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141.
Crossan GP van der Weyden L Rosado IV Langevin F Gaillard PH McIntyre RE;Sanger Mouse Genetics Project Gallagher F Kettunen MI Lewis DY Brindle K Arends MJ Adams DJ Patel KJ 《Nature genetics》2011,43(2):147-152
The evolutionarily conserved SLX4 protein, a key regulator of nucleases, is critical for DNA damage response. SLX4 nuclease complexes mediate repair during replication and can also resolve Holliday junctions formed during homologous recombination. Here we describe the phenotype of the Btbd12 knockout mouse, the mouse ortholog of SLX4, which recapitulates many key features of the human genetic illness Fanconi anemia. Btbd12-deficient animals are born at sub-Mendelian ratios, have greatly reduced fertility, are developmentally compromised and are prone to blood cytopenias. Btbd12(-/-) cells prematurely senesce, spontaneously accumulate damaged chromosomes and are particularly sensitive to DNA crosslinking agents. Genetic complementation reveals a crucial requirement for Btbd12 (also known as Slx4) to interact with the structure-specific endonuclease Xpf-Ercc1 to promote crosslink repair. The Btbd12 knockout mouse therefore establishes a disease model for Fanconi anemia and genetically links a regulator of nuclease incision complexes to the Fanconi anemia DNA crosslink repair pathway. 相似文献
142.
Isidor B Lindenbaum P Pichon O Bézieau S Dina C Jacquemont S Martin-Coignard D Thauvin-Robinet C Le Merrer M Mandel JL David A Faivre L Cormier-Daire V Redon R Le Caignec C 《Nature genetics》2011,43(4):306-308
Hajdu-Cheney syndrome is a rare autosomal dominant skeletal disorder with facial anomalies, osteoporosis and acro-osteolysis. We sequenced the exomes of six unrelated individuals with this syndrome and identified heterozygous nonsense and frameshift mutations in NOTCH2 in five of them. All mutations cluster to the last coding exon of the gene, suggesting that the mutant mRNA products escape nonsense-mediated decay and that the resulting truncated NOTCH2 proteins act in a gain-of-function manner. 相似文献
143.
Pan Q Qiao F Gao C Norman B Optican L Zelenka PS 《Cellular and molecular life sciences : CMLS》2011,68(20):3425-3436
The non-receptor tyrosine kinase Src is a critical regulator of cytoskeletal contraction, cell adhesion, and migration. In
normal cells, Src activity is stringently controlled by Csk-dependent phosphorylation of Src(Y530), and by Cullin-5-dependent
ubiquitinylation, which affects active Src(pY419) exclusively, leading to its degradation by the proteosome. Previous work
has shown that Src activity is also limited by Cdk5, a proline-directed kinase, which has been shown to phosphorylate Src(S75).
Here we show that this phosphorylation promotes the ubiquitin-dependent degradation of Src, thus restricting the availability
of active Src. We demonstrate that Src(S75) phosphorylation occurs in vivo in epithelial cells, and like ubiquitinylation,
is associated only with active Src. Preventing Cdk5-dependent phosphorylation of Src(S75), by site-specific mutation of S75
or by Cdk5 inhibition or suppression, increases Src(Y419) phosphorylation and kinase activity, resulting in Src-dependent
cytoskeletal changes. In transfected cells, ubiquitinylation of Src(S75A) is about 35% that of wild-type Src-V5, and its half-life
is approximately 2.5-fold greater. Cdk5 suppression leads to a comparable decrease in the ubiquitinylation of endogenous Src
and a similar increase in Src stability. Together, these findings demonstrate that Cdk5-dependent phosphorylation of Src(S75)
is a physiologically significant mechanism of regulating intracellular Src activity. 相似文献
144.
Amiot L Ferrone S Grosse-Wilde H Seliger B 《Cellular and molecular life sciences : CMLS》2011,68(3):417-431
Although the expression of the non-classical HLA class I molecule HLA-G was first reported to be restricted to the fetal–maternal
interface on the extravillous cytotrophoblasts, the distribution of HLA-G in normal tissues appears broader than originally
described. HLA-G expression was found in embryonic tissues, in adult immune privileged organs, and in cells of the hematopoietic
lineage. More interestingly, under pathophysiological conditions HLA-G antigens may be expressed on various types of malignant
cells suggesting that HLA-G antigen expression is one strategy used by tumor cells to escape immune surveillance. In this
article, we will focus on HLA-G expression in cancers of distinct histology and its association with the clinical course of
diseases, on the underlying molecular mechanisms of impaired HLA-G expression, on the immune tolerant function of HLA-G in
tumors, and on the use of membrane-bound and soluble HLA-G as a diagnostic or prognostic biomarker to identify tumors and
to monitor disease stage, as well as on the use of HLA-G as a novel therapeutic target in cancer. 相似文献
145.
