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Animal studies show aging varies between individuals as well as between organs within an individual1-4, but whether this is true in humans and its effect on age-related diseases is unknown. We utilized levels of human blood plasma proteins originating from specific organs to measure organ-specific aging differences in living individuals. Using machine learning models, we analysed aging in 11 major organs and estimated organ age reproducibly in five independent cohorts encompassing 5,676 adults across the human lifespan. We discovered nearly 20% of the population show strongly accelerated age in one organ and 1.7% are multi-organ agers. Accelerated organ aging confers 20-50% higher mortality risk, and organ-specific diseases relate to faster aging of those organs. We find individuals with accelerated heart aging have a 250% increased heart failure risk and accelerated brain and vascular aging predict Alzheimers disease (AD) progression independently from and as strongly as plasma pTau-181 (ref. 5), the current best blood-based biomarker for AD. Our models link vascular calcification, extracellular matrix alterations and synaptic protein shedding to early cognitive decline. We introduce a simple and interpretable method to study organ aging using plasma proteomics data, predicting diseases and aging effects.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

The persistence of undetectable disseminated tumour cells (DTCs) after primary tumour resection poses a major challenge to effective cancer treatment.sup.1-3. These enduring dormant DTCs are seeds of future metastases, and the mechanisms that switch them from dormancy to outgrowth require definition. Because cancer dormancy provides a unique therapeutic window for preventing metastatic disease, a comprehensive understanding of the distribution, composition and dynamics of reservoirs of dormant DTCs is imperative. Here we show that different tissue-specific microenvironments restrain or allow the progression of breast cancer in the liver--a frequent site of metastasis.sup.4 that is often associated with a poor prognosis.sup.5. Using mouse models, we show that there is a selective increase in natural killer (NK) cells in the dormant milieu. Adjuvant interleukin-15-based immunotherapy ensures an abundant pool of NK cells that sustains dormancy through interferon-[gamma] signalling, thereby preventing hepatic metastases and prolonging survival. Exit from dormancy follows a marked contraction of the NK cell compartment and the concurrent accumulation of activated hepatic stellate cells (aHSCs). Our proteomics studies on liver co-cultures implicate the aHSC-secreted chemokine CXCL12 in the induction of NK cell quiescence through its cognate receptor CXCR4. CXCL12 expression and aHSC abundance are closely correlated in patients with liver metastases. Our data identify the interplay between NK cells and aHSCs as a master switch of cancer dormancy, and suggest that therapies aimed at normalizing the NK cell pool might succeed in preventing metastatic outgrowth. Liver-resident natural killer (NK) cells sustain the dormancy of disseminated breast cancer cells, and a decrease in NK cells and increase in activated hepatic stellate cells is associated with the formation of liver metastases., Author(s): Ana Luísa Correia [sup.1] [sup.2] [sup.3] , Joao C. Guimaraes [sup.4] [sup.11] , Priska Auf der Maur [sup.1] [sup.3] , Duvini De Silva [sup.1] [sup.2] [sup.11] , Marcel P. [...]

A large scholarship currently holds that before the onset of anthropogenic global warming, natural climatic changes long provoked subsistence crises and, occasionally, civilizational collapses among human societies. This scholarship, which we term the 'history of climate and society' (HCS), is pursued by researchers from a wide range of disciplines, including archaeologists, economists, geneticists, geographers, historians, linguists and palaeoclimatologists. We argue that, despite the wide interest in HCS, the field suffers from numerous biases, and often does not account for the local effects and spatiotemporal heterogeneity of past climate changes or the challenges of interpreting historical sources. Here we propose an interdisciplinary framework for uncovering climate-society interactions that emphasizes the mechanics by which climate change has influenced human history, and the uncertainties inherent in discerning that influence across different spatiotemporal scales. Although we acknowledge that climate change has sometimes had destructive effects on past societies, the application of our framework to numerous case studies uncovers five pathways by which populations survived--and often thrived--in the face of climatic pressures. This Review proposes an interdisciplinary framework for researching climate-society interactions that focuses on the mechanisms through which climate change has influenced societies, and the uncertainties of discerning this influence across different spatiotemporal scales., Author(s): Dagomar Degroot [sup.1] , Kevin Anchukaitis [sup.2] [sup.3] , Martin Bauch [sup.4] , Jakob Burnham [sup.1] , Fred Carnegy [sup.5] , Jianxin Cui [sup.6] , Kathryn de Luna [sup.1] [...]

