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The immune suppressive tumour microenvironment drives recurrence and metastatic disease in prostate cancer. Here authors provide a detailed analysis of the microenvironment via single cell RNA sequencing and high-resolution spatial transcriptomics to identify tumour-dependent changes compared to healthy tissue.

Variants of the 3′−5′ exonuclease TREX1 can cause retinal vasculopathy with cerebral leukoencephalopathy (RVCL). Here, the authors show that RVCL-associated TREX1 variants trigger DNA damage in humans, mice, and Drosophila, and render cells more vulnerable to DNA damage inducing agents.

Phase separation properties are a major determinant of UTX activity in chromatin regulation in tumour suppression, and are dependent on a core intrinsically disordered region of the protein.

A novel antiviral targeting the SARS-CoV-2 PLpro protease shows strong efficacy in a mouse model, preventing lung pathology and reducing brain dysfunction. The study provides proof-of-principle that PLpro inhibition may be a viable strategy for preventing and treating long COVID.

The targeted development of proteome-wide selective covalent probes remains a challenge. Here, the authors show the exploration of the natural product Sulphostin as a starting point for dipeptidyl peptidase 8 and 9 inhibitor development.

Fur farming represents an important hub of cross-species transmission for viral zoonoses.

Grant Stewart, Andrew Jackson, Christopher Mathew, Fowzan Alkuraya and colleagues identify a novel replication fork protein, DONSON, which is important for maintaining genome stability. Mutations in DONSON cause microcephalic dwarfism and lead to stalled replication forks and DNA damage.

Structural and biochemical analyses of human USP30 explain the basis of Lys6-linkage preference and regulation by PINK1 and Parkin, shedding light onto how USP30 can act as a brake on mitophagy.

Mutations in ATP13A2 are associated with lysosomal dysfunction and early onset Parkinson’s disease. Here Bento et al. show that ATP13A2 depletion negatively regulates SYT11, at both transcriptional and post-translational levels, which in turn impairs function of the autophagy-lysosome pathway.

How Polycomb repressive complex 2 (PRC2) is recruited to active chromatin to mediate transcriptional silencing during lineage specification in metazoans has been unclear. New findings now show that PRC2 component PHF19, which associates with the H3K36me3 demethylase NO66, binds the active chromatin mark H3K36me3 through its Tudor domain, leading to PRC2-mediated H3K27 trimethylation, loss of H3K36me3 and transcriptional silencing.

Tetrahydrocannabinol (THC) analogs target the cannabinoid receptor CB1 for therapeutic and psychoactive effects. Here, the authors determine spatiotemporal ligand interactions critical for potency, efficacy, off-rates and drug design.

The PIEZO1 channel and the PECAM1 cell adhesion molecule interact and PIEZO1 cooperates with PECAM1 and CDH5 cell junctions during mechanical stress.

De novo mutations in MSL3 cause an X-linked syndrome affecting both males and females. MSL3 mutations reduce H4K16ac levels and lead to misregulation of cellular pathways involved in morphogenesis, cellular shape, and cell migration.

The on-line isotope separation technique for the production of accelerated beams of radioactive ions has led to important advances in our understanding of atomic nuclei. These are now reviewed, and further prospects are discussed.

Jens Lykke-Andersen, Frank Baas, Joseph Gleeson and colleagues report that mutations in the 3′ exonuclease TOE1 cause pontocerebellar hypoplasia type 7. They further show that these mutations result in the accumulation of incompletely processed small nuclear RNAs, leading to severe, early-onset neurodegeneration.

Pan et al. establish a general photoproximity labeling approach in living cells, applying microenvironment mapping with a HaloTag-based platform (HaloMap) to profile the stress granule proteome and identify ubiquitin-related modulators as key mediators of granule disassembly.

A new study of samples from the Ryugu asteroid reveal a greater diversity of macromolecular organic matter than that found in related carbonaceous meteorites. Researchers find distinct populations of alkyl-aromatic grains, and organic carbonate is found with coarse-grained clay minerals

The cytochrome P450 enzyme CYP1B1 is overexpressed in a variety of tumors, and is correlated with poor treatment outcomes; thus, it is desirable to develop CYP1B1 inhibitors to restore chemotherapy efficacy. Here the authors describe the creation of light-triggered CYP1B1 inhibitors as “prodrugs”, and achieve >6000-fold improvement in potency upon activation with low-energy (660 nm) light.

Subcutaneously injected biomaterial scaffolds mimicking key features of physiological T-cell activation enhance the antitumour activity of intravenously pre-administered CAR-T cells.

Widespread sense-antisense transcripts have been identified in mammalian cells. Many tumour suppressor genes have nearby antisense RNAs, and an antisense RNA to the cyclin-dependent kinase inhibitor p15 can silence the p15 gene by inducing heterochromatin formation.

