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1.
Cerebral cavernous malformations (CCMs) affect 0.1–0.5% of the population resulting in leaky vasculature and severe neurological defects. KRIT1 (Krev interaction trapped-1) mutations associate with ∼40% of familial CCMs. KRIT1 is an effector of Ras-related protein 1 (Rap1) GTPase. Rap1 relocalizes KRIT1 from microtubules to cell membranes to impact integrin activation, potentially important for CCM pathology. We report the 1.95 Å co-crystal structure of KRIT1 FERM domain in complex with Rap1. Rap1-KRIT1 interaction encompasses an extended surface, including Rap1 Switch I and II and KRIT1 FERM F1 and F2 lobes. Rap1 binds KRIT1-F1 lobe using a GTPase-ubiquitin-like fold interaction but binds KRIT1-F2 lobe by a novel interaction. Point mutagenesis confirms the interaction. High similarity between KRIT1-F2/F3 and talin is revealed. Additionally, the mechanism for FERM domains acting as GTPase effectors is suggested. Finally, structure-based alignment of each lobe suggests classification of FERM domains as ERM-like and TMFK-like (talin-myosin-FAK-KRIT-like) and that FERM lobes resemble domain “modules.”  相似文献   
2.
The experiment was aimed at demonstrating the relationship between deformities of the front part of the prosoma accompanied by changes in the brain structure in bicephalous Tegenaria atrica and exposure of their embryos to temperature fluctuations. By exposing spider embryos to alternating temperatures of 14 and 32 °C for the first 10 days of embryonic development, we obtained eight two-headed individuals, subsequently divided into three groups according to morphological differences. We described in detail morphological abnormalities of the prosoma identified in members of each group. Histological examination confirmed a close relationship between morphological deformities and the brain structure of teratogenically changed spiders. The fusion of appendages (pedipalps and chalicerae) was accompanied by the fusion of corresponding ganglia. The absence of appendages (pedipalps) was accompanied by the absence of corresponding ganglia. This correlation may have resulted from previously impaired neuromere development which led to changes in the morphological structure of the prosoma. Since no deformities were identified in control animals, it can be concluded that bicephaly was caused by exposing embryos to alternating temperatures.  相似文献   
3.
Group I metabotropic glutamate receptors (mGlu1 and mGlu5) are coupled to polyphosphoinositide hydrolysis and are involved in activity-dependent forms of synaptic plasticity, both during development and in the adult life. Group I mGlu receptors can also regulate proliferation, differentiation, and survival of neural stem/progenitor cells, which further support their role in brain development. An exaggerated response to activation of mGlu5 receptors may underlie synaptic dysfunction in Fragile X syndrome, the most common inherited form of mental retardation. In addition, group I mGlu receptors are overexpressed in dysplastic neurons of focal cortical dysplasia and hemimegaloencephaly, which are disorders of cortical development associated with chronic epilepsy. Drugs that block the activity of group I mGlu receptors (in particular, mGlu5 receptors) are potentially helpful for the treatment of Fragile X syndrome and perhaps other neurodevelopmental disorders.  相似文献   
4.

Background

Expression quantitative trait loci (eQTL) play an important role in the regulation of gene expression. Gene expression levels and eQTLs are expected to vary from tissue to tissue, and therefore multi-tissue analyses are necessary to fully understand complex genetic conditions in humans. Dura mater tissue likely interacts with cranial bone growth and thus may play a role in the etiology of Chiari Type I Malformation (CMI) and related conditions, but it is often inaccessible and its gene expression has not been well studied. A genetic basis to CMI has been established; however, the specific genetic risk factors are not well characterized.

Results

We present an assessment of eQTLs for whole blood and dura mater tissue from individuals with CMI. A joint-tissue analysis identified 239 eQTLs in either dura or blood, with 79% of these eQTLs shared by both tissues. Several identified eQTLs were novel and these implicate genes involved in bone development (IPO8, XYLT1, and PRKAR1A), and ribosomal pathways related to marrow and bone dysfunction, as potential candidates in the development of CMI.

