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Massively parallel reporter assays across five cell types identify thousands of causal, noncoding regulatory variants among 220,000 loci, revealing diverse regulatory mechanisms shaping complex traits and disease.

Repeated rapid structural MRI scans substantially improve the precision of individual differences in brain change. This allowed for individualized insight into subtle differences in the detected rates of brain aging and neurodegeneration to be detected.

Post-transcriptional regulation of mRNA translation was explored using Ribo-STAMP and single-cell RNA sequencing to reveal cell-type-specific and isoform-specific translation patterns across hippocampal neuronal and non-neuronal cell types, highlighting functional differences between CA1 and CA3.

The authors introduce an unsupervised machine learning module capable of clustering high-dimensional blinking patterns and computing class-wise power spectral densities to probe active trap states. The approach offers advances in contemporary (micro)spectroscopy.

Wang et al. show that promyelocytic leukaemia protein (PML) reduces polyG inclusions via chaperone-mediated disaggregation and proteasome-dependent degradation. This suggests a possible role for PML in various neurodegenerative diseases.

Subcellular compartmentalization of the glycolytic enzyme PFKM regulates cell fate and metabolic switch during skeletal muscle differentiation.

In a randomized experiment in Chelsea, Massachusetts, USA, lower-income individuals who received cash transfers reduced calorie deficits and increased consumption of nutrient-dense, higher-cost foods. Their findings highlight the critical role that income support may have in a high-income country to reduce hunger.

Citizen science data are increasingly used in biodiversity monitoring. This study applies a digital twin approach to biodiversity monitoring using a large citizen science dataset on birds from Finland, demonstrating its potential for ecological forecasting.

Scholl et al. show that PopZ forms filamentous condensates driven by its helical domain and inhibited by its disordered region. Phase-dependent conformations modulate client interactions and disruption of filamentation or condensation impairs cellular function and growth.

The inability of intrinsically photosensitive retinal ganglion cells to shift the circadian clock in the suprachiasmatic nucleus during daytime is caused by light-dependent depolarization block of these cells.

This study finds that native tree extinctions and alien naturalizations are pushing forests towards fast-growing, resource-demanding species. This global shift could affect carbon storage and ecosystem stability, highlighting the need to protect slow-growing trees.

Understanding the organism-wide molecular effects of spaceflight becomes increasingly critical as space exploration accelerates. Here, the authors show that miRNAs mediate microgravity-induced adaptations via extracellular matrix, DNA damage and developmental pathways, as shown by small RNA profiling in 13 organs of mice during and after spaceflight.

Insights into regulatory T cell biology are accelerating therapeutic innovation in cancer immunotherapy, autoimmune diseases and transplant rejection.

Large-effect variants in autism remain elusive. Here, the authors use long-read sequencing to assemble phased genomes for 189 individuals, identifying pathogenic variants in TBL1XR1, MECP2, and SYNGAP1, plus nine candidate structural variants missed by short-read methods.

China’s carbon neutrality and clean-air policies cause global warming from reduced aerosols that nearly offsets cooling from reduced CO2 before 2060, with warming emerging afterwards, calling for early carbon neutrality and more mitigation strategies.

Human genetic variation influences instability of DNA repeats that commonly expand as we age.

Five-year survival data and biomarker analysis of the PRADO extension cohort of the phase 2 OpACIN-neo trial, in which patients with high-risk stage III melanoma received neoadjuvant ipilimumab and nivolumab and underwent pathologic response-directed surgery and adjuvant therapy, show 71% event-free survival and 88% overall survival, with tumor mutational burden, IFNγ signature and PD-L1 expression associated with favorable outcomes.

A soft robotic probe enables continuous in utero monitoring of fetal physiological parameters, including heart rate, blood oxygen saturation, temperature and electrocardiogram data, during open or fetoscopic surgery to provide real-time information on fetal condition and distress.

The hierarchy of DNA repair pathways at stalled replication forks is not fully understood. Here, the authors isolate two mutations in yeast RAD51 with defects in binding to duplex DNA and stalled replication forks, suggesting a role of Rad51 duplex DNA binding in fork stabilization and postreplication repair.

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.