Lubka-Pathak M Shah AA Gallozzi M Müller M Zimmermann U Löwenheim H Pfister M Knipper M Blin N Schimmang T 《Cellular and molecular life sciences : CMLS》2011,68(16):2739-2749
Introduction
Tff3 peptide exerts important functions in cytoprotection and restitution of the gastrointestinal (GI) tract epithelia. Moreover, its presence in the rodent inner ear and involvement in the hearing process was demonstrated recently. However, its role in the auditory system still remains elusive. Our previous results showed a deterioration of hearing with age in Tff3-deficient animals.Results
Present detailed analysis of auditory brain stem response (ABR) measurements and immunohistochemical study of selected functional proteins indicated a normal function and phenotype of the cochlea in Tff3 mutants. However, a microarray-based screening of tissue derived from the auditory central nervous system revealed an alteration of securin (Pttg1) and serpina3n expression between wild-type and Tff3 knock-out animals. This was confirmed by qRT-PCR, immunostaining and western blots.Conclusions
We found highly down-regulated Pttg1 and up-regulated serpina3n expression as a consequence of genetically deleting Tff3 in mice, indicating a potential role of these factors during the development of presbyacusis. 相似文献146.
Freinbichler W Colivicchi MA Stefanini C Bianchi L Ballini C Misini B Weinberger P Linert W Varešlija D Tipton KF Della Corte L 《Cellular and molecular life sciences : CMLS》2011,68(12):2067-2079
The so-called reactive oxygen species (ROS) are defined as oxygen-containing species that are more reactive than O(2) itself, which include hydrogen peroxide and superoxide. Although these are quite stable, they may be converted in the presence of transition metal ions, such as Fe(II), to the highly reactive oxygen species (hROS). hROS may exist as free hydroxyl radicals (HO·), as bound ("crypto") radicals or as Fe(IV)-oxo (ferryl) species and the somewhat less reactive, non-radical species, singlet oxygen. This review outlines the processes by which hROS may be formed, their damaging potential, and the evidence that they might have signaling functions. Since our understanding of the formation and actions of hROS depends on reliable procedures for their detection, particular attention is given to procedures for hROS detection and quantitation and their applicability to in vivo studies. 相似文献
147.
毛乌素沙地的粉尘释放通量观测及DPM模型的野外验证 总被引:5,自引:0,他引:5
目前关于中国粉尘源区的释放通量观测数据很少, 被经常使用的DPM粉尘释放模型在中国源区的可靠性还没有得到验证. 2002年春季在毛乌素沙地开展了野外观测实验, 分别观测了跃移通量、< 10 μm的粉尘释放通量、温度和风速梯度. 观测期间平均摩阻风速在0.26~0.35 m·s-1之间, 实测的跃移通量约在0.07~8.00 g·m-1·s-1之间, 实测和模拟的跃移通量较为一致, 跃移通量方程经验系数取2.61比较合适; 在3次局地的粉尘释放过程中, 实测的粉尘释放通量约在1~3 mg·m-2·s-1之间, 模拟的粉尘释放通量偏高, 说明该模型在低风速条件下还需要校正. 通过与前人数据的比较, 发现松散的砂质土的跃移通量大于具有物理结皮的砂质土和存在大土壤团块的壤质土, 说明在相同摩阻风速条件下, 松散的砂质土的粉尘释放通量最大, 预示中国北方粉尘的主要源地在沙漠和沙漠化的土地. 相似文献
148.
This paper investigated the age-related changes in the expression patterns of maintenance methyltransferase (DNMT1) and de novo methyltransferases (DNMT3a, 3b, 3L) and the chromosome architecture in in-vivo matured mouse oocytes using two-photon laser-scanning microscope. Our results showed that (1) DNMT1 and DNMT3a, 3b, 3L in the oocytes of pubertal mice were located in the cortical region of oocyte cytoplasm. In aging groups, DNMT1 was also located in the cortical region. However, DNMT3a, 3b, 3L had a relatively wider distribution in the oocyte cytoplasm and appeared near the chromosomes. These differences between pubertal and aging groups suggested that aging might affect DNA methylation; (2) the expression of DNMT1, and DNMT3a, 3b in aging groups increased significantly compared to pubertal groups, while, the expression of DNMT3L decreased. These results might be explained by the compensation mechanism among DNMTs, which might be impervious to aging; (3) aging caused increased errors in the distribution and three-dimensional morphology of chromosomes, including the increased total volume and surface area, the high ratio of height to diameter of a circular cylinder enclosing the chromosomes (H/D). Our work provided morphological information for the studies of age-related decline in oocyte qualities. 相似文献
149.
Our world has been changing at an exponential rate.As a result of this rapid growth,we will be forced to make changes in not only the way we live in the environment but also in the environment itself such as designing the cities of the future to be in greater harmony with the increasing population and growing complexity.The paper contains both reflections on global awareness and comprehensive criteria and their priorities for choosing the most desirable city. 相似文献
150.
本文建立了同时考虑轴颈径向位移和歪斜时的滑动轴承动力学模型.对于这种模型,油膜力将扩展为四个广义力分量.文章将相应的动力系数矩阵分解为对称和反对称两部分并讨论其物理性质.然后,本文推导得出该模型的正交变换矩阵,在此基础上导得各向同性的动力系数矩阵表达式,并讨论了诸元素的物理意义.文章最后引入动力系数椭圆的概念以分析非对称动力系数矩阵的变换性质. 相似文献