Fibroblast-like synoviocytes (FLSs) acquire aggressive phenotypes characterized with enhanced migration abilities and inherent invasive qualities in rheumatoid arthritis (RA). Smoothened (Smo) is a key component of sonic hedgehog (Shh) signaling and contributes to tumor cell invasion and metastasis. The objective of this study is to investigate the role of Smo in the modulation of cell migration and explore the underlying molecular mechanism(s). FLSs were isolated from RA synovium. Shh levels were regulated by a Smo agonist (purmorphamine), Smo antagonist (KAAD-cyclopamine), or small interfering RNA targeting the Smo gene (Smo-siRNA) in RA-FLSs. Expression of Smo was detected by real-time PCR and western blot analysis. Cell migration was examined by Transwell assay and activation of Rho GTPases was measured by pull-down assays. Incubation with purmorphamine resulted in a significant increase of cell migration and activation of Rho GTPase signaling compared to controls (P < 0.05). However, treatment with KAAD-cyclopamine or transfection with Smo-siRNA suppressed migration of RA-FLSs and showed an inhibitory effect of Rho GTPase signaling. Together, these results suggest that Smo plays an important role in RA-FLSs migration through activation of Rho GTPase signaling and may contribute to progression of RA, thus, targeting Shh signal may have a therapeutic potential in patients with RA.
Filamentous pathogens, such as fungi and oomycetes, secrete avirulence (AVR) effectors that trigger plant immune responses and provide striking examples of host adaptations. Avr effector genes display different types of allelic variations, including deletions, epigenetic silencing and sequence polymorphisms, to avoid detection. However, how effector sequence polymorphisms enable pathogens to dodge host immune surveillance remains largely unknown. PsAvr3c is a Phytophthora AVR gene that is recognized by soybean carrying Rps3c. PsAvr3c natural alleles display a rich diversity of single nucleotide polymorphisms in field isolates. We combined both site-directed mutagenesis and population sequence surveys to identify a serine substitution of glycine at position 174 in PsAvr3c that resulted in evasion of Rps3c-mediated soybean immunity. The S174G substitution did not affect the nuclear localization of PsAvr3c in planta, which is required to activate Rps3c, but it significantly impaired the binding affinity of PsAvr3c with a previously identified spliceosome-associated protein GmSKRPs. Silencing GmSKRPs specifically impaired PsAvr3c-triggered cell death in Rps3c soybean. This study uncovered a plant Phytophthora pathogen that adapted to a resistant plant through a key amino acid mutation and subsequently reduced the binding affinity with a plant immune regulator to evade host resistance.
The historical experience from developed countries shows that carbon emissions, with the process of urbanization, will exceed the construction industry, transport and other sectors of society and eventually occupy the first. So, it not only has practical significance, but has far-reaching strategic significance to transform the high-carbon construction into low-carbon. The paper describes the direct, indirect and general influences of the construction carbon emissions based on the path analysis and the related statistic data of Jiangsu Province from 1998 to 2007. It provides an effective guidance for the budget and control of the low-carbon development path with the detailed analysis on each factor’s influence and mechanism.
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