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The primary motor cortex (M1) is essential for voluntary fine-motor control and is functionally conserved across mammals1. Here, using high-throughput transcriptomic and epigenomic profiling of more than 450,000 single nuclei in humans, marmoset monkeys and mice, we demonstrate a broadly conserved cellular makeup of this region, with similarities that mirror evolutionary distance and are consistent between the transcriptome and epigenome. The core conserved molecular identities of neuronal and non-neuronal cell types allow us to generate a cross-species consensus classification of cell types, and to infer conserved properties of cell types across species. Despite the overall conservation, however, many species-dependent specializations are apparent, including differences in cell-type proportions, gene expression, DNA methylation and chromatin state. Few cell-type marker genes are conserved across species, revealing a short list of candidate genes and regulatory mechanisms that are responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells. This consensus transcriptomic classification allows us to use patch-seq (a combination of whole-cell patch-clamp recordings, RNA sequencing and morphological characterization) to identify corticospinal Betz cells from layer 5 in non-human primates and humans, and to characterize their highly specialized physiology and anatomy. These findings highlight the robust molecular underpinnings of cell-type diversity in M1 across mammals, and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations.

Elucidating the cellular architecture of the human cerebral cortex is central to understanding our cognitive abilities and susceptibility to disease. Here we used single-nucleus RNA-sequencing analysis to perform a comprehensive study of cell types in the middle temporal gyrus of human cortex. We identified a highly diverse set of excitatory and inhibitory neuron types that are mostly sparse, with excitatory types being less layer-restricted than expected. Comparison to similar mouse cortex single-cell RNA-sequencing datasets revealed a surprisingly well-conserved cellular architecture that enables matching of homologous types and predictions of properties of human cell types. Despite this general conservation, we also found extensive differences between homologous human and mouse cell types, including marked alterations in proportions, laminar distributions, gene expression and morphology. These species-specific features emphasize the importance of directly studying human brain.

The vascular barrier that separates blood from tissues is actively regulated by the endothelium and is essential for transport, inflammation, and haemostasis. Haemodynamic shear stress plays a critical role in maintaining endothelial barrier function, but how this occurs remains unknown. Here we use an engineered organotypic model of perfused microvessels to show that activation of the transmembrane receptor NOTCH1 directly regulates vascular barrier function through a non-canonical, transcription-independent signalling mechanism that drives assembly of adherens junctions, and confirm these findings in mouse models. Shear stress triggers DLL4-dependent proteolytic activation of NOTCH1 to expose the transmembrane domain of NOTCH1. This domain mediates establishment of the endothelial barrier; expression of the transmembrane domain of NOTCH1 is sufficient to rescue defects in barrier function induced by knockout of NOTCH1. The transmembrane domain restores barrier function by catalysing the formation of a receptor complex in the plasma membrane consisting of vascular endothelial cadherin, the transmembrane protein tyrosine phosphatase LAR, and the RAC1 guanidine-exchange factor TRIO. This complex activates RAC1 to drive assembly of adherens junctions and establish barrier function. Canonical transcriptional signalling via Notch is highly conserved in metazoans and is required for many processes in vascular development, including arterial-venous differentiation, angiogenesis and remodelling. We establish the existence of a non-canonical cortical NOTCH1 signalling pathway that regulates vascular barrier function, and thus provide a mechanism by which a single receptor might link transcriptional programs with adhesive and cytoskeletal remodelling.

