We report the first large genome-wide association study (GWAS) in a Chinese population to identify susceptibility variants for psoriasis using a two-stage case-control design. In the first stage, we carried out a genome-wide association analysis in 1,139 cases and 1,132 controls of Chinese Han ancestry using Illumina Human 610-Quad BeadChips. In the second stage, we took top SNPs forward for replication in two independent samples of 5,182 cases and 6,516 controls of Chinese Han ancestry, and 539 cases and 824 controls of Chinese Uygur ancestry. In addition to the strong replication for two known susceptibility loci MHC (rs1265181, P = 1.93 x 10(-208), OR = 22.62) and IL12B (rs3213094, P(combined) = 2.58 x 10(-26), OR = 0.78), we identified a new susceptibility locus within the LCE gene cluster on 1q21 (rs4085613, P(combined) = 6.69 x 10(-30), OR = 0.76).

Infrared and Raman spectroscopy were used to characterize a chromate conversion coating (CCC) on 2024-T3 aluminum aircraft alloy with a long range objective of determining the anticorrosion mechanism of the CCC. Spectra were compared to those from synthetic mixed oxides of aluminum, Cr(III), and Cr(VI) made by treating pure reagents with NaOH. The Fourier transform infrared (FTIR) and Raman spectra of the CCC showed similar behavior to the chromium Ill/VI mixed oxide for both the initial materials and after heat-treatment. Analysis of the CCC and chromium mixed oxide by UV-vis spectroscopy indicated that both have a 3:1 ratio of Cr(III) to Cr(VI). When the chromium mixed oxide was immersed in pH 4 HNO3, the ratio of released H to released Cr(VI) ranged from 0.98 to 1.07. In addition, a compound with a Raman spectrum very similar to that of a CCC was formed by a reaction of Cr(III) hydroxide with Cr2O2, CrO2, or the Alodine chromating bath. The results indicate a strong structural similarity between the Cr-mixed oxide and a major component of the CCC. A likely structure for this common material involves covalent bonding between polymeric Cr(III) hydroxide and Cr202 or CrO . This mixed oxide structure may hydrolyze to release H and soluble chromate.

Activation of the ubiquitously expressed Na-H exchanger, NHE1, results in an increased efflux of intracellular HW. The increase in intracellular pH associated with this H+ efflux may contribute to regulating cell proliferation, differentiation, and neoplastic transformation. Although NHE1 activity is stimulated by growth factors and hormones acting through multiple GTPase-mediated pathways, little is known about how the exchanger is directly regulated. Using expression library screening, we identified a novel protein that specifically binds to NHE1 at a site that is critical for growth factor stimulation of exchange activity. This protein is homologous to calcineurin B and calmodulin and is designated CHP for calcineurin B homologous protein. Like NHE1, CHP is widely expressed in human tissues. Transient overexpression of CHP inhibits serum-and GTPase-stimulated NHEl activity. CHP is a phosphoprotein and expression of constitutively activated GTPases decreases CHP phosphorylation. The phosphorylation state of CHP may therefore be an important signal controlling mitogenic regulation of NHE1.

Various effects of chromate conversion coatings (CCCs) and chromate in solution on the corrosion of AA2024-T3 and pure Al are studied in this work. Raman spectroscopy was used to investigate the nature of chromate in CCCs through a comparison with the spectra of known standards and artificial Cr(III)/Cr(VI) mixed oxides. Chromate was shown to be released from CCCs and to migrate to and protect a nearby, uncoated area in the artificial scratch cell. However, experiments investigating the effect of chromate in solution on anodic dissolution kinetics under potentiostatic control indicated that large chromate concentrations were needed to have an effect.

It is generally accepted that Cr VI in chromate conversion coatings (CCCs) and in SrCrO 4 containing primers c is the critical component in corrosion protective coating systems used on aluminum aircraft alloys such as AA-2024-T3. The ability of a CCC to release Cr VI as soluble chromate species is likely to be important to "self-healing" exhibited by CCCs, in which CrO 4 Ϫ2 or related species can migrate to defects or corrosion sites and inhibit further damage. 1-8 Several investigators have reported that CCCs contain both Cr III and Cr VI 9-11 and a Cr III-Cr VI mixed oxide has been identified as a major CCC component. 12 Furthermore, release of CrO 4 Ϫ2 from a CCC has been demonstrated, as has protection of an initially untreated alloy surface by dilute CrO 4 Ϫ2 in a chloride solution. 7 The mechanism of corrosion protection by chromate is currently being debated, but storage and release of Cr VI by a CCC appear to be essential for its long term protection property. In addition, release of chromate from sparingly soluble SrCrO 4 in primers may also provide a source of dilute chromate for self-healing. The current investigation addresses the storage and release of Cr VI in more detail. The release of Cr VI from a CCC and SrCrO 4 into water and salt solution was monitored quantitatively with ultraviolet-visible (UV-vis) spectroscopy, in order to examine solution concentrations, saturation (if any), release rate, and possibly storage mechanism. By considering a variety of conditions, a quantitative model for Cr VI storage and release was formulated, and its implications for corrosion protection were considered. The kinetics and rate-controlling factors during release will be addressed in a separate communication. Experimental All the chemicals used were analytical grade. Solutions were prepared with "deionized" water (Barnstead, Nanopure 18 M⍀-cm). The absorbance vs. concentration behavior of chromate solutions is complicated by the equilibria between HCrO 4 Ϫ , CrO 4 Ϫ2 , and Cr 2 O 7 Ϫ2 , which depend on both concentration and pH. 13-17 The combined concentration of these species in solution is indicated herein as [Cr VI ]. In order to determine the relationship between UV-vis absorbance and [Cr VI ], solutions of K 2 Cr 2 O 7 were prepared at various concentrations in the range of 1.0 ϫ 10 Ϫ5 M to 4 ϫ 10 Ϫ4 M of Cr VI , and adjusted to different pH values with HClO 4 or NaOH and a pH meter. UV-vis absorption spectra for solutions in 1 cm quartz cuvettes were collected using either a Perkin Elmer Lambda 20 spectrometer or a custom system based on an ISA Triax monochromator. Spectra for one Cr VI concentration are shown in Fig. 1 for a pH range from 2.01-9.47. Since the absorption at 339 nm (A 339) was independent of pH, this wavelength was used to construct the pH-independent calibration curve shown in Fig. 2. The absorbance at 339 nm was preferable to that at 295 nm for quantitative analysis of [Cr VI ] due to the smaller interference from nitrate ion. Over the range of total [Cr VI ] from 1 ϫ 10 Ϫ5 to 4 ϫ 10 Ϫ...

