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11.
In many highly extended rifts on the Earth, tectonic removal of the upper crust exhumes mid-crustal rocks, producing metamorphic core complexes. These structures allow the upper continental crust to accommodate tens of kilometres of extension, but it is not clear how the lower crust and underlying mantle respond. Also, despite removal of the upper crust, such core complexes remain both topographically high and in isostatic equilibrium. Because many core complexes in the western United States are underlain by a flat Moho discontinuity, it has been widely assumed that their elevation is supported by flow in the lower crust or by magmatic underplating. These processes should decouple upper-crust extension from that in the mantle. In contrast, here we present seismic observations of metamorphic core complexes of the western Woodlark rift that show the overall crust to be thinned beneath regions of greatest surface extension. These core complexes are actively being exhumed at a rate of 5-10 km Myr(-1), and the thinning of the underlying crust appears to be compensated by mantle rocks of anomalously low density, as indicated by low seismic velocities. We conclude that, at least in this case, the development of metamorphic core complexes and the accommodation of high extension is not purely a crustal phenomenon, but must involve mantle extension. 相似文献
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13.
Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors 总被引:5,自引:0,他引:5
Al-Tassan N Chmiel NH Maynard J Fleming N Livingston AL Williams GT Hodges AK Davies DR David SS Sampson JR Cheadle JP 《Nature genetics》2002,30(2):227-232
Inherited defects of base excision repair have not been associated with any human genetic disorder, although mutations of the genes mutM and mutY, which function in Escherichia coli base excision repair, lead to increased transversions of G:C to T:A. We have studied family N, which is affected with multiple colorectal adenomas and carcinoma but lacks an inherited mutation of the adenomatous polyposis coli gene (APC) that is associated with familial adenomatous polyposis. Here we show that 11 tumors from 3 affected siblings contain 18 somatic inactivating mutations of APC and that 15 of these mutations are G:C-->A transversions--a significantly greater proportion than is found in sporadic tumors or in tumors associated with familial adenomatous polyposis. Analysis of the human homolog of mutY, MYH, showed that the siblings were compound heterozygotes for the nonconservative missense variants Tyr165Cys and Gly382Asp. These mutations affect residues that are conserved in mutY of E. coli (Tyr82 and Gly253). Tyrosine 82 is located in the pseudo-helix-hairpin-helix (HhH) motif and is predicted to function in mismatch specificity. Assays of adenine glycosylase activity of the Tyr82Cys and Gly253Asp mutant proteins with 8-oxoG:A and G:A substrates show that their activity is reduced significantly. Our findings link the inherited variants in MYH to the pattern of somatic APC mutation in family N and implicate defective base excision repair in predisposition to tumors in humans. 相似文献
14.
4-Hydroxynonenal-modified amyloid-beta peptide inhibits the proteasome: possible importance in Alzheimer's disease 总被引:3,自引:0,他引:3
Shringarpure R Grune T Sitte N Davies KJ 《Cellular and molecular life sciences : CMLS》2000,57(12):1802-1809
The amyloid β-peptide (Aβ) is a 4-kDa species derived from the amyloid precursor protein, which accumulates in the brains of patients with Alzheimer’s
disease. Although we lack full understanding of the etiology and pathogenesis of selective neuron death, considerable data
do imply roles for both the toxic Aβ and increased oxidative stress. Another significant observation is the accumulation of abnormal, ubiquitin-conjugated proteins
in affected neurons, suggesting dysfunction of the proteasome proteolytic system in these cells. Recent reports have indicated
that Aβ can bind and inhibit the proteasome, the major cytoslic protease for degrading damaged and ubiquitin-conjugated proteins.
Earlier results from our laboratory showed that moderately oxidized proteins are preferentially recognized and degraded by
the proteasome; however, severely oxidized proteins cannot be easily degraded and, instead, inhibit the proteasome. We hypothesized
that oxidatively modified Aβ might have a stronger (or weaker) inhibitory effect on the proteasome than does native Aβ. We therefore also investigated the proteasome inhibitory action of Aβ
1–40 (a peptide comprising the first 40 residues of Aβ) modified by the intracellular oxidant hydrogen peroxide, and by the lipid peroxidation product 4-hydroxynonenal (HNE). H2O2 modification of Aβ
1–40 generates a progressively poorer inhibitor of the purified human 20S proteasome. In contrast, HNE modification of Aβ
1–40 generates a progressively more selective and efficient inhibitor of the degradation of fluorogenic peptides and oxidized
protein substrates by human 20S proteasome. This interaction may contribute to certain pathological manifestations of Alzheimer’s
disease
Received 26 September 2000; accepted 26 September 2000 相似文献
15.