Shear stress on arteries produced by blood flow is important for vascular development and homeostasis but can also initiate atherosclerosis.sup.1. Endothelial cells that line the vasculature use molecular mechanosensors to directly detect shear stress profiles that will ultimately lead to atheroprotective or atherogenic responses.sup.2. Plexins are key cell-surface receptors of the semaphorin family of cell-guidance signalling proteins and can regulate cellular patterning by modulating the cytoskeleton and focal adhesion structures.sup.3-5. However, a role for plexin proteins in mechanotransduction has not been examined. Here we show that plexin D1 (PLXND1) has a role in mechanosensation and mechanically induced disease pathogenesis. PLXND1 is required for the response of endothelial cells to shear stress in vitro and in vivo and regulates the site-specific distribution of atherosclerotic lesions. In endothelial cells, PLXND1 is a direct force sensor and forms a mechanocomplex with neuropilin-1 and VEGFR2 that is necessary and sufficient for conferring mechanosensitivity upstream of the junctional complex and integrins. PLXND1 achieves its binary functions as either a ligand or a force receptor by adopting two distinct molecular conformations. Our results establish a previously undescribed mechanosensor in endothelial cells that regulates cardiovascular pathophysiology, and provide a mechanism by which a single receptor can exhibit a binary biochemical nature. PLXND1 is a mechanosensor that is required for endothelial cells to respond to shear stress both in vitro and in vivo by regulating the site-specific distribution of atherosclerotic lesions., Author(s): Vedanta Mehta [sup.1] [sup.2] , Kar-Lai Pang [sup.1] [sup.2] , Daniel Rozbesky [sup.2] [sup.3] , Katrin Nather [sup.1] [sup.2] , Adam Keen [sup.1] [sup.2] , Dariusz Lachowski [sup.4] , [...]

Despite recent advances in crystallography and the availability of G-protein-coupled receptor (GPCR) structures, little is known about the mechanism of their activation process, as only the β2 adrenergic receptor (β2AR) and rhodopsin have been crystallized in fully active conformations. Here we report the structure of an agonist-bound, active state of the human M2 muscarinic acetylcholine receptor stabilized by a G-protein mimetic camelid antibody fragment isolated by conformational selection using yeast surface display. In addition to the expected changes in the intracellular surface, the structure reveals larger conformational changes in the extracellular region and orthosteric binding site than observed in the active states of the β2AR and rhodopsin. We also report the structure of the M2 receptor simultaneously bound to the orthosteric agonist iperoxo and the positive allosteric modulator LY2119620. This structure reveals that LY2119620 recognizes a largely pre-formed binding site in the extracellular vestibule of the iperoxo-bound receptor, inducing a slight contraction of this outer binding pocket. These structures offer important insights into the activation mechanism and allosteric modulation of muscarinic receptors.

An analysis of experiments in which the air around terrestrial plants or plant communities was enriched with carbon dioxide reveals a coordination between the resulting changes in soil carbon stocks and above-ground plant biomass. A meta-analysis of terrestrial CO2-elevation experiments., Author(s): Ana Bastos, Katrin Fleischer Author Affiliations: Effects of rising CO[sub.2] levels on carbon sequestration are coordinated above and below ground In a paper in Nature, Terrer et al .[sup.1] [...]

Macrophages are considered to contribute to chronic inflammatory diseases such as rheumatoid arthritis.sup.1. However, both the exact origin and the role of macrophages in inflammatory joint disease remain unclear. Here we use fate-mapping approaches in conjunction with three-dimensional light-sheet fluorescence microscopy and single-cell RNA sequencing to perform a comprehensive spatiotemporal analysis of the composition, origin and differentiation of subsets of macrophages within healthy and inflamed joints, and study the roles of these macrophages during arthritis. We find that dynamic membrane-like structures, consisting of a distinct population of CX.sub.3CR1.sup.+ tissue-resident macrophages, form an internal immunological barrier at the synovial lining and physically seclude the joint. These barrier-forming macrophages display features that are otherwise typical of epithelial cells, and maintain their numbers through a pool of locally proliferating CX.sub.3CR1.sup.- mononuclear cells that are embedded into the synovial tissue. Unlike recruited monocyte-derived macrophages, which actively contribute to joint inflammation, these epithelial-like CX.sub.3CR1.sup.+ lining macrophages restrict the inflammatory reaction by providing a tight-junction-mediated shield for intra-articular structures. Our data reveal an unexpected functional diversification among synovial macrophages and have important implications for the general role of macrophages in health and disease. Analysis of macrophage subsets within joints reveals a population of CX.sub.3CR1.sup.+ tissue-resident macrophages that form a tight-junction-mediated barrier at the synovial lining, protecting the joint from the invasion of inflammatory cells., Author(s): Stephan Culemann [sup.1] [sup.2] , Anika Grüneboom [sup.1] [sup.2] , José Ángel Nicolás-Ávila [sup.3] , Daniela Weidner [sup.1] [sup.2] , Katrin Franziska Lämmle [sup.1] [sup.2] , Tobias Rothe [sup.1] [...]

