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The homeostasis of myelin in the central nervous system is highly regulated, but the underlying mechanisms are unclear. Here, the authors show that the FBXW7 protein has a role in constraining myelin growth in the developing and adult central nervous system, preventing the accumulation of myelin abnormalities. FBXW7 acts in part through targeting the MYRF transcription factor for degradation.

Doan et al. show that loss of cardiac NAD⁺ is sufficient to drive metabolic derangements, hypertrophic remodeling and lethal arrhythmias in adult mouse hearts, despite maintenance of ejection fraction and bioenergetics.

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.

Weaver and colleagues show that TGFβ-induced collagen deposition and metabolic reprogramming of the breast cancer microenvironment by tumor-associated macrophages restrict the antitumor activity of CD8⁺ T cells in female breast cancer.

The Sonic Hedgehog subgroup of medulloblastoma are characterised by the high infiltration of tumour-associated macrophages (TAMs). Here, the authors show that TAM numbers in patients are associated with better prognosis and that, consistently, in a murine model of medulloblastoma, these TAMs have anti-tumoural properties.

Jason Carroll and colleagues report that the forkhead protein FOXA1 is an important determinant of estrogen receptor binding and show that expression of FOXA1 in non–breast cancer cells is sufficient to confer estrogen receptor binding and response to endocrine treatment.

Tamoxifen is commonly used for breast cancer therapy. This paper shows that the transcriptional repression of the ERBB2 oncogene by tamoxifen in breast cancer cells is affected by an antagonistic interaction between the transcriptional regulators PAX2 and AIB-1. This affects the ability of tamoxifen to inhibit cancer cell proliferation. The relative levels of PAX2 and AIP1 in breast cancer patients treated with tamoxifen correlates with relapse-free survival.

Alterations in glycosylation in tumours facilitate tumour progression. Here, the authors show that pancreatic ductal adenocarcinomas present increased sialylation, which stimulates the polarisation of monocytes via Siglec receptors, resulting in the generation of immune suppressive tumour associated macrophages.

Innate immune cells such as dendritic cells and macrophages can activate the adaptive immune system against cancer by presenting cancer-specific antigens, although this activity is severely limited in macrophages due to their intrinsic lysosomal cysteine protease activity. Here the authors show that a DNA nanodevice specifically targeted to macrophage lysosomes can inhibit cysteine proteases in these cells, restoring their antigen-presenting capability.

Pancreatic cancer-associated fibroblast enhance the expression of sialic acidcontaining glycans, which interact with Siglec7, -9, -10, -15 receptors on myeloid cells, and drive the differentiation to immunosuppressive macrophages.

Notch signaling has a crucial role in T cell acute lymphoblastic leukemia (T-ALL), but γ-secretase inhibitors (GSIs), which block the Notch pathway, cause intestinal toxicity that limits their use. Adolfo Ferrando and his colleagues now report that glucocorticoids can reverse the gut toxicity of GSIs, and GSIs can restore sensitivity of T-ALL cells to glucocorticoids, suggesting that this combination may have clinical utility in T-ALL and other diseases (pages 20–21).

Identifying jets originating from heavy quarks plays a fundamental role in hadronic collider experiments. In this work, the ATLAS Collaboration describes and tests a transformer-based neural network architecture for jet flavour tagging based on low-level input and physics-inspired constraints.

Enhancing vascularization to improve cardiac disease outcomes is a therapeutic approach with limited success. Here, the authors show that cardiac repair is governed by spatiotemporally regulated programs and underline the signaling mechanisms driving vascular deterioration.

Here, the authors apply genetic fate mapping and temporal clonal analysis to study progenitor recruitment and network morphogenesis of murine cardiac Purkinje fibers. Additionally, they characterize how transcription factor dosage regulates cell fate divergence during distinct phases of this process.

Multiregion sequencing is needed to better capture the heterogeneity of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Here, the authors analyse HCC and iCCA tumours with multiregion single-cell RNA-seq, revealing cellular dynamics and communication networks with immune cells.

ZipSeq uses patterned illumination and photocaged oligonucleotides to serially print barcodes onto live, intact tissues for spatially mapping single cell transcriptomes.

In a phase 2 trial of pembrolizumab and cabozantinib in patients with advanced head and neck cancer, a high clinical benefit rate was achieved, which positively correlated with levels of CD8⁺ T cell infiltration but not tumor mutational burden.

Notch receptors can exert different roles in cancer. In this manuscript, the authors reveal that Notch1 activation and EMT promote tumor initiation and cancer cell heterogeneity in squamous cell carcinoma, while the repression of Notch3 by ZEB1 limits Notch1-induced differentiation, permitting Notch1-mediated EMT.

The role of the tumour microenvironment in the response to immune checkpoint inhibitors in metastatic melanoma remains poorly understood. Here, single cell profiling of metastatic melanoma samples identifies associations of the mature dendritic enriched in immunoregulatory molecules subtype with immunotherapy response.

Sawyers and colleagues describe an in vivo platform used to explore the dynamics and key factors of neuroendocrine lineage transformation. They find that Ascl1 depletion blocks plasticity and leads to cancer that is sensitive to castration.

An analysis of POLE and POLD1 mutations distinguishes driver mutations from passengers and explores their functionality. Driver mutations are associated with specific mutational signatures and correlate with immune checkpoint blockage response.