Conclusions

Despite strong overall heterogeneity in expression levels between blood and dura, the majority of cis-eQTLs are shared by both tissues. The power to detect shared eQTLs was improved by using an integrative statistical approach. The identified tissue-specific and shared eQTLs provide new insight into the genetic basis for CMI and related conditions.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-014-1211-8) contains supplementary material, which is available to authorized users.  相似文献   
5.
A total of 289 eggs laid by free-living Canada geese (Branta canadensis canadensis Linnaeus, 1758) in the northwestern part of Germany were collected in spring 2002 and 2003 and examined for shell and embryo parameters. Mean egg mass was 160.88±19.68 g. Approximately 90% of all eggs had a mass between 140 and 185 g. About 90% of all clutches consisted of four to seven eggs. The form index of 90% of all eggs was in the range 62–74. The mean eggshell thickness on the blunt pole was 0.52±0.08 and 0.53±0.07 mm on the long axis. Embryo development follows a square function in the first half of development. Mean embryo length was correlated (P<0.01) with the mean body mass and shell thickness on the blunt pole and on the long axis of the eggs. No significant correlations were found between egg mass and form index and egg mass and shell thickness. Eggs with no visible fertilisation had a mean form index of 68.69±4.53 and fertile eggs had a mean form index of 68.50±3.73. Only 3 of 160 fertile eggs contained embryos with malformations of the beak, vertebral column, or leg. The question of regulating prevailing Canada goose populations is discussed.  相似文献   
6.
目的通过染毒观察二月桂酸二丁基锡(Dibulytin Dilaurate,简称DBTD)对子代胎鼠形态、体重、性别及骨骼发育状的影响。方法按随机分组的原则,将大鼠分为对照组和染毒组,对照组用玉米油,染毒组用DBTD玉米油溶液,浓度分别是2.5 mg/kg体重(1/72 LD50)、10 mg/kg体重(1/18 LD50)和20 mg/kg体重(1/9 LD50),采用灌胃的方式进行染毒,6 d/周,每天同一时间进行染毒,共计染毒48 d。染毒第五周后,各组大鼠与正常雄性大鼠以1:1的比例合笼,合笼期间不染毒,每只雌鼠查到阴栓为妊娠第0天,继续染毒,于妊娠第18天处死取胎鼠。结果1/18 LD50及1/9LD50剂量组中活胎及胎儿的体重明显下降,1/18 LD50剂量组胎儿的性别开始发生明显的变化(P〈0.05)。结论DBTD染毒对大鼠每胎存活数、胎重、胎儿的形态及性别有影响,有一定的生殖毒性。  相似文献   
7.
Of the 414 squirrel monkey pregnancies recorded at this institution since 1977, seven (1.7%) have resulted in offspring with clefts of the lip and/or palate. Associated malformations include a ventricular septal defect, renal agenesis, anal atresia, axial skeletal anomalies, and craniorachischisis (anencephaly and spina bifida). Three of these infants are the result of consanguineous matings.  相似文献   
8.
Cerebral cavernous malformation (CCM) is a disease that affects between 0.1 and 0.5% of the human population, with mutations in CCM3 accounting for ∼15% of the autosomal dominant form of the disease. We recently reported that CCM3 contains an N-terminal dimerization domain (CCM3D) and a C-terminal focal adhesion targeting (FAT) homology domain. Intermolecular protein-protein interactions of CCM3 are mediated by a highly conserved surface on the FAT homology domain and are affected by CCM3 truncations in the human disease. Here we report the crystal structures of CCM3 in complex with three different leucine-aspartate repeat (LD) motifs (LD1, LD2, and LD4) from the scaffolding protein paxillin, at 2.8, 2.7, and 2.5 Å resolution. We show that CCM3 binds LD motifs using the highly conserved hydrophobic patch 1 (HP1) and that this binding is similar to the binding of focal adhesion kinase and Pyk2 FAT domains to paxillin LD motifs. We further show by surface plasmon resonance that CCM3 binds paxillin LD motifs with affinities in the micromolar range, similar to FAK family FAT domains. Finally, we show that endogenous CCM3 and paxillin co-localize in mouse cerebral pericytes. These studies provide a molecular-level framework to investigate the protein-protein interactions of CCM3.  相似文献   
9.
CCM3 mutations are associated with cerebral cavernous malformation (CCM), a disease affecting 0.1–0.5% of the human population. CCM3 (PDCD10, TFAR15) is thought to form a CCM complex with CCM1 and CCM2; however, the molecular basis for these interactions is not known. We have determined the 2.5 Å crystal structure of CCM3. This structure shows an all α-helical protein containing two domains, an N-terminal dimerization domain with a fold not previously observed, and a C-terminal focal adhesion targeting (FAT)-homology domain. We show that CCM3 binds CCM2 via this FAT-homology domain and that mutation of a highly conserved FAK-like hydrophobic pocket (HP1) abrogates CCM3-CCM2 interaction. This CCM3 FAT-homology domain also interacts with paxillin LD motifs using the same surface, and partial CCM3 co-localization with paxillin in cells is lost on HP1 mutation. Disease-related CCM3 truncations affect the FAT-homology domain suggesting a role for the FAT-homology domain in the etiology of CCM.  相似文献   
10.
目的探讨大鼠骨骼发育过程中环境类致畸因子对大鼠骨骼发育的先天性致畸作用。方法应用不同剂量的环境类致畸因子-二噁英(2,3,7,8-tetrachlorodibenzo-p-dioxin,TCDD)构建先天性Wistar大鼠骨骼发育畸形动物模型;茜素红染色法制作并观察透明骨骼标本;采用光镜和透射电镜观察胎鼠趾骨骨化中心的软骨细胞病理学变化及细胞超微结构的改变。结果TCDD在5~15μg/kg浓度下诱导了大鼠骨骼发育畸形,畸形包括:内翻足、脊柱裂、腭裂、无尾畸形等,并存在剂量依赖性生物学效应;光镜下可见在畸形胎鼠的肢端骨化中心软骨发生带缩小,软骨细胞变性。透射扫描电镜下见软骨细胞核内粗面内质网扩张,核基质降解,线粒体嵴不规则。结论在高雌激素水平下,TCDD可以诱导大鼠骨骼发育畸形;TCDD可能通过干扰软骨细胞的形态和功能代谢,引起原发性骨化中心的结构紊乱而发挥骨骼致畸效应。  相似文献   
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