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Mitochondria from diverse organisms are capable of transporting large amounts of Ca(2+) via a ruthenium-red-sensitive, membrane-potential-dependent mechanism called the uniporter. Although the uniporter's biophysical properties have been studied extensively, its molecular composition remains elusive. We recently used comparative proteomics to identify MICU1 (also known as CBARA1), an EF-hand-containing protein that serves as a putative regulator of the uniporter. Here, we use whole-genome phylogenetic profiling, genome-wide RNA co-expression analysis and organelle-wide protein coexpression analysis to predict proteins functionally related to MICU1. All three methods converge on a novel predicted transmembrane protein, CCDC109A, that we now call 'mitochondrial calcium uniporter' (MCU). MCU forms oligomers in the mitochondrial inner membrane, physically interacts with MICU1, and resides within a large molecular weight complex. Silencing MCU in cultured cells or in vivo in mouse liver severely abrogates mitochondrial Ca(2+) uptake, whereas mitochondrial respiration and membrane potential remain fully intact. MCU has two predicted transmembrane helices, which are separated by a highly conserved linker facing the intermembrane space. Acidic residues in this linker are required for its full activity. However, an S259A point mutation retains function but confers resistance to Ru360, the most potent inhibitor of the uniporter. Our genomic, physiological, biochemical and pharmacological data firmly establish MCU as an essential component of the mitochondrial Ca(2+) uniporter.  相似文献   
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Zheng X  Pontes O  Zhu J  Miki D  Zhang F  Li WX  Iida K  Kapoor A  Pikaard CS  Zhu JK 《Nature》2008,455(7217):1259-1262
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CD38, a transmembrane glycoprotein with ADP-ribosyl cyclase activity, catalyses the formation of Ca2+ signalling molecules, but its role in the neuroendocrine system is unknown. Here we show that adult CD38 knockout (CD38-/-) female and male mice show marked defects in maternal nurturing and social behaviour, respectively, with higher locomotor activity. Consistently, the plasma level of oxytocin (OT), but not vasopressin, was strongly decreased in CD38-/- mice. Replacement of OT by subcutaneous injection or lentiviral-vector-mediated delivery of human CD38 in the hypothalamus rescued social memory and maternal care in CD38-/- mice. Depolarization-induced OT secretion and Ca2+ elevation in oxytocinergic neurohypophysial axon terminals were disrupted in CD38-/- mice; this was mimicked by CD38 metabolite antagonists in CD38+/+ mice. These results reveal that CD38 has a key role in neuropeptide release, thereby critically regulating maternal and social behaviours, and may be an element in neurodevelopmental disorders.  相似文献   
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The design of new enzymes for reactions not catalysed by naturally occurring biocatalysts is a challenge for protein engineering and is a critical test of our understanding of enzyme catalysis. Here we describe the computational design of eight enzymes that use two different catalytic motifs to catalyse the Kemp elimination-a model reaction for proton transfer from carbon-with measured rate enhancements of up to 10(5) and multiple turnovers. Mutational analysis confirms that catalysis depends on the computationally designed active sites, and a high-resolution crystal structure suggests that the designs have close to atomic accuracy. Application of in vitro evolution to enhance the computational designs produced a >200-fold increase in k(cat)/K(m) (k(cat)/K(m) of 2,600 M(-1)s(-1) and k(cat)/k(uncat) of >10(6)). These results demonstrate the power of combining computational protein design with directed evolution for creating new enzymes, and we anticipate the creation of a wide range of useful new catalysts in the future.  相似文献   
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The general object of research is to design new idea of the semi-biodegradable,multilayered vascular prosthesis used for the reconstruction of significantly small diameter vascular vessels( microreconstruction). The paper studies the selection of appropriate sterilization technique for resorbable tubular structures made of poly( L-lactide-co-glicolide)( PLAGA) and nonbiodegradable tubular structures made of polypropylene( PP). The designed grafts are characterized by the physical properties as well as mechanical properties according to ISO 7198 ∶ 1998 Standard.Moreover,the process of the grafts fabrication will be explained considering the stages affected the critical properties of the elaborated textile implants. The increase of PLAGA melt-electrospun tubular structures mechanical properties was observed due to the thermal stabilization use. The ethylene oxide( EO) and steam sterilization had a destructive effect on the designed PLAGA meltelectrospun tubular, fibrous structures, whereas the irradiation yielded in the changes in mechanical and physical properties on the acceptable level,taking into account the future clinical applications.  相似文献   
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The aim of this paper is to reconstruct the Jurassic-Early Cretaceous climatic conditions using new isotopic data. Paleobotanical data indicate that a cooling occurred gradually just after Late Triassic, and a temperature minimum was reached in the Pliensbachian. This was followed by a climatic optimum in the early Toarcian, cooling in the late Toarcian and a second climatic optimum in the Oxfordian. Published isotopic thermometry data and our new results on isotopic composition of some Jurassic invertebrate shells from the Russian Platform, Poland, Germany and England generally confirm this pattern, and also indicate a third climatic optimum in the Middle Callovian. Middle-Late Mesozoic adult belemnites apparently lived during their spawning phase, in shallow waters similar to extant Nautilus. However, at least juvenile belemnoids, unlike ammonoids, engaged in significant short-term vertical migrations in the water column, reaching colder waters of the upper bathyal zone.  相似文献   
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Gold concentration usually consists of gravity separation, flotation, cyanidation, or the combination of these processes. The choice among these processes depends on the mineralogical characterization and gold content of the ore. Recently, the recovery of gold using gravity methods has gained attention because of low cost and environmentally friendly operations. In this study, gold pre-concentrates were produced by the stepwise gravity separation and flotation techniques. The Knelson concentrator and conventional flotation were employed for the recovery of gold. Gold bearing ore samples were taken from Gümüşhane Region, northern east part of Turkey. As a result of stepwise Knelson concentration experiments, a gold concentrate assaying around 620 g/t is produced with 41.4wt% recovery. On the other hand, a gold concentrate about 82 g/t is obtained with 89.9wt% recovery from a gold ore assaying 6 g/t Au by direct flotation.  相似文献   
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The search for the earliest fossil evidence of the human lineage has been concentrated in East Africa. Here we report the discovery of six hominid specimens from Chad, central Africa, 2,500 km from the East African Rift Valley. The fossils include a nearly complete cranium and fragmentary lower jaws. The associated fauna suggest the fossils are between 6 and 7 million years old. The fossils display a unique mosaic of primitive and derived characters, and constitute a new genus and species of hominid. The distance from the Rift Valley, and the great antiquity of the fossils, suggest that the earliest members of the hominid clade were more widely distributed than has been thought, and that the divergence between the human and chimpanzee lineages was earlier than indicated by most molecular studies.  相似文献   
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