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AgRP neurons control appetite, but their transcriptional regulation remains a mystery. Here, the authors generate AgRP neuron transcriptional and chromatin accessibility profiles and show that IRF3 mediates the acute hunger-suppressing effects of leptin.

The RNA methyltransferase activity of SPOUT1/CENP-32 is crucial for accurate mitotic spindle organization. Here, the authors describe a neurodevelopmental disorder caused by bi-allelic pathogenic SPOUT1 variants with reduced activity and compromised function in spindle organization.

McGavern and colleagues identified a CD8⁺ T cell population that expresses GZMK in ʽtau-richʼ brains, where it may play a protective role against neurodegeneration.

Here the authors describe a stabilization technology that engineers crosslinks between tyrosine sidechains into a natively folded vaccine immunogen and show that immunogenicity is improved in small animal models by locking the most potently neutralizing epitopes.

Klebanoff and colleagues report that survival and persistence of CAR-T and CAR-NK cells are regulated by a FAS ligand–FAS autoregulatory circuit, showing that disabling FAS signaling enhances their antitumor efficacy in preclinical models.

Meta-analyses in up to 1.3 million individuals identify 87 rare-variant associations with blood pressure traits. On average, rare variants exhibit effects ~8 times larger than the mean effects of common variants and implicate candidate causal genes at associated regions.

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.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

A hyper-stable de novo protein mimic of interleukin-2 computationally designed to not interact with a regulatory T-cell specific receptor subunit has improved therapeutic activity in mouse models of melanoma and colon cancer.

A machine learning approach is used to analyse multi-omics (proteomics, metabolomics and transcriptomics) data, producing genetic scores for more than 17,000 biomolecular traits in human blood, and identifying possible associations with disease.

The Nr4a family of nuclear receptors has been implicated in thymocyte central tolerance via clonal deletion and regulatory T cell induction. Here the authors show, using mouse bone marrow chimeras, that Nr4a1 and Nr4a3 are also redundantly required for Bcl211/BIM induction and contribute to an anergy-like transcriptome in auto-reactive thymocytes.

Coagulation factor VIII deficiency in hemophilia A disrupts clotting and prolongs bleeding. Here, the authors show that vagus nerve stimulation bypasses this defect and improves hemostasis in hemophilia A mice through a mechanism requiring acetylcholine-secreting ChAT⁺ T lymphocytes in spleen and α7nAChR on circulating platelets.

Analysis of 14,106 tumor genomes highlights recurrent mutations in mitochondrial ribosomal RNA encoded within the mitochondrial genome. Mutations occur at hotspot positions and are under strong purifying selection in the germline.

Genome-wide analyses identify 30 independent loci associated with obsessive–compulsive disorder, highlighting genetic overlap with other psychiatric disorders and implicating putative effector genes and cell types contributing to its etiology.

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.

The number of individuals in a given space influences animal interactions and network dynamics. Here the authors identify general rules underlying density dependence in animal networks and reveal some fundamental differences between spatial and social dynamics.

Orthogonal chimeric receptors containing intracellular domains for IL-4R, IL-20R, IL-22R and GCSFR reprogram T cells to promote distinct natural and synthetic cell states with functional and therapeutic implications.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

This study identifies transcription factor 7-like 2 (TCF7L2) as a key regulator of hepatic metabolic zonation, and demonstrates that disruption to the transcriptional activity of TCF7L2 exacerbates the development of dietary-induced hepatic fibrosis.

LKB1 tumour suppressor gene is frequently mutated in lung adenocarcinoma. Here the authors show that in genetically engineered mouse models of lung cancer Lkb1 restoration induces growth arrest and drives neoplastic cells toward a more differentiated and less proliferative alveolar type II cell-like state via C/EBP-mediated reprogramming.

Antibodies that lock KRAS mutants in inactive conformations facilitate drug discovery.

A study finds that a protease called granzyme K can activate the entire complement cascade, explaining how it can drive destructive inflammation in inflammatory diseases such as rheumatoid arthritis.

Anandasabapathy and colleagues show that the inhibitory receptor PD-1 impacts the specification of tissue-resident memory T cells in the skin.

Chronic infection with SARS-CoV-2 leads to the emergence of viral variants that show reduced susceptibility to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma.

Lundgren et al. show that in response to transient cold exposure, a distinct subpopulation of brown adipocytes carries out a lipogenic response involving production of acylcarnitines, which enables an improved thermogenic response to secondary cold exposure.

