in an unbiased manner; its strength is demonstrated in coronary artery disease.

The establishment of glucose-regulated insulin secretion from pancreatic β-cells requires multiple transcription factors but is incompletely understood. Here, the authors show that Mediator complex subunit MED15 is vital for this process of β-cell maturation, highlighting its role in coordinating transcriptional control of insulin production and secretion.

Advancing the oxygen evolution reaction understanding requires probing catalysts’ microscale dynamics in operando but is highly challenging. Here, authors use compressive Raman imaging to unravel the charge compensation pathways in a crystalline oxygen evolution catalyst, α-Li₂IrO₃.

The TRPM7 channel enables endosomal acidification, which is vital for the entry of many enveloped viruses. Here, the authors show that loss of TRPM7 protects cells from various pandemic-threat viruses, pointing to a new strategy for broad-spectrum antiviral drugs.

Bacteria often express multiple adhesive proteins (adhesins) for biofilm formation, but it is often unclear whether adhesins have specialized or redundant roles. Here, the authors show that Vibrio cholerae uses two adhesins with overlapping but distinct functions to achieve robust adhesion to diverse surfaces.

HP1 proteins are rapidly evolving heterochromatin factors that are essential for silencing. Here, the authors identify an interface where subtle amino acid changes can lead to novel epigenetic inheritance phenotypes, acting as an effector toggle switch to regulate the persistence of epigenetic memory.

The authors report signal enhancements in high-resolution liquid-state NMR by a new setup for dynamic nuclear polarization. Two-dimensional NMR techniques are used to transfer hyperpolarization within the nuclei of molecules such as metabolites or drugs.

Defective insulin secretion is observed early in the development of diabetes. Here the authors report that β cell-specific deficiency of the insulin prohormone convertase 1/3 (PC1/3) leads not only to hyperglycemia, but also to hyperphagic obesity in mice.

MYC activation can sensitise cells to apoptosis upon glutamine withdrawal. Here the authors show that MYC activation enhances global transcription and translation that creates a metabolic demand, while glutamine limitation causes a metabolic demand and supply imbalance through loss of TCA energetics and thus, sensitises cells to apoptosis.

Zika virus (ZIKV) infection suppresses the induction of dendritic cell (DC)-derived immunity, but the underlying mechanistical insights are still lacking. Here the authors show, using in vitro systems profiling of DC transcriptome and epigenome, that ZIKV specifically alters SREBP2-related expression of inflammation- and metabolism-related genes to modulate DC functions.

Antigen-specific immunosuppression can be enhanced by genetically modifying mesenchymal stromal cells with chimaeric antigen receptors, as shown for the treatment of graft-versus-host disease in mice.

Exportin-1 (XPO1) was identified as the target of small molecules suppressing T cell activation. Selective disruption of the chromatin scaffolding function of XPO1 without blocking nuclear export implicates XPO1 as a target in autoimmunity.

The actin methyltransferase SETD3, by virtue of its ability to interact with the viral 2A protein and independently of its enzymatic activity, is necessary for RNA replication of several enteroviruses in cell culture and in vivo.

Rearrangements of the Ig loci are essential for generating antibody diversity but abnormal translocations can be a driving event for myeloma. Here Walker et al. perform whole exome sequencing on myeloma patients to capture the diversity of mutational changes.

Remodelling of the actin cytoskeleton occurs during plant immune responses to pathogens. Here Lu et al. show that this process requires the calcium-dependent kinase CPK3 which phosphorylates actin depolymerizing factor 4 and is required for both PAMP and effector-triggered immunity in Arabidopsis.

FOXA1 pioneer transcription factor is recurrently mutated in primary and metastatic prostate tumors. Here, authors identify a set of six cis-regulatory elements in the FOXA1 regulatory plexus harboring somatic SNVs in primary prostate tumors and characterize their role in regulating FOXA1 expression and prostate cancer cell growth.

Off-target effects and the feasibility for AAV-mediated delivery are the major barriers impeding the clinical in vivo application of base editors. Here, the authors report the small size AAV-deliverable Cas9-ABE variant that has improved on-target editing efficiency and reduced RNA-off target footprint.

Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.

Mutations in LRRK2 and GBA1, which encodes glucocerebrosidase (GCase), are associated with Parkinson’s disease. Here the authors show that LRRK2 is a negative regulator of lysosomal GCase activity, using dopaminergic neurons derived from iPSCs from PD patients with LRRK2 mutations.

An improved, fully re-annotated Aedes aegypti genome assembly (AaegL5) provides insights into the sex-determining M locus, chemosensory systems that help mosquitoes to hunt humans and loci involved in insecticide resistance and will help to generate intervention strategies to fight this deadly disease vector.

The mechanical microenvironment influences stem cell pluripotency. Here, the authors culture stem cells in microgels with controlled volumetric confinement and identify Plakoglobin as a mechanoresponsive regulator of pluripotency in mouse and human.

Chronic differentiation in Toxoplasma gondii is controlled by a positive feedback loop between BFD1 and BFD2.

Activation of the glycerol shunt mimics calorie restriction, protects from glucotoxicity, and promotes healthy aging. Here, Possik et al. uncover the underlying mechanism and identify the AMPK-TFEB autophagy pathway as critical to the healthy aging phenotype.

The authors demonstrate that cells that are deficient in H3K9 trimethylation display more compact mitotic chromosomes decorated with aberrantly high H3S10 phosphorylation and H3K27 trimethylation. By quantitative proteomics, they show that H3K9 trimethylation is essential for mitotic bookmarking by Esrrb and thus for the maintenance of epigenetic memory during cell division.