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81.
Rolandos Constantinides Stavroulla Xenophontos Pavlos Neophytou Shinsuke Nomura Alkis Pierides C. Constantinou Deltas 《Human genetics》1997,99(5):644-647
The PKD1 gene, which is responsible for the most common form of autosomal dominant polycystic kidney disease, has recently
been cloned and sequenced. Many disease-causing mutations have been characterized in this gene, most of them resulting in
premature protein termination. However, mutation analysis is not routinely implemented for family investigations in a clinical
setting, because of the large size and complexity of the gene. Instead, genetic linkage analysis using highly polymorphic
CA dinucleotide repeats that map around the gene is still the method of choice. Recently, a few intragenic polymorphisms have
been described that are also useful for linkage studies. Here, a new diallelic polymorphism is described for amino acid residue
4058, Ala/Val4058, with allelic frequencies of 0.88 and 0.12, respectively, and a heterozygosity of 0.23, in the Greek and
Greek-Cypriot populations. Interestingly, this polymorphism and Ala4091-A/G, which has previously been described in Caucasians,
were not detected in DNA from 44 Japanese samples tested. This is particularly important when allelic frequencies in a particular
population are used for linkage analysis of families of different ethnic origin. Also, observation of the two polymorphisms
together as haplotypes suggests that the Ala/Val4058 polymorphism occurred more recently than the establishment of the Ala4091-A/G
polymorphism, and specifically on the G allele.
Received: 24 September 1996 相似文献
82.
Cyanidin Chloride inhibits ovariectomy‐induced osteoporosis by suppressing RANKL‐mediated osteoclastogenesis and associated signaling pathways 下载免费PDF全文
83.
Vacuolar-type H(+)-ATPases (V-ATPases) are macromolecular proton pumps that acidify intracellular cargos and deliver protons across the plasma membrane of a variety of specialized cells, including bone-resorbing osteoclasts. Extracellular acidification is crucial for osteoclastic bone resorption, a process that initiates the dissolution of mineralized bone matrix. While the importance of V-ATPases in osteoclastic resorptive function is well-defined, whether V-ATPases facilitate additional aspects of osteoclast function and/or formation remains largely obscure. Here we report that the V-ATPase accessory subunit Ac45 participates in both osteoclast formation and function. Using a siRNA-based approach, we show that targeted suppression of Ac45 impairs intracellular acidification and endocytosis, both are prerequisite for osteoclastic bone resorptive function in vitro. Interestingly, we find that knockdown of Ac45 also attenuates osteoclastogenesis owing to a reduced fusion capacity of osteoclastic precursor cells. Finally, in an effort to gain more detailed insights into the functional role of Ac45 in osteoclasts, we attempted to generate osteoclast-specific Ac45 conditional knockout mice using a Cathepsin K-Cre-LoxP system. Surprisingly, however, insertion of the neomycin cassette in the Ac45-Flox(Neo) mice resulted in marked disturbances in CNS development and ensuing embryonic lethality thus precluding functional assessment of Ac45 in osteoclasts and peripheral bone tissues. Based on these unexpected findings we propose that, in addition to its canonical function in V-ATPase-mediated acidification, Ac45 plays versatile roles during osteoclast formation and function. 相似文献
84.
Evidence of reciprocal regulation between the high extracellular calcium and RANKL signal transduction pathways in RAW cell derived osteoclasts 总被引:3,自引:0,他引:3
Xu J Wang C Han R Pavlos N Phan T Steer JH Bakker AJ Joyce DA Zheng MH 《Journal of cellular physiology》2005,202(2):554-562
During bone resorption, osteoclasts are exposed to high Ca2+ concentrations (up to 40 mM). The role of high extracellular Ca2+ in receptor activator of NF-kappaB ligand (RANKL)-mediated osteoclast survival and their functional interrelationship is unclear. In this study, we show that RANKL enhances osteoclast tolerance to high extracellular Ca2+ by protecting the cell from cell death in a dose dependent manner. We have provided evidence that RANKL does this by attenuating high extracellular Ca2+-induced Ca2+ elevations. Moreover, we have found that high extracellular Ca2+-induced cell death was partially inhibited by a caspase-3 inhibitor, suggesting caspase-3-mediated apoptosis is involved. Conversely, using reporter gene assays and Western blot analysis, we have demonstrated that high extracellular Ca2+ desensitizes the RANKL-induced activation of NF-kappaB and c-Jun N-terminal kinase (JNK), and inhibits constitutive and RANKL-stimulated ERK phosphorylation, indicating a negative feed-back mechanism via specific RANKL signaling pathways. Taken together, this study provides evidence for a reciprocal regulation between high extracellular Ca2+ and RANKL signaling in RAW cell derived osteoclasts. Our data imply a cross talk mechanism of extracellular Ca2+ on osteoclast survival through the regulation of RANKL. 相似文献
85.
Wear particle-induced peri-implant loosening (Aseptic prosthetic loosening) is one of the most common causes of total joint arthroplasty. It is well established that extensive bone destruction (osteolysis) by osteoclasts is responsible for wear particle-induced peri-implant loosening. Thus, inhibition of osteoclastic bone resorption should prevent wear particle induced osteolysis and may serve as a potential therapeutic avenue for prosthetic loosening. Here, we demonstrate for the first time that saliphenylhalamide, a new V-ATPase inhibitor attenuates wear particle-induced osteolysis in a mouse calvarial model. In vitro biochemical and morphological assays revealed that the inhibition of osteolysis is partially attributed to a disruption in osteoclast acidification and polarization, both a prerequisite for osteoclast bone resorption. Interestingly, the V-ATPase inhibitor also impaired osteoclast differentiation via the inhibition of RANKL-induced NF-κB and ERK signaling pathways. In conclusion, we showed that saliphenylhalamide affected multiple physiological processes including osteoclast differentiation, acidification and polarization, leading to inhibition of osteoclast bone resorption in vitro and wear particle-induced osteolysis in vivo. The results of the study provide proof that the new generation V-ATPase inhibitors, such as saliphenylhalamide, are potential anti-resorptive agents for treatment of peri-implant osteolysis. 相似文献
86.
We study the trajectory of an allele that affects a polygenic trait selected toward a phenotypic optimum. Furthermore, conditioning on this trajectory we analyze the effect of the selected mutation on linked neutral variation. We examine the well-characterized two-locus two-allele model but we also provide results for diallelic models with up to eight loci. First, when the optimum phenotype is that of the double heterozygote in a two-locus model, and there is no dominance or epistasis of effects on the trait, the trajectories of selected mutations rarely reach fixation; instead, a polymorphic equilibrium at both loci is approached. Whether a polymorphic equilibrium is reached (rather than fixation at both loci) depends on the intensity of selection and the relative distances to the optimum of the homozygotes at each locus. Furthermore, if both loci have similar effects on the trait, fixation of an allele at a given locus is less likely when it starts at low frequency and the other locus is polymorphic (with alleles at intermediate frequencies). Weaker selection increases the probability of fixation of the studied allele, as the polymorphic equilibrium is less stable in this case. When we do not require the double heterozygote to be at the optimum we find that the polymorphic equilibrium is more difficult to reach, and fixation becomes more likely. Second, increasing the number of loci decreases the probability of fixation, because adaptation to the optimum is possible by various combinations of alleles. Summaries of the genealogy (height, total length, and imbalance) and of sequence polymorphism (number of polymorphisms, frequency spectrum, and haplotype structure) next to a selected locus depend on the frequency that the selected mutation approaches at equilibrium. We conclude that multilocus response to selection may in some cases prevent selective sweeps from being completed, as described in previous studies, but that conditions causing this to happen strongly depend on the genetic architecture of the trait, and that fixation of selected mutations is likely in many instances. 相似文献
87.
