The structure of complement C3b provides insights into complement activation and regulation

The human complement system is an important component of innate immunity. Complement-derived products mediate functions contributing to pathogen killing and elimination. However, inappropriate activation of the system contributes to the pathogenesis of immunological and inflammatory diseases. Complement component 3 (C3) occupies a central position because of the manifold biological activities of its activation fragments, including the major fragment, C3b, which anchors the assembly of convertases effecting C3 and C5 activation. C3 is converted to C3b by proteolysis of its anaphylatoxin domain, by either of two C3 convertases. This activates a stable thioester bond, leading to the covalent attachment of C3b to cell-surface or protein-surface hydroxyl groups through transesterification. The cleavage and activation of C3 exposes binding sites for factors B, H and I, properdin, decay accelerating factor (DAF, CD55), membrane cofactor protein (MCP, CD46), complement receptor 1 (CR1, CD35) and viral molecules such as vaccinia virus complement-control protein. C3b associates with these molecules in different configurations and forms complexes mediating the activation, amplification and regulation of the complement response. Structures of C3 and C3c, a fragment derived from the proteolysis of C3b, have revealed a domain configuration, including six macroglobulin domains (MG1-MG6; nomenclature follows ref. 5) arranged in a ring, termed the beta-ring. However, because neither C3 nor C3c is active in complement activation and regulation, questions about function can be answered only through direct observations on C3b. Here we present a structure of C3b that reveals a marked loss of secondary structure in the CUB (for 'complement C1r/C1s, Uegf, Bmp1') domain, which together with the resulting translocation of the thioester domain provides a molecular basis for conformational changes accompanying the conversion of C3 to C3b. The total conformational changes make many proposed ligand-binding sites more accessible and create a cavity that shields target peptide bonds from access by factor I. A covalently bound N-acetyl-l-threonine residue demonstrates the geometry of C3b attachment to surface hydroxyl groups.     

ALKALINE PULP OF CORN STALKS

Pulping of corn stalks was studied in soda,soda-anthraquinone (AQ), kraft and kraft-AQ processes. The time, temperature and alkali concentration were varied in soda process. In respect to kappa number and pulp yield, 1 hour cooking at 1400C in 14% alkali were best conditions for corn stalks pulping. Pulp yield was increased by 5.5% and kappa number was reduced by 4.4 points with an addition of 0.05% AQ in the soda liquor. Breaking length was better in soda-AQ process than soda process but tear strength was inferior. In the kraft process, pulp yield was increased with increasing sulphidity and decreasing active alkali. The effectiveness of AQ in the low and high sulphidity kraft process was studied. Results showed that AQ was more effective in low sulphidity than high sulphidity. Strength properties in kraft processes were better than the soda and soda-AQ processes.     

Substrate-targeting gamma-secretase modulators

Selective lowering of Abeta42 levels (the 42-residue isoform of the amyloid-beta peptide) with small-molecule gamma-secretase modulators (GSMs), such as some non-steroidal anti-inflammatory drugs, is a promising therapeutic approach for Alzheimer's disease. To identify the target of these agents we developed biotinylated photoactivatable GSMs. GSM photoprobes did not label the core proteins of the gamma-secretase complex, but instead labelled the beta-amyloid precursor protein (APP), APP carboxy-terminal fragments and amyloid-beta peptide in human neuroglioma H4 cells. Substrate labelling was competed by other GSMs, and labelling of an APP gamma-secretase substrate was more efficient than a Notch substrate. GSM interaction was localized to residues 28-36 of amyloid-beta, a region critical for aggregation. We also demonstrate that compounds known to interact with this region of amyloid-beta act as GSMs, and some GSMs alter the production of cell-derived amyloid-beta oligomers. Furthermore, mutation of the GSM binding site in the APP alters the sensitivity of the substrate to GSMs. These findings indicate that substrate targeting by GSMs mechanistically links two therapeutic actions: alteration in Abeta42 production and inhibition of amyloid-beta aggregation, which may synergistically reduce amyloid-beta deposition in Alzheimer's disease. These data also demonstrate the existence and feasibility of 'substrate targeting' by small-molecule effectors of proteolytic enzymes, which if generally applicable may significantly broaden the current notion of 'druggable' targets.     

Effect of quarry dust addition on the performance of controlled low-strength material made from industrial waste incineration bottom ash

The performance of industrial waste incineration bottom ash in controlled low-strength material (CLSM) was investigated in this paper, as the quarry dust was added. CLSM mixtures were made from the industrial waste incineration bottom ash, quarry dust, and cement. Tests for fresh density, bleeding, compressive strength, shear strength, hydraulic conductivity, and excavatability were carried out. The compressive strength ranges from 60 kPa to 6790 kPa, the friction angle varies from 5° to 19°, and the cohesion is from 4 to 604 kPa. Most of the mixtures are found to be non-excavatable. It is indicated that the quarry dust addition increases the compressive strength and shear parameters, decreases bleeding, and increases the removability modulus.     

