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To celebrate the journal’s 25th anniversary, we asked 13 researchers to offer a glimpse of what their research field might look like in 2050. They consider how technological breakthroughs — for example, artificial intelligence-powered virtual cells — could transform our understanding of how molecules, organelles and cells behave in different contexts, revolutionize therapies and enable the design of resilient crops.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

A lipid nanoparticle is used to deliver mRNA to hematopoietic stem cells in macaques.

The extracellular matrix is remodeled to form complex interconnected network structures that regulate stem cell behaviors. Here, the authors modulate extracellular matrix-like networks using magnetic nano-blockers, adjusting stem cell behavior by changing ligand inter-cluster connectivity. This dynamic system provides new insights into cell-material interactions for tissue regeneration.

Deubiquitinating enzymes play an essential role in myocardial hypertrophy. Here, the authors show the beneficial effects of a cardiomyocyte-derived deubiquitinating enzyme, USP13, in hypertrophic cardiomyocytes and identify a cardiomyocyte-specific USP13-STAT1 axis in regulating cardiac hypertrophy.

ALOX5 contributes to the tubular injury in IRI-induced AKI through enhancing ferroptosis in the renal tubular cells and might be a novel target for the prevention and treatment of IRI-induced AKI.

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

Wang and colleagues revealed how oleic acid produced by thymic epithelial cells could affect the developing thymocytes to differentiate into peripheral regulatory T cells.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

In studies using mouse models of psoriasis, a spectrum of innate lymphoid cell types is reconfigured and converges via multiple trajectories on a type 3-like state, demonstrating the range and flexibility of innate lymphoid cell responses in the skin.

Rap1 is a telomeric protein that is highly expressed in cancers. Here, the authors show that Rap1 interacts with several DNA repair proteins independent of its telomere function to enhance DNA repair and that its deficiency leads to accelerated tumorigenesis, but enhanced sensitivity to genotoxic stress.

HEP14, a PKC pathway activator, enhances ovarian regeneration of human adipose-derived stem cells for regenerative potential by activating the PKC-ERK1/2 pathway to upregulate MMP1, PDGFD, and STC1 in premature ovarian insufficiency and aging mice.

A meta-analysis of genome-wide association studies of type 2 diabetes (T2D) identifies more than 600 T2D-associated loci; integrating physiological trait and single-cell chromatin accessibility data at these loci sheds light on heterogeneity within the T2D phenotype.

Two recently discovered bird fossils from the Late Jurassic Zhenghe Fauna demonstrate that highly derived bird-like features and the origin of birds appeared much earlier in the Jurassic period than previously estimated.

Late-stage acute liver failure (ALF) has limited therapies. The authors show that the bioactive compound SCM-198 extends the ALF treatment window from 3 to 24 hours in mice by selectively targeting the identified AdipoR2-CaM-CaMKII-NOS3-NO axis.

Here the authors identify 128 regions of the genome associated with blood pressure traits in 100,000 Chinese adults. Blood pressure traits contributed differently to CVD risk, with only pulse pressure independently causally associated with carotid plaque.

Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.

Regulating oxidative phosphorylation and restoring redox homeostasis are crucial in neurological disorders. Here, the authors develop a top-down membrane self-assembly strategy to develop stem cell-derived artificial organelles (SAOs) that mimic mitochondrial oxidative phosphorylation without the risks associated with stem cell therapy.

Guided bone regeneration (GBR) membranes are used to treat bone defects, but face challenges in regulating the immune microenvironment. Here, Yang et al. report a Janus collagen-based barrier membrane that modulates the osteoimmune microenvironment to effectively promote bone regeneration.

Many recent proteomics studies use either Olink or SomaScan platforms to quantify proteins in high-throughput, but the consistency between the two is unclear. Here, the authors measure proteins in the same samples using both platforms, finding only modest correlation, and compare associations with genetic variants and disease.

Mesenchymal condensation is essential for cartilage development. Here, the authors report on a cell-adaptable supramolecular hydrogel to replicate the hypoxic environment and structural support needed for cartilage organoid formation and study the metabolic reprogramming involved.

MicroRNAs play an important role in stem cell fate and tumorigenesis. In this work, the authors show that miR-31 controls mammary stem cell self-renewal and tumorigenesis by simultaneously activating Wnt/β-catenin and repressing TGFβ signaling pathways.

Hypercholesterolemia and vascular inflammation both contribute to the pathogenesis of atherosclerosis, but how hypercholesterolemia initiates vascular inflammation is not fully understood. Here the authors report that crosstalk between macrophages and endothelial cells mediated by the cholesterol metabolite 27-hydroxycholesterol drives vascular inflammation and contributes to atherosclerosis in male mice.

Tao et al. show that epidermal growth factor receptor and insulin-like growth factor 1 receptor activation enhances thymidine kinase 1 expression through ERK phosphorylation and deubiquitylation mediated by ubiquitin carboxyl-terminal hydrolase 9X, thus enhancing enzyme activity-dependent DNA synthesis and enzyme activity-independent glycolysis.

Upon nutrient stress in hepatocellular carcinoma, the glycolytic enzyme PFKL facilitates mitochondria tethering to lipid droplets to engage lipid mobilization and ensure nutrient supply.

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 flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

This study uncovered genetic associations with environmental sensitivity in psychiatric and neurodevelopmental traits in an international collaboration using data from more than 21,000 monozygotic twins—the largest genetic study of monozygotic twin differences to date.

A genome-wide association study meta-analysis combined with multiomics data of osteoarthritis identifies 700 effector genes as well as biological processes with a convergent involvement of multiple effector genes; 10% of these genes express the target of approved drugs.

Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.

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.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

A multi-ancestry genome-wide association study for age at menarche followed by fine mapping and downstream analysis implicates 665 pubertal timing genes, such as the G-protein-coupled receptor 83 (GPR83) and other genes expressed in the ovaries involved in the DNA damage response.

Deubiquitinating of key proteins may be involved in podocyte injury and diabetic kidney disease (DKD). Here, the authors show that OTUD5 in podocytes alleviates DKD through deubiquitinating TAK1 at the K158 site, preventing TAK1 phosphorylation and inflammatory responses in podocytes.

An avialan species from the Zhenghe Fauna—a collection of vertebrate fossils from the Late Jurassic of China—had an unusual combination of features, including very long hindlimbs, suggesting that it had a terrestrial or wading lifestyle.

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.

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.

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.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

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.

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.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.