Patients with glioblastoma currently do not sufficiently benefit from recent breakthroughs in cancer treatment that use checkpoint inhibitors.sup.1,2. For treatments using checkpoint inhibitors to be successful, a high mutational load and responses to neoepitopes are thought to be essential.sup.3. There is limited intratumoural infiltration of immune cells.sup.4 in glioblastoma and these tumours contain only 30-50 non-synonymous mutations.sup.5. Exploitation of the full repertoire of tumour antigens--that is, both unmutated antigens and neoepitopes--may offer more effective immunotherapies, especially for tumours with a low mutational load. Here, in the phase I trial GAPVAC-101 of the Glioma Actively Personalized Vaccine Consortium (GAPVAC), we integrated highly individualized vaccinations with both types of tumour antigens into standard care to optimally exploit the limited target space for patients with newly diagnosed glioblastoma. Fifteen patients with glioblastomas positive for human leukocyte antigen (HLA)-A*02:01 or HLA-A*24:02 were treated with a vaccine (APVAC1) derived from a premanufactured library of unmutated antigens followed by treatment with APVAC2, which preferentially targeted neoepitopes. Personalization was based on mutations and analyses of the transcriptomes and immunopeptidomes of the individual tumours. The GAPVAC approach was feasible and vaccines that had poly-ICLC (polyriboinosinic-polyribocytidylic acid-poly-l-lysine carboxymethylcellulose) and granulocyte-macrophage colony-stimulating factor as adjuvants displayed favourable safety and strong immunogenicity. Unmutated APVAC1 antigens elicited sustained responses of central memory CD8.sup.+ T cells. APVAC2 induced predominantly CD4.sup.+ T cell responses of T helper 1 type against predicted neoepitopes. In a phase I trial, highly individualized peptide vaccines against unmutated tumour antigens and neoepitopes elicited sustained responses in CD8.sup.+ and CD4.sup.+ T cells, respectively, in patients with newly diagnosed glioblastoma., Author(s): Norbert Hilf [sup.1] , Sabrina Kuttruff-Coqui [sup.1] , Katrin Frenzel [sup.2] , Valesca Bukur [sup.2] , Stefan Stevanovic [sup.3] [sup.4] , Cécile Gouttefangeas [sup.3] [sup.4] [sup.5] , Michael Platten [...]

The Saccharomyces cerevisiae Pif1 helicase is the prototypical member of the Pif1 DNA helicase family, which is conserved from bacteria to humans. Here we show that exceptionally potent G-quadruplex unwinding is conserved among Pif1 helicases. Moreover, Pif1 helicases from organisms separated by more than 3 billion years of evolution suppressed DNA damage at G-quadruplex motifs in yeast. The G-quadruplex-induced damage generated in the absence of Pif1 helicases led to new genetic and epigenetic changes. Furthermore, when expressed in yeast, human PIF1 suppressed both G-quadruplex-associated DNA damage and telomere lengthening.

Plastic debris is thought to be widespread in freshwater ecosystems globally1. However, a lack of comprehensive and comparable data makes rigorous assessment of its distribution challenging2,3. Here we present a standardized cross-national survey that assesses the abundance and type of plastic debris (>250 μm) in freshwater ecosystems. We sample surface waters of 38 lakes and reservoirs, distributed across gradients of geographical position and limnological attributes, with the aim to identify factors associated with an increased observation of plastics. We find plastic debris in all studied lakes and reservoirs, suggesting that these ecosystems play a key role in the plastic-pollution cycle. Our results indicate that two types of lakes are particularly vulnerable to plastic contamination: lakes and reservoirs in densely populated and urbanized areas and large lakes and reservoirs with elevated deposition areas, long water-retention times and high levels of anthropogenic influence. Plastic concentrations vary widely among lakes; in the most polluted, concentrations reach or even exceed those reported in the subtropical oceanic gyres, marine areas collecting large amounts of debris4. Our findings highlight the importance of including lakes and reservoirs when addressing plastic pollution, in the context of pollution management and for the continued provision of lake ecosystem services.Analysis of plastic debris found in surface waters shows that lakes and reservoirs in densely populated and urbanized regions, as well as those with elevated deposition areas, are particularly vulnerable to plastic contamination. [ABSTRACT FROM AUTHOR]