Notch and Delta are transmembrane proteins that allow neighbouring cells to communicate during development. Here, quantitative time-lapse microscopy has been used to show that the response of Notch to Delta on a neighbouring cell is graded, whereas its response to Delta on the same cell is sharp and occurs at a fixed threshold. A mathematical model explores how this new design principle enhances the sharpness of developmental boundaries set by classical lateral inhibition.

The mechanisms that regulate the body’s response to exercise are poorly understood. Here, Rode et al. show that the mechanically activated cation channel Piezo1 is a molecular sensor of physical exercise in the endothelium that triggers endothelial communication to mesenteric vessel muscle cells, leading to vasoconstriction.

A Study Identifies Broad-Spectrum Pan-Coronavirus Antiviral Drugs Targeting Host Protein Quality Control Mechanisms And Reports Development Of A Bsl2-Level Cell-Integrated Sars-Cov-2 Replicon, Which Can Be Used For High-Throughput Screening.

Structural and single-molecule analyses show the CTPase, KorB, is a sliding DNA clamp that interacts with a clamp-locking protein KorA to inhibit gene expression over distances of more than 1 kb in the multi-drug resistance RK2 plasmid.

Attachment of the ubiquitin-like modifier UFM1 to 60S ribosomes has a critical function in the release and recycling of stalled or terminated ribosomes from the endoplasmic reticulum membrane.

An interbacterial toxin that catalyses the deamination of cytidines within double-stranded DNA forms part of a CRISPR-free, RNA-free base editing system that enables manipulation of human mitochondrial DNA.

Mapping spliceosome engagement with pre-mRNAs using iCLIP reveals how the position and strength of branchpoints affect the crosslinking patterns of spliceosomal factors.

The CENP-A chaperone HJURP associates with Mis18α, Mis18β, and M18BP1 to target centromeres and deposit new CENP-A. Here the authors provide evidence that two repeats in human HJURP previously proposed to be functionally distinct are interchangeable and bind concomitantly to the 4:2:2 Mis18α:Mis18β:M18BP1 complex without dissociating it.

The P2X1 receptor is a promising target for the development of a non-hormonal male contraceptive. Here, researchers determined the atomic structure of the P2X1 receptor, revealing opportunities for developing drugs to target this receptor.

The modification of proteins with O-linked β-N-acetylglucosamine (OGlcNAc) plays roles in regulation of numerous cellular functions while incorrect O-GlcNAcylation patterns are linked to disease. Here, the authors report a cryo-EM structure of full-length O-GlcNAc transferase (OGT), the only enzyme responsible for O-GlcNAcylation.

The potential tumorigenicity of human pluripotent stem cells (hPSCs) limits their application in cell therapies. Ben-David et al.identify the tight-junction protein Claudin-6 as a cell-surface marker of hPSCs, and demonstrate three Claudin-6-based strategies to remove tumorigenic hPSCs from mixed cell cultures.

A nation’s ambitious scientific goals are bringing in the best from around the world.

The Main protease of SARS-CoV-2 is key for viral replication, but its maturation process is still not completely understood. Here, the authors not only reveal unique details from the first step of maturation, but also demonstrate how different classes of inhibitor can block this step.

Durable agonism of NPR1 achieved with a novel investigational monoclonal antibody could mirror the positive hemodynamic changes in blood pressure and heart failure identified in humans with lifelong exposure to NPR1 coding variants.

Here the authors identify the transcription factor MEF2C as essential for human NK cell function and viral immunity in mice and humans. This control is exerted via regulation of lipid metabolism, and deficiency in MEF2C can be overcome by oleic acid supplementation.

The RhoGEF GEF-H1 is normally sequestered on microtubules via binding dynein light-chain Tctex-1, and is activated by microtubule depolymerization. Here, Meiri et al. describe a new model of GEF-H1 activation by GPCRs, whereby both the Gα and Gβγ subunits bind to GEF-H1 and Tctex-1, respectively, to displace GEF-H1 from intact microtubules.

Co-transcriptional splicing of pre-mRNAs has been proposed to involve exon tethering to the elongating RNA polymerase II. By inserting a fast-cleaving ribozyme in the nascent transcript, the linear integrity of the transcript is found to be key to splicing, arguing against tethering and for a pathway that clears such disrupted transcripts.

Targeting peptides from unmutated cancer drivers that are expressed in tumours but not in normal tissues using peptide-centric chimeric antigen receptors shows potential as treatment for cancer.

High-throughput screening and structure-guided design identified small-molecule inhibitors that prevent the interaction between N-terminally acetylated E2 conjugating enzyme UBE2M and DCN1, an E3 ligase for the ubiquitin-like protein Nedd8.