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Chemotherapeutic antifolates, such as methotrexate (MTX), impair cancer cell proliferation by inhibiting nucleotide synthesis. Here, the authors show that MTX sustains an autarkic mitochondrial one-carbon metabolism leading to serine synthesis to promote cancer cell migration and metastasis.

Adult kidney organoids, or tubuloids, originate from CD24⁺ epithelial cells. Tubuloids represent a functional kidney tubule and can be used to model autosomal dominant polycystic kidney disease and study drug response.

Membrane-bound E3 ubiquitin ligases RNF43 and ZNRF3 are overexpressed in colorectal cancer, and can be repurposed using proteolysis-targeting antibodies (PROTABs) to selectively degrade cell-surface receptors in tumours.

APOE4 is associated with widespread gene expression changes across all cell types of the human brain, altered cholesterol homeostasis and transport signalling pathways, and decreased myelination in the brain.

The authors determined high-resolution cryo-EM structures of the lentiviral intasome — the nucleoprotein complex that inserts viral DNA into a host chromosome — and show that the architecture comprising 16 integrase subunits is critical for its function.

Depletion of BRD4 reduces the chromatin occupancy of NIPBL, resulting in aberrant genome folding. Loss of BRD4 impedes neural crest differentiation, which can be rescued by depletion of WAPL.

Single-cell combinatorial indexed cytometry sequencing (SCITO-seq) combines split-pool indexing and droplet-based single-cell sequencing for single-cell protein profiling.

Dual RNA sequencing and a time course infection model of vaginal epithelial cells with four Candida pathogens reveal a homogenous protective mitochondria-associated type I interferon host response at early time points, followed by distinct species-specific pathogenicity patterns.

Mutations in the CHKB gene cause muscular dystrophy. Here, the authors show that in mouse models of the disease changes in lipid metabolism are associated with decreased PPAR signaling, and show PPAR agonists can rescue expression of injury markers in myocytes in vitro.

Clinical and genetic phenotyping of consanguineous family cases of neonatal syndromic diabetes and type 2 diabetes, combined with in-depth functional studies in pluripotent stem cells, reveals a role for genetic variants of ONECUT1 in monogenic and multifactorial diabetes.

Biosensors are key to engineered biological systems. Here the authors demonstrate rapid de novo in vitro evolution of RNA biosensors of small molecules in a fully automated system.

Age-related macular degeneration is characterized by lipid-rich drusen deposits underneath the retinal pigment epithelium (RPE). Here the authors report an in vitro iPSC-RPE model for AMD that recapitulates drusen and RPE atrophy, and identify two drugs that reduce drusen deposits and restore RPE epithelial phenotype.

While genome-wide association studies have yielded thousands of trait-associated loci, identifying causal variants remains challenging. Here, the authors perform seven genomics assays in various cell types to prioritize genetic variants in the TNFAIP3 locus, and report high-priority variants within disease-associated haplotypes.

Leidal et al. show that the LC3-conjugation pathway, which is part of the autophagy machinery, controls extracellular vesicle cargo loading and secretion of RNA-binding proteins.

The gut microbiota member Bacteroides thetaiotaomicron can utilize various complex N-glycans, including those from immunoglobulins, via a complex and diverse set of enzymes encoded by multiple non-adjacent loci.

Knottin is a cystine knot peptide. Here, the authors develop a knottin-based tracer for positron emission tomography and demonstrate its ability to detect cancer and idiopathic pulmonary fibrosis through selective binding to integrin αvβ₆.

UDP-glucuronic acid is a component of the extracellular matrix. Here, the authors report biallelic variants in the gene encoding UDP-Glucose 6-Dehydrogenase (UGDH) in individuals affected by developmental epileptic encephalopathies that impair UGDH stability, oligomerization, or enzymatic activity in vitro.

Mutations in TREM2 alter risk for Alzheimer’s disease, though the mechanisms underlying risk in human cells are unclear. Here, the authors use iPS-microglia and chimeric mice to highlight altered survival, phagocytosis, migration, and transcriptional programs in microglia lacking TREM2.

Methods to directly label active neurons are still lacking. Here the authors develop CaMPARI2, a photoconvertible fluorescent protein sensor for neuronal activity with improved brightness and calcium binding kinetics, as well as an antibody to amplify the activated sensor signal in fixed samples.

The biological pump is the key ecological component that links carbon and energy flow from oceanic surface waters to the abyss. Here the authors show that the elemental composition and energy content of sinking particulate matter can be used to develop a more comprehensive understanding of energy flow networks in the sea.

The authors map chromatin accessibility after cytokinin treatment in Arabidopsis using fluorescence activated nuclei sorting and ATAC-seq. Regions of chromatin accessibility changes are preferentially located upstream of genes that respond transcriptionally to the hormone, and are enriched in type-B response regulator binding motifs.

Mutations in pre-mRNA processing factors cause autosomal dominant retinitis pigmentosa. Here the authors provide insights into the pathophysiological mechanisms underlying non-syndromic retinal disease caused by heterozygous mutations in genes encoding ubiquitously expressed splicing factors.

Deep profiling of transcriptomes, metabolomes, cytokines, and proteomes, alongside changes in the microbiome, in samples from individuals with and without prediabetes reveal insights into inter-individual variability and associations between changes in the microbiome and other factors.