The anaerobic formation and oxidation of methane involve unique enzymatic mechanisms and cofactors, all of which are believed to be specific for C[sub.1]-compounds. Here we show that an anaerobic thermophilic enrichment culture composed of dense consortia of archaea and bacteria apparently uses partly similar pathways to oxidize the C[sub.4] hydrocarbon butane. The archaea, proposed genus Candidatus Syntrophoarchaeum, show the characteristic autofluorescence of methanogens, and contain highly expressed genes encoding enzymes similar to methyl-coenzyme M reductase. We detect butyl-coenzyme M, indicating archaeal butane activation analogous to the first step in anaerobic methane oxidation. In addition, Ca. Syntrophoarchaeum expresses the genes encoding -oxidation enzymes, carbon monoxide dehydrogenase and reversible C[sub.1] methanogenesis enzymes. This allows for the complete oxidation of butane. Reducing equivalents are seemingly channelled to HotSeep-1, a thermophilic sulfate-reducing partner bacterium known from the anaerobic oxidation of methane. Genes encoding 16S rRNA and methyl-coenzyme M reductase similar to those identifying Ca. Syntrophoarchaeum were repeatedly retrieved from marine subsurface sediments, suggesting that the presented activation mechanism is naturally widespread in the anaerobic oxidation of short-chain hydrocarbons., Author(s): Rafael Laso-Prez [1, 2]; Gunter Wegener (corresponding author) [1, 2, 3]; Katrin Knittel [1]; Friedrich Widdel [1]; Katie J. Harding [1]; Viola Krukenberg [1, 2]; Dimitri V. Meier [1]; [...]

In the vertebrate visual system, all output of the retina is carried by retinal ganglion cells. Each type encodes distinct visual features in parallel for transmission to the brain. How many such 'output channels' exist and what each encodes are areas of intense debate. In the mouse, anatomical estimates range from 15 to 20 channels, and only a handful are functionally understood. By combining two-photon calcium imaging to obtain dense retinal recordings and unsupervised clustering of the resulting sample of more than 11,000 cells, here we show that the mouse retina harbours substantially more than 30 functional output channels. These include all known and several new ganglion cell types, as verified by genetic and anatomical criteria. Therefore, information channels from the mouse eye to the mouse brain are considerably more diverse than shown thus far by anatomical studies, suggesting an encoding strategy resembling that used in stateof-the-art artificial vision systems., Visual processing begins in the retina (reviewed in ref. 1). Here, photoreceptors feed into bipolar cells (2), which provide input to a diverse set of retinal ganglion cells (RGCs). Each [...]

During cap-dependent eukaryotic translation initiation, ribosomes scan messenger RNA from the 5' end to the first AUG start codon with favourable sequence context (1,2). For many mRNAs this AUG belongs to a short upstream open reading frame (uORF) (3), and translation of the main downstream ORF requires re-initiation, an incompletely understood process (1,4-6). Re-initiation is thought to involve the same factors as standard initiation (1,5,7). It is unknown whether any factors specifically affect translation re-initiation without affecting standard cap-dependent translation. Here we uncover the non-canonical initiation factors density regulated protein (DENR) and multiple copies in T-cell lymphoma-1 (MCT-1; also called MCTS1 in humans) as the first selective regulators of eukaryotic re-initiation. mRNAs containing upstream ORFs with strong Kozak sequences selectively require DENR-MCT-1 for their proper translation, yielding a novel class of mRNAs that can be co-regulated and that is enriched for regulatory proteins such as oncogenic kinases. Collectively, our data reveal that cells have a previously unappreciated translational control system with a key role in supporting proliferation and tissue growth., Cellular protein abundance depends largely on mRNA translation (8). Little is known about how translation of specific sets of mRNAs can be coordinately regulated (9,10). mRNAs with uORFs require re-initiation [...]