Takumi Ueda Naoko Nomoto Masamichi Koga Hiroki Ogasa Yuuta Ogawa Masahiko Matsumoto Pavlos Stampoulis Koji Sode Hiroaki Terasawa Ichio Shimada 《The Plant cell》2012,24(10):4173-4186
In the photosynthetic light reactions of plants and cyanobacteria, plastocyanin (Pc) plays a crucial role as an electron carrier and shuttle protein between two membrane protein complexes: cytochrome b6f (cyt b6f) and photosystem I (PSI). The rapid turnover of Pc between cyt b6f and PSI enables the efficient use of light energy. In the Pc-cyt b6f and Pc-PSI electron transfer complexes, the electron transfer reactions are accomplished within <10−4 s. However, the mechanisms enabling the rapid association and dissociation of Pc are still unclear because of the lack of an appropriate method to study huge complexes with short lifetimes. Here, using the transferred cross-saturation method, we investigated the residues of spinach (Spinacia oleracea) Pc in close proximity to spinach PSI and cyt b6f, in both the thylakoid vesicle–embedded and solubilized states. We demonstrated that the hydrophobic patch residues of Pc are in close proximity to PSI and cyt b6f, whereas the acidic patch residues of Pc do not form stable salt bridges with either PSI or cyt b6f, in the electron transfer complexes. The transient characteristics of the interactions on the acidic patch facilitate the rapid association and dissociation of Pc. 相似文献
88.
Chim SM Qin A Tickner J Pavlos N Davey T Wang H Guo Y Zheng MH Xu J 《The Journal of biological chemistry》2011,286(25):22035-22046
Angiogenesis is required for bone development, growth, and repair. It is influenced by the local bone environment that involves cross-talks between endothelial cells and adjacent bone cells. However, data regarding factors that directly contribute to angiogenesis by bone cells remain poorly understood. Here, we report that EGFL6, a member of the epidermal growth factor (EGF) repeat superfamily proteins, induces angiogenesis by a paracrine mechanism in which EGFL6 is expressed in osteoblastic-like cells but promotes migration and angiogenesis of endothelial cells. Co-immunoprecipitation assays revealed that EGFL6 is secreted in culture medium as a homodimer protein. Using scratch wound healing and transwell assays, we found that conditioned medium containing EGFL6 potentiates SVEC (a simian virus 40-transformed mouse microvascular endothelial cell line) endothelial cell migration. In addition, EGFL6 promotes the endothelial cell tube-like structure formation in Matrigel assays and angiogenesis in a chick embryo chorioallantoic membrane. Furthermore, we show that EGFL6 recombinant protein induces phosphorylation of ERK in SVEC endothelial cells. Inhibition of ERK impaired EGFL6-induced ERK activation and endothelial cell migration. Together, these results demonstrate, for the first time, that osteoblastic-like cells express EGFL6 that is capable of promoting endothelial cell migration and angiogenesis via ERK activation. Thus, the EGLF6 mediates a paracrine mechanism of cross-talk between vascular endothelial cells and osteoblasts and might offer an important new target for the potential treatment of bone diseases, including osteonecrosis, osteoporosis, and fracture healing. 相似文献
89.
Mice fed a high-fat, low-carbohydrate ketogenic diet (KD) exhibit marked changes in hepatic metabolism and energy homeostasis. Here, we identify liver-derived fibroblast growth factor 21 (FGF21) as an endocrine regulator of the ketotic state. Hepatic expression and circulating levels of FGF21 are induced by both KD and fasting, are rapidly suppressed by refeeding, and are in large part downstream of PPARα. Importantly, adenoviral knockdown of hepatic FGF21 in KD-fed mice causes fatty liver, lipemia, and reduced serum ketones, due at least in part to altered expression of key genes governing lipid and ketone metabolism. Hence, induction of FGF21 in liver is required for the normal activation of hepatic lipid oxidation, triglyceride clearance, and ketogenesis induced by KD. These findings identify hepatic FGF21 as a critical regulator of lipid homeostasis and identify a physiological role for this hepatic hormone. 相似文献
90.
M Eisenhardt A Glässner B Krämer C Körner B Sibbing P Kokordelis HD Nischalke T Sauerbruch U Spengler J Nattermann 《PloS one》2012,7(7):e38846