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Extracellular proteasomes are found in the Arabidopsis apoplastic fluid and shown to participate in biotic defense by proteolytically digesting pathogen proteins into microbe-associated molecular pattern epitopes specifically recognized by the pathogen-triggered innate immune response system.

The human endoderm-derived organoid cell atlas (HEOCA) presents an integrative analysis of single-cell transcriptomes across different conditions, sources and protocols. It compares cell types and states between models, and harmonizes cell annotations through mapping to primary tissues.

A nested pattern of interactions is thought to promote species persistence in mutualistic ecological networks. In this study, Staniczenko et al. introduce a spectral graph measure of nestedness, to show that nestedness is maximally destabilizing and demonstrate that empirical species preferences are not quantitatively nested.

Polyamines produced by gut bacteria have been proposed to contribute to inflammatory bowel diseases. Here, Nauta et al. show that bacteria can produce a noncanonical polyamine intermediate that functions similarly to deoxyhypusine synthase inhibitors, activates mitochondrial stress responses, and inhibits nematode development and mouse macrophage differentiation.

Liver macrophages are a major obstacle to extrahepatic drug delivery. This study identifies the receptor–ligand interactions that they use to capture circulating nanoparticles and leverages this understanding to engineer nanoparticles that escape macrophage uptake.

scooby achieves DNA sequence-based single-cell level modeling of RNA-sequencing coverage and ATAC-sequencing insertion profiles by adapting a deep learning model that predicts bulk RNA-sequencing coverage.

Transcriptomic and proteomic analyses show that high levels of the extracellular-matrix protein osteopontin are associated with the attenuated foreign-body response elicited by breast silicone implants wrapped with acellular dermal matrix.

Analyses of genome and exome sequencing data identify rare coding and structural variants associated with atrial fibrillation and highlight genetic links between atrial fibrillation and cardiomyopathies.

MYC amplification is an independent prognostic factor for the most aggressive subgroup (Group 3) of pediatric medulloblastoma (G3 MB). Here, the authors highlight the role of the RNA-binding protein, Musashi-1 (MSI1) in G3 MB and identify MSI1-bound targets sharing MYC associated pathways.

Rocks and dust from the asteroid Bennu contain some of the molecular building blocks of life on Earth, such as amino acids and nucleobases. They also carry ammonia that formed billions of years ago in cold, distant regions of our Solar System.

HORNET, a method that uses unsupervised machine learning and deep neural networks to analyse atomic force microscopy data enables structural determination of RNA molecules in multiple conformations.

CAR-T cells engineered with αPD-L1–IL-12 fusion proteins show antitumour activity in mouse models of prostate and ovarian cancer.

In this genomic analysis of peripheral blood samples of the phase 3 CheckMate-067 trial of ipilimumab (IPI) versus nivolumab (NIVO) versus ipilimumab and nivolumab (IPI-NIVO) in melanoma, the status of certain mitochondrial haplogroups in patients was associated therapeutic resistance to NIVO or IPI-NIVO, a finding validated in an independent cohort.

T-cell acute lymphoblastic leukemia is a highly aggressive disease with varying recurrence rates. Here, the authors build a single cell transcriptomic atlas of childhood T-cell acute lymphoblastic leukaemia (T-ALL). They identified a distinctive cancer cell state that correlates with high risk, treatment refractory T-ALL.

Fungi exhibit remarkable morphological and ecological diversity. An analysis of the genomes of 123 fungi and relatives shows gradual loss of protist genes, major gene turnover and duplication leading to the evolution of modern traits of filamentous fungi.

Fine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions.

Here the authors combine a deep generative model with structure-based drug design and prospectively validate functionally active, nanomolar, A_2A adenosine receptor ligands and solve their crystal structures to close the Artificial Intelligence Structure-Based Drug Design loop.

Microglial states throughout remyelination are incompletely understood. Here, the authors show that microglia form several states during the early stages of remyelination that coalesce into a partially resolved state that is dysregulated with age.

Exome-sequencing analyses of a large cohort of patients with type 2 diabetes and control individuals without diabetes from five ancestries are used to identify gene-level associations of rare variants that are associated with type 2 diabetes.

Koplev et al. apply interactive system analyses to infer and characterize gene-regulatory networks (GRNs) active within and across tissues that cause cardiometabolic disease and coronary artery disease (CAD). By including GWAS in the integrative analysis, the provided multiorgan framework of GRNs is suggested to explain significantly more heritability of CAD than what has been achieved by analyzing GWAS alone.

Allele-preferential transcription factor binding can influence pancreatic ductal adenocarcinoma risk loci function. Here, the authors show allele-specific JunB and JunD binding at chr1p36.33 and propose a role for KLHL17 in protein homeostasis by mitigating inflammation.

The RNA endonuclease CPSF3 was identified as the cellular efficacy target of the small molecule JTE-607, revealing pre-mRNA processing as a vulnerability in cancers such as Ewing’s sarcoma that are characterized by aberrant transcription.

Tigers are an endangered species and therefore understanding their genetic architecture could aid conservation efforts. Here, the authors report the first genome sequence of the Amur tiger and, through close species comparative genomic analysis, provide insight into the genome organization, evolutionary divergence and diversity of big cats.

