Modelling liver disease in vitro requires systems that replicate disease progression1,2. Current tissue-derived organoids do not reproduce the complex cellular composition and tissue architecture observed in vivo3. Here, we describe a multicellular organoid system composed of adult hepatocytes, cholangiocytes and mesenchymal cells that recapitulates the architecture of the liver periportal region and, when manipulated, models aspects of cholestatic injury and biliary fibrosis. We first generate reproducible hepatocyte organoids with a functional bile canaliculi network that retain morphological features of in vivo tissue. By combining these with cholangiocytes and portal fibroblasts, we generate assembloids that mimic the cellular interactions of the periportal region. Assembloids are functional, consistently draining bile from bile canaliculi into the bile duct. Of note, manipulating the relative number of portal mesenchymal cells is sufficient to induce a fibrotic-like state, independently of an immune compartment. By generating chimeric assembloids of mutant and wild-type cells, or after gene knockdown, we show proof of concept that our system is amenable to investigating gene function and cell-autonomous mechanisms. Together, we demonstrate that liver assembloids represent a suitable in vitro system to study bile canaliculi formation, bile drainage and how different cell types contribute to cholestatic disease and biliary fibrosis in an all-in-one model.

Terrestrial planets-Mercury, Venus, Earth and Mars-formed by the accretion of smaller objects. The Earth was probably the latest terrestrial planet to form and reached about 99% of its final mass within about 60-100 Myr after condensation of the first solids in the Solar System. This Review examines the disproportionate role of the last approximately 1% of planetary growth, or late accretion, in controlling the long-term evolution of the Earth and other terrestrial planets. Late accretion may have been responsible for shaping Earth's distinctive geophysical and chemical properties and generating pathways conducive to prebiotic chemistry. Differences in the late accretion of a planet may provide a rationale for interpreting the distinct properties of Venus and Earth (for example, tectonism, atmospheric composition, water content), the surface dichotomy of Mars and the high core-to-silicate mass ratio of Mercury. Large collisions and ensuing processes are likely to occur and modulate the evolution of rocky exoplanets as well, and they should be considered in our quest to find Earth-like worlds.

Since the discovery of resting-state functional connectivity in the human brain, this neuroimaging approach has revolutionized the study of neural architecture. Once considered noise, the functional significance of spontaneous low-frequency fluctuations across large-scale brain networks has now been investigated in more than 25,000 publications. In this Review, we provide a historical overview and thoughts regarding potential future directions for resting-state functional MRI (rsfMRI) research, highlighting the most informative analytic approaches that have been developed to reveal the brain's intrinsic spatiotemporal organization. We review the collaborative efforts that have led to the widespread use of rsfMRI in neuroscience, with an emphasis on methodological innovations that have been made possible by contributions from electrical and biomedical engineering, physics, mathematics and computer science. We focus on key theoretical and methodological advances that will be necessary for further progress in the field, highlighting the need for further integration with new developments in whole-brain computational modelling, more sophisticated approaches to brain-behaviour mapping, greater mechanistic insights from concurrent measurement of neurophysiology, and greater appreciation of the problem of generalization failure in machine learning applications. We propose that rsfMRI has the potential for even greater clinical relevance when it is fully integrated with population neuroscience and global health initiatives in the service of precision psychiatry.