排序方式: 共有29条查询结果,搜索用时 15 毫秒
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Won H Lee HR Gee HY Mah W Kim JI Lee J Ha S Chung C Jung ES Cho YS Park SG Lee JS Lee K Kim D Bae YC Kaang BK Lee MG Kim E 《Nature》2012,486(7402):261-265
Autism spectrum disorder (ASD) is a group of conditions characterized by impaired social interaction and communication, and restricted and repetitive behaviours. ASD is a highly heritable disorder involving various genetic determinants. Shank2 (also known as ProSAP1) is a multi-domain scaffolding protein and signalling adaptor enriched at excitatory neuronal synapses, and mutations in the human SHANK2 gene have recently been associated with ASD and intellectual disability. Although ASD-associated genes are being increasingly identified and studied using various approaches, including mouse genetics, further efforts are required to delineate important causal mechanisms with the potential for therapeutic application. Here we show that Shank2-mutant (Shank2(-/-)) mice carrying a mutation identical to the ASD-associated microdeletion in the human SHANK2 gene exhibit ASD-like behaviours including reduced social interaction, reduced social communication by ultrasonic vocalizations, and repetitive jumping. These mice show a marked decrease in NMDA (N-methyl-D-aspartate) glutamate receptor (NMDAR) function. Direct stimulation of NMDARs with D-cycloserine, a partial agonist of NMDARs, normalizes NMDAR function and improves social interaction in Shank2(-/-) mice. Furthermore, treatment of Shank2(-/-) mice with a positive allosteric modulator of metabotropic glutamate receptor 5 (mGluR5), which enhances NMDAR function via mGluR5 activation, also normalizes NMDAR function and markedly enhances social interaction. These results suggest that reduced NMDAR function may contribute to the development of ASD-like phenotypes in Shank2(-/-) mice, and mGluR modulation of NMDARs offers a potential strategy to treat ASD. 相似文献
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Geomagnetic intensity variations over the past 780 kyr obtained from near-seafloor magnetic anomalies 总被引:2,自引:0,他引:2
Knowledge of past variations in the intensity of the Earth's magnetic field provides an important constraint on models of the geodynamo. A record of absolute palaeointensity for the past 50 kyr has been compiled from archaeomagnetic and volcanic materials, and relative palaeointensities over the past 800 kyr have been obtained from sedimentary sequences. But a long-term record of geomagnetic intensity should also be carried by the thermoremanence of the oceanic crust Here we show that near-seafloor magnetic anomalies recorded over the southern East Pacific Rise are well correlated with independent estimates of geomagnetic intensity during the past 780 kyr. Moreover, the pattern of absolute palaeointensity of seafloor glass samples from the same area agrees with the well-documented dipole intensity pattern for the past 50 kyr. A comparison of palaeointensities derived from seafloor glass samples with global intensity variations thus allows us to estimate the ages of surficial lava flows in this region. The record of geomagnetic intensity preserved in the oceanic crust should provide a higher-time-resolution record of crustal accretion processes at mid-ocean ridges than has previously been obtainable. 相似文献
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W Zhou EA Otto A Cluckey R Airik TW Hurd M Chaki K Diaz FP Lach GR Bennett HY Gee AK Ghosh S Natarajan S Thongthip U Veturi SJ Allen S Janssen G Ramaswami J Dixon F Burkhalter M Spoendlin H Moch MJ Mihatsch J Verine R Reade H Soliman M Godin D Kiss G Monga G Mazzucco K Amann F Artunc RC Newland T Wiech S Zschiedrich TB Huber A Friedl GG Slaats JA Joles R Goldschmeding J Washburn RH Giles S Levy A Smogorzewska F Hildebrandt 《Nature genetics》2012,44(8):910-915
Chronic kidney disease (CKD) represents a major health burden. Its central feature of renal fibrosis is not well understood. By exome sequencing, we identified mutations in FAN1 as a cause of karyomegalic interstitial nephritis (KIN), a disorder that serves as a model for renal fibrosis. Renal histology in KIN is indistinguishable from that of nephronophthisis, except for the presence of karyomegaly. The FAN1 protein has nuclease activity and acts in DNA interstrand cross-link (ICL) repair within the Fanconi anemia DNA damage response (DDR) pathway. We show that cells from individuals with FAN1 mutations have sensitivity to the ICL-inducing agent mitomycin C but do not exhibit chromosome breakage or cell cycle arrest after diepoxybutane treatment, unlike cells from individuals with Fanconi anemia. We complemented ICL sensitivity with wild-type FAN1 but not with cDNA having mutations found in individuals with KIN. Depletion of fan1 in zebrafish caused increased DDR, apoptosis and kidney cysts. Our findings implicate susceptibility to environmental genotoxins and inadequate DNA repair as novel mechanisms contributing to renal fibrosis and CKD. 相似文献