Preclinical studies indicate that myeloproliferative neoplasms (MPN) may be sensitive to the estrogen receptor modulator, tamoxifen. Here, the authors present a phase II clinical trial reporting the efficacy of tamoxifen in MPN and analysis of peripheral haematopoietic stem cells to identify potential predictive signatures of responders.

Analysis of genomic data from 25 distantly related plant species shows signatures of selection on the same gene families and functions that repeatedly contributed to local adaptation to climate.

Using microbiome data analysis and a self-establishing metabolically cooperating yeast community model, the authors show that the presence of auxotrophs in a microbial community increases metabolic interactions between cells and fosters antimicrobial drug tolerance.

Malaria mosquitoes use their ears to detect the flight tones of mating partners in the swarm as part of the courtship ritual. Here, the authors describe the auditory role of octopamine as a modulator of auditory plasticity in malaria mosquitoes and identify the main receptors involved in this process.

Meng et al. develop the adeno-associated virus 9-based therapy CM-YAP^on to transiently and inducibly express YAP in the heart. In mice, CM-YAP^on promoted cardiomyocyte cell cycle reentry and reprogrammed the cardiac microenvironment. The CM-YAP^on gene therapy improved cardiac function after myocardial infarction (MI) and conferred cardioprotection before MI.

Human brain structure changes throughout the lifespan. Brouwer et al. identified genetic variants that affect rates of brain growth and atrophy. The genes are linked to early brain development and neurodegeneration and suggest involvement of metabolic processes.

Thomas, Noishiki, Gaddam et al. used thrombotic vascular tissues and iPSC-derived cardiac organoids to show that COVID-19-induced endotheliitis and cytokine release disrupt endothelial–cardiomyocyte crosstalk and contribute to cardiac dysfunction in long COVID.

Integrated multi-omics analysis uncovers the role of the vascular disease-associated gene PHACTR1 in regulating mitochondrial dynamics, iron metabolism, and cell cycle.

Markov, Ren, Senkow and colleagues report that in patients with severe SARS-CoV-2 pneumonia, alveolar T cell interferon responses targeting structural SARS-CoV-2 proteins characterized patients who recovered, whereas responses against nonstructural proteins and activation of NF-κB were associated with poor outcomes.

Blood metabolites are influenced by a combination of genetic and environmental factors. Here, Yousri and colleagues perform a whole-exome sequencing study in combination with a metabolomics analysis to identify metabolic quantitative trait loci in a Middle Eastern population.

Post-growth scholarship seeks to address the limitations of growth-oriented mitigation scenarios by exploring the potential of profound socio-economic transformations. This Perspective synthesizes core principles for modelling post-growth futures.

The activity of the tumour-suppressor protein p53 is repressed in the thymus to augment fluctuations in background chromatin accessibility as a means of mediating ectopic gene expression and immune tolerance.

An international consortium reports the genomic sequence for ten Drosophila species, and compares them to two other previously published Drosophila species. These data are invaluable for drawing evolutionary conclusions across an entire phylogeny of species at once.

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.

Azacitidine (AZA) response in myelodysplastic neoplasms is unpredictable. Here, the authors show in a phase 2 trial that while global methylation changes did not differ by response, baseline and initial CpG methylation differences in HSPCs predicted AZA response.

Prioritized Single-Cell ProtEomics (pSCoPE) introduces the concept of using priority levels that define the temporal order of peptide analysis for single-cell proteomic analysis. Prioritized data acquisition aims to simultaneously optimize the consistency, sensitivity, depth and accuracy of protein quantification.

Multidrug-resistant (MDR) tuberculosis threatens global control of tuberculosis disease. Here, the authors investigate mechanisms underlying the collateral sensitivity of MDR Mycobacterium tuberculosis to the ATP synthase inhibitor bedaquiline.

Here, the authors apply genome-scale metabolic network reconstructions to metagenomic data obtained from human vaginal swabs to identify bacterial vaginosis-associated bacterial metabolic interactions, and validate in vitro microbial metabolites implicated in host estrogen receptor binding.

Researchers use spatial light modulators to create beams with locally varying spatial coherence, and show that the space and spatial frequency information of the beams can be measured simultaneously.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) is a rare but life-threatening severe cutaneous drug reaction mediated by CD8⁺ T cells. Here the authors characterise the immune response in skin samples at the site of tissue damage from patients affected with SJS/TEN and compare this to healthy skin or blister fluid and find populations of CD8⁺ T cell clonotypes expressing cytotoxic mediator molecules.

Total in vitro biosynthesis can reveal unusual pathways evolved by nature to produce natural products. Here the authors report on enzymatic cascades, comprising a cryptic methylation sequence, efficiently delivering β-lactone-containing peptide proteasome inhibitors with promising anticancer activity.

Yeast exhibit oscillations that share features with circadian rhythms. The authors show that bioenergetic constraints promote oscillatory behaviour: resources are stored until supplies can support translational bursting, this is licensed by ion transport and release from membrane-less compartments.

Application of pluripotent cells in regenerative medicine requires an understanding of how they exit pluripotency. Here the authors demonstrate support for the idea that pluripotency exit involves pluripotent intermediates that exhibit lineage bias by identifying and trapping a mesoderm biased sub-state in culture.

Although ulcerative colitis (UC) is a major type of inflammatory bowel disease, attempts to model it fully have fallen short. Here the authors use patient-derived iPS cells to develop a UC organoid model that recapitulates disease histological and functional features, and confirm the role of CXCL8/CXCR1 in pathogenesis.