Myelosuppressive injuries lead to chronic MAPK activation and impair blood reconstitution. Here, the authors show that chronic activation endothelial MAPK impairs hematopoietic stem cell (HSC) function through NFkB signaling, and that post-myelosuppressive HSC defects can be reversed by administration of Stem Cell Growth Factor SCGFa.

The role of autoantibodies in bullous pemphigoid (BP) and their impact on keratinocytes and the response to BP pathology remains underexplored. By leveraging transcriptomics analysis and large-scale protein assays, here the authors identify keratinocyte MyD88 as a regulator of the pro-inflammatory response in BP, uncovering the role of keratinocytes in this disease pathology.

Senescent cells in fat and liver are shown to attract M1-like macrophages with increased expression of the NAD-consuming enzyme CD38, leading to their local accumulation and providing a mechanism for the age-associated decline in tissue NAD⁺ levels.

Systematic discovery of proteins interacting with low-abundance RNAs is challenging. Here, the authors develop an enhanced HyPro technology to identify proteins associated with compact RNA compartments and single RNA molecules, revealing early defects in ALS-linked mutant C9orf72 transcripts.

A cross-ancestry meta-analysis of genome-wide association studies identifies association signals for stroke and its subtypes at 89 (61 new) independent loci, reveals putative causal genes, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as potential drug targets, and provides cross-ancestry integrative risk prediction.

Through circuit dissection in juvenile, adolescent and adult mice, Klune, Goodpaster and colleagues reveal multiple developmental switches in mPFC–NAc and mPFC–BLA pathways that underlie developmental transitions in threat avoidance behavior.

A single-cell resolution image-based genome-wide CRISPR screen, analysed with deep learning and random forest models, identified host factors regulating Ebola virus infection at distinct stages in the viral life cycle.

mRNA vaccines targeting SARS-CoV-2 also sensitize tumours to immune checkpoint inhibitors.

Chen et al. find that cerebellar Purkinje cells directly inhibit neurons in parabrachial nuclei that in turn influence many forebrain regions. This alternative output pathway could enable the cerebellum to regulate emotions, anxiety, aggression and affect.

A study of the evolution of the SARS-CoV-2 virus in England between September 2020 and June 2021 finds that interventions capable of containing previous variants were insufficient to stop the more transmissible Alpha and Delta variants.

NOTCH3 signalling is shown to be the underlying driver of the differentiation and expansion of a subset of synovial fibroblasts implicated in the pathogenesis of rheumatoid arthritis.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

How lung epithelial and endothelial cells develop into alveoli is a major knowledge gap, with implications for lung repair in preterm infants. Here, the authors establish a transcriptomic atlas of human neonatal lung disease, identifying semaphorins as pivotal mediators of organogenesis and injury.

Cryptosporidium infection can cause severe diarrhea with limited treatment options available. Here, Lunde et al. perform a drug repositioning screen with a library of benzoxaboroles and identify AN7973 as potent inhibitor of intracellular parasite development with good efficacy in murine and neonatal dairy calf disease models.

Marine sponges host bacteria that produce diverse bioactive compounds. Here, the authors conduct a large-scale metagenomic, single-bacterial and biochemical study to reveal the untapped biosynthetic potential of ‘Entotheonella’ symbionts, a talented producer taxon from microbial dark matter.

Small CRISPR Cas9 proteins have potential in gene therapies but generally have poor editing efficiency or specificity and often recognize sub-optimal PAM sequences. Here the authors characterise four small nucleases and use protein engineering to create effective in vivo editors.

Vaccination against one viral strain can result in cross-reactive antibodies against another viral strain. In this study, the vaccination of mice against the 2009 H1N1 virus is shown to protect mice from the 1918 Spanish influenza virus, which resulted in millions of deaths worldwide.

Many animals, including mammals and insects, like slightly acidic yet dislike highly acidic foods, but how animals discriminate low from high acidity is unclear. Here the authors demonstrate that the fruit fly uses an evolutionarily conserved taste receptor to distinguish low from high concentrations of acid.

Wnt signaling functions in tissue homeostasis and tumorigenesis. Here the authors show that ROR2, a Wnt receptor, plays roles not only in transducing Wnt signaling, but also in regulation of DNA damage response critical for stem cell maintenance.