Genome-wide mapping of oestrogen receptor-α binding sites in primary breast cancer tissues shows that oestrogen receptor binding is dynamically regulated and that the expression of genes near differentially bound regulatory regions is associated with clinical outcome.

Rebecca Fitzgerald and colleagues used genome sequence analyses to study the progression from premalignant Barrett's esophagus to esophageal adenocarcinoma (EAC) and found that the majority of recurrently mutated genes in EAC were also mutated in precursor lesions and that only mutations in TP53 and SMAD4 were stage specific.

Mixed lineage kinase domain-like (MLKL) is the terminal protein in the pro-inflammatory necroptotic cell death program. Here the authors show that MLKL trafficking and plasma membrane accumulation are crucial necroptosis checkpoints, and that accumulation of phosphorylated MLKL at intercellular junctions promotes necroptosis.

Salvagno et al. demonstrated that blocking tumour-associated macrophages in breast cancer enhances the efficacy of chemotherapeutics by promoting intratumoural type I interferon responses.

BamA carries out the essential process of folding outer membrane β-barrels in Gram-negative bacteria and is a potential antibiotic target. Here, the authors discover macrocyclic peptide inhibitors that trap BamA in distinct structural conformations.

A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.

The Eμ-Myc lymphoma mouse model has been invaluable in the study of this disease. Here, the authors use multiple sequencing strategies to analyse the tumours in these mice and find recurrent inactivating mutations in Bcor, suggesting that this gene has a negative role in Mycsignalling.

Muppidi and colleagues show that loss of Gα13 drives B cell lymphomas preferentially in the mesenteric lymph nodes. They find that Gα13 is required to counteract mTORC1 and Myc signaling that is driven by the availability of dietary glutamine.

Epigenetic markers are potential biomarkers for diabetes and related complications. Here, the authors identify CpG sites associated with kidney function and its subsequent decline using both single-site and multisite analyses, which are shown to have functional significance in the kidney.

The Rpd3L HDAC complex is an ancient chromatin-modifying complex found in diverse eukaryotes. Here, authors describe the cryo-EM structure of the yeast complex and show that key features are preserved in the human complex.

Snelling et al. describe the methods used to establish a pregnancy register in the QResearch database. The resulting algorithm successfully sorts and consolidates delivery and pregnancy loss (incl. terminations) records from primary and secondary care datasets, creating a valuable resource for future research into pregnant populations in England.

Nutrient manipulation of low-phosphorus soil in an old growth Amazon rainforest shows that phosphorus availability drives forest productivity and is likely to limit the response to increasing atmospheric CO₂ concentrations.

Germination of Bacillus subtilis spores in response to L-alanine requires a putative membrane receptor consisting of three proteins. Here, Artzi et al. use evolutionary co-variation analysis and functional assays of mutants to provide evidence that one of the proteins, GerAB, likely acts as the L-alanine sensor.

Entanglement was observed in top–antitop quark events by the ATLAS experiment produced at the Large Hadron Collider at CERN using a proton–proton collision dataset with a centre-of-mass energy of √s  = 13 TeV and an integrated luminosity of 140 fb⁻¹.

Adjuvant therapies in renal cell carcinoma (RCC) disrupt multiple steps of the metastatic cascade. Results from clinical trials to assess adjuvant treatment with immunotherapeutic agents in patients with resected clear cell RCC were promising, but the utility of tyrosine kinase inhibitors in this setting was not clearly shown. In this Perspective, the authors provide an overview of completed and ongoing clinical trials for adjuvant treatment of RCC, highlighting future directions and challenges in the field.

Boulgakoff et al. show that during cardiac regeneration, ventricular trabeculae participate in the repair of the contractile myocardium resulting in an excessive production of immature Purkinje fibers forming a hyperplastic PF network and altered ventricular conduction.

A monoclonal antibody that binds NINJ1 and inhibits NINJ1 oligomerization prevents plasma membrane rupture in dying cells, resulting in decreased inflammation of surrounding tissue in mice.

An integrated analysis of several cohorts shows that clonal, antigen-experienced T cells are found in the cerebrospinal fluid of patients with Alzheimer’s disease, suggesting that the adaptive immune system has a role in age-related neurodegeneration.

Modulation of PI3Kγ activity regulates macrophage polarization during inflammation and cancer, whilst combining PI3Kγ inhibition with immune checkpoint inhibitors leads to synergistic tumour-inhibitory effects.

The authors uncover a new role for the RNA-binding protein Msi2 in the regulation of hematopoietic stem cell homeostasis and leukemogenesis. Msi2 is required for the maintenance of the balance between progenitor renewal and differentiation, and its overexpression cooperates with oncogenic events to induce aggressive leukemia. Msi2 expression is also elevated in human myeloid leukemias and may be a new prognostic marker and therapeutic target in acute myeloid leukemia.

Mammalian genomes are scattered with repetitive sequences, but their biology remains largely elusive. Here, the authors show that transcription can initiate from short tandem repetitive sequences, and that genetic variants linked to human diseases are preferentially found at repeats with high transcription initiation level.

The genome sequence and genetic diversity of European ash (Fraxinus excelsior) trees reveals the species’ varying susceptibility to ash dieback.