Primary cilia are implicated in the pathogenesis of autosomal-dominant polycystic kidney disease (ADPKD), which results from defects in polycystin-1 (PC1), but the function of PC1 remains poorly understood. Here, we show that PC1 undergoes proteolytic cleavage that results in nuclear translocation of its cytoplasmic tail. The PC1 tail interacts with the transcription factor STAT6 and the coactivator P100, and it stimulates STAT6-dependent gene expression. Under normal conditions, STAT6 localizes to primary cilia of renal epithelial cells. Cessation of apical fluid flow results in nuclear translocation of STAT6. Cyst-lining cells in ADPKD exhibit elevated levels of nuclear STAT6, P100, and the PC1 tail. Exogenous expression of the human PC1 tail results in renal cyst formation in zebrafish embryos. These results identify a novel mechanism of cilia function in the transduction of a mechanical signal to changes of gene expression involving PC1 and show that this pathway is inappropriately activated in ADPKD.

Mutations in polycystin-1 (PC1) lead to autosomal-dominant polycystic kidney disease (ADPKD), a leading cause of renal failure for which no treatment is available. PC1 is an integral membrane protein, which has been implicated in the regulation of multiple signaling pathways including the JAK/STAT pathway. Here we show that membrane-anchored PC1 activates STAT3 in a JAK2-dependent manner, leading to tyrosine phosphorylation and transcriptional activity. The C-terminal cytoplasmic tail of PC1 can undergo proteolytic cleavage and nuclear translocation. Tail-cleavage abolishes the ability of PC1 to directly activate STAT3 but the cleaved PC1 tail now coactivates STAT3 in a mechanism requiring STAT phosphorylation by cytokines or growth factors. This leads to an exaggerated cytokine response. Hence, PC1 can regulate STAT activity by a dual mechanism. In ADPKD kidneys PC1 tail fragments are overexpressed, including a unique ∼15-kDa fragment (P15). STAT3 is strongly activated in cyst-lining epithelial cells in human ADPKD, and orthologous and nonorthologous polycystic mouse models. STAT3 is also activated in developing, postnatal kidneys but inactivated in adult kidneys. These results indicate that STAT3 signaling is regulated by PC1 and is a driving factor for renal epithelial proliferation during normal renal development and during cyst growth.A utosomal-dominant polycystic kidney disease (ADPKD) is a common life-threatening genetic disease and leading cause of renal failure (1-4). Epithelial-lined cysts develop due to excessive proliferation leading to renal enlargement and destruction of functional renal tissue. No treatment is available to slow disease progression. PKD1 gene mutations cause the majority of cases but the exact function of its gene product, polycystin-1 (PC1), has remained poorly understood. Confusing the issue is the fact that both loss of PC1 as well as PC1 overexpression lead to renal cyst growth in mouse models. Furthermore, in human ADPKD, each clonal cyst within the same patient is thought to exhibit a unique combination of germline and acquired mutations that results in a cyst-by-cyst mosaic of genotypes and resulting variation of expression levels of PC1 harboring various mutations. PC1 has also been implicated in a puzzling variety of intracellular signaling events including JAK-STAT signaling (5, 6) and it has been difficult to elucidate which of these functions may be most important for renal cyst growth in ADPKD.Disruption of primary cilia in kidney epithelial cells leads to proliferation and cyst growth (7). PC1 has been shown to function in ciliary mechanotransduction, and a potential molecular mechanism emerged from the discovery that PC1 undergoes proteolytic cleavage, releasing the C-terminal cytoplasmic tail (∼30 kDa) from the membrane, followed by nuclear translocation (2, 5). PC1 cleavage is triggered upon the cessation of luminal fluid flow (2). The cleaved PC1 tail interacts with the transcription factors STAT6 and P100, enhances STAT6 activity, and STAT6 translocates between ...