16.
A highly polymorphic DNA marker linked to adult polycystic kidney disease on chromosome 16 总被引:27,自引:0,他引:27
S T Reeders M H Breuning K E Davies R D Nicholls A P Jarman D R Higgs P L Pearson D J Weatherall 《Nature》1985,317(6037):542-544
Adult polycystic kidney disease (APCKD) is a common and often lethal multi-organ disease with an autosomal dominant pattern of inheritance; approximately 1 in 1,000 people carry the mutant gene. The major pathological abnormality is the development and progressive enlargement of cysts in several organs including the liver, pancreas and spleen as well as the kidneys. The basic biochemical defect which leads to the formation of cysts remains unknown. Cyst development, which is not retarded by any known therapy, leads to irreversible renal failure and death at a mean age of 51 unless dialysis or transplantation are used. Patients with the disease account for 9% of chronic dialysis requirement. The first symptoms tend to occur in the fourth decade, after most patients have reproduced. Presymptomatic diagnosis depends on the ultrasonographic detection of cysts, but exclusion cannot be achieved by this means; 34% of at-risk patients in the second decade and 14% in the third will go on to develop cysts after negative diagnosis. The low sensitivity of diagnostic techniques in this critical age-range imposes severe limitations on genetic counselling and the condition cannot be identified prenatally. Hence we have searched for a linkage marker for APCKD; we show here that the APCKD locus is closely linked to the alpha-globin locus on the short arm of chromosome 16 (zeta = 25.85, theta = 0.05). 相似文献
17.
18.
Insulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility 总被引:30,自引:0,他引:30
C Julier R N Hyer J Davies F Merlin P Soularue L Briant G Cathelineau I Deschamps J I Rotter P Froguel 《Nature》1991,354(6349):155-159
A class of alleles at the VNTR (variable number of tandem repeat) locus in the 5' region of the insulin gene (INS) on chromosome 11p is associated with increased risk of insulin-dependent diabetes mellitus (IDDM), but family studies have failed to demonstrate linkage. INS is thought to contribute to IDDM susceptibility but this view has been difficult to reconcile with the lack of linkage evidence. We thus investigated polymorphisms of INS and neighbouring loci in random diabetics, IDDM multiplex families and controls. HLA-DR4-positive diabetics showed an increased risk associated with common variants at polymorphic sites in a 19-kilobase segment spanned by the 5' INS VNTR and the third intron of the gene for insulin-like growth factor II (IGF2). As INS is the major candidate gene from this region, diabetic and control sequence were compared to identify all INS polymorphisms that could contribute to disease susceptibility. In multiplex families the IDDM-associated alleles were transmitted preferentially to HLA-DR4-positive diabetic offspring from heterozygous parents. The effect was strongest in paternal meioses, suggesting a possible role for maternal imprinting. Our results strongly support the existence of a gene or genes affecting HLA-DR4 IDDM susceptibility which is located in a 19-kilobase region of INS-IGF2. Our results also suggest new ways to map susceptibility loci in other common diseases. 相似文献
19.
Jialu Chen Jemima J. Davies Alister S. Goodfellow Sarah M.D. Hall Helena G. Lancaster Xinyu Liu Cameron J. Rhodes Wuzong Zhou 《自然科学进展(英文版)》2021,31(1):141-151
Dendritic silver and copper crystals were produced via Galvanic replacement reactions on zinc and aluminum plates, respectively. The growth orientations of these metals were determined using electron microscopy. The results showed that a fast crystal growth associated with a high concentration of metal cations led to kinetically controlled growth along the <112> axes of the cubic close-packed structures. However, a slow growth rate resulted in thermodynamically controlled growth along the [111] axis. The crystal growth was not found to rely upon the direct deposition of metal cations at crystallographic sites on crystal facets, but instead, hydrated metal cations deposited on the crystal surface to form an amorphous coating layer, followed by the reduction of metal cations and crystallization at the crystal/coating interface. Twin defects and stacking faults were often observed across the whole particle and commonly observed ?{422} diffraction spots were explained by stacking faults rather than by the possible presence of any superstructures. The present work offers evidences to claim that both the crystal growth rate and Coulomb interaction between negatively charged crystal surface and metal cations play an important role in the formation of metal dendrites in replacement reactions. 相似文献
20.
DNA methylation profiling of human chromosomes 6, 20 and 22 总被引:24,自引:0,他引:24