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.

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.

DNA double-strand breaks endanger genome stability. Here, the authors present cryo-EM structures showing how Ku70/80 and DNA-PK bind DNA ends on nucleosomes, offering a mechanistic model for break recognition within chromatin.

Bacteria secrete polysaccharides essential for colonization and infections. Here, the authors reveal the structure and mechanism of WzaB, a Class-3 OPX protein, uncovering a distinct trans-envelope secretion complex driving critical polysaccharide export in diderm bacteria.

How white matter develops along the length of major tracts in humans remains unknown. Here, the authors identify fundamental patterns of human white matter development along distinct axes that reflect brain organization.

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 functions of the vast majority of brain-expressed spliced isoforms are unknown. Here the authors describe an isoform-resolution perturbation system coupled to a single cell transcriptomics read-out, and through this approach identify neuronal microexons that control autism-linked signatures underlying neuronal maturation and function

Climate change can alter when and how animals grow, breed, and migrate, but it is unclear whether this allows populations to persist. This global study shows that shifts in seasonal timing are key to helping vertebrate species maintain population growth under global warming.

In this study, the authors model the current mechanical properties of the seafloor of Jupiter’s icy moon Europa, and find those rocks to be too strong to allow the kind of fracturing that, on Earth, enables rock–water chemical reactions on which chemosynthetic life relies.

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.

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.

Effective early detection and intervention strategies for lung cancer are urgently needed. The authors of this Review summarize the current state of lung cancer screening and provide future directions for optimal implementation, including biomarker development. They also discuss precancer interception strategies that could transform both lung cancer prevention and early intervention.

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.

Baird et al. present the phase 2 PIONEER trial findings on the antitumor activity of combining aromatase inhibitor letrozole with megestrol in postmenopausal women with operable estrogen-receptor-positive human epidermal-growth-factor-receptor-2-negative breast cancer.

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.

Stable adipocytes resist lipolysis in healthy states but are highly susceptible to a catecholamine-independent, neurosystemic pathway-driven catabolic state.

Here the authors provide an explanation for 95% of examined predicted loss of function variants found in disease-associated haploinsufficient genes in the Genome Aggregation Database (gnomAD), underscoring the power of the presented analysis to minimize false assignments of disease risk.

Human genetic loci that associate with composition of the oral microbiome are identified using saliva-derived DNA, where the same host genetics also shapes oral health and genetic variation in oral bacteria.

MAGPIE is a computational framework for co-registering spatially-resolved transcriptomics, metabolomics and tissue morphology for integrated downstream analysis. Case studies across lung, brain and breast reveal coordinated cross-modality molecular changes.

As Nature Aging celebrates its fifth anniversary, the journal asks some of the researchers who contributed to the journal early on to reflect on the past and the future of aging and age-related disease research, the impact of the field on human health now and in the future, and what challenges need to be addressed to ensure sustained progress.

Here the authors report a randomized controlled trial showing that a previously developed artificial intelligence model estimates patient mortality risk as accurately as doctors and standard risk scores, but did not change clinical care decisions in the emergency department. This suggests that prediction accuracy alone does not necessarily translate into real-world clinical impact.

The authors developed a 5.82 g magnetically inner-actuated millirobot capable of carrying over 300 times its own weight. The high thrust and payload capability enable it to navigate tough terrains, such as sand, viscous oil, and confined spaces.

Tree longevity is thought to increase in harsh environments, but global evidence of drivers is lacking. Here, the authors find two different pathways for tree longevity: slow growth in resource limited environments and increasing tree stature and/or slow growth in competitive environments.

An approach combining BONCAT, stable isotope probing and metaproteomics showcases the hidden metabolic interconnectivity of microorganisms within an anaerobic digestion community.

Rizzollo et al. show that BDH2 participates in iron distribution between cellular compartments, which sets the threshold for the ferroptosis vulnerability of the melanoma cell phenotypes, ultimately affecting their metastatic capacity

Mycobacterium tuberculosis protein Ku is involved in DNA repair and a potential drug target. Here, using cryo-EM and complementary approaches, the authors obtain insights into Ku oligomerization and mechanisms of function in DNA synapsis.