Bone morphogenetic protein 2 (BMP2), a member of the transforming growth factor-β (TGF-β) super-family, is one of the main chondrogenic growth factors involved in cartilage regeneration. BMP2 is known to induce chondrogenic differentiation in various types of stem cells in vitro. However, BMP2 also induces osteogenic differentiation and endochondral ossification in mesenchymal stem cells (MSCs). Although information regarding BMP2-induced chondrogenic and osteogenic differentiation within the same system might be essential for cartilage tissue engineering, few studies concerning these issues have been conducted. In this study, BMP2 was identified as a regulator of chondrogenic differentiation, osteogenic differentiation and endochondral bone formation within the same system. BMP2 was used to regulate chondrogenic and osteogenic differentiation in stem cells within the same culture system in vitro and in vivo. Any changes in the differentiation markers were assessed. BMP2 was found to induce chondrogenesis and osteogenesis in vitro via the expression of Sox9, Runx2 and its downstream markers. According to the results of the subcutaneous stem cell implantation studies, BMP2 not only induced cartilage formation but also promoted endochondral ossification during ectopic bone/cartilage formation. In fetal limb cultures, BMP2 promoted chondrocyte hypertrophy and endochondral ossification. Our data reveal that BMP2 can spontaneously induce chondrogenic differentiation, osteogenic differentiation and endochondral bone formation within the same system. Thus, BMP2 can be used in cartilage tissue engineering to regulate cartilage formation but has to be properly regulated for cartilage tissue engineering in order to retain the cartilage phenotype.

Calcineurin, a Ca 2؉ /calmodulin-stimulated protein phosphatase, plays a key role in T-cell activation by regulating the activity of NFAT (nuclear factor of activated T cells), a family of transcription factors required for the synthesis of several cytokine genes. Calcineurin is the target of the immunosuppressive drugs cyclosporin A and FK506 complexed with their cytoplasmic receptors cyclophilin and FKBP12, respectively. In this study we report that calcineurin is also the target of a recently identified Ca 2؉ -binding protein, CHP (for calcineurin homologous protein), which shares a high degree of homology with the regulatory B subunit of calcineurin and with calmodulin. In Jurkat and HeLa cells, overexpression of CHP specifically impaired the nuclear translocation and transcriptional activity of NFAT but had no effect on AP-1 transcriptional activity and only a small (<25%) inhibitory effect on the transcriptional activity of NFB. Further study indicated that CHP inhibits calcineurin activity. In cells overexpressing CHP, the phosphatase activity of immunoprecipitated calcineurin was inhibited by ϳ50%; and in a reconstituted assay, the activity of purified calcineurin was inhibited up to 97% by the addition of purified recombinant CHP in a dose-dependent manner. Moreover, prolonged activation of Jurkat cells was associated with a decreased abundance of CHP, suggesting a possible regulatory mechanism allowing activation of calcineurin. CHP, therefore, is a previously unrecognized endogenous inhibitor of calcineurin activity.Stimulation of T cells results in the induction of several cytokine genes that are involved in the control of T-cell proliferation and immune responses (1-3). One of the signaling pathways mediating T-cell receptor activation involves the elevation of intracellular calcium ([Ca 2ϩ ] i ) and the activation of a key signaling enzyme, calcineurin (4, 5). A rise in [Ca 2ϩ ] i leads to the activation of calcineurin and the dephosphorylation and nuclear translocation of NFAT (nuclear factor of activated T cells).1 This in turn drives transcription of response genes such as the cytokines interleukin (IL)-2 and IL-4 and the CD44 ligand (6 -11). Calcineurin is a heterodimeric enzyme consisting of a catalytic A subunit (CnA) and a tightly associated Ca 2ϩ -binding regulatory B subunit (CnB) (12, 13). Maximal calcineurin phosphatase activity requires the Ca 2ϩ -dependent binding of calmodulin (CaM) to the CnA-CnB complex at a domain independent of the CnB-binding site on CnA (14).We recently identified a novel, ubiquitously expressed, Ca 2ϩ -binding protein, CHP (for calcineurin homologous protein), which shares a high degree of similarity with CnB (65%) and CaM (59%) (15). Although CHP was originally identified by screening a library to detect proteins that interacted with the Na ϩ /H ϩ exchanger isoform NHE1, subsequent studies indicated that CHP has actions that are independent of its regulation of NHE1. Overexpression of CHP in mutant NHE-deficient fibroblasts inhibits cell proliferation, ...

Our results have identified a new function of SFRP2 and shed new light on the molecular mechanism underlying directed differentiation of stem cells of dental origin.