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The identification of cellular targets for natural products that potently inhibit the growth of cancer cell lines implicates oxysterol-binding proteins in the growth of cancer cells. These natural products, termed ORPphilins, also affect sphingomyelin biosynthesis.

There is still a need for effective HIV vaccines. In this phase I clinical trial, the authors show that an HIV-1 vaccine candidate, ConM SOSIP.v7, is well-tolerated in HIV-negative adults and that it elicits a strain-specific neutralising antibody response that differed between female and male participants.

A national classification system of wetland hydrologic connectivity to streams, which could be applied globally, demonstrates and advances current understanding of how wetland connectivity affects surface water quality.

The tumour-suppressor protein BRCA2 is discovered to have a previously undescribed role in maintaining genomic integrity and the sensitivity of PARP1 inhibitors.

Ryan et al. report a highly conserved mechanism by which arginine induces changes in hypervirulent Klebsiella pneumoniae bacterial cell surface capsule. K. pneumoniae arginine sensing is critical for full virulence potential.

Polymer thin films that emit and absorb circularly polarised light are promising in achieving important technological advances, but the origin of the large chiroptical effects in such films has remained elusive. Here the authors demonstrate that in non-aligned polymer thin films, large chiroptical effects are caused by magneto-electric coupling, not structural chirality as previously assumed.

A detailed spatiotemporal roadmap of the human female and male reproductive tracts during key periods of sexual differentiation provides new cellular and molecular insights into how early axial gradients lead to specific cell lineages and tissue structures.

Streptococcus thermophilus phages circumvent host CRISPR defences via AcrIIIA2, which complexes with enolase, a highly abundant glycolysis enzyme, to block phage RNA binding.

Bacteroides thetaiotaomicron is a human gut microbe and an emergent model organism. Here, Ryan et al. generate single-nucleotide resolution RNA-seq data for this bacterium and map transcription start sites and noncoding RNAs, one of which modulates expression of metabolic enzymes.

Mitochondrial dysfunction underlies a multitude of human diseases. Here, the authors show that partial inhibition of the vacuolar-type H⁺-ATPase enhances cell fitness under mitochondrial stress.

An enzyme-free system that translates DNA into sequence-defined non-nucleic acid polymers including polyethylene glycol, α-(D)-peptides and β-peptides is described. Sequence-defined polymers with molecular weights of 26 kDa containing 16 consecutively coupled building blocks and 90 densely functionalized β-amino acids were translated from DNA templates using this strategy.

The two hereditary breast cancer susceptibility genes, BRCA1 and BRCA2, have roles in responding to DNA damage. When they are mutated or absent, genomic instability, a contributory factor to cancer development, results. Studies of BRCA2 have been hampered by its large size, which makes purification of the full-length protein challenging. These authors report the first in vitro characterization of full-length BRCA2 and delineate the different ways by which BRCA2 facilitates RAD51-mediated homologous recombination.

Turley and colleagues find that Gremlin1-expressing lymph node fibroblastic reticular cells support dendritic cell homeostasis via provision of FLT3L.

Benchmarking of scATAC-seq protocols demonstrates the effects of data quality on downstream analyses.

UNC119 is a protein localized to the non-motile primary cilia. Here, Zhang et al. report the crystal structure of UNC119 and provide biochemical and cellular evidence that UNC119 is a lipid-binding protein that mediates G protein trafficking. The authors also show that that UNC119 function is conserved from GPCR trafficking in C. elegans olfactory neuron to transducin trafficking in mammalian photoreceptors.

Reduced sulfate aerosols due to ship fuel regulation may increase shortwave radiation on the Great Barrier Reef, exacerbating the impact of marine heatwaves on coral bleaching, according to model analysis of ship emission impacts on aerosols, clouds and solar radiation.

Pathogenic variants in UNC13A underlie a novel neurodevelopmental syndrome, with three subtypes defined by distinct genotypes with varying clinical and functional impacts characterized in cellular and animal models.

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.

Apoptotic cells often release extracellular vesicles that aid in their clearance and provide molecular information to cellular neighbours. Here, the authors show that some adherent apoptotic cells also create vesicles that remain attached at the site of death.

Intravascularly infused extracellular matrix from ventricular myocardium binds to leaky vasculature and induces the regeneration of inflamed heart tissue, as shown in rats and pigs.

Different patterns of nucleosome exposure by developmentally indispensable pioneer transcription factors and enabling of a nucleosome remodeler complex reveal mechanisms of gene regulatory initiation within compacted chromatin.

Analyses of samples from patients with acute myeloid leukaemia reveal that drug response is associated with mutational status and gene expression; the generated dataset provides a basis for future clinical and functional studies of this disease.

Silencing of endogenous retroviral elements (ERVs) is mediated by KAP1. Here, the authors describe the molecular mechanism by which KAP1 induces structural reorganization and multimerization of HP1α and maintains inaccessible chromatin at ERVs in mouse embryonic stem cells.

This paper identifies Tripartite motif-containing 28 (TRIM28) as a novel modulator of steroid hormone signaling. TRIM28 deficiency disrupts uterine cell functions and composition leading to fertility defects

Non-syndromic orofacial cleft is a relatively common congenital anomaly. Many non-coding genetic variants are associated with this disorder but only a subset is functional. Here the authors use reporter assays and stem cells to reveal members of this subset.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

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.

The cryo-electron microscopy structures of an early spliceosome complex in yeast reveal a unified mechanism for defining introns and exons and also for back-splicing to generate circular RNA.

In Pyrococcus furiosus, histones bind and bend DNA to enable integration of new spacer fragments into CRISPR loci.

Adeno-associated viruses (AAVs) can be targeted in a tissue-specific manner, but their tissue accumulation cannot be assessed in a non-invasive manner. Here the authors conjugate a multivalent chelator labelled with Cu-64 to the surface of AAVs and image the brain accumulation of the PHB.eB capsid by PET.

Data collected from more than 2,000 taxa provide an unparalleled opportunity to quantify how extreme wildfires affect biodiversity, revealing that the largest effects on plants and animals were in areas with frequent or recent past fires and within extensively burnt areas.