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1.
Eukaryotic ribosome biogenesis involves ∼200 assembly factors, but how these contribute to ribosome maturation is poorly understood. Here, we identify a network of factors on the nascent 60S subunit that actively remodels preribosome structure. At its hub is Rsa4, a direct substrate of the force-generating ATPase Rea1. We show that Rsa4 is connected to the central protuberance by binding to Rpl5 and to ribosomal RNA (rRNA) helix 89 of the nascent peptidyl transferase center (PTC) through Nsa2. Importantly, Nsa2 binds to helix 89 before relocation of helix 89 to the PTC. Structure-based mutations of these factors reveal the functional importance of their interactions for ribosome assembly. Thus, Rsa4 is held tightly in the preribosome and can serve as a “distribution box,” transmitting remodeling energy from Rea1 into the developing ribosome. We suggest that a relay-like factor network coupled to a mechano-enzyme is strategically positioned to relocate rRNA elements during ribosome maturation.  相似文献   
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Knowledge of breeding ecology is required for many conservation interventions. The Seychelles Black Parrot Coracopsis barklyi, endemic to the island of Praslin, is vulnerable to extinction. We aimed to improve understanding of C. barklyi breeding ecology to aid conservation planning. We present the results of four years of research, including nesting cavity characteristics and availability, reproductive success, breeding parameters, parental behaviour and reproductive strategy. Thirty-six breeding attempts were studied over the four seasons. Nests were mainly located in Coco de Mer palms Lodoicea maldivica. Deeper cavities with more canopy cover were preferred. There may be a shortage of high-quality nesting cavities in intensive breeding seasons. Average clutch size was 2.2 eggs, incubation period was c. 15 d and egg fertility was 71%. Rats were key nest predators, causing the failure of up to 33% of breeding attempts. The probability of nest success was 53%. At least 57% of fledglings survived their first year. This species breeds cooperatively and practices a highly unusual side-by-side copulation. We discuss the implications of the results in the context of former, ongoing and potential conservation measures for C. barklyi including translocation, invasive species management, nest box provisioning, habitat restoration and further research.  相似文献   
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Collective migration of mechanically coupled cell layers is a notable feature of wound healing, embryonic development, and cancer progression. In confluent epithelial sheets, the dynamics have been found to be highly heterogeneous, exhibiting spontaneous formation of swirls, long-range correlations, and glass-like dynamic arrest as a function of cell density. In contrast, the flow-like properties of one-sided cell-sheet expansion in confining geometries are not well understood. Here, we studied the short- and long-term flow of Madin-Darby canine kidney (MDCK) cells as they moved through microchannels. Using single-cell tracking and particle image velocimetry (PIV), we found that a defined averaged stationary cell current emerged that exhibited a velocity gradient in the direction of migration and a plug-flow-like profile across the advancing sheet. The observed flow velocity can be decomposed into a constant term of directed cell migration and a diffusion-like contribution that increases with density gradient. The diffusive component is consistent with the cell-density profile and front propagation speed predicted by the Fisher-Kolmogorov equation. To connect diffusion-mediated transport to underlying cellular motility, we studied single-cell trajectories and occurrence of vorticity. We discovered that the directed large-scale cell flow altered fluctuations in cellular motion at short length scales: vorticity maps showed a reduced frequency of swirl formation in channel flow compared with resting sheets of equal cell density. Furthermore, under flow, single-cell trajectories showed persistent long-range, random-walk behavior superimposed on drift, whereas cells in resting tissue did not show significant displacements with respect to neighboring cells. Our work thus suggests that active cell migration manifests itself in an underlying, spatially uniform drift as well as in randomized bursts of short-range correlated motion that lead to a diffusion-mediated transport.  相似文献   
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Current challenges to global food security require sustainable intensification of agriculture through initiatives that include more efficient use of nitrogen (N), increased protein self‐sufficiency through homegrown crops, and reduced N losses to the environment. Such challenges were addressed in a continental‐scale field experiment conducted over 3 years, in which the amount of total nitrogen yield (Ntot) and the gain of N yield in mixtures as compared to grass monocultures (Ngainmix) was quantified from four‐species grass–legume stands with greatly varying legume proportions. Stands consisted of monocultures and mixtures of two N2‐fixing legumes and two nonfixing grasses. The amount of Ntot of mixtures was significantly greater (P ≤ 0.05) than that of