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A gene therapy method using AAV can help deliver HIV-fighting antibodies long-term, but the body often rejects them. Here the authors show that a short course of the drug rapamycin helps prevent host anti-drug antibody responses, showing successful antibody delivery in mice and monkeys.

Green roofs enhance urban ecosystem services, but the long-term vegetation health and design’s impact is underexplored. This study shows a temporal increase in vegetation health and identifies key factors and thresholds that support sustained vegetation health, offering guidance for effective green roof planning and design.

A systematic review and meta-analysis of clinical trials investigating the efficacy and safety of obesity management medications reported tirzepatide and semaglutide to be the most effective in reducing body weight and obesity-related complications.

Analysis of human Robertsonian chromosomes originating from 13, 14 and 21 reveal that they result from breaks at the SST1 macrosatellite DNA array and recombination between homologous sequences surrounding SST1.

Understanding collective behaviour is an important aspect of managing the pandemic response. Here the authors show in a large global study that participants that reported identifying more strongly with their nation reported greater engagement in public health behaviours and support for public health policies in the context of the pandemic.

The authors in this work identify an in vivo CNS active bifunctional degrader of GSK3. This was discovered via development of orthogonally reactive linker chemistry and a direct-to-biology screen that was able to provide hits of in vivo chemical probe quality.

Panoptes, an anti-phage defence system against virus-mediated immune suppression, is revealed.

Breugnathair elgolensis gen. et sp. nov., an early squamate identified from a newly discovered Middle Jurassic skeleton on the Isle of Skye, provides new evidence on the origins of snakes.

A post hoc analysis of a multicentre, randomised trial showed that prediabetes remission is possible without total weight loss—providing weight is distributed to subcutaneous deposits as opposed to visceral ones.

This study shows that p300/CBP-dependent H2B acetylation is crucial for maintaining transcription of oncogenic gene programs in androgen receptor-driven prostate cancer.

Conditional ablation experiments show that key components of the synaptonemal complex protect double Holliday junction recombination intermediates to ensure their resolution into crossover products, which are required for accurate chromosome segregation during meiosis.

Sequencing analyses of human prefrontal cortex from donors ranging in age from 0.4 to 104 years show that ageing correlates with an accumulation of somatic mutations in short housekeeping genes and a reduction in the expression of these genes.

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.

Zhang, Lahry, Cipurko et al. show that the microbial metabolites queuine and preQ₁ modify the same host tRNA. PreQ₁-tRNA reduces cell proliferation, slows tumour growth, decreases the translation of ribosomal proteins and is cleaved by IRE1 on the ER ribosome.

Using well-calibrated statistical methods the authors jointly analyze Undiagnosed Diseases Network genomes, identifying known and novel disease genes. Software is publicly available to support future cross-cohort rare disease discovery efforts.

The authors report Acheulean hominin occupation of eastern Britain during glacial marine isotope stages 17–16 and again in glacial marine isotope stage 12 via stone tools in sediments dated to 712,000 to 424,000 years ago.

A report from the first 2,000 newborns enrolled in the Early Check program, which offered genome screening covering 198 genes associated with early-onset diseases, shows the feasibility and potential clinical utility of the approach, leading to 28 true positive results.

Free energy calculations are an essential tool to identify targets for individual proteins. Here, authors describe free energy perturbation (FEP+) calculations to optimise on target and off-target potencies for the discovery of potent Wee1 inhibitors with kinome-wide selectivity.

Chronic care manages long-term, progressive conditions, while acute care handles short-term ones. Here, authors show chronic conditions account for most of the global health burden, with 68% of DALYs and 93% of YLDs attributed to chronic care needs.

An understanding of the molecular mechanisms promoting the generation of immunoregulatory and tumour-promoting monocytes and macrophages is key to breaking the cycle of tumour myelopoiesis and developing more effective myeloid-targeting therapies.

The authors study kagome superconductor LaRu3Si2 under pressure up to 40 GPa. They find a superconducting dome as a function of pressure, with Tc reaching its maximum when the coexisting charge order remains long-range.

Perineural invasion and cancer-induced nerve injury of tumour-associated nerves are associated with poor response to anti-PD-1 therapy, which can be reversed by combining anti-PD-1 therapy with anti-inflammatory interventions.

Li et al. discovered that the cytotoxic synthetic small molecule BRD1732 is directly ubiquitinated in cells. Ubiquitination of BRD1732 is E3 ligase dependent and leads to inhibition of proteasomal degradation.

The axial Higgs mode is theoretically attributed to a hidden ferroaxial component of charge order. In rare-earth tritellurides, this ferroaxial order is now shown to be induced by intertwined orbital and charge orders.

