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621.
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
622.
623.
Morwood MJ Soejono RP Roberts RG Sutikna T Turney CS Westaway KE Rink WJ Zhao JX van den Bergh GD Due RA Hobbs DR Moore MW Bird MI Fifield LK 《Nature》2004,431(7012):1087-1091
Excavations at Liang Bua, a large limestone cave on the island of Flores in eastern Indonesia, have yielded evidence for a population of tiny hominins, sufficiently distinct anatomically to be assigned to a new species, Homo floresiensis. The finds comprise the cranial and some post-cranial remains of one individual, as well as a premolar from another individual in older deposits. Here we describe their context, implications and the remaining archaeological uncertainties. Dating by radiocarbon (14C), luminescence, uranium-series and electron spin resonance (ESR) methods indicates that H. floresiensis existed from before 38,000 years ago (kyr) until at least 18 kyr. Associated deposits contain stone artefacts and animal remains, including Komodo dragon and an endemic, dwarfed species of Stegodon. H. floresiensis originated from an early dispersal of Homo erectus (including specimens referred to as Homo ergaster and Homo georgicus) that reached Flores, and then survived on this island refuge until relatively recently. It overlapped significantly in time with Homo sapiens in the region, but we do not know if or how the two species interacted. 相似文献
624.
625.
Mutations in ABCC6 cause pseudoxanthoma elasticum 总被引:21,自引:0,他引:21
Bergen AA Plomp AS Schuurman EJ Terry S Breuning M Dauwerse H Swart J Kool M van Soest S Baas F ten Brink JB de Jong PT 《Nature genetics》2000,25(2):228-231
Pseudoxanthoma elasticum (PXE) is a heritable disorder of the connective tissue. PXE patients frequently experience visual field loss and skin lesions, and occasionally cardiovascular complications. Histopathological findings reveal calcification of the elastic fibres and abnormalities of the collagen fibrils. Most PXE patients are sporadic, but autosomal recessive and dominant inheritance are also observed. We previously localized the PXE gene to chromosome 16p13.1 (refs 8,9) and constructed a physical map. Here we describe homozygosity mapping in five PXE families and the detection of deletions or mutations in ABCC6 (formerly MRP6) associated with all genetic forms of PXE in seven patients or families. 相似文献
626.
de Winter JP Rooimans MA van Der Weel L van Berkel CG Alon N Bosnoyan-Collins L de Groot J Zhi Y Waisfisz Q Pronk JC Arwert F Mathew CG Scheper RJ Hoatlin ME Buchwald M Joenje H 《Nature genetics》2000,24(1):15-16
Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder with locus heterogeneity. None of the 'responsible' genes have previously been identified. Some BBS cases (approximately 10%) remain unassigned to the five previously mapped loci. McKusick-Kaufma syndrome (MKS) includes hydrometrocolpos, postaxial polydactyly and congenital heart disease, and is also inherited in an autosomal recessive manner. We ascertained 34 unrelated probands with classic features of BBS including retinitis pigmentosa (RP), obesity and polydactyly. The probands were from families unsuitable for linkage because of family size. We found MKKS mutations in four typical BBS probands (Table 1). The first is a 13-year-old Hispanic girl with severe RP, PAP, mental retardation and obesity (BMI >40). She was a compound heterozygote for a missense (1042GA, G52D) and a nonsense (1679TA, Y264stop) mutation in exon 3. Cloning and sequencing of the separate alleles confirmed that the mutations were present in trans. A second BBS proband (from Newfoundland), born to consanguineous parents, was homozygous for two deletions (1316delC and 1324-1326delGTA) in exon 3, predicting a frameshift. An affected brother was also homozygous for the deletions, whereas an unaffected sibling had two normal copies of MKKS. Both the proband and her affected brother had RP, PAP, mild mental retardation, morbid obesity (BMI >50 and 37, respectively), lobulated kidneys with prominent calyces and diabetes mellitus (diagnosed at ages 33 and 30, respectively). A deceased sister (DNA unavailable) had similar phenotypic features (RP with blindness by age 13, BMI >45, abnormal glucose tolerance test and IQ=64, vaginal atresia and syndactyly of both feet). Both parents and the maternal grandfather were heterozygous for the deletions. Genotyping with markers from the MKKS region confirmed homozygosity at 20p12 in both affected individuals. 相似文献
627.
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
628.
Dominant isolated renal magnesium loss is caused by misrouting of the Na(+),K(+)-ATPase gamma-subunit 总被引:6,自引:0,他引:6
Meij IC Koenderink JB van Bokhoven H Assink KF Groenestege WT de Pont JJ Bindels RJ Monnens LA van den Heuvel LP Knoers NV 《Nature genetics》2000,26(3):265-266
Primary hypomagnesaemia is composed of a heterogeneous group of disorders characterized by renal or intestinal Mg(2+) wasting, often associated with disturbances in Ca(2+) excretion. We identified a putative dominant-negative mutation in the gene encoding the Na(+), K(+)-ATPase gamma-subunit (FXYD2), leading to defective routing of the protein in a family with dominant renal hypomagnesaemia. 相似文献
629.
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
630.
Effects of mechanical forces on maintenance and adaptation of form in trabecular bone 总被引:33,自引:0,他引:33
The architecture of trabecular bone, the porous bone found in the spine and at articulating joints, provides the requirements for optimal load transfer, by pairing suitable strength and stiffness to minimal weight according to rules of mathematical design. But, as it is unlikely that the architecture is fully pre-programmed in the genes, how are the bone cells informed about these rules, which so obviously dictate architecture? A relationship exists between bone architecture and mechanical usage--while strenuous exercise increases bone mass, disuse, as in microgravity and inactivity, reduces it. Bone resorption cells (osteoclasts) and bone formation cells (osteoblasts) normally balance bone mass in a coupled homeostatic process of remodelling, which renews some 25% of trabecular bone volume per year. Here we present a computational model of the metabolic process in bone that confirms that cell coupling is governed by feedback from mechanical load transfer. This model can explain the emergence and maintenance of trabecular architecture as an optimal mechanical structure, as well as its adaptation to alternative external loads. 相似文献