A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition

Mutations affecting ciliary components cause ciliopathies. As described here, we investigated Tectonic1 (Tctn1), a regulator of mouse Hedgehog signaling, and found that it is essential for ciliogenesis in some, but not all, tissues. Cell types that do not require Tctn1 for ciliogenesis require it to localize select membrane-associated proteins to the cilium, including Arl13b, AC3, Smoothened and Pkd2. Tctn1 forms a complex with multiple ciliopathy proteins associated with Meckel and Joubert syndromes, including Mks1, Tmem216, Tmem67, Cep290, B9d1, Tctn2 and Cc2d2a. Components of this complex co-localize at the transition zone, a region between the basal body and ciliary axoneme. Like Tctn1, loss of Tctn2, Tmem67 or Cc2d2a causes tissue-specific defects in ciliogenesis and ciliary membrane composition. Consistent with a shared function for complex components, we identified a mutation in TCTN1 that causes Joubert syndrome. Thus, a transition zone complex of Meckel and Joubert syndrome proteins regulates ciliary assembly and trafficking, suggesting that transition zone dysfunction is the cause of these ciliopathies.     

Nck adaptor proteins link nephrin to the actin cytoskeleton of kidney podocytes

The glomerular filtration barrier in the kidney is formed in part by a specialized intercellular junction known as the slit diaphragm, which connects adjacent actin-based foot processes of kidney epithelial cells (podocytes). Mutations affecting a number of slit diaphragm proteins, including nephrin (encoded by NPHS1), lead to renal disease owing to disruption of the filtration barrier and rearrangement of the actin cytoskeleton, although the molecular basis for this is unclear. Here we show that nephrin selectively binds the Src homology 2 (SH2)/SH3 domain-containing Nck adaptor proteins, which in turn control the podocyte cytoskeleton in vivo. The cytoplasmic tail of nephrin has multiple YDxV sites that form preferred binding motifs for the Nck SH2 domain once phosphorylated by Src-family kinases. We show that this Nck-nephrin interaction is required for nephrin-dependent actin reorganization. Selective deletion of Nck from podocytes of transgenic mice results in defects in the formation of foot processes and in congenital nephrotic syndrome. Together, these findings identify a physiological signalling pathway in which nephrin is linked through phosphotyrosine-based interactions to Nck adaptors, and thus to the underlying actin cytoskeleton in podocytes. Simple and widely expressed SH2/SH3 adaptor proteins can therefore direct the formation of a specialized cellular morphology in vivo.     

Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination

Nephronophthisis (NPHP), an autosomal recessive cystic kidney disease, leads to chronic renal failure in children. The genes mutated in NPHP1 and NPHP4 have been identified, and a gene locus associated with infantile nephronophthisis (NPHP2) was mapped. The kidney phenotype of NPHP2 combines clinical features of NPHP and polycystic kidney disease (PKD). Here, we identify inversin (INVS) as the gene mutated in NPHP2 with and without situs inversus. We show molecular interaction of inversin with nephrocystin, the product of the gene mutated in NPHP1 and interaction of nephrocystin with beta-tubulin, a main component of primary cilia. We show that nephrocystin, inversin and beta-tubulin colocalize to primary cilia of renal tubular cells. Furthermore, we produce a PKD-like renal cystic phenotype and randomization of heart looping by knockdown of invs expression in zebrafish. The interaction and colocalization in cilia of inversin, nephrocystin and beta-tubulin connect pathogenetic aspects of NPHP to PKD, to primary cilia function and to left-right axis determination.     

Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin

Nephronophthisis (NPHP) is the most frequent genetic cause of chronic renal failure in children. Identification of four genes mutated in NPHP subtypes 1-4 (refs. 4-9) has linked the pathogenesis of NPHP to ciliary functions. Ten percent of affected individuals have retinitis pigmentosa, constituting the renal-retinal Senior-Loken syndrome (SLSN). Here we identify, by positional cloning, mutations in an evolutionarily conserved gene, IQCB1 (also called NPHP5), as the most frequent cause of SLSN. IQCB1 encodes an IQ-domain protein, nephrocystin-5. All individuals with IQCB1 mutations have retinitis pigmentosa. Hence, we examined the interaction of nephrocystin-5 with RPGR (retinitis pigmentosa GTPase regulator), which is expressed in photoreceptor cilia and associated with 10-20% of retinitis pigmentosa. We show that nephrocystin-5, RPGR and calmodulin can be coimmunoprecipitated from retinal extracts, and that these proteins localize to connecting cilia of photoreceptors and to primary cilia of renal epithelial cells. Our studies emphasize the central role of ciliary dysfunction in the pathogenesis of SLSN.     

Neue Gesichtspunkte zum 5. Buch Euklids

Summary The author's purpose is to read the main work of Euclid with modern eyes and to find out what knowledge a mathematician of today, familiar with the works of V. D. Waerden and Bourbaki, can gain by studying Euclid's theory of magnitudes, and what new insight into Greek mathematics occupation with this subject can provide.The task is to analyse and to axiomatize by modern means (i) in a narrower sense Book V. of the Elements, i.e. the theory of proportion of Eudoxus, (ii) in a wider sense the whole sphere of magnitudes which Euclid applies in his Elements. This procedure furnishes a clear picture of the inherent structure of his work, thereby making visible specific characteristics of Greek mathematics.After a clarification of the preconditions and a short survey of the historical development of the theory of proportions (Part I of this work), an exact analysis of the definitions and propositions of Book V. of the Elements is carried out in Part II. This is done word by word. The author applies his own system of axioms, set up in close accordance with Euclid, which permits one to deduce all definitions and propositions of Euclid's theory of magnitudes (especially those of Books V. and VI.).In this way gaps and tacit assumptions in the work become clearly visible; above all, the logical structure of the system of magnitudes given by Euclid becomes evident: not ratio — like something sui generis — is the governing concept of Book V., but magnitudes and their relation of having a ratio form the base of the theory of proportions. These magnitudes represent a well defined structure, a so-called Eudoxic Semigroup with the numbers as operators; it can easily be imbedded in a general theory of magnitudes equally applicable to geometry and physics.The transition to ratios — a step not executed by Euclid — is examined in Part III; it turns out to be particularly unwieldy. An elegant way opens up by interpreting proportion as a mapping of totally ordered semigroups. When closely examined, this mapping proves to be an isomorphism, thus suggesting the application of the modern theory of homomorphism. This theory permits a treatment of the theory of proportions as developed by Eudoxus and Euclid which is hardly surpassable in brevity and elegance in spite of its close affinity to Euclid. The generalization to a classically founded theory of magnitudes is now self-evident.

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Vorgelegt von J. E. Hofmann     

考虑加载历史的约束混凝土动力本构模型

客观描述高应变率作用下的约束混凝土的力学行为需要考虑加载历史.将具有该特点的Eibl和SchmidtHurtienne凝土动力模型推广,使之适用于约束混凝土.采用四段式约束混凝土单轴受压应力-应变曲线,以确定模型中的静力损伤发展;利用混凝土动力试验结果并通过数值迭代,给出约束混凝土动力损伤延迟中参数的确定方法,从而得到了模型中的动力损伤延迟.算例表明,给出的方法可以较客观地描述一定范围应变率作用下约束混凝土的力学行为.     

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10?12) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10?11) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10??) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10?11) and a tag SNP for NAT2 acetylation status (P = 4 × 10?11), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis.