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991.
Marian Plotkin Stanislav Volynchik Zahava Barkay David J.Bergman Jacob S.Ishay 《动物学研究》2009,30(1):65-73
东方大黄蜂(胡蜂)Vespa orientalis(膜翅目Vespinae属)的胃部表皮黄色颗粒位于黄色条纹区域。从黄色颗粒产生至在这一区域扩散,这个过程就是胃部黄颜色形成的过程。用几种电子显微镜研究了黄色颗粒的微观形态和发育过程。结果显示黄色颗粒由20—25 µm厚的一层组成,包括总表皮在内厚度约为40—45 µm。从上面看,在上述的区域能看到许多直径大约为0.5 µm周边光感受器细胞(PPC)。在每个黄色颗粒,能观察到一个肌样包膜,它位于一个由9根原纤维组装而成的圆圈内部。黄色颗粒成熟的过程包含通过导管的渗透增加初生黄色粒子数量,这些初生粒子又发育或增生成次生粒子,次生粒子逐渐布满整个区域。在这些黄色粒子层内可产生类似于肝的功能活动。 相似文献
992.
Galina A. Gusarova Laura A. Dada Aileen M. Kelly Chaya Brodie Lee A. Witters Navdeep S. Chandel Jacob I. Sznajder 《Molecular and cellular biology》2009,29(13):3455-3464
Hypoxia promotes Na,K-ATPase endocytosis via protein kinase Cζ (PKCζ)-mediated phosphorylation of the Na,K-ATPase α subunit. Here, we report that hypoxia leads to the phosphorylation of 5′-AMP-activated protein kinase (AMPK) at Thr172 in rat alveolar epithelial cells. The overexpression of a dominant-negative AMPK α subunit (AMPK-DN) construct prevented the hypoxia-induced endocytosis of Na,K-ATPase. The overexpression of the reactive oxygen species (ROS) scavenger catalase prevented hypoxia-induced AMPK activation. Moreover, hypoxia failed to activate AMPK in mitochondrion-deficient ρ0-A549 cells, suggesting that mitochondrial ROS play an essential role in hypoxia-induced AMPK activation. Hypoxia-induced PKCζ translocation to the plasma membrane and phosphorylation at Thr410 were prevented by the pharmacological inhibition of AMPK or by the overexpression of the AMPK-DN construct. We found that AMPK α phosphorylates PKCζ on residue Thr410 within the PKCζ activation loop. Importantly, the activation of AMPK α was necessary for hypoxia-induced AMPK-PKCζ binding in alveolar epithelial cells. The overexpression of T410A mutant PKCζ prevented hypoxia-induced Na,K-ATPase endocytosis, confirming that PKCζ Thr410 phosphorylation is essential for this process. PKCζ activation by AMPK is isoform specific, as small interfering RNA targeting the α1 but not the α2 catalytic subunit prevented PKCζ activation. Accordingly, we provide the first evidence that hypoxia-generated mitochondrial ROS lead to the activation of the AMPK α1 isoform, which binds and directly phosphorylates PKCζ at Thr410, thereby promoting Na,K-ATPase endocytosis.When exposed to low oxygen levels (hypoxia), cells develop adaptative strategies to maintain adequate levels of ATP (21). These strategies include increasing the efficiency of energy-producing pathways, mostly through anaerobic glycolysis, while decreasing energy-consuming processes such as Na,K-ATPase activity (30). Alveolar hypoxia occurs in many respiratory disorders, and it has been shown to decrease epithelial active Na+ transport, leading to impaired fluid reabsorption (37, 41, 42). Active Na+ transport and, thus, alveolar fluid reabsortion are effected mostly via apical sodium channels and the basolateral Na,K-ATPase (32, 38, 42). We have reported previously that hypoxia inhibits Na,K-ATPase activity by promoting its endocytosis from the plasma membrane by a mechanism that requires the generation of mitochondrial reactive oxygen species (ROS) and the phosphorylation of the Na,K-ATPase α subunit at Ser18 by protein kinase Cζ (PKCζ) (8, 9).The 5′-AMP-activated protein kinase (AMPK) is a heterotrimeric Ser/Thr kinase composed of a catalytic α subunit and regulatory β and γ subunits. Both isoforms of the AMPK catalytic subunit (α1 and α2) form complexes with noncatalytic subunits. The α1 subunit is ubiquitously expressed, whereas the α2 subunit isoform is expressed predominantly in tissues like the liver, heart, and skeletal muscle (36). The α1 and α2 subunit isoforms have ∼90% homology in their N-terminal catalytic domains and ∼60% homology in their C-terminal domains (36), suggesting that they may have distinct downstream targets (31). AMPK activation requires phosphorylation at Thr172 in the activation loop of the α subunit by upstream kinases (12, 19). Findings from recent studies suggest that AMPK is an important signaling intermediary in coupling ion transport and metabolism (15). Indeed, it has been reported that the pharmacological activation of AMPK inhibits amiloride- and ouabain-sensitive epithelial Na+ transport (15). Moreover, the activities of the epithelial Na+ channel (ENaC) (2, 17), the Na,K-ATPase (40), and the cystic fibrosis transmembrane conductance regulator (17) have been shown to be inhibited by AMPK. Here, we provide evidence that hypoxia, via mitochondrial ROS, leads to AMPK activation and that AMPK binds to and directly phosphorylates PKCζ in an isoform-specific manner, thus promoting Na,K-ATPase endocytosis in alveolar epithelial cells (AEC). 相似文献
993.
