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An inhibitor of NAPE-PLD involved in lipid biosynthesis lowers levels of the endocannabinoid anandamide and other N-acylethanolamines in cells and mouse brain and activates the hypothalamus–pituitary–adrenal axis and impaired fear extinction.

Small GTPases of the RAS family classically function as molecular switches, adopting on and off conformations dependent on bound nucleotides. Here the authors reveal MRAS, closely related to archetypal RAS, is completely deficient in GTP exchange.

KDM4C regulates cathepsin L-mediated histone H3 N-terminal tail clipping through grainyhead-like 2 (GRHL2) methylation in breast cancer. This link between the cellular redox state and chromatin remodeling might represent a therapeutic target in KDM4C-amplified tumors.

Here, the authors provide molecular insight into the remarkable ability of Tardigrades to withstand high levels of radiation by demonstrating that their Dsup protein interacts with multiple surfaces of the nucleosome to protect the genome from oxidative DNA damage.

The MmpL5/MmpS5 efflux system is crucial for drug extrusion and siderophore export in M. tuberculosis. Here, the authors report its high-resolution cryo-EM structures, revealing a unique trimeric assembly and a flexible extracellular stalk.

Latorre-Muro et al. show that the cytosolic chaperone PPID drives insertion of the mitochondrial import receptor TOM70 into the mitochondrial outer membrane, thereby regulating body temperature, glucose homeostasis and body weight in obese mice.

During SARS-CoV-2 infection caspase-8 fuels harmful inflammation independent of apoptosis. Genetic loss of caspase-8 reduces cytokine levels, lowers viral load and mitigates disease severity, revealing non-apoptotic caspase-8 as a key driver of severe COVID-19.

Lin, Geng and colleagues identify a non-canonical AHR pathway that is activated by canonical AHR inhibitors, promoting the proliferation of quiescent endothelial cells with potential applications in cell therapy.

α-Synuclein and tau can form multiple amyloid structures or strains that are associated with different neurodegenerative diseases, suggesting a strain–toxicity relationship. Now, it has been shown that O-GlcNAc modification of α-synuclein results in the formation of an amyloid strain that is largely nonpathogenic in vivo, supporting structure-dependent toxicity and another protective role for O-GlcNAc.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

A mass spectrometry-based approach globally identifies protein regulators of metabolism and reveals the role of LRRC58 in controlling cysteine catabolism.

Some cancer patients first present with metastases where the location of the primary is unidentified; these are difficult to treat. In this study, using machine learning, the authors develop a method to determine the tissue of origin of a cancer based on whole sequencing data.

Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

Structural and biochemical studies of the Mycobacterium smegmatis hydrogenase Huc provides insights into how [NiFe] hydrogenases oxidize trace amounts of atmospheric hydrogen and transfer the electrons liberated via quinone transport.

Genetic analyses of ancestrally diverse populations show evidence of heterogeneity across ancestries and provide insights into clinical implications, highlighting the importance of including ancestrally diverse populations to maximize genetic discovery and reduce health disparities.

The small molecule SRI-41315 induces the degradation of the translation termination factor eRF1 to enhance stop codon readthrough. Coelho, Yip et al. reveal that SRI-41315 is a metal-dependent molecular glue that traps eRF1 on terminating ribosomes.

Here the authors assemble a toolkit to probe K48–K63-branched ubiquitin chain function. By identifying specific binders and deubiquitinases and engineering a specific nanobody, they reveal the importance of these chains in p97-dependent processes.

Hypertrophic cardiomyopathy-causing mutations in cardiac myosin disrupt its auto-inhibited OFF state, leading to hypercontractility. Here, the authors show that disease-linked mutations remote from intramolecular OFF state interfaces can allosterically impair myosin autoinhibition

An RNA aptamer and a ribozyme are both observed to retain a surprising degree of activity despite backbone heterogeneity caused by the presence of non-natural 2′–5′ phosphodiester linkages. These results suggest that absolute regioselectivity of non-enzymatic replication may not have been required for the emergence of RNA as the first biopolymer.

The folding of outer membrane proteins (OMPs) is catalyzed by the βbarrel assembly machinery (BAM). Here, structural and functional analyses of BAM stabilized in distinct conformations elucidate the roles of lateral gate opening and interactions of BAM with the lipid bilayer in OMP assembly.

Effective and regulated activation of the Mcm2-7 helicase underlies faithful genome replication. Here the authors reveal mechanistic detail how the pre-loading complex proteins TopBP1 and GINS interact and, thus, how the helicase activator GINS loads on Mcm2-7 during replication origin firing.

The authors report Acheulean hominin occupation of eastern Britain during glacial marine isotope stages 17–16 and again in glacial marine isotope stage 12 via stone tools in sediments dated to 712,000 to 424,000 years ago.