grass monocultures at the majority of evaluated sites in all 3 years. Ntot and thus Ngainmix increased with increasing legume proportion up to one‐third of legumes. With higher legume percentages, Ntot and Ngainmix did not continue to increase. Thus, across sites and years, mixtures with one‐third proportion of legumes attained ~95% of the maximum Ntot acquired by any stand and had 57% higher Ntot than grass monocultures. Realized legume proportion in stands and the relative N gain in mixture (Ngainmix/Ntot in mixture) were most severely impaired by minimum site temperature (R = 0.70, P = 0.003 for legume proportion; R = 0.64, P = 0.010 for Ngainmix/Ntot in mixture). Nevertheless, the relative N gain in mixture was not correlated to site productivity (P = 0.500), suggesting that, within climatic restrictions, balanced grass–legume mixtures can benefit from comparable relative gains in N yield across largely differing productivity levels. We conclude that the use of grass–legume mixtures can substantially contribute to resource‐efficient agricultural grassland systems over a wide range of productivity levels, implying important savings in N fertilizers and thus greenhouse gas emissions and a considerable potential for climate change mitigation.  相似文献   
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Exon junction complexes (EJCs) link nuclear splicing to key features of mRNA function including mRNA stability, translation, and localization. We analyzed the formation of EJCs by the spliceosome, the physiological EJC assembly machinery. We studied a comprehensive set of eIF4A3, MAGOH, and BTZ mutants in complete or C-complex–arrested splicing reactions and identified essential interactions of EJC proteins during and after EJC assembly. These data establish that EJC deposition proceeds through a defined intermediate, the pre-EJC, as an ordered, sequential process that is coordinated by splicing. The pre-EJC consists of eIF4A3 and MAGOH-Y14, is formed before exon ligation, and provides a binding platform for peripheral EJC components that join after release from the spliceosome and connect the core structure with function. Specifically, we identified BTZ to bridge the EJC to the nonsense-mediated messenger RNA (mRNA) decay protein UPF1, uncovering a critical link between mRNP architecture and mRNA stability. Based on this systematic analysis of EJC assembly by the spliceosome, we propose a model of how a functional EJC is assembled in a strictly sequential and hierarchical fashion, including nuclear splicing-dependent and cytoplasmic steps.  相似文献   
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Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk for several neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia (FTD). Homozygous TREM2 missense mutations, such as p.T66M, lead to the FTD‐like syndrome, but how they cause pathology is unknown. Using CRISPR/Cas9 genome editing, we generated a knock‐in mouse model for the disease‐associated Trem2 p.T66M mutation. Consistent with a loss‐of‐function mutation, we observe an intracellular accumulation of immature mutant Trem2 and reduced generation of soluble Trem2 similar to patients with the homozygous p.T66M mutation. Trem2 p.T66M knock‐in mice show delayed resolution of inflammation upon in vivo lipopolysaccharide stimulation and cultured macrophages display significantly reduced phagocytic activity. Immunohistochemistry together with in vivo TSPO small animal positron emission tomography (μPET) demonstrates an age‐dependent reduction in microglial activity. Surprisingly, perfusion magnetic resonance imaging and FDG‐μPET imaging reveal a significant reduction in cerebral blood flow and brain glucose metabolism. Thus, we demonstrate that a TREM2 loss‐of‐function mutation causes brain‐wide metabolic alterations pointing toward a possible function of microglia in regulating brain glucose metabolism.  相似文献   
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In mammals, glucocorticoids (GCs) and their intracellular receptor, the glucocorticoid receptor (GR), represent critical checkpoints in the endocrine control of energy homeostasis. Indeed, aberrant GC action is linked to severe metabolic stress conditions as seen in Cushing's syndrome, GC therapy and certain components of the Metabolic Syndrome, including obesity and insulin resistance. Here, we identify the hepatic induction of the mammalian conserved microRNA (miR)‐379/410 genomic cluster as a key component of GC/GR‐driven metabolic dysfunction. Particularly, miR‐379 was up‐regulated in mouse models of hyperglucocorticoidemia and obesity as well as human liver in a GC/GR‐dependent manner. Hepatocyte‐specific silencing of miR‐379 substantially reduced circulating very‐low‐density lipoprotein (VLDL)‐associated triglyceride (TG) levels in healthy mice and normalized aberrant lipid profiles in metabolically challenged animals, mediated through miR‐379 effects on key receptors in hepatic TG re‐uptake. As hepatic miR‐379 levels were also correlated with GC and TG levels in human obese patients, the identification of a GC/GR‐controlled miRNA cluster not only defines a novel layer of hormone‐dependent metabolic control but also paves the way to alternative miRNA‐based therapeutic approaches in metabolic dysfunction.  相似文献   
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