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221.
222.
Adams DJ Biggs PJ Cox T Davies R van der Weyden L Jonkers J Smith J Plumb B Taylor R Nishijima I Yu Y Rogers J Bradley A 《Nature genetics》2004,36(8):867-871
Embryonic stem cell technology revolutionized biology by providing a means to assess mammalian gene function in vivo. Although it is now routine to generate mice from embryonic stem cells, one of the principal methods used to create mutations, gene targeting, is a cumbersome process. Here we describe the indexing of 93,960 ready-made insertional targeting vectors from two libraries. 5,925 of these vectors can be used directly to inactivate genes with an average targeting efficiency of 28%. Combinations of vectors from the two libraries can be used to disrupt both alleles of a gene or engineer larger genomic changes such as deletions, duplications, translocations or inversions. These indexed vectors constitute a public resource (Mutagenic Insertion and Chromosome Engineering Resource; MICER) for high-throughput, targeted manipulation of the mouse genome. 相似文献
223.
224.
Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass 总被引:31,自引:0,他引:31
Chen AS Marsh DJ Trumbauer ME Frazier EG Guan XM Yu H Rosenblum CI Vongs A Feng Y Cao L Metzger JM Strack AM Camacho RE Mellin TN Nunes CN Min W Fisher J Gopal-Truter S MacIntyre DE Chen HY Van der Ploeg LH 《Nature genetics》2000,26(1):97-102
Genetic and pharmacological studies have defined a role for the melanocortin-4 receptor (Mc4r) in the regulation of energy homeostasis. The physiological function of Mc3r, a melanocortin receptor expressed at high levels in the hypothalamus, has remained unknown. We evaluated the potential role of Mc3r in energy homeostasis by studying Mc3r-deficient (Mc3r(-/-)) mice and compared the functions of Mc3r and Mc4r in mice deficient for both genes. The 4-6-month Mc3r-/- mice have increased fat mass, reduced lean mass and higher feed efficiency than wild-type littermates, despite being hypophagic and maintaining normal metabolic rates. (Feed efficiency is the ratio of weight gain to food intake.) Consistent with increased fat mass, Mc3r(-/-) mice are hyperleptinaemic and male Mc3r(-/-) mice develop mild hyperinsulinaemia. Mc3r(-/-) mice did not have significantly altered corticosterone or total thyroxine (T4) levels. Mice lacking both Mc3r and Mc4r become significantly heavier than Mc4r(-/-) mice. We conclude that Mc3r and Mc4r serve non-redundant roles in the regulation of energy homeostasis. 相似文献
225.
Sasaki S De Franceschi S Elzerman JM van der Wiel WG Eto M Tarucha S Kouwenhoven LP 《Nature》2000,405(6788):764-767
The Kondo effect--a many-body phenomenon in condensed-matter physics involving the interaction between a localized spin and free electrons--was discovered in metals containing small amounts of magnetic impurities, although it is now recognized to be of fundamental importance in a wide class of correlated electron systems. In fabricated structures, the control of single, localized spins is of technological relevance for nanoscale electronics. Experiments have already demonstrated artificial realizations of isolated magnetic impurities at metallic surfaces, nanoscale magnets, controlled transitions between two-electron singlet and triplet states, and a tunable Kondo effect in semiconductor quantum dots. Here we report an unexpected Kondo effect in a few-electron quantum dot containing singlet and triplet spin states, whose energy difference can be tuned with a magnetic field. We observe the effect for an even number of electrons, when the singlet and triplet states are degenerate. The characteristic energy scale is much larger than in the ordinary spin-1/2 case. 相似文献
226.
Forest F Grenyer R Rouget M Davies TJ Cowling RM Faith DP Balmford A Manning JC Procheş S van der Bank M Reeves G Hedderson TA Savolainen V 《Nature》2007,445(7129):757-760
One of the biggest challenges for conservation biology is to provide conservation planners with ways to prioritize effort. Much attention has been focused on biodiversity hotspots. However, the conservation of evolutionary process is now also acknowledged as a priority in the face of global change. Phylogenetic diversity (PD) is a biodiversity index that measures the length of evolutionary pathways that connect a given set of taxa. PD therefore identifies sets of taxa that maximize the accumulation of 'feature diversity'. Recent studies, however, concluded that taxon richness is a good surrogate for PD. Here we show taxon richness to be decoupled from PD, using a biome-wide phylogenetic analysis of the flora of an undisputed biodiversity hotspot--the Cape of South Africa. We demonstrate that this decoupling has real-world importance for conservation planning. Finally, using a database of medicinal and economic plant use, we demonstrate that PD protection is the best strategy for preserving feature diversity in the Cape. We should be able to use PD to identify those key regions that maximize future options, both for the continuing evolution of life on Earth and for the benefit of society. 相似文献
227.