La 2 NiMnO 6 has been reported to exhibit a paramagnetic to ferromagnetic transition with a transition temperature of ∼260 K. However, most of its magnetic properties, such as the saturation magnetization and even the transition temperature, appear to vary considerably among different reports. This is possibly because the crystallographic structure as well as the extent of the anti-site disorder (ASD) at the Ni/Mn sites are strongly influence by the choice of synthesis routes. There are diverse reports connecting the extent of ASD to the valencies of Ni and Mn ion, such as, Ni 2+-Mn 4+ and Ni 3+-Mn 3+ including suggestions of thermally induced valence transitions. Consequently, these reports arrive at very different conclusions on the mechanism behind magnetic properties of La 2 NiMnO 6. To address the correlation between ASD and valency, we have carried out a comparative study of two monoclinic La 2 NiMnO 6 polycrystal with different degrees of ASD. Using a combination of x-ray absorption spectroscopy, x-ray magnetic circular dichroism and magnetometry, we conclude that the valency of the transition metal ions, and the transition temperature are insensitive to the extent of ASD. However, we find the magnetic moment decreases strongly with an increasing ASD. We attribute this effect to the introduction of antiferromagnetic interactions in the anti-site disordered regions.

Autosomal-dominant (AD) polycystic kidney disease (PKD) is a leading cause of renal failure in the United States, and currently lacks available treatment options to slow disease progression. Mutations in the gene coding for polycystin-1 (PC1) underlie the majority of cases but the function of PC1 has remained poorly understood. We have previously shown that PC1 regulates the transcriptional activity of signal transducer and activator of transcription-6 (STAT6). Here we show that STAT6 is aberrantly activated in cyst-lining cells in PKD mouse models. Activation of the STAT6 pathway leads to a positive feedback loop involving auto/ paracrine signaling by IL13 and the IL4/13 receptor. The presence of IL13 in cyst fluid and the overexpression of IL4/13 receptor chains suggests a mechanism of sustained STAT6 activation in cysts. Genetic inactivation of STAT6 in a PKD mouse model leads to significant inhibition of proliferation and cyst growth and preservation of renal function. We show that the active metabolite of leflunomide, a drug approved for treatment of arthritis, inhibits STAT6 in renal epithelial cells. Treatment of PKD mice with this drug leads to amelioration of the renal cystic disease similar to genetic STAT6 inactivation. These results suggest STAT6 as a promising drug target for treatment of ADPKD.signal transduction | cytokines | preclinical

Nephrogenic systemic fibrosis (NSF) is a fibrotic disease generating intense interest due to its recent discovery, and unknown cause. It appears confined to patients with renal disease and presents as grossly thickened, indurated, tight skin that is woody to palpation. Histologically, the dermis contains thickened collagen bundles, numerous plump fibroblast-like cells, and elevated hyaluronan expression. Recent data suggest a link between the use of gadolinium chelate as an MRI contrast agent and the onset of the disease. Fibroblasts from the lesions of six NSF patients, all of whom were exposed to gadodiamide, were compared with control fibroblasts for hyaluronan and collagen synthesis. Serum from NSF patients was assessed for fibroblast hyaluronan-stimulating activity, collagen synthesis, and gadodiamide for its effect on fibroblast proliferation and matrix synthesis. NSF fibroblasts synthesized excess levels of hyaluronan and collagen compared with control fibroblasts, with up to 2.8-fold and 3.3-fold increases, respectively. NSF patient serum stimulated control fibroblast hyaluronan synthesis by up to 7-fold, and collagen synthesis by up to 2.4-fold. 1 mM gadodiamide added to culture medium stimulated fibroblast growth in a dose-dependent manner, decreasing their doubling time from 28 h to 22 h, and increasing the maximum cell density. Even a short exposure to gadodiamide stimulated cell growth, suggesting that the cells were activated by the gadodiamide. The growth of fibroblasts within contracted collagen lattices was also significantly stimulated by gadodiamide, while fibroblasts exposed to gadodiamide synthesized increased levels of hyaluronan. Control fibroblasts exposed to gadodiamide, and NSF fibroblasts exhibited an extensive pericellular coat of hyaluronan, and expressed alpha-smooth muscle actin. Gadolinium chloride did not affect fibroblast growth. This report demonstrates that NSF fibroblasts synthesize excess levels of hyaluronan and collagen, and that gadodiamide stimulates control fibroblast growth, matrix synthesis, and differentiation into myofibroblasts, suggesting a possible role for gadodiamide in the pathophysiology of NSF.

