Browse Articles

Psilocybin’s lasting action requires pyramidal cell types and 5-HT2A receptors

Age-related blood condition counteracted with a common diabetes drug

Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis

Abstract Somatic DNMT3A-R882 codon mutations drive the most common form of clonal haematopoiesis (CH) and are associated with increased acute myeloid leukaemia (AML) risk1,2. Preventing expansion of DNMT3A-R882-mutant haematopoietic stem/progenitor cells (HSPCs) may therefore avert progression to AML. To identify DNMT3A-R882-mutant-specific vulnerabilities, we conducted a genome-wide CRISPR screen on primary mouse Dnmt3a R882H/+ HSPCs. Among the 640 vulnerability genes identified, many were involved in mitochondrial metabolism, and metabolic flux analysis confirmed enhanced oxidative phosphorylation use in Dnmt3a R882H/+ versus Dnmt3a +/+ (WT) HSPCs. We selected citrate/malate transporter Slc25a1 and complex I component Ndufb11, for which pharmacological inhibitors are available, for downstream studies. In vivo administration of SLC25A1 inhibitor CTPI2 and complex I inhibitors IACS-010759 and metformin suppressed post-transplantation clonal expansion of Dnmt3a R882H/+, but not WT, long-term haematopoietic stem cells. The effect of metformin was recapitulated using a primary human DNMT3A-R882 CH sample. Notably, analysis of 412,234 UK Biobank participants showed that individuals taking metformin had a markedly lower prevalence of DNMT3A-R882-mutant CH, after controlling for potential confounders including glycated haemoglobin, diabetes and body mass index. Collectively, our data propose modulation of mitochondrial metabolism as a therapeutic strategy for prevention of DNMT3A-R882-mutant AML.

Air pollution modulates trends and variability of the global methane budget

PLA2G15 is a BMP hydrolase and its targeting ameliorates lysosomal disease

Deep Visual Proteomics maps proteotoxicity in a genetic liver disease

Abstract Protein misfolding diseases, including α1-antitrypsin deficiency (AATD), pose substantial health challenges, with their cellular progression still poorly understood1–3. We use spatial proteomics by mass spectrometry and machine learning to map AATD in human liver tissue. Combining Deep Visual Proteomics (DVP) with single-cell analysis4,5, we probe intact patient biopsies to resolve molecular events during hepatocyte stress in pseudotime across fibrosis stages. We achieve proteome depth of up to 4,300 proteins from one-third of a single cell in formalin-fixed, paraffin-embedded tissue. This dataset reveals a potentially clinically actionable peroxisomal upregulation that precedes the canonical unfolded protein response. Our single-cell proteomics data show α1-antitrypsin accumulation is largely cell-intrinsic, with minimal stress propagation between hepatocytes. We integrated proteomic data with artificial intelligence-guided image-based phenotyping across several disease stages, revealing a late-stage hepatocyte phenotype characterized by globular protein aggregates and distinct proteomic signatures, notably including elevated TNFSF10 (also known as TRAIL) amounts. This phenotype may represent a critical disease progression stage. Our study offers new insights into AATD pathogenesis and introduces a powerful methodology for high-resolution, in situ proteomic analysis of complex tissues. This approach holds potential to unravel molecular mechanisms in various protein misfolding disorders, setting a new standard for understanding disease progression at the single-cell level in human tissue.

Lipid-degrading small molecule kills cancer cells by ferroptosis

Author Correction: Larval microbiota primes the Drosophila adult gustatory response

Giant activity-induced elasticity in entangled polymer solutions

Abstract One of the key achievements of equilibrium polymer physics is the prediction of scaling laws governing the viscoelastic properties of entangled polymer systems, validated in both natural polymers, such as DNA, and synthetic polymers, including polyethylene, which form materials like plastics. Recently, focus has shifted to active polymers systems composed of motile units driven far from equilibrium, such as California blackworms, self-propelled biopolymers, and soft robotic grippers. Despite their growing importance, we do not yet understand their viscoelastic properties and universal scaling laws. Here, we use Brownian dynamics simulations to investigate the viscoelastic properties of highly-entangled, flexible self-propelled polymers. Our results demonstrate that activity enhances the elasticity by orders of magnitude due to the emergence of grip forces at entanglement points, leading to its scaling with polymer length ∼ L. Furthermore, activity fluidizes the suspension, with the long-time viscosity scaling as ∼ L 2, compared to ∼ L 3 in passive systems. These insights open new avenues for designing activity-responsive polymeric materials.