Michele Jacob Leslie A. Todd R. Sonali Majumdar Yingzhu Li Ken-ichi Yamamoto Ellen Puré 《Cellular signalling》2009,21(8):1308-1316
There are two key processes underlying ligand-induced receptor endocytosis: receptor ubiquitylation and remodeling of the actin cytoskeleton. Tyrosine kinases play critical roles in both receptor endocytosis and actin reorganization. Interestingly, members of the Abl family are the only known tyrosine kinases that possess an actin-binding domain and thus have the potential to directly regulate the actin cytoskeleton. However, the role of non-transforming cAbl in receptor endocytosis remains undefined. We report that cAbl promotes ligand-induced antigen receptor endocytosis in B lymphocytes. We show that pharmacologic inhibition or genetic deletion of cAbl causes a defect in tyrosine phosphorylation of the cytoskeletal adapter CrkII. cAbl inhibition or ablation also impairs Rac activation downstream of CrkII, as well as antigen receptor capping and endocytosis. Although phosphorylation of CrkII has been suggested to maintain it in a closed inactive conformation, we demonstrate that it is in fact essential for the activation of Rac. On the other hand, association of CrkII with cCbl, a key mediator of receptor ubiquitylation, does not require CrkII phosphorylation and is cAbl-independent. Phosphorylation of cCbl itself is also cAbl-independent. Our results thus indicate that CrkII links receptor engagement to cytoskeletal remodeling by coupling cCbl- and cAbl-mediated signaling pathways that cooperatively regulate ligand-induced receptor endocytosis. 相似文献
994.
The ancestors of rock ptarmigan Lagopus muta originated in the Beringia area well before the disruption of the Beringian land bridge. They spread westwards to Siberia and eastwards to the North American arctic and Greenland. The distribution of rock ptarmigan has been affected by glaciations restricting it to geographically limited refugia. Today the species has a circumpolar distribution in arctic tundra and alpine habitats, with up to 30 subspecies recognised based on morphological characters. We sequenced the mitochondrial control region for 72 individuals and genotyped 69 individuals for 12 microsatellite loci to investigate neutral genetic variation within and among five rock ptarmigan populations, Greenland, Iceland, Scandinavia, Svalbard and Taimyr. Genetic structure among the studied samples was high, overall FST estimated from microsatellite loci was 0.18 and only one out of 16 mtDNA haplotypes was found in more than one population. Genetic variation ( h, π, He , allelic richness) was slightly lower in the Svalbard population than in other populations, suggesting a low effective population size, possibly due to isolation following colonisation. An unrooted network and a phylogenetic tree showed that the Scandinavian population has diverged from the other populations by at least ten mutational steps, probably due to independent colonisation of Europe and subsequent long-term isolation, and rules out Scandinavia as a source for colonisation of Svalbard. Alignment with partial control region sequences from other studies showed that the haplotype that was central in our network and found on Svalbard and in Taimyr, most likely corresponds to a haplotype found in Siberia, Alaska and the Canadian Arctic, but not in Greenland, Scandinavia and Iceland. This suggests an eastern origin of rock ptarmigan in Svalbard, although this question cannot be settled conclusively. 相似文献
995.
Mark D’Ascenzo Carl Meacham Jacob Kitzman Christina Middle Jim Knight Roger Winer Miroslav Kukricar Todd Richmond Thomas J. Albert Anne Czechanski Leah Rae Donahue Jason Affourtit Jeffrey A. Jeddeloh Laura Reinholdt 《Mammalian genome》2009,20(7):424-436
Forward genetics (phenotype-driven approaches) remain the primary source for allelic variants in the mouse. Unfortunately,
the gap between observable phenotype and causative genotype limits the widespread use of spontaneous and induced mouse mutants.
As alternatives to traditional positional cloning and mutation detection approaches, sequence capture and next-generation
sequencing technologies can be used to rapidly sequence subsets of the genome. Application of these technologies to mutation
detection efforts in the mouse has the potential to significantly reduce the time and resources required for mutation identification
by abrogating the need for high-resolution genetic mapping, long-range PCR, and sequencing of individual PCR amplimers. As
proof of principle, we used array-based sequence capture and pyrosequencing to sequence an allelic series from the classically
defined Kit locus (~200 kb) from each of five noncomplementing Kit mutants (one known allele and four unknown alleles) and have successfully identified and validated a nonsynonymous coding
mutation for each allele. These data represent the first documentation and validation that these new technologies can be used
to efficiently discover causative mutations. Importantly, these data also provide a specific methodological foundation for
the development of large-scale mutation detection efforts in the laboratory mouse.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
M. D’Ascenzo and C. Meacham contributed equally to this work. 相似文献
996.
997.