Single-cell sequencing methods have enabled in-depth analysis of the diversity of cell types and cell states in a wide range of organisms. These tools focus predominantly on sequencing the genomes.sup.1, epigenomes.sup.2 and transcriptomes.sup.3 of single cells. However, despite recent progress in detecting proteins by mass spectrometry with single-cell resolution.sup.4, it remains a major challenge to measure translation in individual cells. Here, building on existing protocols.sup.5-7, we have substantially increased the sensitivity of these assays to enable ribosome profiling in single cells. Integrated with a machine learning approach, this technology achieves single-codon resolution. We validate this method by demonstrating that limitation for a particular amino acid causes ribosome pausing at a subset of the codons encoding the amino acid. Of note, this pausing is only observed in a sub-population of cells correlating to its cell cycle state. We further expand on this phenomenon in non-limiting conditions and detect pronounced GAA pausing during mitosis. Finally, we demonstrate the applicability of this technique to rare primary enteroendocrine cells. This technology provides a first step towards determining the contribution of the translational process to the remarkable diversity between seemingly identical cells. Highly sensitive ribosome profiling of single cells at single-codon resolution enables identification of distinct cell cycle-dependent translational dynamic states in individual cells., Author(s): Michael VanInsberghe [sup.1] , Jeroen van den Berg [sup.1] , Amanda Andersson-Rolf [sup.1] , Hans Clevers [sup.1] , Alexander van Oudenaarden [sup.1] Author Affiliations: (1) Oncode Institute, Hubrecht Institute-KNAW [...]

The formation and preservation of cratons--the oldest parts of the continents, comprising over 60 per cent of the continental landmass--remains an enduring problem. Key to craton development is how and when the thick strong mantle roots that underlie these regions formed and evolved. Peridotite melting residues forming cratonic lithospheric roots mostly originated via relatively low-pressure melting and were subsequently transported to greater depth by thickening produced by lateral accretion and compression. The longest-lived cratons were assembled during Mesoarchean and Palaeoproterozoic times, creating the stable mantle roots 150 to 250 kilometres thick that are critical to preserving Earth's early continents and central to defining the cratons, although we extend the definition of cratons to include extensive regions of long-stable Mesoproterozoic crust also underpinned by thick lithospheric roots. The production of widespread thick and strong lithosphere via the process of orogenic thickening, possibly in several cycles, was fundamental to the eventual emergence of extensive continental landmasses--the cratons. Cratons are the oldest parts of the Earth's continents; this Review concludes that the production of widespread, thick and strong lithosphere via the process of orogenic thickening was fundamental to the eventual emergence of extensive continental landmasses., Author(s): D. Graham Pearson [sup.1] , James M. Scott [sup.2] , Jingao Liu [sup.3] , Andrew Schaeffer [sup.4] , Lawrence Hongliang Wang [sup.5] , Jeroen van Hunen [sup.6] , Kristoffer [...]

The most promising quantum algorithms require quantum processors that host millions of quantum bits when targeting practical applications.sup.1. A key challenge towards large-scale quantum computation is the interconnect complexity. In current solid-state qubit implementations, an important interconnect bottleneck appears between the quantum chip in a dilution refrigerator and the room-temperature electronics. Advanced lithography supports the fabrication of both control electronics and qubits in silicon using technology compatible with complementary metal oxide semiconductors (CMOS).sup.2. When the electronics are designed to operate at cryogenic temperatures, they can ultimately be integrated with the qubits on the same die or package, overcoming the 'wiring bottleneck'.sup.3-6. Here we report a cryogenic CMOS control chip operating at 3 kelvin, which outputs tailored microwave bursts to drive silicon quantum bits cooled to 20 millikelvin. We first benchmark the control chip and find an electrical performance consistent with qubit operations of 99.99 per cent fidelity, assuming ideal qubits. Next, we use it to coherently control actual qubits encoded in the spin of single electrons confined in silicon quantum dots.sup.7-9 and find that the cryogenic control chip achieves the same fidelity as commercial instruments at room temperature. Furthermore, we demonstrate the capabilities of the control chip by programming a number of benchmarking protocols, as well as the Deutsch-Josza algorithm.sup.10, on a two-qubit quantum processor. These results open up the way towards a fully integrated, scalable silicon-based quantum computer. A cryogenic CMOS control chip operating at 3 K is used to demonstrate coherent control and simple algorithms on silicon qubits operating at 20 mK., Author(s): Xiao Xue [sup.1] [sup.2] , Bishnu Patra [sup.1] [sup.2] [sup.3] , Jeroen P. G. van Dijk [sup.1] [sup.2] [sup.3] , Nodar Samkharadze [sup.1] [sup.4] , Sushil Subramanian [sup.5] , [...]

