Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome

Protein-protein interaction analyses have uncovered a ciliary and basal body protein network that, when disrupted, can result in nephronophthisis (NPHP), Leber congenital amaurosis, Senior-L?ken syndrome (SLSN) or Joubert syndrome (JBTS). However, details of the molecular mechanisms underlying these disorders remain poorly understood. RPGRIP1-like protein (RPGRIP1L) is a homolog of RPGRIP1 (RPGR-interacting protein 1), a ciliary protein defective in Leber congenital amaurosis. We show that RPGRIP1L interacts with nephrocystin-4 and that mutations in the gene encoding nephrocystin-4 (NPHP4) that are known to cause SLSN disrupt this interaction. RPGRIP1L is ubiquitously expressed, and its protein product localizes to basal bodies. Therefore, we analyzed RPGRIP1L as a candidate gene for JBTS and identified loss-of-function mutations in three families with typical JBTS, including the characteristic mid-hindbrain malformation. This work identifies RPGRIP1L as a gene responsible for JBTS and establishes a central role for cilia and basal bodies in the pathophysiology of this disorder.     

管材超声检测中导波模式及频厚积的选择

用轴向功率流分布来选择检测自由管状结构的最佳导波模式及其最佳频厚积 ,并将混合边界元法应用于管状结构 ,对其结果的有效性进行了验证 .结果表明 :对于自由管材 ,用超声纵向L(0 ,1)模式检测时 ,频厚积在 0 .15MHz·mm以下时较为灵敏 ;用L(0 ,2 )模式检测时 ,在 1.4～ 1.8MHz·mm之间对检测管壁中央的缺陷较灵敏 ;用L(0 ,3)模式检测时 ,在 2 .0MHz·mm以下对管内外表面上的缺陷都较灵敏 .轴向功率流分布能有效地选择检测的最佳导波模式及其频厚积 .     

肌肉自发振动过程中结合几率与化学反应速率的变化

定量分析肌球蛋白与肌动蛋白丝的结合几率及相关化学反应的速率常数,对于准确掌握肌肉收缩的内在机制具有非常重要的意义.以肌肉自发振动的实验结果为依据,从振动过程所满足的动力学方程出发,推导出结合几率与肌丝滑行速度及肌节长度之间的定量关系,并求得化学反应速率随肌肉收缩的速度变化而改变的数学规律.结果显示,结合几率的基准值由溶液中主要化学成分的浓度决定;结合几率的变化值与肌肉收缩的速度成正比,与肌节长度成反比;而化学反应速率随收缩速度按指数规律变化.上述结果与实验值基本一致.     

Identification of stem cells in small intestine and colon by marker gene Lgr5

The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. It is currently believed that four to six crypt stem cells reside at the +4 position immediately above the Paneth cells in the small intestine; colon stem cells remain undefined. Lgr5 (leucine-rich-repeat-containing G-protein-coupled receptor 5, also known as Gpr49) was selected from a panel of intestinal Wnt target genes for its restricted crypt expression. Here, using two knock-in alleles, we reveal exclusive expression of Lgr5 in cycling columnar cells at the crypt base. In addition, Lgr5 was expressed in rare cells in several other tissues. Using an inducible Cre knock-in allele and the Rosa26-lacZ reporter strain, lineage-tracing experiments were performed in adult mice. The Lgr5-positive crypt base columnar cell generated all epithelial lineages over a 60-day period, suggesting that it represents the stem cell of the small intestine and colon. The expression pattern of Lgr5 suggests that it marks stem cells in multiple adult tissues and cancers.     

Oxysterols direct immune cell migration via EBI2

Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) is a G-protein-coupled receptor that is required for humoral immune responses; polymorphisms in the receptor have been associated with inflammatory autoimmune diseases. The natural ligand for EBI2 has been unknown. Here we describe the identification of 7α,25-dihydroxycholesterol (also called 7α,25-OHC or 5-cholesten-3β,7α,25-triol) as a potent and selective agonist of EBI2. Functional activation of human EBI2 by 7α,25-OHC and closely related oxysterols was verified by monitoring second messenger readouts and saturable, high-affinity radioligand binding. Furthermore, we find that 7α,25-OHC and closely related oxysterols act as chemoattractants for immune cells expressing EBI2 by directing cell migration in vitro and in vivo. A critical enzyme required for the generation of 7α,25-OHC is cholesterol 25-hydroxylase (CH25H). Similar to EBI2 receptor knockout mice, mice deficient in CH25H fail to position activated B cells within the spleen to the outer follicle and mount a reduced plasma cell response after an immune challenge. This demonstrates that CH25H generates EBI2 biological activity in vivo and indicates that the EBI2-oxysterol signalling pathway has an important role in the adaptive immune response.     

Experimentelle Reversion von Tumorzellen in vivo

Summary European eels with fast growing epidermal papillomas (cauliflower disease) were treated with quinine-sulphate. At concentrations of 15 to 60 mg/l and after 8 weeks of treatment, there occurred newly formed mucous cells and club cells in the tumor tissue. Tight contact between all cells was reestablished. The nucleus-plasma-relation had evidently decreased. Electron microscopical studies showed a restauration of degenerated cell organelles, especially of the outer membrane. Growth rate of the tumors was reduced, and at a concentration of 60 mg/l the tumor tissue ceased growing from the beginning of treatment.     

Mechanism of the fall in blood pressure after ‘unclamping’ in rats with Goldblatt-type hypertension

Résumé Chez le rat hypertendu par constriction partielle d'une artère rénale et néphrectomie controlatérale, la suppression chirurgicale de la constriction entraîne une normalisation de la pression artérielle et une excrétion urinaire importante d'eau et de sodium; la ligature préalable de l'uretère empêche la normalisation de la pression.