Inducible genetic labelling of haematopoietic stem cells (HSCs) and linked mathematical modelling show that at least 30% of all HSCs are productive, and that adult haematopoiesis is largely sustained by 'short-term' downstream stem cells that operate near self-renewal in the steady state; HSC fate mapping provides a quantitative model for better understanding of HSC functions in health and disease. Following haematopoiesis in vivo Most of what we know of the properties of haematopoietic stem cells (HSCs) is derived from transplantation and reconstitution of an emptied blood and immune system. Relatively little is known about how HSCs behave under physiological conditions. It was reported recently that normal haematopoeisis in adults is driven by thousands of long-lived progenitors rather than classic HSCs. Hans-Reimer Rodewald and colleagues have used inducible genetic labelling of primitive HSCs in a mouse model, combined with mathematical modelling, to show that although HSCs participate in establishment of the blood system in early life, steady-state haematopoiesis depends mainly on progenitors that are able to self-renew but also receive rare input from long-term HSCs. This input is increased following physiological challenges. Haematopoietic stem cells (HSCs) are widely studied by HSC transplantation into immune- and blood-cell-depleted recipients. Single HSCs can rebuild the system after transplantation.sup.1,2,3,4,5. Chromosomal marking.sup.6, viral integration.sup.7,8,9 and barcoding.sup.10,11,12 of transplanted HSCs suggest that very low numbers of HSCs perpetuate a continuous stream of differentiating cells. However, the numbers of productive HSCs during normal haematopoiesis, and the flux of differentiating progeny remain unknown. Here we devise a mouse model allowing inducible genetic labelling of the most primitive Tie2.sup.+ HSCs in bone marrow, and quantify label progression along haematopoietic development by limiting dilution analysis and data-driven modelling. During maintenance of the haematopoietic system, at least 30% or ~5,000 HSCs are productive in the adult mouse after label induction. However, the time to approach equilibrium between labelled HSCs and their progeny is surprisingly long, a time scale that would exceed the mouse's life. Indeed, we find that adult haematopoiesis is largely sustained by previously designated 'short-term' stem cells downstream of HSCs that nearly fully self-renew, and receive rare but polyclonal HSC input. By contrast, in fetal and early postnatal life, HSCs are rapidly used to establish the immune and blood system. In the adult mouse, 5-fluoruracil-induced leukopenia enhances the output of HSCs and of downstream compartments, thus accelerating haematopoietic flux. Label tracing also identifies a strong lineage bias in adult mice, with several-hundred-fold larger myeloid than lymphoid output, which is only marginally accentuated with age. Finally, we show that transplantation imposes severe constraints on HSC engraftment, consistent with the previously observed oligoclonal HSC activity under these conditions. Thus, we uncover fundamental differences between the normal maintenance of the haematopoietic system, its regulation by challenge, and its re-establishment after transplantation. HSC fate mapping and its linked modelling provide a quantitative framework for studying in situ the regulation of haematopoiesis in health and disease., Author(s): Katrin Busch [sup.1] , Kay Klapproth [sup.1] , Melania Barile [sup.2] , Michael Flossdorf [sup.2] , Tim Holland-Letz [sup.3] , Susan M. Schlenner [sup.4] [sup.5] , Michael Reth [sup.6] [...]

To determine the origin of adult tissue-resident macrophages, a mouse lineage tracing study has revealed that these cells derive from erythro-myeloid progenitors in the yolk sac that are distinct from fetal and adult haematopoietic stem cells. The origin of adult myeloid cells The developmental origin of tissue-resident macrophage progenitors and their contribution to macrophages in fetal and adult organs relative to bone marrow macrophages are still unclear. Using lineage tracing, Elisa Gomez Perdiguero et al. identify a population of yolk-sac-derived progenitors -- distinct from fetal and adult haematopoetic stem cells -- that gives rise to erythrocytes, macrophages, granulocytes and monocytes in the young mouse fetus, and to the vast majority of adult tissue-resident macrophages. Most haematopoietic cells renew from adult haematopoietic stem cells (HSCs).sup.1,2,3, however, macrophages in adult tissues can self-maintain independently of HSCs.sup.4,5,6,7. Progenitors with macrophage potential in vitro have been described in the yolk sac before emergence of HSCs.sup.8,9,10,11,12,13, and fetal macrophages.sup.13,14,15 can develop independently of Myb.sup.4, a transcription factor required for HSC.sup.16, and can persist in adult tissues.sup.4,17,18. Nevertheless, the origin of adult macrophages and the qualitative and quantitative contributions of HSC and putative non-HSC-derived progenitors are still unclear.sup.19. Here we show in mice that the vast majority of adult tissue-resident macrophages in liver (Kupffer cells), brain (microglia), epidermis (Langerhans cells) and lung (alveolar macrophages) originate from a Tie2.sup.+ (also known as Tek) cellular pathway generating Csf1r.sup.+ erythro-myeloid progenitors (EMPs) distinct from HSCs. EMPs develop in the yolk sac at embryonic day (E) 8.5, migrate and colonize the nascent fetal liver before E10.5, and give rise to fetal erythrocytes, macrophages, granulocytes and monocytes until at least E16.5. Subsequently, HSC-derived cells replace erythrocytes, granulocytes and monocytes. Kupffer cells, microglia and Langerhans cells are only marginally replaced in one-year-old mice, whereas alveolar macrophages may be progressively replaced in ageing mice. Our fate-mapping experiments identify, in the fetal liver, a sequence of yolk sac EMP-derived and HSC-derived haematopoiesis, and identify yolk sac EMPs as a common origin for tissue macrophages., Author(s): Elisa Gomez Perdiguero [sup.1] , Kay Klapproth [sup.2] , Christian Schulz [sup.1] , Katrin Busch [sup.2] , Emanuele Azzoni [sup.3] , Lucile Crozet [sup.1] , Hannah Garner [sup.1] , [...]