c-di-GMP does not bind H-NS, nor inhibits H-NS binding DNA

Efficient cavity-mediated energy transfer between photosynthetic light harvesting complexes from strong to weak coupling regime

Abstract Excitation energy transfer between photosynthetic light-harvesting complexes is vital for highly efficient primary photosynthesis. Controlling this process is the key for advancing the emerging artificial photosynthetic systems. Here, we experimentally demonstrate the enhanced excitation energy transfer between photosynthetic light-harvesting 2 complexes (LH2) mediated through the Fabry-Pérot optical microcavity. Using intensity-dependent pump-probe spectroscopy, we analyse the exciton-exciton annihilation (EEA) due to inter-LH2 energy transfer. Comparing EEA in LH2 within cavity samples and the bare LH2 films, we observe enhanced EEA in cavities indicating improved excitation energy transfer via coupling to a common cavity mode. Surprisingly, the effect remains even in the weak coupling regime. The enhancement is attributed to the additional connectivity between LH2s introduced by the resonant optical microcavity. Our results suggest that optical microcavities can be a strategic tool for modifying excitation energy transfer between molecular complexes, offering a promising approach towards efficient artificial light harvesting.

The phased pan-genome of tetraploid European potato

Abstract Potatoes were first brought to Europe in the sixteenth century1,2. Two hundred years later, one of the species had become one of the most important food sources across the entire continent and, later, even the entire world3. However, its highly heterozygous, autotetraploid genome has complicated its improvement since then4–7. Here we present the pan-genome of European potatoes generated from phased genome assemblies of ten historical potato cultivars, which includes approximately 85% of all haplotypes segregating in Europe. Sequence diversity between the haplotypes was extremely high (for example, 20× higher than in humans), owing to numerous introgressions from wild potato species. By contrast, haplotype diversity was very low, in agreement with the population bottlenecks caused by domestication and transition to Europe. To illustrate a practical application of the pan-genome, we converted it into a haplotype graph and used it to generate phased, megabase-scale pseudo-genome assemblies of commercial potatoes (including the famous French fries potato ‘Russet Burbank’) using cost-efficient short reads only. In summary, we present a nearly complete pan-genome of autotetraploid European potato, we describe extraordinarily high sequence diversity in a domesticated crop, and we outline how this resource might be used to accelerate genomics-assisted breeding and research.

Green energy and steel imports reduce Europe’s net-zero infrastructure needs

Abstract Importing renewable energy to Europe may offer many potential benefits, including reduced energy costs, lower pressure on infrastructure development, and less land use within Europe. However, open questions remain: on the achievable cost reductions, how much should be imported, whether the energy vector should be electricity, hydrogen, or derivatives like ammonia or steel, and their impact on Europe’s infrastructure needs. This study integrates a global energy supply chain model with a European energy system model to explore net-zero emission scenarios with varying import volumes, costs, and vectors. We find system cost reductions of 1-10%, within import cost variations of  ± 20%, with diminishing returns for larger import volumes and a preference for methanol, steel and hydrogen imports. Keeping some domestic power-to-X production is beneficial for integrating variable renewables, leveraging local carbon sources and power-to-X waste heat. Our findings highlight the need for coordinating import strategies with infrastructure policy and reveal maneuvering space for incorporating non-cost decision factors.

A cryptic role for reciprocal helping in a cooperatively breeding bird

Abstract Identifying the mechanisms that underlie cooperation is fundamental to biology1. The most complex form of cooperation in vertebrates occurs in cooperative breeders, in which helpers forego reproduction and assist in raising the young of others, typically relatives2. Not all cooperative societies, however, are kin-based—nearly half of all avian3 and mammalian4 cooperative breeders form mixed-kin societies, much like those of humans5. Kin selection in mixed-kin societies occurs when individuals gain indirect fitness from the preferential helping of relatives6, but helpers also frequently assist non-kin7, highlighting a potential role for direct fitness in stabilizing cooperative societies7,8. Here, using a 20-year study of superb starlings (Lamprotornis superbus), we examined how direct and indirect fitness jointly influence helping behaviour. Although we detected kin-biased helping (demonstrating kin selection), non-kin helping was common despite opportunities to aid kin. Unexpectedly, specific pairs maintained long-term reciprocal helping relationships by swapping social roles across their lifetimes—a subtle pattern of reciprocity requiring decades of observation to detect. Given the frequency of non-kin helping and the occurrence of reciprocal helping among both kin and non-kin, helping behaviour in superb starlings seems to be greatly influenced by direct fitness. However, the relative importance of direct and indirect fitness varied with helpers’ sex and dispersal history. By uncovering a cryptic yet crucial role of long-term reciprocal helping, we suggest that reciprocity may be an underappreciated mechanism promoting the stability of cooperatively breeding societies.

