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Fessler and colleagues report that loss of the IFN-γ-induced GTPase IRGM1 results in autoinflammatory disease. Deficient IRGM1 activity led to defective lysosomal maturation and impaired mitophagy, prompting the release of cytosolic mtDNA and thereby activating the cGAS–STING pathway.

Genetic and functional studies implicate allele-specific regulation of OAS1 splicing and nonsense-mediated decay in COVID-19 severity. The OAS1 risk haplotype is also associated with reduced SARS-CoV-2 clearance in a clinical trial with pegIFN-λ1.

Tarpey et al. carry out a large-scale systematic sequencing of the majority of X-chromosome coding exons from 208 families with multiple individuals with mental retardation and a pattern of transmission compatible with X linkage in order to identify XLMR-causative mutations. They find several mutations that appear to be causative in loci already known to be involved in XLMR, as well as new data about those loci, and make inferences about the role of the different classes of variants in these diseases.

Bacterial Rhs proteins constitute a diverse family of secreted toxins. Here, the authors present a cryo-electron microscopy structure of an Rhs protein from Pseudomonas aeruginosa and provide insights into the mechanisms by which the protein delivers its encapsulated pore-forming toxin fragment to the bacterial membrane.

Comparative RNA-seq, ChIP–seq and quantitative phosphoproteomics reveal how the blast fungus uses the Pmk1 MAP kinase to regulate a network of transcription factors that orchestrate the complex transcriptome changes necessary for infecting rice plants.

In participants from a randomized controlled trial, doxy-PEP use over 6 months minimally affected the gut microbiome’s taxonomic composition but increased the abundance and active expression of tetracycline antibiotic resistance genes.

Multi-ancestry meta-analyses of genome-wide association studies for self-reported physical activity during leisure time, leisure screen time, sedentary commuting and sedentary behavior at work identify 99 loci associated with at least one of these traits.

Placental-site trophoblastic tumors (PSTTs) are often resistant to chemotherapy and have a high incidence of lung metastasis. Cole et al. report the case of a 52-year-old woman who was diagnosed with metastatic chemoresistant PSTT. The patient was managed with abdominal hysterectomy, salpingo-oophrectomy, radiotherapy, chemotherapy, and thoracotomy with wedge resection. The authors discuss the treatment options for patients with PSTTs, especially for those with persistent metastatic disease.

In this largest whole-exome sequencing study of epilepsies to date, the Epi25 Collaborative identified extremely rare variants that confer risk for diverse epilepsy subtypes, highlighting roles in synaptic transmission and neuronal excitability.

Here the authors provide a single-cell characterization of cerebrospinal fluid and blood of newly diagnosed multiple sclerosis (MS) patients, revealing altered composition of lymphocyte and monocyte subsets, validated by other methods including the interrogation of the TFH subset in mouse models of MS.

A recently developed gene targeting procedure shows promise for the efficient correction of genetic defects in vivo but many questions have yet to be answered (pages 285–290).

Corona phase molecular recognition (CoPhMoRe) involves the deposition of a heteropolymer onto a nanoparticle surface, providing a recognition site for a given analyte. Here, the authors show that CoPhMoRe can be used to selectively detect proteins (fibrinogen) with high selectivity, including in a complex serum environment.

The response rate of relapsed/refractory acute myeloid leukemia patients to PD-1 checkpoint blockade is low and unpredictable. Authors here show by single cell RNA sequencing, T cell receptor profiling and genomic analysis that the phenotypes and repertoire of CD8 + T cells and loss of chromosome 7/7q are important determinants of response.

Chromosome-scale assembly for the cultivated octoploid strawberry (Fragaria × ananassa) uncovers the origin and evolutionary processes that shaped this complex allopolyploid, providing a useful resource for genome-wide analyses and molecular breeding.

The molecular circuitry that drives dendrite formation during osteocytogenesis remains poorly understood. Here the authors show that deletion of Sp7, a gene linked to rare and common skeletal disease, in mature osteoblasts and osteocytes causes severe defects in osteocyte dendrites.

PEA-15 is a scaffold protein that regulates the localization and phosphorylation of the MAP kinase ERK2. By solving the structure of the PEA-15/ERK2 complex, the authors show that PEA-15 restrains ERK2 in a spring-loaded, activated form.

Bacteria can grow as free living planktonic cells or as part of surface-associated biofilms. Here the authors show, for the opportunistic pathogen Pseudomonas aeruginosa, that cells recently dispersed from biofilms are physiologically different from, and more virulent than, planktonic and biofilm cells.

A device architecture based on indium arsenide–aluminium heterostructures with a gate-defined superconducting nanowire allows single-shot interferometric measurement of fermion parity and demonstrates an assignment error probability of 1%.

