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Type 2 conventional dendritic cells (cDC2) are important immune activators in adults, but their development and functions at the neonatal stage remain unclear. Here the authors show, using fate-mapping and single-cell RNA sequencing, that neonatal cDC2 come from multiple origins, but converge functionally as potent immune activators upon proper stimuli.

Here, the authors identify widespread disease associations of gut archaea, particularly in colorectal cancer, with further experiments revealing Methanobrevibacter smithii cooperation with cancer-associated bacteria and co-production of metabolites with tumor-modulating potential.

Genome-wide association meta-analysis identifies 58 independent risk loci for major anxiety disorders among individuals of European ancestry and implicates GABAergic signaling as a potential mechanism underlying genetic risk for these disorders.

T cell immunity declines with thymic atrophy, but thymic cell grafts rescue T cell function.

HIV remission of more than 6 years was achieved in a patient with functional viral co-receptors after CCR5 wild-type/Δ32 allogeneic stem cell transplantation, providing evidence of other mechanisms that can be harnessed to attain long-term remission.

Astrocytes display diverse molecular and functional features in the brain, but the developmental origins of this heterogeneity are not well understood. Here, the authors show that two separate progenitor types give rise to distinct cortical astrocyte subtypes with specialized roles.

Topoisomerases resolve topological DNA stress via double-strand breaks and are established targets of cancer chemotherapies. Here, the authors link genomic binding of TOP2B with localized mutational processes in cancer genomes that include prominent driver genes and translocation hotspots.

A hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of ALS and FTD. Here, the authors demonstrate CRISPR/Cas9 excision of the expansion results in a rescue of disease mechanisms in vivo and in vitro.

The multipotency of basal stem cells is directly regulated by luminal cells through the secretion of TNF, and, following luminal cell ablation, the Notch, Wnt and EGFR signalling pathways reactivate basal cell multipotency.

Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

Neuroendocrine differentiation of epithelial tumor cells can contribute to cancer cell resistance and survival. Here, the authors show that dysregulated c-Myc promotes neuroendocrine differentiation in pancreatic ductal adenocarcinoma, leading to poor survival and chemoresistance.

Inducible genetic mosaics can provide information about cellular lineages that are otherwise difficult to obtain. Here the authors report a mosaic knockout system called Red2Flpe-SCON, which allows lineage tracing of wild-type and mutant cells using a multicolour fluorescent reporter in mice.

Metabolic reprogramming is a hallmark of pancreatic ductal adenocarcinoma (PDA). Here, the authors show that in PDA cells redox and central carbon metabolism are driven by an eIF4F dependent translation program, and combined targeting of eIF4A and glutaminase can impact PDA proliferation.

Sharir et al. overhaul the classical model and show that proliferating inner-enamel progenitors generate all epithelial lineages and their Notch1-expressing progeny convert into ameloblasts after injury.

Combining transcriptomics, mathematical modelling and in vivo gene editing, this study shows that Sfrp2 contributes to stripe formation and hair colour in the African striped mouse.

Hegazy and colleagues demonstrate that epithelial oncostatin M receptor expression drives gut inflammation and tumor formation.

Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

Circulating Ly6C^lo monocytes are thought to be derived from Ly6C^hi subset. Here the authors show that Notch signalling is activated in Ly6C^locells and is required for their differentiation, and that Notch ligands that initiate this signalling are provided by a subset of endothelial cells.

Antimicrobial resistance genes that have been mobilized between bacterial species represent a subset of the naturally occurring resistome. Here, the authors compare the abundance, diversity and geographical patterns of acquired resistance genes with latent resistance genes in global sewage metagenomes.

Dong and Sun et al. show that adipogenesis regulatory cells in murine white adipose tissue inhibit adipogenesis through RSPO2, which regulates maturation of early progenitor cells via Lgr4.

Benoit, Ganea et al. show that changes in axon initial segment (AIS) length in the prefrontal cortex of mice accompany fear learning and extinction, revealing AIS plasticity as a key feature of neuronal adaptation and memory formation.

Here, Miranda-Cervantes et al. identified pantothenate kinase 4 (PanK4) as a key regulator of muscle metabolism. Deleting PanK4 impairs fatty acid oxidation and glucose uptake, leading to glucose intolerance, while increasing PanK4 enhances glucose metabolism, highlighting its potential in promoting metabolic health.

Some cancer patients first present with metastases where the location of the primary is unidentified; these are difficult to treat. In this study, using machine learning, the authors develop a method to determine the tissue of origin of a cancer based on whole sequencing data.

Geminin regulates DNA replication by binding CDT1 and preventing MCM helicase loading. Using a reconstituted system and structural modelling, the authors find geminin inhibits via steric clash with MCM, not by blocking the CDT1–MCM interface. Combined with CDK activity, it fully halts licensing.

Arterial macrophages develop from either yolk sac or bone marrow progenitors. Here, the author show that ageing-induced reduction of arterial macrophages is not replenished by bone marrow-derived cells, but under inflammatory conditions circulating monocytes are recruited to maintain homeostasis, while arterial macrophages of yolk sac origin carry out tissue repair.

