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Inhibitors of the protein kinase Wee1 are promising drugs for cancer therapy. Here, the authors show that these drugs activate the integrated stress response via GCN2, synergising with mRNA translation defects. They suggest strategies such as PROTACs or ISR inhibitors to improve WEE1 mediated toxicity.

Viruses generally have compact genomes, resulting in many viral mRNAs with short 5’ untranslated regions. An antiviral complex exploits this feature of viral mRNAs to selectively inhibit viral protein synthesis and repress viral replication.

Hepatitis E virus exists in two forms in patients: naked and quasi-enveloped. Using a new imaging method, the authors found that these forms enter cells through different pathways, directed by interaction of the capsid protein with integrin beta 1.

In this study, the authors assess the global response to the toxic aldehyde glyoxal (GO) in Pseudomonas aeruginosa, suggesting that GO controls quorum sensing during infection through a mechanism involving a novel protein, ArqI.

Understanding the induced and cross reactive immunity to sarbecoviruses is an important step in rationale and widely applicable vaccine design. Here the authors use a multivalent S2 subunit vaccine and demonstrate protection in female mice against SARS-CoV-2-like and SARS-CoV-1-like coronaviruses.

A method termed ac⁴C-seq is introduced for the transcriptome-wide mapping of the RNA modification N⁴-acetylcytidine, revealing widespread temperature-dependent acetylation that facilitates thermoadaptation in hyperthermophilic archaea.

Scanning transmission electron microscopy is a powerful material probe, but constrained to large atomic number samples due to the issues of beam damage and weak scattering. Here, Ophus et al.propose a method that produces linear phase contrast in a focused electron beam to image dose-sensitive objects.

RH5, which is part of the trimeric RCR-complex essential for invasion, is a vaccine candidate for malaria. Here, Williams et al. show that monoclonal antibodies targeting each of the three proteins in the RCR-complex can work together to more effectively block the invasion of red blood cells by Plasmodium falciparum and design a combination vaccine candidate.

Bats are remarkably tolerant to viral infections and their unique immune system, characterized by high level of tissue protection and dampened inflammatory responses, contributes to their longevity. Here authors show that the diversity of the bat antibody repertoire changes according to the body temperature and metabolic activity of the animals and higher activity directs their specificity towards eliminating damaged epithelial and endothelial cells.

The bioavailability of NAD is vital for muscle health. Here, the authors unveil a pathway from glucose sensing to muscle NAD modulation via the TAS1R2 receptor, suggesting TAS1R2 as a therapeutic target for muscle health preservation.

The bacterial pathogen Chlamydia trachomatis replicates within a vacuole known as an inclusion. Here, Linton et al. show that in multiply infected cells, apposing inclusions form unique membrane-contact sites that regulate membrane fusion.

Optimised nanobody-based quenchbodies are developed through rational design and in vitro evolution, enabling improved protein detection with up to 2.4-fold fluorescence increase and 2 nM sensitivity for IL-6.

Grainger et al. demonstrate that, in zebrafish and human cells, EGFR-mediated phosphorylation of Fzd9b promotes internalization of the Wnt9a–Fzd9b–LRP signalosome and subsequent signal transduction.

High-throughput DNA or RNA labelling with optimized Oligopaints (HiDRO) reveals more than 300 factors that influence genome folding during interphase, including 43 genes that were validated as either increasing or decreasing interactions between topologically associating domains.

Chlamydia trachomatis forms membrane-bound inclusions inside the host cell that are decorated with IncA, a SNARE-like protein that promotes the fusion of inclusions. Here, Cingolani et al. show that the protein folds into a non-canonical four-helix bundle and identify an intramolecular clamp required for membrane fusion.

Fumarate metabolism regulates the innate immune response through a mechanism in which high levels of fumarate result in the generation of mitochondrial-derived vesicles and the release of mitochondrial DNA into the cytosol, which activates inflammatory pathways.

An HLA- and gluten-dependent mouse model of coeliac disease with villous atrophy provides evidence for the cooperative role of IL-15 and gluten-specific CD4⁺ T cells in licensing the full activation of cytotoxic T cells that are necessary for inducing epithelial damage.

A genome-wide association meta-analysis study here shows novel genetic loci to be associated to body fat percentage, and describes cross-phenotype association that further demonstrate a close relationship between adiposity and cardiovascular disease risk.

Response to chemotherapy in patients with pancreatic ductal adenocarcinoma (PDAC) is often limited. Here, the authors report improved response to chemotherapy in PDAC patients with hyperglycaemia and investigate the underlying mechanism via glucose-mediated disruption of redox metabolism

Statin therapy is associated with numerous cellular effects. Here, the authors show that statin treatment increases post-translational modifications on fatty acid synthase in the active site, revealing communication between the cholesterol and lipid biosynthetic pathways.

Joseph Gleeson and colleagues report that biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy marked by lysosome-autophagosome dysfunction. Their findings suggest a role for SNX14 in mediating lysosome-autophagosome fusion.

Genome-wide CRISPR screens in mouse cancer cell lines are used to identify a core, conserved set of genes and pathways that govern how cancer cells evade killing by cytotoxic T lymphocytes.

Understanding the immune response to SARS-CoV-2 is dependent on being able to distinguish COVID-19 immune responses from cross-reactive immune responses to other coronaviruses. Here the authors show that choice of antigens and whether an ICS, ELISPOT or T cell proliferation assay is used has a major effect on this discriminatory ability.