Most haematopoietic cells renew from adult haematopoietic stem cells (HSCs) (1-3), however, macrophages in adult tissues can self-maintain independently of HSCs (4-7). Progenitors with macrophage potential in vitro have been described in the yolk sac before emergence of HSCs (8-13), and fetal macrophages (13-15) can develop independently of Myb (4), a transcription factor required for HSC (16), and can persist in adult tissues (4,17,18). Nevertheless, the origin of adult macrophages and the qualitative and quantitative contributions of HSC and putative non-HSC-derived progenitors are still unclear (19). Here we show in mice that the vast majority of adult tissue-resident macrophages in liver (Kupffer cells), brain (microglia), epidermis (Langerhans cells) and lung (alveolar macrophages) originate from a [Tie2.sup.+] (also known as Tek) cellular pathway generating [Csf1r.sup.+] erythro-myeloid progenitors (EMPs) distinct from HSCs. EMPs develop in the yolk sac at embryonic day (E) 8.5, migrate and colonize the nascent fetal liver before E10.5, and give rise to fetal erythrocytes, macrophages, granulocytes and monocytes until at least E16.5. Subsequently, HSC-derived cells replace erythrocytes, granulocytes and monocytes. Kupffer cells, microglia and Langerhans cells are only marginally replaced in one-year-old mice, whereas alveolar macrophages may be progressively replaced in ageing mice. Our fate-mapping experiments identify, in the fetal liver, a sequence of yolk sac EMP-derived and HSC-derived haematopoiesis, and identify yolk sac EMPs as a common origin for tissue macrophages., Csf1r-expressing cells in the mouse embryo give rise to tissue-resident macrophages in adult tissues (4). To identify in the developing embryo the site of origin of Csf1r-expressing cells, we performed [...]

Cooperation is central to the emergence of multicellular life; however, the means by which the earliest collectives (groups of cells) maintained integrity in the face of destructive cheating types is unclear. One idea posits cheats as a primitive germ line in a life cycle that facilitates collective reproduction. Here we describe an experiment in which simple cooperating lineages of bacteria were propagated under a selective regime that rewarded collective-level persistence. Collectives reproduced via life cycles that either embraced, or purged, cheating types. When embraced, the life cycle alternated between phenotypic states. Selection fostered inception of a developmental switch that underpinned the emergence of collectives whose fitness, during the course of evolution, became decoupled from the fitness of constituent cells. Such development and decoupling did not occur when groups reproduced via a cheat-purging regime. Our findings capture key events in the evolution of Darwinian individuality during the transition from single cells to multicellularity., Cooperation has a central role in the evolution of multicellularity (1-8). Even under laboratory conditions, simple undifferentiated groups of cooperating cells readily evolve; however, such groups are often short lived: [...]

Author(s): Katrin J. Meissner (corresponding author) [1]; Timothy J. Bralower (corresponding author) [2] On page 573, Gutjahr et al . [1] report a fundamental breakthrough in our understanding of a [...]

In many neurodegenerative disorders, the spread of protein aggregates underlies disease progression in the brain. A receptor molecule has now been found that mediates the neuronal uptake of one such harmful protein. LRP1 protein mediates propagation of tau in the brain., Author(s): Katrin Deinhardt Author Affiliations: A receptor that lets dementia-associated tau proteins into neurons A key characteristic of many neurodegenerative diseases is the slow accumulation of misfolded protein deposits in [...]