By analysing the smartphone data of 2,112,288 participants, in particular observing and comparing the activity of the same individual in two different environments, we find that increases in the walkability of environments result in increases in daily physical activity, providing evidence of the importance of the built environment on physical health.

Many autoimmune and genetic causes of sporadic late-onset cerebellar ataxia (SLOCA) can now be identified, but some individuals remain categorized as having idiopathic SLOCA. Wirth and colleagues discuss advanced genomic techniques that might identify additional ‘missing’ SLOCA causes, potential prognostic biomarkers and progress towards effective treatments.

The unprecedented June 2023 marine heatwave in north-western Europe had a 10% annual likelihood, with climate change accelerating the risk of similar events, according to ensemble climate model simulations.

Climate beliefs do not exist in isolation but form an interconnected network known as a belief system. This study analyses the density and inconsistency of belief systems and their associations with informational and socioeconomic factors to inform effective climate change communication strategies.

Pathology-oriented multiplexing (PathoPlex) represents a framework for widespread access to multiplexed imaging and computational image analysis of clinical specimens at a relatively high throughput and subcellular resolution.

Bacterial Type I polyketide synthases are responsible for producing both lifesaving medicines and virulence factors, yet their stepwise mechanism remains elusive. Here, Burkart et al. characterize acyl carrier protein bound states of mycocerosic acid synthase from Mycobacterium tuberculosis through crosslinking and cryo-EM.

The arts, according to a systematic synthesis of data from 95 studies (across 26 countries), may support non-communicable disease prevention by providing opportunities for increased physical activity, and helping to address social forces that contribute to health inequities.

The authors explore how short tandem repeats in DNA sequences affect risk of Alzheimer’s disease. They find that individuals who carry a high burden of expanded repeats in their DNA have a more than three-fold increased risk for Alzheimer’s disease.

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 chemical-genetic and lipidomics analyses, the clinical candidate oncology drug tegavivint induced an unconventional form of nonapoptotic cell death that required the lipid metabolic enzyme trans-2,3-enoyl-CoA reductase.

An initial draft of the human pangenome is presented and made publicly available by the Human Pangenome Reference Consortium; the draft contains 94 de novo haplotype assemblies from 47 ancestrally diverse individuals.

This study reveals that epithelial cells can reduce their apical surface area via macropinocytosis to relieve tissue crowding, offering a reversible alternative to cell extrusion and highlighting a new mechanism of tissue remodeling under stress.

A high-bandwidth neuromotor interface offers performant out-of-the-box generalization across people.

Nonninger et al. identify the TFEB–TGFβ signaling axis as a regulator of stem cell resilience that protects against a senescence-like state during the adult diapause in Caenorhabditis elegans, a mechanism conserved in vertebrate aging and mammalian cancer.

Here the authors compare the efficacy between sacubitril/valsartan and valsartan in improving diffuse myocardial fibrosis in patients with hypertensive heart disease, assessed as change in interstitial volume with cardiovascular magnetic resonance. The results show potential myocardial benefits of sacubitril/valsartan beyond blood pressure control.

The native anaplastic lymphoma kinase (ALK) oncofetal protein is expressed in neuroblastoma and in multiple pediatric and adult solid tumors. Here, the authors show an ALK-directed antibody-drug conjugate with therapeutic efficacy in ALK-expressing preclinical models.

Genome-wide approaches have uncovered the vast microbial and viral diversity across ecosystems. This Review explores advances in metagenomics, single-cell sequencing and functional profiling to elucidate the evolution, biogeography and ecological dynamics of Earth’s microbiomes.

Wind turbine retirement will result in large end-of-life material flows that must be managed. This Review discusses material reuse and recycling options for composites, steel, rare-earth elements and concrete.

In this study, the authors present antimalarial drug resistance surveillance data from Uganda over the period 2019-2024. They measure ex vivo susceptibility to nine standard antimalarials in 1,114 isolates and characterise sequences of markers of drug susceptibility.

Genome-wide analyses in over one million self-reported cases and controls identify genetic variants associated with stuttering and find genetic correlations with autism, depression and impaired musical rhythm, supporting a potential neurological basis for stuttering.

Endoplasmic reticulum exit sites (ERES) are specialized ER subdomains that regulate the export of secreted cargo. This Roadmap explores how ERES integrate biochemical and mechanical signals to coordinate trafficking and proposes a multidisciplinary strategy to investigate their function, including in disease.

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.

Gangliosides play crucial roles in the nervous system, with aberrant metabolism linked to diseases like cancer and neurodegeneration, but tools to visualize and detect gangliosides remain limited and non-specific. Here, the authors introduce MM-JH-2, a dual fluorescent and Raman-active probe, enabling specific ganglioside labeling and differentiation between cells that differ in ganglioside biosynthetic flux.