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Land management impacts ecosystem functions. Here, the authors conduct field experiments in Germany assessing ecosystem variables in cropland and grasslands showing that sustainable agricultural practices enhance ecological and economic benefits.

Observations from the Lucy spacecraft of the small main-belt asteroid (152830) Dinkinesh reveals unexpected complexity, with a longitudinal trough and equatorial ridge, as well as the discovery of the first contact binary satellite.

Hyperactivation of the toll-like receptors (TLRs) have been implicated as risk factors for more severe forms of disease in COVID-19 and metabolic (dysfunction) associated fatty liver disease (MAFLD). Here the authors report that MBOAT7 is reduced in macrophages of patients with MAFLD and COVID-19, and acts as a negative regulator of TLR signalling.

Studies using genetic screening, biophysical characterization and structural reconstitution elucidate the mechanism of action and enable rational design of a new class of functional compounds that glue target proteins to E3 ligases via intramolecularly bridging two domains to enhance intrinsic protein–protein interactions and promote target ubiquitination and degradation.

The transition of androgen receptor-dependent prostate cancer to a therapy resistant cancer with neuroendocrine phenotype is an important process that remains poorly understood. Here, the authors show that PKCλ/ι-loss promotes epigenetic reprogramming resulting in a TGFβ resistance programme via transcriptional upregulation of translational machinery.

Kinase inhibitors are widely used to treat cancer, however patients frequently develop resistance. Here, the authors investigate adaption mechanisms during drug persistence and show that stimulation of the innate immunity sensor RIG-I enhances cancer cell death when combined with kinase inhibition.

Vitamin E metabolites are proposed to have signalling capacity, but how they may regulate immune responses is still unclear. Here the authors show that a vitamin E metabolite, α-T-13′-COOH, can inhibit 5-lipoxygenase and thereby suppress the synthesis of lipid mediators of immune activation and inflammatory responses.

Polymethine dyes are bright and red-shifted fluorophores that lack an intrinsic turn-on mechanism, which leads to non-specific staining when applied to biological samples. Now the fluorescence of polymethine dyes was masked through an intracellular cyclization strategy that gets reversed upon binding an intended macromolecular target, providing specificity for live-cell imaging.

Rhabdoid tumors (RT) are aggressive paediatric cancers with yet unknown cells of origin. Here, the authors establish genetically engineered mouse models of RT and, using single-cell RNA-seq and epigenomics, identify potential cells of origin for the SHH and MYC subtypes.

Using mosaic variant barcode analysis, clonal dynamics of specific cell types are deconvolved in the human forebrain.

J-domain proteins (JDPs) regulate Hsp70 function and specificity. Here, authors combine functional assays and cryoEM to describe the structure of a dynamic tubular assembly of DNAJA2, a class A JDP, and its stabilizing interdomain interactions.

Therapeutic T cells engineered to recognize tumour antigens are frequently short-lived and acquire unfavourable phenotypes in tumours. Here authors show that a tandem approach using autologous T cells targeted against the tumour antigen NY-ESO-1, followed by transfer of hematopoietic stem cells with the same specificity in the clinical trial NCT03240861, provides a safe and promising therapeutic option.

Biological degradation of glycosides involves, alongside hydrolysis, β-elimination for glycosidic bond cleavage. Here, the authors report an O-glycoside β-eliminase from Agrobacterium tumefaciens that converts the C3-oxidized O-β-d-glucoside of phloretin into the aglycone and the 2-hydroxy-3-keto-d-glycal elimination product, and suggest convergent evolution of β-eliminase active sites for the cleavage of natural product 3-keto-O-glycosides.

RNA ligases are present across all forms of life. Here, the hitherto uncharacterised human protein C12orf29 was identified as a human enzyme promoting RNA ligation between 5′-PO₄ and 3′-OH termini. This data provides the groundwork for establishing a human RNA repair pathway.

In this study the authors identify a possible link between the gene FAM222A and brain atrophy. The protein it encodes is found to accumulate in plaques seen in Alzheimer’s disease, and functional analysis suggests it interacts with amyloid-beta.

Citizen science taps the efforts of non-experts. Here, authors describe Drugit, an extension of the crowdsourcing game Foldit, and its use in designing a non-peptide binder of Von Hippel Lindau E3 ligase for use with proteolysis targeting chimeras.

Blockade of lymphotoxin β-receptor (LTβR) signalling restores WNT signalling and epithelial repair in a model of chronic obstructive pulmonary disease.

Immature particles of flaviviruses transmitted by mosquitoes are known to be non-infectious. Here, the authors show that immature tick-borne flaviviruses stay infectious in vivo and using structural modeling they resolve unique structural features that distinguish tick-borne from mosquito-borne flaviviruses.

Reduced fitness of the tumor microenvironment is mediated by a long non-coding RNA expressed in tumors.

Temporary bioelectronics can complement classical therapies in non-chronic treatments. Here, the authors describe the minimally invasive implantation of bioresorbable electrodes in the brain that form in situ from water-dispersed nanoparticles and show no tissue damage after bioresorption.

Arrayed CRISPR libraries with each plasmid encoding an array of four non-overlapping single-guide RNAs allow for the efficient genome-wide ablation, activation and epigenetic silencing of human protein-coding genes.

A substrate-guided design strategy generated highly potent inhibitors of the biosynthesis of the genotoxin colibactin by human gut bacteria. These inhibitors also enable a generalizable approach for chemically guided natural product discovery.

Rare mutations in the high requirement temperature protein A1 (HTRA1) cause cerebral vasculopathy. Here, authors establish mechanistically distinct protein repair approaches to reverse the deleterious effects of pathogenic mutations interfering with the assembly and protease function of HTRA1.

