IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis

Insulin-like growth-factor-binding proteins (IGFBPs) bind to and modulate the actions of insulin-like growth factors (IGFs). Although some of the actions of IGFBPs have been reported to be independent of IGFs, the precise mechanisms of IGF-independent actions of IGFBPs are largely unknown. Here we report a previously unknown function for IGFBP-4 as a cardiogenic growth factor. IGFBP-4 enhanced cardiomyocyte differentiation in vitro, and knockdown of Igfbp4 attenuated cardiomyogenesis both in vitro and in vivo. The cardiogenic effect of IGFBP-4 was independent of its IGF-binding activity but was mediated by the inhibitory effect on canonical Wnt signalling. IGFBP-4 physically interacted with a Wnt receptor, Frizzled 8 (Frz8), and a Wnt co-receptor, low-density lipoprotein receptor-related protein 6 (LRP6), and inhibited the binding of Wnt3A to Frz8 and LRP6. Although IGF-independent, the cardiogenic effect of IGFBP-4 was attenuated by IGFs through IGFBP-4 sequestration. IGFBP-4 is therefore an inhibitor of the canonical Wnt signalling required for cardiogenesis and provides a molecular link between IGF signalling and Wnt signalling.     

Geophysical evidence from the MELT area for compositional controls on oceanic plates

Magnetotelluric and seismic data, collected during the MELT experiment at the southern East Pacific Rise, constrain the distribution of melt beneath this mid-ocean-ridge spreading centre and also the evolution of the oceanic lithosphere during its early cooling history. Here we focus on structures imaged at distances approximately 100 to 350 km east of the ridge crest, corresponding to seafloor ages of approximately 1.3 to 4.5 million years (Myr), where the seismic and electrical conductivity structure is nearly constant and independent of age. Beginning at a depth of about 60 km, we image a large increase in electrical conductivity and a change from isotropic to transversely anisotropic electrical structure, with higher conductivity in the direction of fast propagation for seismic waves. Conductive cooling models predict structure that increases in depth with age, extending to about 30 km at 4.5 Myr ago. We infer, however, that the structure of young oceanic plates is instead controlled by a decrease in water content above a depth of 60 km induced by the melting process beneath the spreading centre.     

Effects of denervation and local 6-hydroxydopamine injection on testicular growth in rats

Summary Denervation and local 6-hydroxydopamine injection on day 13 caused a decrease in the testicular weight by days 42 to 70, which was due primarily to a disturbance in the growth of seminiferous tubules.     

A new pyroglutamylpeptide (Pyr-Lys-Ser) isolated from the venom ofAgkistrodon halys blomhoffii

Zusammenfassung Es wird über die Strukturklärung eines neuen pyroglutaminsäurehaltigen Peptids aus dem Gift vonAgkistrodon halys blomhoffii berichtet.     

Endothelial dysfunction in the klotho mouse and downregulation of klotho gene expression in various animal models of vascular and metabolic diseases

The human aging process is associated with vascular endothelial dysfunction. However, humoral factors which might protect against endothelial dysfunction during aging have not yet been identified. We recently identified the klotho gene as a possible regulator of human aging. In the present study using the klotho-deficient heterozygous mouse, we examined whether the Klotho protein is a humoral factor protecting against endothelial dysfunction. We further cloned rat klotho cDNA and investigated whether klotho mRNA expression in rat kidney is altered under pathological conditions such as hypertension, hyperlipidemia, renal failure, and inflammatory stress. The Klotho protein itself, or its metabolites, promotes endothelial NO production in aorta as well as arterioles, and klotho mRNA in kidney is downregulated under sustained circulatory stress.     

Meta-analysis identifies nine new loci associated with rheumatoid arthritis in the Japanese population

Rheumatoid arthritis is a common autoimmune disease characterized by chronic inflammation. We report a meta-analysis of genome-wide association studies (GWAS) in a Japanese population including 4,074 individuals with rheumatoid arthritis (cases) and 16,891 controls, followed by a replication in 5,277 rheumatoid arthritis cases and 21,684 controls. Our study identified nine loci newly associated with rheumatoid arthritis at a threshold of P < 5.0 × 10(-8), including B3GNT2, ANXA3, CSF2, CD83, NFKBIE, ARID5B, PDE2A-ARAP1, PLD4 and PTPN2. ANXA3 was also associated with susceptibility to systemic lupus erythematosus (P = 0.0040), and B3GNT2 and ARID5B were associated with Graves' disease (P = 3.5 × 10(-4) and 2.9 × 10(-4), respectively). We conducted a multi-ancestry comparative analysis with a previous meta-analysis in individuals of European descent (5,539 rheumatoid arthritis cases and 20,169 controls). This provided evidence of shared genetic risks of rheumatoid arthritis between the populations.     

民族表象与文化实践:以云南傣族孔雀舞为例

通过剖析傣族孔雀舞的事例来研究中国政府的文艺政策是以何种形式与少数民族的文化传统相结合,并在社会主义体制下如何参与展示民族形象的。认为中国共产党为了使统一的多民族的国家形象化,所以想通过民族舞蹈改变人们对少数民族既存的形象和想象,并期待民族舞蹈对展示的"想象的共同体"发挥积极的作用。     

The Shigella flexneri effector OspI deamidates UBC13 to dampen the inflammatory response

Many bacterial pathogens can enter various host cells and then survive intracellularly, transiently evade humoral immunity, and further disseminate to other cells and tissues. When bacteria enter host cells and replicate intracellularly, the host cells sense the invading bacteria as damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) by way of various pattern recognition receptors. As a result, the host cells induce alarm signals that activate the innate immune system. Therefore, bacteria must modulate host inflammatory signalling and dampen these alarm signals. How pathogens do this after invading epithelial cells remains unclear, however. Here we show that OspI, a Shigella flexneri effector encoded by ORF169b on the large plasmid and delivered by the type ΙΙΙ secretion system, dampens acute inflammatory responses during bacterial invasion by suppressing the tumour-necrosis factor (TNF)-receptor-associated factor 6 (TRAF6)-mediated signalling pathway. OspI is a glutamine deamidase that selectively deamidates the glutamine residue at position 100 in UBC13 to a glutamic acid residue. Consequently, the E2 ubiquitin-conjugating activity required for TRAF6 activation is inhibited, allowing S. flexneri OspI to modulate the diacylglycerol-CBM (CARD-BCL10-MALT1) complex-TRAF6-nuclear-factor-κB signalling pathway. We determined the 2.0 ? crystal structure of OspI, which contains a putative cysteine-histidine-aspartic acid catalytic triad. A mutational analysis showed this catalytic triad to be essential for the deamidation of UBC13. Our results suggest that S. flexneri inhibits acute inflammatory responses in the initial stage of infection by targeting the UBC13-TRAF6 complex.