Two chemical series, oxalamides and benozothiazoles, produced toxicity in particular lung cancer cells. These compounds were metabolized in these sensitive cells by the cytochrome P450 enzyme CYP4F11 into potent inhibitors of stearoyl CoA desaturase.

FERONIA prevents polyspermy in Arabidopsis by enabling pectin-stimulated nitric oxide accumulation at the filiform apparatus after the first pollen tube arrives, which disengages LURE1 chemoattraction to prevent late-arriving pollen tubes from entering the ovule.

Thomas, Egan et al. report that hexokinase 2 localizes to the nucleus of leukaemic and normal haematopoietic cells to maintain stemness by interacting with nuclear proteins and modulating chromatin accessibility independently of its kinase activity.

tRNAs are linked with their cognate amino acid by aminoacyl tRNA synthetases (ARS). Here, the authors report a developmental encephalopathy associated with biallelic VARS variants (valyl-tRNA synthetase) that lead to loss of function, as determined by several in vitro assays and a vars knockout zebrafish model.

Here, using mouse genetics, biochemistry and cell-based experiments, the authors reveal that shieldin primarily catalyzes DNA priming and polymerase-dependent fill-in synthesis at 5′ recessed DNA ends during the joining of activation-induced cytidine deaminase-dependent DNA breaks.

Computational design enables the generation of a chimeric construct of the RAS exchange factor SOS that is specifically activated by a small molecule. The expression of this construct in different cell types reveals distinct phosphorylation kinetics.

Septins are cytoskeletal proteins that form a ring at the cytokinetic furrow. Now an analogous 'molecular corset' of septins is found to be required for T lymphocyte migration.

DNA methylation in the brain is a dynamic process, but gene-specific regulation of this process is poorly understood. Here, Day and colleagues show that extra-coding RNAs interact with DNA methyltransferases and regulate neuronal DNA methylation to control gene expression in locus-specific manner in neurons.

Infant gliomas behave differently to their childhood or adult counterparts. Here, the authors perform a large-scale genetic analysis of these tumours, revealing genetic alterations which may offer therapeutic opportunities.

Targeting cellular glucose metabolism is a therapeutic strategy in human diseases such as autoimmunity or cancer. Here, the authors demonstrate the druggability of phosphoglycolate phosphatase, and validate an alternative approach to control glycolysis.

Anthony Shum, Jordan Orange, James Lupski and colleagues show that mutations in the coatamer subunit gene COPA cause an autoimmune syndrome characterized by inflammatory arthritis and interstitial lung disease. They further show that the mutations disrupt ER-Golgi transport, leading to ER stress and altered T cell function.

Winter and colleagues demonstrate that metabolic adaptation to nutrient stress in the tumor microenvironment of pancreatic cancer leads to a dependency on IDH1, which is therapeutically actionable regardless of IDH1 mutation status.

A case–control study investigating the causes of recent cases of acute hepatitis of unknown aetiology in 32 children identifies an association between adeno-associated virus infection and host genetics in disease susceptibility.

Limited tumor cell delivery is a major challenge for the efficacious delivery of siRNAs to silence traditionally undruggable oncogenes. Here the authors optimize siRNAs for in situ binding to albumin through C18 lipid modifications and show the application of the lead conjugate structure for targeting MCL1 in orthotopic breast tumors in mice.

Through genome-wide and focused CRISPR screens, Zhang et al. discover that loss of PRC2 or KMT2D-COMPASS enables distinct EMT trajectories, which exert differential effects on the metastatic capability of carcinoma cells.

Glioma stem-like cells (GSCs) exhibit plasticity during proneural-to-mesenchymal transition. Here the authors show that extracellular vesicles from endothelial cells can promote this transition of GSCs through activation of MMPs and NFkB, and inactivation of NOTCH.

The delivery of oligonucleotides disrupting the secondary structure of single-guide RNAs and of short interfering RNAs targeting Cas9 mRNA can enhance lipid-nanoparticle-mediated gene editing in vivo in tissues other than the liver.

Sequence analysis identifies gain-of-function somatic mutations in GNA11 or GNAQ in CTNNB1-mutant aldosterone-producing adenomas. Most patients with these mutations presented during puberty, pregnancy or menopause, with elevated LHCGR expression.

In vitro and in vivo data show that ER protein CNPY2 initiates the PERK–CHOP signaling pathway to trigger the unfolded protein response (UPR) and contributes to hepatic steatosis.

Understanding of the genetic factors and molecular mechanisms underlying neurodevelopmental disorders remains incomplete. In this study, authors show that microdeletions in the gene ANKS1B lead to loss of the neuronal synapse-enriched protein AIDA-1 and to a novel neurodevelopmental syndrome

NLRP3 inflammasomes trigger release of IL-1 to promote tissue injury. Here, Li et al identify a ZFYVE21-Rubicon-RNF34 (ZRR) signaling complex localizing to endosomes and modulating complement-mediated inflammasome activity in vitro and in vivo.

Cox and colleagues develop PXS-5505, a first-in-class selective pan-lysyl oxidase inhibitor and show that it reduces chemotherapy-induced desmoplasia and stiffness, thereby improving chemotherapy response and survival in pancreatic cancer models.