AI-Based screening for thoracic aortic aneurysms in routine breast MRI

Abstract Prognosis for thoracic aortic aneurysms is significantly worse for women than men, with a higher mortality rate observed among female patients. The increasing use of magnetic resonance breast imaging (MRI) offers a unique opportunity for simultaneous detection of both breast cancer and thoracic aortic aneurysms. We retrospectively validate a fully-automated artificial neural network (ANN) pipeline on 5057 breast MRI examinations from public (Duke University Hospital/EA1141 trial) and in-house (Erlangen University Hospital) data. The ANN, benchmarked against 3D-ground-truth segmentations, clinical reports, and a multireader panel, demonstrates high technical robustness (dice/clDice 0.88-0.91/0.97-0.99) across different vendors and field strengths. The ANN improves aneurysm detection rates by 3.5-fold compared with routine clinical readings, highlighting its potential to improve early diagnosis and patient outcomes. Notably, a higher odds ratio (OR = 2.29, CI: [0.55,9.61]) for thoracic aortic aneurysms is observed in women with breast cancer or breast cancer history, suggesting potential further benefits from integrated simultaneous assessment for cancer and aortic aneurysms.

Maximizing meiotic crossover rates reveals the map of Crossover Potential

Abstract Sexual dysmorphism in the number and distribution of meiotic crossovers is seen across species but is poorly understood. Here, we disrupt multiple anti-crossover pathways in hermaphrodite Arabidopsis and analyze thousands of female and male progeny genomes. The greatest crossover increase is seen in zyp1 recq4 mutants, with a 12-fold rise in females and 4.5-fold in males. Additional manipulation of crossover regulators does not further increase crossovers but shifts the balance between crossover pathways, suggesting competition for a shared, limited precursor pool. While wild-type crossover patterns differ between sexes, mutant crossover landscapes converge on a unique distinct profile, which we term Crossover Potential (CO P ). CO P can be accurately predicted using only sequence and chromatin features. We propose that CO P reflects the density of eligible recombination precursors, which is determined by genomic features and is thus identical across sexes, with sexual dimorphism resulting solely from differential regulation of their maturation into crossovers.

Light-microscopy-based connectomic reconstruction of mammalian brain tissue

Abstract The information-processing capability of the brain’s cellular network depends on the physical wiring pattern between neurons and their molecular and functional characteristics. Mapping neurons and resolving their individual synaptic connections can be achieved by volumetric imaging at nanoscale resolution 1,2 with dense cellular labelling. Light microscopy is uniquely positioned to visualize specific molecules, but dense, synapse-level circuit reconstruction by light microscopy has been out of reach, owing to limitations in resolution, contrast and volumetric imaging capability. Here we describe light-microscopy-based connectomics (LICONN). We integrated specifically engineered hydrogel embedding and expansion with comprehensive deep-learning-based segmentation and analysis of connectivity, thereby directly incorporating molecular information into synapse-level reconstructions of brain tissue. LICONN will allow synapse-level phenotyping of brain tissue in biological experiments in a readily adoptable manner.

Author Correction: Immune phenotyping of diverse syngeneic murine brain tumors identifies immunologically distinct types

Global dominance of seasonality in shaping lake-surface-extent dynamics

Laboratory mice engrafted with natural gut microbiota possess a wildling-like phenotype

Abstract Conventional laboratory mice housed under specific pathogen-free (SPF) conditions are the standard model in biomedical research. However, in recent years, many rodent-based studies have been deemed irreproducible, raising questions about the suitability of mice as model organisms. Emerging evidence indicates that variability in SPF microbiota plays a significant role in data inconsistencies across laboratories. Although efforts have been made to standardize microbiota, existing microbial consortia lack the complexity and resilience necessary to replicate interactions in free-living mammals. We present a robust, feasible and standardizable approach for transplanting natural gut microbiota from wildlings into laboratory mice. Following engraftment, these TXwildlings adopt a structural and functional wildling-like microbiota and host physiology toward a more mature immune system, with characteristics similar to those of adult humans. We anticipate that adopting wild mouse-derived microbiota as standard for laboratory mouse models will improve the reproducibility and generalizability of basic and preclinical biomedical research.