Tumour vasculature influences drug delivery. Here, the authors show that SOD3 re-expression enhances doxorubicin delivery and effects through normalization of tumour vasculature via the HIF-2a/VE-cadherin pathway.

Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.

CAR and PXR receptors are known to regulate metabolism, however, there is no dual human ligand suitable for therapy. Here, the authors show a CAR agonist/PXR antagonist, MI-883, which regulates cholesterol/bile acid homeostasis by leveraging CAR and PXR activations in plasma cholesterol regulation.

A comprehensive analysis of brain somatic mosaicism across the neocortex demonstrates the origins and distribution patterns of cells within the human brain.

Gain-of-function mutations in CTNNB1 (encoding for b-catenin) leading to deregulated Wnt/β-catenin signaling are frequently observed in patients with hepatocellular carcinoma (HCC). Here the authors show that inhibiting b-catenin with lipid nanoparticles encapsulating siRNA targeting CTNNB1 impairs tumor growth and promotes anti-tumor immunity in preclinical HCC models.

The generation of reactive oxygen species (ROS) in photodynamic cancer treatments is limited by low intraturmoural oxygen availability. Here the authors show that irradiation of a silicon phthalocyanine leads to uncaging of a biologically active molecule or to ROS formation in an oxygen-dependent manner.

Untargeted metabolomics demonstrate that apoptotic brown adipocytes release a specific pattern of metabolites with purine metabolites being highly enriched, and inosine is identified as a metabolite released during apoptosis regulating thermogenic fat and counteracting obesity.

Dysregulated CD4 T cells have been implicated in autoimmune liver disease, but their phenotypes and origin are still unclear. Here the authors profile circulating, autoreactive CD4 T cells to find transcription signatures similar to tissue-activated, exhausted T cells, thereby hinting a tissue origin for these circulation CD4 T cells.

Renilla luciferase is a popular bioluminescent enzyme, but the molecular details of its mechanism of action on luciferins such as coelenterazine remained elusive. Now, protein crystal structures and biochemical analyses provide an atomistic description of its catalytic mechanism.

The µ-opioid receptor is a key clinical target. Here, the authors describe nanobody NbE, a selective and high affinity antagonist, which is downsized to small cyclic peptides. The work enables unique receptor targeting based on nanobody interaction.

The engagement of immunological memory is a key component to the protective anti-SARS-CoV-2 B and T cell responses. Here the authors assess the B and T cells of a cohort of UK healthcare workers in response to infection and longitudinally track the compartment showing distinct trajectories following early priming.

Macrocyclic peptides can be genetically encoded and synthesized in cells; however, the programmable diversity is limited. Now, macrocycles containing two non-canonical amino acids have been genetically encoded and synthesized in codon-reassigned Syn61Δ3 cells. Incorporating diverse hydroxy acids in Syn61Δ3 cells enables the synthesis of non-natural depsipeptides containing either one or two ester bonds.

The large coding potential of vaccinia virus (VV) vectors is a defining feature. Here the authors present vaccinia virus vector-adapted chemogenetic switches enabling temporal and dose control of viral replication and transgene expression, implementation of complex tunable transgene circuitry, and generation of safer, more efficacious vectors.

Two algal proteins, MITH1 and SAGA1, play key roles in formation of membranes that deliver CO₂ to the pyrenoid, a CO₂-concentrating organelle. Their discovery marks a key milestone towards engineering a pyrenoid into land plants for improved yields.

Lipoic acid is a food supplement and approved neuropathy drug but lacks known molecular targets. Here, Lechner et al. employ chemoproteomic target deconvolution to demonstrate that (R)- but not (S)-lipoic acid stereoselectively inhibits histone deacetylases at physiologically achievable doses.

It is unclear how microbial-induced inflammation promotes neoplastic transformation in colitis-associated cancer (CAC). Here, the authors use models of CAC to show that inflammation induces 8-oxoguanine lesions in DNA, and that antioxidants can reduce these DNA lesions as well as CAC.

Immunoglobulin A (IgA) has two subclasses, IgA1 and IgA2, but differential effects on inflammation are unclear. Here the authors show that IgA2, when compared with IgA1, has stronger pro-inflammatory functions associated with changed glycosylation and higher disease scores in patients with rheumatoid arthritis.

The circadian clock and the cell cycle systems coordinate global physiology. Here the authors show that MYC represses the clock genes, together with MIZ1, and induces proliferation, suggesting that MYC inversely modulates cell cycle and circadian clock genes.

RNA binding protein HDLBP (or Vigilin) localizes in the endoplasmic reticulum (ER) membrane. Here the authors show that HDLBP contributes to translation of ER-targeted mRNAs.

Bacterial growth rate depends on the number of active ribosomes and translation elongation rate. Matamouros et al. show that Corynebacterium glutamicum, a gram-positive model species, uses a different strategy than Escherichia coli during slow growth by strongly reducing the translation elongation rate while keeping a high number of active ribosomes.

The Omicron variant evades vaccine-induced neutralization but also fails to form syncytia, shows reduced replication in human lung cells and preferentially uses a TMPRSS2-independent cell entry pathway, which may contribute to enhanced replication in cells of the upper airway. Altered fusion and cell entry characteristics are linked to distinct regions of the Omicron spike protein.

Spatial molecular imaging analysis of human pancreatic adenocarcinomas describes multicellular neighborhoods in the tumor microenvironment. Ligand–receptor analysis using optimal transport-based SCOTIA identifies interleukin-6 as a mediator of chemoresistance.