A broad range of brain pathologies critically relies on the vasculature, and cerebrovascular disease is a leading cause of death worldwide. However, the cellular and molecular architecture of the human brain vasculature remains incompletely understood1. Here we performed single-cell RNA sequencing analysis of 606,380 freshly isolated endothelial cells, perivascular cells and other tissue-derived cells from 117 samples, from 68 human fetuses and adult patients to construct a molecular atlas of the developing fetal, adult control and diseased human brain vasculature. We identify extensive molecular heterogeneity of the vasculature of healthy fetal and adult human brains and across five vascular-dependent central nervous system (CNS) pathologies, including brain tumours and brain vascular malformations. We identify alteration of arteriovenous differentiation and reactivated fetal as well as conserved dysregulated genes and pathways in the diseased vasculature. Pathological endothelial cells display a loss of CNS-specific properties and reveal an upregulation of MHC class II molecules, indicating atypical features of CNS endothelial cells. Cell–cell interaction analyses predict substantial endothelial-to-perivascular cell ligand–receptor cross-talk, including immune-related and angiogenic pathways, thereby revealing a central role for the endothelium within brain neurovascular unit signalling networks. Our single-cell brain atlas provides insights into the molecular architecture and heterogeneity of the developing, adult/control and diseased human brain vasculature and serves as a powerful reference for future studies.Endothelial cells from vascular-dependent central nervous system (CNS) diseases reveal reactivated fetal pathways, display common hallmarks of disease — including a partial loss of arteriovenous specification and CNS-specific properties as well as an upregulation of MHC class II receptors — and play a key role in the human brain neurovascular unit across development, adulthood and disease. [ABSTRACT FROM AUTHOR]

A defining pathological feature of most neurodegenerative diseases is the assembly of proteins into amyloid that form disease-specific structures1. In Alzheimer’s disease, this is characterized by the deposition of β-amyloid and tau with disease-specific conformations. The in situ structure of amyloid in the human brain is unknown. Here, using cryo-fluorescence microscopy-targeted cryo-sectioning, cryo-focused ion beam-scanning electron microscopy lift-out and cryo-electron tomography, we determined in-tissue architectures of β-amyloid and tau pathology in a postmortem Alzheimer’s disease donor brain. β-amyloid plaques contained a mixture of fibrils, some of which were branched, and protofilaments, arranged in parallel arrays and lattice-like structures. Extracellular vesicles and cuboidal particles defined the non-amyloid constituents of β-amyloid plaques. By contrast, tau inclusions formed parallel clusters of unbranched filaments. Subtomogram averaging a cluster of 136 tau filaments in a single tomogram revealed the polypeptide backbone conformation and filament polarity orientation of paired helical filaments within tissue. Filaments within most clusters were similar to each other, but were different between clusters, showing amyloid heterogeneity that is spatially organized by subcellular location. The in situ structural approaches outlined here for human donor tissues have applications to a broad range of neurodegenerative diseases.The in-tissue architectures of β-amyloid and tau pathology in a postmortem Alzheimer’s disease donor brain are determined, showing fibril heterogeneity is spatially organized by subcellular location and suggesting applications to a broad range of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

The biological carbon pump is the process by which CO2 is transformed to organic carbon via photosynthesis, exported through sinking particles, and finally sequestered in the deep ocean. While the intensity of the pump correlates with plankton community composition, the underlying ecosystem structure driving the process remains largely uncharacterized. Here we use environmental and metagenomic data gathered during the Tara Oceans expedition to improve our understanding of carbon export in the oligotrophic ocean. We show that specific plankton communities, from the surface and deep chlorophyll maximum, correlate with carbon export at 150 m and highlight unexpected taxa such as Radiolaria and alveolate parasites, as well as Synechococcus and their phages, as lineages most strongly associated with carbon export in the subtropical, nutrient-depleted, oligotrophic ocean. Additionally, we show that the relative abundance of a few bacterial and viral genes can predict a significant fraction of the variability in carbon export in these regions.

