Browse Articles

Uncovering the prevalence, key biogenesis enzymes, and biological significance of archaeal lipoproteins

Robotic system takes chemistry into hyperspace

Targeting prostaglandin E2 receptor 2 in Schwann cells inhibits inflammatory pain but not inflammation

The great university shake-up: four charts show how global higher education is changing

FUSION: a web-based application for in-depth exploration of multi-omics data with brightfield histology

Molecular basis of ParA ATPase activation by the CTPase ParB during bacterial chromosome segregation

Abstract DNA segregation by bacterial ParABS systems is mediated by transient tethering interactions between nucleoid-bound dimers of the ATPase ParA and centromere (parS)-associated complexes of the clamp-forming CTPase ParB. The lifetime of these interactions is limited by the ParB-dependent activation of ParA ATPase activity. Here, we elucidate the functional interplay between ParA and ParB in the model bacterium Myxococcus xanthus. We demonstrate that the N-terminal ParA-binding motif of ParB associates with a conserved bipartite binding pocket at the ParA dimer interface, in a manner dependent on ParB clamp closure. Moreover, we show that ParB and non-specific DNA interact cooperatively with ParA and synergistically induce structural changes in its Walker A and Walker B motifs that correlate with the activation of ParA ATPase activity. These results advance our understanding of the mechanism underlying DNA transport by the ParABS system and may help to unravel the mode of action of related cargo-positioning systems.

Artery formation in the intestinal wall and mesentery by intestine-derived Esm1+ endothelial cells

Abstract Arterial blood transport into peripheral organs is indispensable for developmental growth, homeostasis and tissue repair. While it is appreciated that defective formation or compromised function of arteries is associated with a range of human diseases, the cellular and molecular mechanisms mediating arterial development remain little understood for most organs. Here, we show with genetic approaches that a small subpopulation of endothelial cells inside the intestinal villi of the embryonic mouse, characterized by the expression of endothelial cell-specific molecule 1 (Esm1/endocan), gives rise to arterial endothelium in the intestinal wall but also in the distant mesenteric vasculature. This involves cell migration but also substantial changes in morphology and gene expression. Immunohistochemistry and single cell RNA-sequencing confirm that intestinal Esm1 + cells have a distinct molecular profile and the capacity to undergo arterial differentiation. Genetic approaches establish that artery formation by the progeny of Esm1 + cells requires integrin β1 and signaling by the growth factor VEGF-C and its receptor VEGFR3. The sum of these findings demonstrates that Esm1 + cells inside the villus capillary network contribute to the formation of intestinal and mesenteric arteries during development.

Advancing sustainable agricultural transformation through the synergy of automated experimental platforms and living labs

Fragmentation and multithreading of experience in the default-mode network

Abstract Reliance on internal predictive models of the world is central to many theories of human cognition. Yet it is unknown whether humans acquire multiple separate internal models, each evolved for a specific domain, or maintain a globally unified representation. Using fMRI during naturalistic experiences (movie watching and narrative listening), we show that three topographically distinct midline prefrontal cortical regions perform distinct predictive operations. The ventromedial PFC updates contextual predictions (States), the anteromedial PFC governs reference frame shifts for social predictions (Agents), and the dorsomedial PFC predicts transitions across the abstract state spaces (Actions). Prediction-error-driven neural transitions in these regions, indicative of model updates, coincided with subjective belief changes in a domain-specific manner. We find these parallel top-down predictions are unified and selectively integrated with visual sensory streams in the Precuneus, shaping participants’ ongoing experience. Results generalized across sensory modalities and content, suggesting humans recruit abstract, modular predictive models for both vision and language. Our results highlight a key feature of human world modeling: fragmenting information into abstract domains before global integration.

Amplified local cooling effect of forestation in warming Europe

The Biodiversity Cell Atlas: mapping the tree of life at cellular resolution

Autonomous artificial intelligence prescribing a drug to prevent severe acute graft-versus-host disease in HLA-haploidentical transplants

Exercise improves survival of some people with colon cancer, clinical trial shows

Observed regimes of submesoscale dynamics in the Southern Ocean seasonal ice zone

The geoeconomic turn in decarbonization

The shutdown of food digestion due to endoplasmic reticulum homeostasis disruption acts as a protective mechanism in C. elegans

Fighting climate change takes more than data — it needs wonder, love and hope

When AI rejects your grant proposal: algorithms are helping to make funding decisions

Prevalence of loss-of-function, gain-of-function and dominant-negative mechanisms across genetic disease phenotypes

Abstract Molecular disease mechanisms caused by mutations in protein-coding regions are diverse, but they can be broadly categorised into loss-of-function, gain-of-function and dominant-negative effects. Accurately predicting these mechanisms is important, since therapeutic strategies can exploit these mechanisms. Computational predictors tend to perform less well at the identification of pathogenic gain-of-function and dominant-negative variants. Here, we develop a protein structure-based missense loss-of-function likelihood score that can separate recessive loss of function and dominant loss of function from alternative disease mechanisms. Using missense loss-of-function scores, we estimate the prevalence of molecular mechanisms across 2,837 phenotypes in 1,979 Mendelian disease genes, finding that dominant-negative and gain-of-function mechanisms account for 48% of phenotypes in dominant genes. Applying missense loss-of-function scores to genes with multiple phenotypes reveals widespread intragenic mechanistic heterogeneity, with 43% of dominant and 49% of mixed-inheritance genes harbouring both loss-of-function and non-loss-of-function mechanisms. Furthermore, we show that combining missense loss-of-function scores with phenotype semantic similarity enables the prioritisation of dominant-negative mechanisms in mixed-inheritance genes. Our structure-based approach, accessible via a Google Colab notebook, offers a scalable tool for predicting disease mechanisms and advancing personalised medicine.

How universities came to be — and why they are in trouble now