A single-step synthesis of nitrogen-doped graphene sheets decorated with cobalt hydroxide nanoflakes for the determination of dopamine

Nitrogen-doped reduced graphene oxide(NrGO)sheets decorated with Co(OH)_2nanoflakes were prepared by a single-step hydrothermal process.The morphological and structural characterizations of as synthesized Nr GO@Co(OH)_2nanoflakes were performed by field emission scanning electron microscopy(FESEM),EDX-mapping and X-ray diffraction(XRD).Nr GO@Co(OH)_2nanoflakes modified glassy carbon electrode(GCE)was used for electrochemical sensing of dopamine in neutral medium.The nanocomposite modified electrode showed enhanced electrochemical sensing ability for the detection of dopamine and the limit of detection(Lo D)was found to be 0.201μM with a sensitivity value of 0.0286±0.002 m A m M~(-1).Interference studies revealed that Nr GO@Co(OH)_2─GCE endow excellent selectivity for DA detection even in the presence of higher concentration of common co-existing physiological interfering analytes.Additionally,proposed sensor demonstrated excellent performance in urine samples with promising reproducibility and stability.     

高贝利特硫铝酸盐水泥水化过程的电化学阻抗谱

利用电化学阻抗谱法研究高贝利特硫铝酸盐水泥水化过程,得到不同水灰比下(0.6、0.8、1.0)的电化学阻抗谱曲线,并提出一种考虑弥散效应和水泥/电极界面扩散过程的等效电路模型,分析水泥水化过程中电化学阻抗参数和分形维数的变化规律.研究表明:不同水灰比下,高贝利特硫铝酸盐水泥的电化学阻抗谱具有相同的变化趋势.在整个水化过程中,随着龄期的增加和水灰比的减小,阻抗参数值和孔体积的分形维数增大,水泥的总孔隙率减小,结构变得密实;孔表面的分形维数则随着龄期的增加和水灰比的减小而减小.     

Impairment of dendritic cells and adaptive immunity by anthrax lethal toxin

Anthrax poses a clear and present danger as an agent of biological terrorism. Infection with Bacillus anthracis, the causative agent of anthrax, if untreated can result in rampant bacteraemia, multisystem dysfunction and death. Anthrax lethal toxin (LT) is a critical virulence factor of B. anthracis, which occurs as a complex of protective antigen and lethal factor. Here we demonstrate that LT severely impairs the function of dendritic cells--which are pivotal to the establishment of immunity against pathogens--and host immune responses by disrupting the mitogen-activated protein (MAP) kinase intracellular signalling network. Dendritic cells exposed to LT and then stimulated with lipopolysaccharide do not upregulate co-stimulatory molecules, secrete greatly diminished amounts of proinflammatory cytokines, and do not effectively stimulate antigen-specific T cells in vivo. Furthermore, injections of LT induce a profound impairment of antigen-specific T- and B-cell immunity. These data suggest a role for LT in suppressing host immunity during B. anthracis infections, and represent an immune evasion strategy, where a microbe targets MAP kinases in dendritic cells to disarm the immune response.     

Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci

We carried out a genome-wide association study of type-2 diabetes (T2D) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P < 10(-4) for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry. In the combined analysis, we identified common genetic variants at six loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) newly associated with T2D (P = 4.1 × 10(-8) to P = 1.9 × 10(-11)). SNPs at GRB14 were also associated with insulin sensitivity (P = 5.0 × 10(-4)), and SNPs at ST6GAL1 and HNF4A were also associated with pancreatic beta-cell function (P = 0.02 and P = 0.001, respectively). Our findings provide additional insight into mechanisms underlying T2D and show the potential for new discovery from genetic association studies in South Asians, a population with increased susceptibility to T2D.     

Hes-1 regulates the excitatory fate of neural progenitors through modulation of <Emphasis Type="Italic">Tlx3 (HOX11L2)</Emphasis> expression

Tlx3 (HOX11L2) is regarded as one of the selector genes in excitatory versus inhibitory fate specification of neurons in distinct regions of the nervous system. Expression of Tlx3 in a post-mitotic immature neuron favors a glutamatergic over GABAergic fate. The factors that regulate Tlx3 have immense importance in the fate specification of glutamatergic neurons. Here, we have shown that Notch target gene, Hes-1, negatively regulates Tlx3 expression, resulting in decreased generation of glutamatergic neurons. Down-regulation of Hes-1 removed the inhibition on Tlx3 promoter, thus promoting glutamatergic differentiation. Promoter–protein interaction studies with truncated/mutated Hes-1 protein suggested that the co-repressor recruitment mediated through WRPW domain of Hes-1 has contributed to the repressive effect. Our results clearly demonstrate a new and unique role for canonical Notch signaling through Hes-1, in neurotransmitter/subtype fate specification of neurons in addition to its known functional role in proliferation/maintenance of neural progenitors.