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221.
Mice lacking the folic acid-binding protein Folbp1 are defective in early embryonic development. 总被引:15,自引:0,他引:15
J A Piedrahita B Oetama G D Bennett J van Waes B A Kamen J Richardson S W Lacey R G Anderson R H Finnell 《Nature genetics》1999,23(2):228-232
Periconceptional folic acid supplementation reduces the occurrence of several human congenital malformations, including craniofacial, heart and neural tube defects. Although the underlying mechanism is unknown, there may be a maternal-to-fetal folate-transport defect or an inherent fetal biochemical disorder that is neutralized by supplementation. Previous experiments have identified a folate-binding protein (Folbp1) that functions as a membrane receptor to mediate the high-affinity internalization and delivery of folate to the cytoplasm of the cell. In vitro, this receptor facilitates the accumulation of cellular folate a thousand-fold relative to the media, suggesting that it may be essential in cytoplasmic folate delivery in vivo. The importance of an adequate intracellular folate pool for normal embryogenesis has long been recognized in humans and experimental animals. To determine whether Folbp1 is involved in maternal-to-fetal folate transport, we inactivated Folbp1 in mice. We also produced mice lacking Folbp2, another member of the folate receptor family that is GPI anchored but binds folate poorly. Folbp2-/- embryos developed normally, but Folbp1-/- embryos had severe morphogenetic abnormalities and died in utero by embryonic day (E) 10. Supplementing pregnant Folbp1+/- dams with folinic acid reversed this phenotype in nullizygous pups. Our results suggest that Folbp1 has a critical role in folate homeostasis during development, and that functional defects in the human homologue (FOLR1) of Folbp1 may contribute to similar defects in humans. 相似文献
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224.
Zusammenfassung Es wurden Mäuse des C3H/HeJ-Stammes nach Entwöhnung bis zum Alter von 125 Tagen unter verschiedenen Umweltbedingungen wie Temperatur, relative Luftfeuchtigkeit und Käfigdichte aufgezogen. Je höher Temperatur, relative Luftfeuchtigkeit und je grösser die Käfigdichte, um so grösser waren die Körpergewichtsverluste. Umwelttemperatur, Feuchtigkeit und Käfigdichte beeinflussten zusammen das Überleben der Mäuse nach Schwimmen. 相似文献
225.
Abrupt changes in the Asian southwest monsoon during the Holocene and their links to the North Atlantic Ocean 总被引:42,自引:0,他引:42
During the last ice age, the Indian Ocean southwest monsoon exhibited abrupt changes that were closely correlated with millennial-scale climate events in the North Atlantic region, suggesting a mechanistic link. In the Holocene epoch, which had a more stable climate, the amplitude of abrupt changes in North Atlantic climate was much smaller, and it has been unclear whether these changes are related to monsoon variability. Here we present a continuous record of centennial-scale monsoon variability throughout the Holocene from rapidly accumulating and minimally bioturbated sediments in the anoxic Arabian Sea. Our monsoon proxy record reveals several intervals of weak summer monsoon that coincide with cold periods documented in the North Atlantic region--including the most recent climate changes from the Medieval Warm Period to the Little Ice Age and then to the present. We therefore suggest that the link between North Atlantic climate and the Asian monsoon is a persistent aspect of global climate. 相似文献
226.
Friedrich R Panizzi P Fuentes-Prior P Richter K Verhamme I Anderson PJ Kawabata S Huber R Bode W Bock PE 《Nature》2003,425(6957):535-539
Many bacterial pathogens secrete proteins that activate host trypsinogen-like enzyme precursors, most notably the proenzymes of the blood coagulation and fibrinolysis systems. Staphylococcus aureus, an important human pathogen implicated in sepsis and endocarditis, secretes the cofactor staphylocoagulase, which activates prothrombin, without the usual proteolytic cleavages, to directly initiate blood clotting. Here we present the 2.2 A crystal structures of human alpha-thrombin and prethrombin-2 bound to a fully active staphylocoagulase variant. The cofactor consists of two domains, each with three-helix bundles; this is a novel fold that is distinct from known serine proteinase activators, particularly the streptococcal plasminogen activator streptokinase. The staphylocoagulase fold is conserved in other bacterial plasma-protein-binding factors and extracellular-matrix-binding factors. Kinetic studies confirm the importance of isoleucine 1 and valine 2 at the amino terminus of staphylocoagulase for zymogen activation. In addition to making contacts with the 148 loop and (pro)exosite I of prethrombin-2, staphylocoagulase inserts its N-terminal peptide into the activation pocket of bound prethrombin-2, allosterically inducing functional catalytic machinery. These investigations demonstrate unambiguously the validity of the zymogen-activation mechanism known as 'molecular sexuality'. 相似文献
227.
New molecular model for the long-range elasticity of elastin 总被引:3,自引:0,他引:3
228.
Sex-hormone-binding globulin is an oestrogen amplifier 总被引:4,自引:0,他引:4
229.
Zusammenfassung Sprague-Dawley-Ratten, die eine kombinierte Belastung mit 7,12-Dimethylbenz()anthrazen und Aktinomyzin D überleben, weisen eine drastisch erniedrigte tastbare Tumorinzidenz auf. Kontrolltiere erhielten nur das Karzinogen. 相似文献
230.
Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16(Ink4a)-p19(Arf) pathway 总被引:1,自引:0,他引:1
Bulavin DV Phillips C Nannenga B Timofeev O Donehower LA Anderson CW Appella E Fornace AJ 《Nature genetics》2004,36(4):343-350
Modulation of tumor suppressor activities may provide new opportunities for cancer therapy. Here we show that disruption of the gene Ppm1d encoding Wip1 phosphatase activated the p53 and p16 (also called Ink4a)-p19 (also called ARF) pathways through p38 MAPK signaling and suppressed in vitro transformation of mouse embryo fibroblasts (MEFs) by oncogenes. Disruption of the gene Cdkn2a (encoding p16 and p19), but not of Trp53 (encoding p53), reconstituted cell transformation in Ppm1d-null MEFs. In vivo, deletion of Ppm1d in mice bearing mouse mammary tumor virus (MMTV) promoter-driven oncogenes Erbb2 (also called c-neu) or Hras1 impaired mammary carcinogenesis, whereas reduced expression of p16 and p19 by methylation-induced silencing or inactivation of p38 MAPK correlated with tumor appearance. We conclude that inactivation or depletion of the Wip1 phosphatase with resultant p38 MAPK activation suppresses tumor appearance by modulating the Cdkn2a tumor-suppressor locus. 相似文献