Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cdelta

Protein kinase C (PKC), which comprises 11 closely related isoforms, has been implicated in a wide variety of cellular processes, such as growth, differentiation, secretion, apoptosis and tumour development. Among the PKC isotypes, PKC-delta is unique in that its overexpression results in inhibition of cell growth. Here we show that mice that lack PKC-delta exhibit expansion of the B-lymphocyte population with the formation of numerous germinal centres in the absence of stimulation. The rate of proliferation in response to stimulation was greater for B cells from PKC-delta-deficient mice than for those from wild-type mice. Adoptive transfer experiments suggested that the hyperproliferation phenotype is B-cell autonomous. Production of interleukin-6 was markedly increased in B cells of PKC-delta-null mice as a result of an increase in the DNA-binding activity of NF-IL6. Furthermore, the PKC-delta-deficient mice contain circulating autoreactive antibodies and display immune-complex-type glomerulonephritis, as well as lymphocyte infiltration in many organs. These results suggest that PKC-delta has an indispensable function in negative regulation of B-cell proliferation, and is particularly important for the establishment of B-cell tolerance.     

Vegetation Spatial Heterogeneity of Different Soil Regions in Inner Mongolia, China

The vegetation spatial heterogeneity and ecological characteristics in different soil regions were analyzed by surveying the vegetation in 12 different soil regions of Inner Mongolia, China, including conifer- ous-broadleaf deciduous forests, shrub, grassland, and desert regions with 1122 large 2 cm × 2 cm quad- rats (actual size 30 km × 30 km, referred to as L-quadrat hereafter) in about 1.18 million km2. Each L- quadrat was divided into four small 1 cm × 1 cm quadrats (actual size 15 km × 15 km, S-quadrat). The vegetation was analyzed based on the beta-binomial distribution to describe the frequency of occurrence and spatial heterogeneity for each kind of vegetation. The weighted average of the heterogeneity of all vegeta- tion in the same soil region provides a measure of the soil regional landscape level heterogeneity which de- scribes the spatial complexity of the regional landscape composition of the existing vegetation. Comparison of the vegetation characteristics in the 12 soil regions shows that, the calcic gray soil has the highest average vegetation type per quadrat. The largest soil region is calcic chestnut soil and has the most vegetation types. Every soil region has its own dominant vegetation sequence which dominates in occurrence and dominant vegetation types which dominates in spatial heterogeneity. For the Inner Mongolian vegetation, the weighted average of the heterogeneity is 0.60 and the vegetation diversity index is 4.47.     

Periostin in vitreoretinal diseases

Proliferative vitreoretinal diseases such as diabetic retinopathy, proliferative vitreoretinopathy (PVR), and age-related macular degeneration are a leading cause of decreased vision and blindness in developed countries. In these diseases, retinal fibro(vascular) membrane (FVM) formation above and beneath the retina plays an important role. Gene expression profiling of human FVMs revealed significant upregulation of periostin. Subsequent analyses demonstrated increased periostin expression in the vitreous of patients with both proliferative diabetic retinopathy and PVR. Immunohistochemical analysis showed co-localization of periostin with α-SMA and M2 macrophage markers in FVMs. In vitro, periostin blockade inhibited migration and adhesion induced by PVR vitreous and transforming growth factor-β2 (TGF-β2). In vivo, a novel single-stranded RNAi agent targeting periostin showed the inhibitory effect on experimental retinal and choroidal FVM formation without affecting the viability of retinal cells. These results indicated that periostin is a pivotal molecule for FVM formation and a promising therapeutic target for these proliferative vitreoretinal diseases.     

Cloning of adiponectin receptors that mediate antidiabetic metabolic effects

Adiponectin (also known as 30-kDa adipocyte complement-related protein; Acrp30) is a hormone secreted by adipocytes that acts as an antidiabetic and anti-atherogenic adipokine. Levels of adiponectin in the blood are decreased under conditions of obesity, insulin resistance and type 2 diabetes. Administration of adiponectin causes glucose-lowering effects and ameliorates insulin resistance in mice. Conversely, adiponectin-deficient mice exhibit insulin resistance and diabetes. This insulin-sensitizing effect of adiponectin seems to be mediated by an increase in fatty-acid oxidation through activation of AMP kinase and PPAR-alpha. Here we report the cloning of complementary DNAs encoding adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2) by expression cloning. AdipoR1 is abundantly expressed in skeletal muscle, whereas AdipoR2 is predominantly expressed in the liver. These two adiponectin receptors are predicted to contain seven transmembrane domains, but to be structurally and functionally distinct from G-protein-coupled receptors. Expression of AdipoR1/R2 or suppression of AdipoR1/R2 expression by small-interfering RNA supports our conclusion that they serve as receptors for globular and full-length adiponectin, and that they mediate increased AMP kinase and PPAR-alpha ligand activities, as well as fatty-acid oxidation and glucose uptake by adiponectin.     

Ferroelectricity from iron valence ordering in the charge-frustrated system LuFe2O4

Ferroelectric materials are widely used in modern electric devices such as memory elements, filtering devices and high-performance insulators. Ferroelectric crystals have a spontaneous electric polarization arising from the coherent arrangement of electric dipoles (specifically, a polar displacement of anions and cations). First-principles calculations and electron density analysis of ferroelectric materials have revealed that the covalent bond between the anions and cations, or the orbital hybridization of electrons on both ions, plays a key role in establishing the dipolar arrangement. However, an alternative model-electronic ferroelectricity-has been proposed in which the electric dipole depends on electron correlations, rather than the covalency. This would offer the attractive possibility of ferroelectric materials that could be controlled by the charge, spin and orbital degrees of freedom of the electron. Here we report experimental evidence for ferroelectricity arising from electron correlations in the triangular mixed valence oxide, LuFe(2)O(4). Using resonant X-ray scattering measurements, we determine the ordering of the Fe(2+) and Fe(3+) ions. They form a superstructure that supports an electric polarization consisting of distributed electrons of polar symmetry. The polar ordering arises from the repulsive property of electrons-electron correlations-acting on a frustrated geometry.     

Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity

Helicobacter pylori cagA-positive strains are associated with gastritis, ulcerations and gastric adenocarcinoma. CagA is delivered into gastric epithelial cells and, on tyrosine phosphorylation, specifically binds and activates the SHP2 oncoprotein, thereby inducing the formation of an elongated cell shape known as the 'hummingbird' phenotype. In polarized epithelial cells, CagA also disrupts the tight junction and causes loss of apical-basolateral polarity. We show here that H. pylori CagA specifically interacts with PAR1/MARK kinase, which has an essential role in epithelial cell polarity. Association of CagA inhibits PAR1 kinase activity and prevents atypical protein kinase C (aPKC)-mediated PAR1 phosphorylation, which dissociates PAR1 from the membrane, collectively causing junctional and polarity defects. Because of the multimeric nature of PAR1 (ref. 14), PAR1 also promotes CagA multimerization, which stabilizes the CagA-SHP2 interaction. Furthermore, induction of the hummingbird phenotype by CagA-activated SHP2 requires simultaneous inhibition of PAR1 kinase activity by CagA. Thus, the CagA-PAR1 interaction not only elicits the junctional and polarity defects but also promotes the morphogenetic activity of CagA. Our findings revealed that PAR1 is a key target of H. pylori CagA in the disorganization of gastric epithelial architecture underlying mucosal damage, inflammation and carcinogenesis.