A targeted protein stabilization platform termed deubiquitinase-targeting chimera (DUBTAC) was developed based on heterobifunctional small molecules consisting of a deubiquitinase OTUB1 recruiter linked to a protein-targeting ligand.

α/β-hydrolase domain-containing protein 11 (ABHD11) is a mitochondrial hydrolase, and its expression in CD4 + T-cells has been linked to remission status in rheumatoid arthritis. Here the authors report that pharmacological inhibition of ABHD11 modulates T-cell effector function via increased 24,25-epoxycholesterol biosynthesis and subsequent liver X receptor activation.

Results of an early-phase breast cancer prevention trial demonstrate the potential for breast cancer prevention in premenopausal women with anti-progestin therapy by inducing epithelial–stromal remodelling and suppression of luminal progenitors.

Rab3GAP, a guanine nucleotide exchange factor for Rab18, regulates membrane trafficking and lipid droplet metabolism. The authors elucidated its molecular structure, mapped its potential substrate binding interface, and uncovered that disease-associated mutations likely impair Rab18 binding.

A significant challenge in modern drug development is the comprehensive profiling of covalent inhibitors. Here, the authors develop COOKIE-Pro, an unbiased method for quantifying the binding kinetics of irreversible covalent inhibitors on a proteome-wide scale.

Bacterial secretion systems are key to pathogenesis, as they secrete the many virulence factors needed for host colonization. Bioinformatic and functional analyses have identified a transport and assembly module (TAM) in proteobacteria that may be necessary for biogenesis of the autotransporter family of virulence factors.

Breast cancer cells interact with neighbouring adipocytes, but the mechanisms are not fully understood. Here, the authors show that triple-negative breast cancer (TNBC) cells transfer cAMP through gap junctions, activating lipolysis in tumour-associated adipocytes to promote TNBC growth.

The core circadian transcription factor BMAL1 regulates circadian-dependent myocardial injury.

Toxoplasma gondii evolved two ISWI remodellers, TgSNF2h and TgSNF2L. TgSNF2h forms a complex that insulates active genes, regulates MORC-driven sexual commitment and ensures precise gene expression, safeguarding the parasite’s developmental program.

They determine four cryo-EM structures of NiV polymerases from different strains and establish RdRp enzymatic assays for anti-NiV drug discovery. A back-priming RdRp activity and the binding between RdRp core and CD domains in NiV L were identified.

Hyper-phosphorylated tau accumulates in Alzheimer’s disease; but the roles of these phosphorylation sites are unclear. Here the authors show that phosphorylation of a single site, pSer416, limits its turnover and promotes accumulation.

Understanding the infection parameters and host responses against SARS-CoV-2 require data from large cohorts using standardized methods. Here, the authors optimize a serum ELISA protocol that has minimal cross-reactivity and flexible sample collection workflow in an attempt to standardize data generation and help inform on COVID-19 pandemic and immunity.

Centromeres play an essential function in faithful chromosome segregation. Here, the authors demonstrate the mechanism by which human cells dynamically modulate the activity of the Bloom’s syndrome helicase complex to safeguard centromere integrity throughout mitotic progression.

A post-translational backbone extension acyl rearrangement (BEAR) reaction has now been developed that converts a ribosomal protein product into a new product containing a β-peptide, γ-peptide or δ-peptide backbone. BEAR reactions represent a general strategy to install extended backbones into genetically encoded proteins and peptides expressed in cells.

Deubiquitinases are proteases that cleave after the C-terminus of ubiquitin to hydrolyze ubiquitin chains and cleave ubiquitin from substrates. Here the authors describe a reactive-site-centric chemoproteomics approach to studying deubiquitinase activity, and expand the repertoire of known deubiquitinases.

Cellular lysine residues can be both methylated and acetylated on the same sidechain to form N^ε-acetyl-N^ε-methyllysine (Kacme), which is found on histone H4 across a range of species and across mammalian tissues and is associated with active chromatin.

Although Archaea encode proteasomes highly related to those of eukaryotes, archaeal ubiquitin-like proteins are less conserved and not known to function in protein conjugation, complicating our understanding of the origins of ubiquitination. Two small archaeal modifier proteins, SAMP1 and SAMP2, structurally similar to ubiquitin, are now reported to form protein conjugates in the archaeon Haloferax volcanii.

Using biochemistry, chemical biology, and cryo-EM, Maiwald et al. elucidate how TRIP12 forms K29 linkages and K29/K48-linked branched ubiquitin chains, revealing a mechanism for polyubiquitylation shared by some HECT E3s.

Hunter et al. use RNA labelling to investigate RNA transfer between organs in mice. They show that RNA potentially moves en masse from liver to kidney and that this movement is augmented in acute liver injury, although the physiological relevance of the phenomenon is not yet known.

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.

ABP profiling identifies uncharacterized S. aureus serine hydrolases, including the surface-localized FphB, which processes lipid ester substrates and is required for infection in vivo. An FphB inhibitor reduces in vivo bacterial load.