Patrick J. Riss Jacob M. Hooker David Alexoff Sung-Won Kim Joanna S. Fowler Frank Rösch 《Bioorganic & medicinal chemistry letters》2009,19(15):4343-4345
PR04.MZ was designed as a highly selective dopamine transporter inhibitor, derived from natural cocaine. Its binding profile indicates that [11C]PR04.MZ may be suited as a PET radioligand for the non-invasive exploration of striatal and extrastriatal DAT populations. As a key feature, its structural design facilitates both, labelling with fluorine-18 at its terminally fluorinated butynyl moiety and carbon-11 at its methyl ester function. The present report concerns the efficient [11C]MeI mediated synthesis of [11C]PR04.MZ from an O-desmethyl precursor trifluoroacetic acid salt with Rb2CO3 in DMF in up to 95 ± 5% labelling yield. A preliminary μPET-experiment demonstrates the reversible, highly specific binding of [11C]PR04.MZ in the brain of a male Sprague–Dawley rat. 相似文献
998.
Richard C. Page Sangwon Lee Jacob D. Moore Stanley J. Opella Timothy A. Cross 《Protein science : a publication of the Protein Society》2009,18(1):134-146
The structural characterization of small integral membrane proteins pose a significant challenge for structural biology because of the multitude of molecular interactions between the protein and its heterogeneous environment. Here, the three‐dimensional backbone structure of Rv1761c from Mycobacterium tuberculosis has been characterized using solution NMR spectroscopy and dodecylphosphocholine (DPC) micelles as a membrane mimetic environment. This 127 residue single transmembrane helix protein has a significant (10 kDa) C‐terminal extramembranous domain. Five hundred and ninety distance, backbone dihedral, and orientational restraints were employed resulting in a 1.16 Å rmsd backbone structure with a transmembrane domain defined at 0.40 Å. The structure determination approach utilized residual dipolar coupling orientation data from partially aligned samples, long‐range paramagnetic relaxation enhancement derived distances, and dihedral restraints from chemical shift indices to determine the global fold. This structural model of Rv1761c displays some influences by the membrane mimetic illustrating that the structure of these membrane proteins is dictated by a combination of the amino acid sequence and the protein's environment. These results demonstrate both the efficacy of the structural approach and the necessity to consider the biophysical properties of membrane mimetics when interpreting structural data of integral membrane proteins and, in particular, small integral membrane proteins. 相似文献
999.
Jacob R. Hascalovici† Jacob Vaya‡ Soliman Khatib‡ Christina A. Holcroft§ Hillel Zukor† Wei Song Zoe Arvanitakis¶ David A. Bennett¶ Hyman M. Schipper† 《Journal of neurochemistry》2009,110(4):1241-1253
The objective of this study was to ascertain the impact of aging and Alzheimer's disease (AD) on brain cholesterol (CH), CH precursors, and oxysterol homeostasis. Altered CH metabolism and up-regulation of heme oxygenase-1 (HO-1) are characteristic of AD-affected neural tissues. We recently determined that HO-1 over-expression suppresses total CH levels by augmenting liver X receptor-mediated CH efflux and enhances oxysterol formation in cultured astroglia. Lipids and proteins were extracted from postmortem human frontal cortex derived from subjects with sporadic AD, mild cognitive impairment (MCI), and no cognitive impairment ( n = 17 per group) enrolled in the Religious Orders Study, an ongoing clinical-pathologic study of aging and AD. ELISA was used to quantify human HO-1 protein expression from brain tissue and gas chromatography–mass spectrometry to quantify total CH, CH precursors, and relevant oxysterols. The relationships of sterol/oxysterol levels to HO-1 protein expression and clinical/demographic variables were determined by multivariable regression and non-parametric statistical analyses. Decreased CH, increased oxysterol and increased CH precursors concentrations in the cortex correlated significantly with HO-1 levels in MCI and AD, but not no cognitive impairment. Specific oxysterols correlated with disease state, increasing neuropathological burden, neuropsychological impairment, and age. A model featuring compensated and de-compensated states of altered sterol homeostasis in MCI and AD is presented based on the current data set and our earlier in vitro work. 相似文献
1000.
Androgens affect cognitive processes in both humans and animals. The effects of androgens may be limited to certain cognitive domains, specifically spatial memory, but this hypothesis remains elusive. Here, we tested castrated and sham-operated mice in various behavioral tasks to ask whether androgens affect multiple or specific cognitive domains in male mice. Castration impaired spatial working memory performance in the delayed matching to place water maze task following a 1-h, but not a 1-min, retention interval, as has been reported for rats. In contrast, castration had no effect on novel object recognition memory, spatial reference memory in the water maze, motor coordination, or passive avoidance memory. Castration increased anxiety-like behavior in the open field test, but not the elevated zero maze. Finally, we assessed the effects of androgen replacement with non-aromatizable dihydrotestosterone on spatial working memory following various retention intervals. Dihydrotestosterone recovered spatial memory performance following a 24-h, but not a 1-h retention interval, and had no effect at other retention intervals. These data support that in male mice androgens specifically affect spatial working memory performance, and that the neurobiological processes underlying spatial memory formation may be differentially affected by androgens. 相似文献