Global syphilis prevalence has been increasing. Sequencing and analysis of a global collection of 726 Treponema pallidum samples reveal globally circulating lineages linked to a rapid expansion occurring since the end of the twentieth century.

Analysis of large genomic datasets, including gnomAD, reveals that partial LRRK2 loss of function is not strongly associated with diseases, serving as an example of how human genetics can be leveraged for target validation in drug discovery.

Anti-TRBC1 antibody–drug conjugates may offer a more potent T cell cancer therapy by bypassing the fratricide that may be limiting the efficacy of anti-TRBC1 CAR T cells in the clinical trial for patients with T cell cancers.

A bead-based fluorescence sandwich immunoassay implemented in a custom microfluidic chip can continuously measure glucose and insulin with picomolar sensitivity and sub-second resolution.

Integrated analysis of transcriptome, open chromatin region and chromatin conformation capture data from subjects with acute myeloid leukemia (AML) harboring defined transcription factor and signaling molecule alterations provide insights into the subtype-specific regulatory network in AML.

As labs and lecture halls empty, go out of this world with our regular reviewers' recommendations for stellar holiday reading.

Results from the phase 3 placebo-controlled MAPP2 trial show that MDMA-assisted therapy reduces post-traumatic stress disorder (PTSD) symptoms and functional impairment in a diverse population with moderate to severe PTSD.

Generating organized kidney tissues from human pluripotent stem cell is a major challenge. Here, Freedman et al. describe a differentiation system forming spheroids and tubular structures, characteristic of these kidney structures, and using CRISPR/Cas9, delete PKD1/2, to model polycystic kidney disease.

Cell free DNA fragmentation is a promising biomarker for disease, but its epigenetic regulation is incompletely understood. Here, the authors investigated the effects of DNA methylation in the production of cfDNA fragmentation, and corelate these changes with gene expression in human cancer.

Across 16 countries, this research finds consistent cognitive and social predictors of COVID-19 misinformation susceptibility, and shows how accuracy prompts and literacy tips reduce misinformation sharing and how wisdom of crowds can identify false claims cross-culturally.

A study reports single-cell RNA-sequencing profiles for more than 1.6 million cell nuclei from 101 whole mouse embryos including 22 mutant and 4 wild-type genotypes, from one experiment.

Analysis of whole-genome sequence data from 3,474 families finds an excess of private, likely gene-disrupting variants in individuals with autism. These variants are under purifying selection and suggest candidate genes not previously associated with autism.

Transgenic RNA ‘sponges’ that inhibit specific microRNAs are valuable tools for functional studies. Fulga et al. present a library of conditional microRNA sponges in Drosophila, and reveal widespread involvement of microRNAs in the maintenance of adult muscle structure and function.

Whole-genome sequencing analysis of individuals with primary immunodeficiency identifies new candidate disease-associated genes and shows how the interplay between genetic variants can explain the variable penetrance and complexity of the disease.

Here the authors provide a resource for ovarian cancer combining spatial transcriptomics, genomics, CRISPR Perturb-seq screens and in silico methods to focus on T cells and natural killer cells in the tumor and their role in immune evasion.

In a first step toward developing autologous tissue grafts for the treatment of children with intestinal failure, patient-derived jejunal organoids seeded on scaffolds of decellularized human intestinal matrix formed grafts that had jejunal properties and formed luminal structures when transplanted into mice.

As photosynthesis requires water, its transport to and within leaves is a potential determinant of photosynthetic productivity. This comparison of 30 species of Viburnum shows how variations in venation architecture constrain photosynthetic rate.

Multi-ancestry genome-wide analyses identify new risk loci for age-related macular degeneration. Ancestry-specific analyses identify distinct effects at major risk loci, including smaller effect sizes for CFH risk alleles in haplotypes of African ancestry.

A valuation of the flood risk reduction services of coral habitats to people, property, economies and infrastructure in the United States finds that these benefits exceed US$1.8 billion annually.

The BRAIN Initiative Cell Census Network has constructed a multimodal cell census and atlas of the mammalian primary motor cortex in a landmark effort towards understanding brain cell-type diversity, neural circuit organization and brain function.

Hypermutation and microsatellite burden determine responses and long-term survival following PD-1 blockade in children and young adults with refractory cancers resulting from germline DNA replication repair deficiency.

Experiments and computer simulations show that Janus ellipsoids can self-assemble into self-limiting fibres that have shape-memory properties and can be actuated by applying an external electric field.

Restoration of coronary blood flow after a heart attack may lead to reperfusion injury and pathologic iron deposition. Here, the authors perform magnetic susceptibility imaging showing its association with iron in a large animal model of myocardial infarction during wound healing, and showing feasibility in acute myocardial infarction patients undergoing percutaneous coronary intervention.