Egress of flaviviruses and involved host pathways are not well understood. Here, the authors show that Lyn is a critical host kinase for Dengue and Zika virus egress resulting in infectious virus progenies within autophagosome-derived vesicles, which might help the virus to evade antibody responses.

Marrs et al. show that the serine hydrolase α/β-hydrolase domain 6 (ABHD6) controls the accumulation and efficacy of the endocannabinoid 2-arachidonoylglycerol at cannabinoid receptors. ABHD6 is located post-synaptically and its selective inhibition permits the induction of cannabinoid receptor–dependent long-term depression by otherwise subthreshold stimulations.

Derivation of human induced pluripotent stem cells (hiPSCs) produces primed hiPSCs that can in turn be converted to naive hiPSCs. Here, the authors directly reprogram somatic cells to form both naive and primed isogenic hiPSCs and confirm the similarity of naive hiPSCs to their in vivo counterparts.

Metagenomic and metatranscriptomic analyses of stool samples from 308 individuals over time indicate that longitudinal sampling is important for detecting dynamic functional features of the gut microbiome.

There are two technical impediments for using purified Wnt proteins in serum-free stem cell cultures: rapid loss of activity and toxicity of detergents to stem cell self-renewal. Here, the authors show that lipid-stabilized Wnt3a can establish long-term culture of human intestinal and liver organoids.

Protein scaffolds can serve as alternatives to antibodies in a range of applications. Here, the authors report the design and development of Alphabody™, a protein scaffold featuring a single-chain antiparallel triple-helix coiled-coil fold that the authors use to develop Alphabodies that can neutralize human IL-23 with high specificity and affinity.

Saponin-based adjuvants are being explored as vaccine components as they induce high levels of antigen cross-presentation, but it is unknown how. Here the authors show that these adjuvants enhance cross-presentation by driving production of lipid bodies inside CD11b dendritic cells.

Barcode-enabled sequencing of tetrads (BEST) allows isolation and genotyping of individual yeast spores while maintaining their tetrad relationships.

In certain microbes, the anaerobic oxidation of methane can be linked to the reduction of nitrates and nitrites. Here it is shown that this occurs through the intermediate production of oxygen. This brings the number of known biological pathways for oxygen production to four, with implications for our understanding of life on the early Earth.

The RNA polymerase II C-terminal domain acts as a hub to coordinate transcription and nascent mRNA processing. Here the authors identify a phosphorylation-dependent switch in thetrans-to-cisisomerization of proline in the CTD heptad repeats that make those repeats susceptible to further modifications by regulatory enzymes.

Crohn’s disease is associated with altered intestinal microbiota. Here, the authors show that the microbe Atopobium parvulumis associated with Crohn’s disease patients, triggers colitis in a mouse model, and that scavenging microbe-induced hydrogen sulfide improved symptoms in mice.

Viscoelastic gels can be made by using flow to induce structure into solutions containing surfactant micelles. However, the gels disintegrate soon after flow stoppage. By using a microfluidic-assisted laminar-flow process to generate very high extension rates, it is now shown that permanent gels can be made, creating new opportunities for applications.

A human neurodevelopmental model fills the current knowledge gap in the cellular biology of Williams syndrome and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain.

A microbiota- and IL-1β-dependent axis of IL-2 production by group-3 innate lymphoid cells is shown in a mouse model to be necessary to maintain immunological homeostasis and regulatory T cells in the small intestine.

The correction of genetic defects in utero could allow for improved outcomes of gene therapy. Here, the authors demonstrate safe delivery of nanoparticles to fetal mouse tissues, and show that nanoparticles containing peptide nucleic acids to edit the beta-globin gene are effective in a mouse model of beta-thalassemia.

Arne Pfeufer, Aravinda Chakravarti and colleagues from the QTSCD consortium report genetic associations influencing the QT interval duration, a measure of cardiac repolarization which is a risk factor for sudden cardiac death, in five genome-wide association studies.

Respiratory syncytial virus causes lung infections in children, immunocompromised adults, and in the elderly. Here the authors show that a chemical inhibitor to a viral fusion protein is effective in reducing viral titre and ameliorating infection in rodents and neonatal lambs.

New fluorescent biosensors enable the first super-resolution imaging of enzyme activity in live cells via fluorescence fluctuation increase by contact (FLINC).

Botulinum neurotoxins (BoNTs) are thought to require complex gangliosides, a group of glycosphingolipids, as essential co-receptors to target neurons. Here, the authors show that BoNT/DC represents an exception to this rule and that an extended loop in BoNT/DC penetrates directly into neuronal membranes.

Steinberg and colleagues show that long-chain fatty acyl-CoA esters are endogenous ligands for the drug-binding domain of AMPK β1–containing isoforms, and that such binding is critical for enhancement of fatty acid oxidation. These data may help explain how AMPK integrates responses to ketogenic diets, fasting or endurance exercise across distinct tissues in the absence of changes in adenine nucleotides.

Rare earth elements are critical components of clean energy technologies, but less than 1% are recycled due to high costs of recovery. Here the authors develop a ligand that selectively precipitates rare earth elements from aqueous media as a function of pH to facilitate the separation of binary rare earth mixtures.

Batchelder et al. report a new penem class antibiotic, T405, which exhibits potent activity against M. abscessus and clinical isolates from cystic fibrosis patients. The development of resistance to T405 is inhibited with the addition of a β-lactamase inhibitor, avibactam. Its clinical potential is further demonstrated by T405 displaying a favourable pharmacokinetic profile in mice with an absence of toxicity.