Classification is an important task at which both biological and artificial neural networks excel.sup.1,2. In machine learning, nonlinear projection into a high-dimensional feature space can make data linearly separable.sup.3,4, simplifying the classification of complex features. Such nonlinear projections are computationally expensive in conventional computers. A promising approach is to exploit physical materials systems that perform this nonlinear projection intrinsically, because of their high computational density.sup.5, inherent parallelism and energy efficiency.sup.6,7. However, existing approaches either rely on the systems' time dynamics, which requires sequential data processing and therefore hinders parallel computation.sup.5,6,8, or employ large materials systems that are difficult to scale up.sup.7. Here we use a parallel, nanoscale approach inspired by filters in the brain.sup.1 and artificial neural networks.sup.2 to perform nonlinear classification and feature extraction. We exploit the nonlinearity of hopping conduction.sup.9-11 through an electrically tunable network of boron dopant atoms in silicon, reconfiguring the network through artificial evolution to realize different computational functions. We first solve the canonical two-input binary classification problem, realizing all Boolean logic gates.sup.12 up to room temperature, demonstrating nonlinear classification with the nanomaterial system. We then evolve our dopant network to realize feature filters.sup.2 that can perform four-input binary classification on the Modified National Institute of Standards and Technology handwritten digit database. Implementation of our material-based filters substantially improves the classification accuracy over that of a linear classifier directly applied to the original data.sup.13. Our results establish a paradigm of silicon-based electronics for small-footprint and energy-efficient computation.sup.14. The nonlinearity of hopping conduction in a disordered network of boron dopant atoms in silicon is used to perform nonlinear classification and feature extraction., Author(s): Tao Chen [sup.1] , Jeroen van Gelder [sup.1] , Bram van de Ven [sup.1] , Sergey V. Amitonov [sup.1] , Bram de Wilde [sup.1] , Hans-Christian Ruiz Euler [sup.1] [...]

The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.

WASP-107b is a warm (approximately 740 K) transiting planet with a Neptune-like mass of roughly 30.5 M⊕ and Jupiter-like radius of about 0.94 RJ (refs. 1,2), whose extended atmosphere is eroding3. Previous observations showed evidence for water vapour and a thick, high-altitude condensate layer in the atmosphere of WASP-107b (refs. 4,5). Recently, photochemically produced sulfur dioxide (SO2) was detected in the atmosphere of a hot (about 1,200 K) Saturn-mass planet from transmission spectroscopy near 4.05 μm (refs. 6,7), but for temperatures below about 1,000 K, sulfur is predicted to preferably form sulfur allotropes instead of SO2 (refs. 8–10). Here we report the 9σ detection of two fundamental vibration bands of SO2, at 7.35 μm and 8.69 μm, in the transmission spectrum of WASP-107b using the Mid-Infrared Instrument (MIRI) of JWST. This discovery establishes WASP-107b as the second irradiated exoplanet with confirmed photochemistry, extending the temperature range of exoplanets exhibiting detected photochemistry from about 1,200 K down to about 740 K. Furthermore, our spectral analysis reveals the presence of silicate clouds, which are strongly favoured (around 7σ) over simpler cloud set-ups. Furthermore, water is detected (around 12σ) but methane is not. These findings provide evidence of disequilibrium chemistry and indicate a dynamically active atmosphere with a super-solar metallicity.The JWST MIRI transmission spectrum of WASP-107b, a transiting planet with Neptune-like mass and Jupiter-like radius, shows observations of sulfur dioxide and silicate clouds but no methane in its atmosphere, providing evidence of disequilibrium chemistry and active photochemistry. [ABSTRACT FROM AUTHOR]

Earths body tidealso known as the solid Earth tide, the displacement of the solid Earths surface caused by gravitational forces from the Moon and the Sunis sensitive to the density of the two Large Low Shear Velocity Provinces (LLSVPs) beneath Africa and the Pacific. These massive regions extend approximately 1,000 kilometres upward from the base of the mantle and their buoyancy remains actively debated within the geophysical community. Here we use tidal tomography to constrain Earths deep-mantle buoyancy derived from Global Positioning System (GPS)-based measurements of semi-diurnal body tide deformation. Using a probabilistic approach, we show that across the bottom two-thirds of the two LLSVPs the mean density is about 0.5 per cent higher than the average mantle density across this depth range (that is, its mean buoyancy is minus 0.5 per cent), although this anomaly may be concentrated towards the very base of the mantle. We conclude that the buoyancy of these structures is dominated by the enrichment of high-density chemical components, probably related to subducted oceanic plates or primordial material associated with Earths formation. Because the dynamics of the mantle is driven by density variations, our result has important dynamical implications for the stability of the LLSVPs and the long-term evolution of the Earth system., Author(s): Harriet C. P. Lau (corresponding author) [1]; Jerry X. Mitrovica [1]; James L. Davis [2]; Jeroen Tromp [3]; Hsin-Ying Yang [4, 5]; David Al-Attar [6] Earths elastic structure and [...]