Methods for the analysis of metabolites in cells often require sample disruption and lack spatio-temporal resolution. Here, the authors show that Raman spectroscopy can directly detect fumarate in living cells and animal tissues ex vivo.

Huda Zoghbi and colleagues report that loss of the ATXN1–CIC protein complex in the developing mouse forebrain results in hyperactivity and defects in learning and memory. Loss of Cic in specific brain regions causes social interaction defects, and patients with de novo CIC mutations present signs of hyperactivity, autism spectrum disorder and intellectual disability.

Accurate segmentation of ischemic stroke lesions from brain MRI is crucial for timely diagnosis and treatment planning. Here, the authors present DeepISLES, an AI ensemble for stroke MRI analysis that outperforms previous methods and matches expert radiologist performance in identifying stroke lesions.

CSF total tau (t-tau), often used as a marker of neuronal damage, is more strongly linked to synaptic degeneration. Here, the authors show that t-tau better reflects synaptic dysfunction than axonal or neuronal loss in Alzheimer’s disease.

How the numerous neuron subpopulations in the lateral (CeL) and medial (CeM) subdivisions of the central amygdala regulate appetitive behavior is poorly understood. Here, the authors report that appetitive neurons are confined to the CeM with separate subpopulations driving water only, versus water or food consumption.

Brown adipose cells contribute to body temperature maintenance by converting lipids and glucose into heat, and can be found in white adipose tissue. Wolfrum and colleagues find a population of cells in white adipose tissue that can adopt brown or white characteristics in response to cold.

The hypothalamus is a brain region rich in functionally segregated neurons. Here Romanov and colleagues use single-cell RNA sequencing to distinguish 62 neuronal subtypes and define their neuropeptide and neurotransmitter makeup. They then show that onecut-3-containing dopamine neurons populate the periventricular area and are wired into the circadian circuitry.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Targeting histone deacetylases (HDACs) alone has shown limited success in solid tumours. Here, authors report that the HDAC1/2 inhibitor romidepsin confers responsiveness to receptor tyrosine kinase inhibitors, with enhanced therapeutic effects in models of hepatocellular carcinoma, leading to tumour regression and an immune-stimulatory profile.

The dorsal peduncular area of the mouse brain functions as a network hub that integrates diverse cortical and thalamic inputs to regulate neuroendocrine and autonomic responses.

Common variable immunodeficiency disorder (CVID) is a primary immunodeficiency with autoimmune comorbidity. Here, Li et al. show shared genetic susceptibility with autoimmune diseases, identifying the first non HLA risk locus at CLEC16Ain the largest CVID genetic study to date.

Natural products have historically made a major contribution to pharmacotherapy, but also present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization. This Review discusses recent technological developments — including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances — that are enabling a revitalization of natural product-based drug discovery.

Immune responses to pancreatic ductal adenocarcinoma can be inhibited by cancer cells. Here the authors show that high levels of progranulin in PDAC inhibits immune responses by reducing MHC class I antigen presentation through enhanced degradation of MHC class I via autophagy.

Notch signaling is known to modulate macrophage polarization. Hu and colleagues show that the Notch–RBP-J axis controls the expression of M1 macrophage–specific genes by promoting translation of the transcription factor IRF8.

Current cardiac mapping systems provide either electrical or optical readouts. Here the authors report a panoramic opto-electrical measurement and stimulation (POEMS) system which embraces the entire ventricular surface of mouse hearts, allowing flexible combinations of optical and electrical recording and stimulation modalities.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

Dendritic cells initiate and regulate adaptive immunity and differ according to gut anatomical location. Here the authors show that DC residing in the upper and lower intestines show differential PD-L1 and XCR1 expression and drive specific T cell responses to prevent gut inflammation.

The mechanisms that trigger neurodegeneration in demyelinating disease are unclear. Here, the authors find that impaired remyelination induces a DLK-mediated loss of retinal ganglion cells (RGCs), and that efficient remyelination or DLK inhibition block RGC death.

Manipulation of TIM-1-expressing B cells enables engagement of the second arm of adaptive immunity to promote anti-tumour immunity and inhibit tumour growth.

Genome-wide association meta-analyses of attention-deficit/hyperactivity disorder symptom measures and clinical diagnoses identify new risk loci, highlight putative effector genes and yield improved polygenic risk scores.

This study describes sensing of circulating cell-free DNA after stroke as the mechanism leading to recurrent ischemic events.

Antisense oligonucleotide (ASO) cellular activity requires endosomal escape. Here, the authors show that disrupting Golgi-endosome protein AP1M1 enhances ASO activity by prolonging ASO endosomal residence and increasing the likelihood of endosomal escape.

Hybrid superconductor-semiconductor devices offer a promising platform for topological superconductivity. Here, Ke and Moehle et al. create ballistic Josephson junctions in InSb quantum wells and use magnetic and electric fields to control their free energy landscape.