Silver bismuth iodide (Ag−Bi−I) light absorbers are interesting candidates as lead-free and low-toxic metal-halide materials for solar cell applications. In this work, the partial exchange of bismuth, Bi, with antimony, Sb, is investigated in samples prepared from a solution targeting stoichiometry AgBi 2 I 7 . Samples with a gradually increased exchange of Bi by Sb are prepared and light absorption measurements show that the absorption edge is gradually blueshifted with increasing the amount of Sb. This trend in the shift in combination with the X-ray diffraction and X-ray photoelectron spectroscopy measurements, suggest that new materials with a mixture of Sb and Bi are formed. The density functional theory based electronic structure calculations reproduce the trend observed in the experiments when including spin−orbit coupling, which indicates the importance of relativistic effects in these materials. X-ray photoelectron spectroscopy is used to characterize the materials, and confirms the exchange of Bi to Sb in the samples. When Sb is included in the material, the grain size changes between 50 and 200 nm and the solar cell performance also changes. An optimal power conversion efficiency with excellent reproducibility and stability is obtained for a solar cell with the ratio of Sb/Bi equal to 3.

La 0.7 Ce 0.3 MnO 3 is a relatively new addition to the family of colossal magnetoresistive manganites, in which the cerium ion is believed to be in the Ce4+ state. In this article, we report the magnetotransport properties of laser ablated La0.7Ce0.3MnO3 films on LaAlO3, and the effect of varying the ambient oxygen pressure during growth and the film thickness. We observe that the transport and magnetic properties of the film depend on the oxygen pressure, surface morphology, film thickness, and epitaxial strain. The films were characterized by x-ray diffraction using a four-circle goniometer. We observe an increase in the metal-insulator transition temperature with decreasing oxygen pressure. This is in direct contrast to the oxygen pressure dependence of La0.7Ca0.3MnO3 films and suggests the electron doped nature of the La0.7Ce0.3MnO3 system. With decreasing film thickness we observe an increase in the metal-insulator transition temperature. This is associated with a compression of the unit cell in the a-b plane due to epitaxial strain. On codoping with 50% Ca at the Ce site, the system (La0.7Ca0.15Ce0.15MnO3) is driven into an insulating state suggesting that the electrons generated by Ce4+ are compensated by the holes generated by Ca2+, thus making the average valence at the rare-earth site 3+ as in the parent material LaMnO3.

Metal halide compounds with photovoltaic properties prepared from solution have received increased attention for utilization in solar cells. In this work, low-toxicity cesium bismuth iodides are synthesized from solution, and their photovoltaic and optical properties as well as electronic and crystal structures are investigated. The X-ray diffraction patterns reveal that a CsI/BiI3 precursor ratio of 1.5:1 can convert pure rhombohedral BiI3 to pure hexagonal Cs3Bi2I9, but any ratio intermediate of this stoichiometry and pure BiI3 yields a mixture containing the two crystalline phases Cs3Bi2I9 and BiI3, with their relative fraction depending on the CsI/BiI3 ratio. Solar cells from the series of compounds are characterized, showing the highest efficiency for the compounds with a mixture of the two structures. The energies of the valence band edge were estimated using hard and soft X-ray photoelectron spectroscopy for more bulk and surface electronic properties, respectively. On the basis of these measurements, together with UV–vis–near-IR spectrophotometry, measuring the band gap, and Kelvin probe measurements for estimating the work function, an approximate energy diagram has been compiled clarifying the relationship between the positions of the valence and conduction band edges and the Fermi level.