Author(s): Daniel Obrist (corresponding author) [1, 2]; Yannick Agnan [2, 3]; Martin Jiskra [4]; Christine L. Olson [2]; Dominique P. Colegrove [5]; Jacques Hueber [5]; Christopher W. Moore [2, 6]; [...]

Author(s): Waiz Karim [1, 2, 3]; Clelia Spreafico [4]; Armin Kleibert [5]; Jens Gobrecht [2]; Joost VandeVondele [4]; Yasin Ekinci (corresponding author) [2]; Jeroen A. van Bokhoven (corresponding author) [1, [...]

Insulin resistance is a forerunner state of ischaemic cardiovascular disease and type 2 diabetes. Here we show how the human gut microbiome impacts the serum metabolome and associates with insulin resistance in 277 non-diabetic Danish individuals. The serum metabolome of insulin-resistant individuals is characterized by increased levels of branched- chain amino acids (BCAAs), which correlate with a gut microbiome that has an enriched biosynthetic potential for BCAAs and is deprived of genes encoding bacterial inward transporters for these amino acids. Prevotella copri and Bacteroides vulgatus are identified as the main species driving the association between biosynthesis of BCAAs and insulin resistance, and in mice we demonstrate that P. copri can induce insulin resistance, aggravate glucose intolerance and augment circulating levels of BCAAs. Our findings suggest that microbial targets may have the potential to diminish insulin resistance and reduce the incidence of common metabolic and cardiovascular disorders., Insulin resistance (IR) and metabolic syndrome are risk factors for both type 2 diabetes and ischaemic cardiovascular diseases, pathologies that are in epidemic growth worldwide. Mounting evidence suggests a link [...]

Mammalian Wnt proteins are believed to act as short-range signals (1-4), yet have not been previously visualized in vivo. Self-renewal, proliferation and differentiation are coordinated along a putative Wnt gradient in the intestinal crypt (5). Wnt3 is produced specifically by Paneth cells (6,7). Here we have generated an epitopetagged, functional Wnt3 knock-in allele. Wnt3 covers basolateral membranes of neighbouring stem cells. In intestinal organoids, Wnt3-transfer involves direct contact between Paneth cells and stem cells. Plasma membrane localization requires surface expression of Frizzled receptors, which in turn is regulated by the transmembrane E3 ligases Rnf43/Znrf3 and their antagonists Lgr4-5/R-spondin. By manipulating Wnt3 secretion and by arresting stem-cell proliferation, we demonstrate that Wnt3 mainly travels away from its source in a cell-bound manner through cell division, and not through diffusion. We conclude that stem-cell membranes constitute a reservoir for Wnt proteins, while Frizzled receptor turnover and 'plasma membrane dilution' through cell division shape the epithelial Wnt3 gradient., Distinct mechanisms have been proposed as to how gradients of secreted Wnt protein control growth and patterning during animal development. Evidence exists for highly localized activity between adjacent cells (1-3), [...]

In recent years, several associations between common chronic human disorders and altered gut microbiome composition and function have been reported (1, 2). In most of these reports, treatment regimens were not controlled for and conclusions could thus be confounded by the effects of various drugs on the microbiota, which may obscure microbial causes, protective factors or diagnostically relevant signals. Our study addresses disease and drug signatures in the human gut microbiome of type 2 diabetes mellitus (T2D). Two previous quantitative gut metagenomics studies of T2D patients that were unstratified for treatment yielded divergent conclusions regarding its associated gut microbial dysbiosis (3, 4). Here we show, using 784 available human gut metagenomes, how antidiabetic medication confounds these results, and analyse in detail the effects of the most widely used antidiabetic drug metformin. We provide support for microbial mediation of the therapeutic effects of metformin through short-chain fatty acid production, as well as for potential microbiota-mediated mechanisms behind known intestinal adverse effects in the form of a relative increase in abundance of Escherichia species. Controlling for metformin treatment, we report a unified signature of gut microbiome shifts in T2D with a depletion of butyrate-producing taxa (3, 4). These in turn cause functional microbiome shifts, in part alleviated by metformin-induced changes. Overall, the present study emphasizes the need to disentangle gut microbiota signatures of specific human diseases from those of medication., T2D is a disorder of elevated blood glucose levels (hyperglycaemia) primarily due to insulin resistance and inadequate insulin secretion, with rising global prevalence. Genetic and environmental risk factors are known, [...]

In response to DNA damage, tissue homoeostasis is ensured by protein networks promoting DNA repair, cell cycle arrest or apoptosis. DNA damage response signalling pathways coordinate these processes, partly by propagating gene-expression-modulating signals. DNA damage influences not only the abundance of messenger RNAs, but also their coding information through alternative splicing. Here we show that transcription-blocking DNA lesions promote chromatin displacement of late-stage spliceosomes and initiate a positive feedback loop centred on the signalling kinase ATM. We propose that initial spliceosome displacement and subsequent R-loop formation is triggered by pausing of RNA polymerase at DNA lesions. In turn, R-loops activate ATM, which signals to impede spliceosome organization further and augment ultraviolet-irradiation-triggered alternative splicing at the genome-wide level. Our findings define R-loop-dependent ATM activation by transcription-blocking lesions as an important event in the DNA damage response of non-replicating cells, and highlight a key role for spliceosome displacement in this process., The DNA damage response (DDR), an intricate protein network that promotes DNA repair, translesion synthesis, cell cycle arrest or apoptosis, has evolved to counteract the detrimental effects of DNA lesions [...]

Crypt stem cells represent the cells of origin for intestinal neoplasia. Both mouse and human intestinal stem cells can be cultured in medium containing the stem-cell-niche factors WNT, R-spondin, epidermal growth factor (EGF) and noggin over long time periods as epithelial organoids that remain genetically and phenotypically stable. Here we utilize CRISPR/Cas9 technology for targeted gene modification of four of the most commonly mutated colorectal cancer genes (APC, P53 (also known as TP53), KRAS and SMAD4) in cultured human intestinal stem cells. Mutant organoids can be selected by removing individual growth factors from the culture medium. Quadruple mutants grow independently of all stem-cell-niche factors and tolerate the presence of the P53 stabilizer nutlin-3. Upon xenotransplantation into mice, quadruple mutants grow as tumours with features of invasive carcinoma. Finally, combined loss of APC and P53 is sufficient for the appearance of extensive aneuploidy, a hallmark of tumour progression., The adenoma-carcinoma sequence proposes that the sequential acquisition of specific genetic alterations underlies the progression of colorectal cancer (CRC) (1). Activation of the WNT pathway, most commonly through inactivating mutations [...]

Myelin is required for the function of neuronal axons in the central nervous system, but the mechanisms that support myelin health are unclear. Although macrophages in the central nervous system have been implicated in myelin health1, it is unknown which macrophage populations are involved and which aspects they influence. Here we show that resident microglia are crucial for the maintenance of myelin health in adulthood in both mice and humans. We demonstrate that microglia are dispensable for developmental myelin ensheathment. However, they are required for subsequent regulation of myelin growth and associated cognitive function, and for preservation of myelin integrity by preventing its degeneration. We show that loss of myelin health due to the absence of microglia is associated with the appearance of a myelinating oligodendrocyte state with altered lipid metabolism. Moreover, this mechanism is regulated through disruption of the TGFβ1–TGFβR1 axis. Our findings highlight microglia as promising therapeutic targets for conditions in which myelin growth and integrity are dysregulated, such as in ageing and neurodegenerative disease2,3.Resident microglia in the central nervous system are identified as the specific macrophage population that regulates myelin growth and integrity. [ABSTRACT FROM AUTHOR]

The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. It is currently believed that four to six crypt stem cells reside at the +4 position immediately above [...]