Magnetic polarity stratigraphy of loess in West Qinling (Mts.) demonstrates that loess began to deposit in West Qinling at ca. 800 kaBP. Its material may come from the nearby Tibetan Plateau to the west. This suggests that a sharp change in air circulation and surface environment on and around the Tibetan Plateau occurred at that time. 相似文献
228.
van der Burg M van Zelm MC Driessen GJ van Dongen JJ 《Cellular and molecular life sciences : CMLS》2012,69(1):59-73
Primary antibody deficiencies (PAD) form the largest group of inherited disorders of the immune system. They are characterized
by a marked reduction or absence of serum immunoglobulins (Ig) due to disturbed B cell differentiation and by a poor response
to vaccination. PAD can be divided into agammaglobulinemia, Ig class switch recombination deficiencies, and idiopathic hypogammaglobulinemia.
Over the past 20 years, defects have been identified in 18 different genes, but in many PAD patients the underlying gene defects
have not been found. Diagnosis of known PAD and discovery of new PAD is important for good patient care. In this review, we
present the effects of genetic defects in the context of normal B cell differentiation, and we discuss how new technical developments
can support understanding and discovering new genetic defects in PAD. 相似文献
229.
Uusi-Rauva K Kyttälä A van der Kant R Vesa J Tanhuanpää K Neefjes J Olkkonen VM Jalanko A 《Cellular and molecular life sciences : CMLS》2012,69(12):2075-2089
CLN3 is an endosomal/lysosomal transmembrane protein mutated in classical juvenile onset neuronal ceroid lipofuscinosis, a fatal inherited neurodegenerative lysosomal storage disorder. The function of CLN3 in endosomal/lysosomal events has remained elusive due to poor understanding of its interactions in these compartments. It has previously been shown that the localisation of late endosomal/lysosomal compartments is disturbed in cells expressing the most common disease-associated CLN3 mutant, CLN3?ex7-8 (c.462-677del). We report here that a protracted disease causing mutant, CLN3E295K, affects the properties of late endocytic compartments, since over-expression of the CLN3E295K mutant protein in HeLa cells induced relocalisation of Rab7 and a perinuclear clustering of late endosomes/lysosomes. In addition to the previously reported disturbances in the endocytic pathway, we now show that the anterograde transport of late endosomal/lysosomal compartments is affected in CLN3 deficiency. CLN3 interacted with motor components driving both plus and minus end microtubular trafficking: tubulin, dynactin, dynein and kinesin-2. Most importantly, CLN3 was found to interact directly with active, guanosine-5'-triphosphate (GTP)-bound Rab7 and with the Rab7-interacting lysosomal protein (RILP) that anchors the dynein motor. The data presented in this study provide novel insights into the role of CLN3 in late endosomal/lysosomal membrane transport. 相似文献
230.
Peche V Shekar S Leichter M Korte H Schröder R Schleicher M Holak TA Clemen CS Ramanath-Y B Pfitzer G Karakesisoglou I Noegel AA 《Cellular and molecular life sciences : CMLS》2007,64(19-20):2702-2715
Cyclase-associated proteins (CAPs) are evolutionarily conserved proteins with roles in regulating the actin cytoskeleton and in signal transduction. Mammals have two CAP genes encoding the related CAP1 and CAP2. We studied the distribution and subcellular localization of CAP1 and CAP2 using specific antibodies. CAP1 shows a broad tissue distribution, whereas CAP2 is significantly expressed only in brain, heart and skeletal muscle, and skin. CAP2 is found in the nucleus in undifferentiated myoblasts and at the M-line of differentiated myotubes. In PAM212, a mouse keratinocyte cell line, CAP2 is enriched in the nucleus, and sparse in the cytosol. By contrast, CAP1 localizes to the cytoplasm in PAM212 cells. In human skin, CAP2 is present in all living layers of the epidermis localizing to the nuclei and the cell periphery. In in vitro studies, a C-terminal fragment of CAP2 interacts with actin, indicating that CAP2 has the capacity to bind to actin. 相似文献