Apoptotic cells are considered to be a major source for autoantigens in autoimmune diseases such as systemic lupus erythematosus (SLE). In agreement with this, defective clearance of apoptotic cells ...has been shown to increase disease susceptibility. Still, little is known about how apoptotic cell-derived self-antigens activate autoreactive B cells and where this takes place. In this study, we find that apoptotic cells are taken up by specific scavenger receptors expressed on macrophages in the splenic marginal zone and that mice deficient in these receptors have a lower threshold for autoantibody responses. Furthermore, antibodies against scavenger receptors are found before the onset of clinical symptoms in SLE-prone mice, and they are also found in diagnosed SLE patients. Our findings describe a novel mechanism where autoantibodies toward scavenger receptors can alter the response to apoptotic cells, affect tolerance, and thus promote disease progression. Because the autoantibodies can be detected before onset of disease in mice, they could have predictive value as early indicators of SLE.
Podocyte foot process effacement accompanied by actin cytoskeleton rearrangements is a cardinal feature of many progressive human proteinuric diseases.
By microarray profiling of mouse glomerulus, ...SCHIP1 emerged as one of the most highly enriched transcripts. We detected Schip1 protein in the kidney glomerulus, specifically in podocytes foot processes. Functionally, Schip1 inactivation in zebrafish by morpholino knock-down results in foot process disorganization and podocyte loss leading to proteinuria. In cultured podocytes Schip1 localizes to cortical actin-rich regions of lamellipodia, where it forms a complex with Nherf2 and ezrin, proteins known to participate in actin remodeling stimulated by PDGFβ signaling. Mechanistically, overexpression of Schip1 in vitro causes accumulation of cortical F-actin with dissolution of transversal stress fibers and promotes cell migration in response to PDGF-BB stimulation. Upon actin disassembly by latrunculin A treatment, Schip1 remains associated with the residual F-actin-containing structures, suggesting a functional connection with actin cytoskeleton possibly via its interaction partners. A similar assay with cytochalasin D points to stabilization of cortical actin cytoskeleton in Schip1 overexpressing cells by attenuation of actin depolymerisation.
Schip1 is a novel glomerular protein predominantly expressed in podocytes, necessary for the zebrafish pronephros development and function. Schip1 associates with the cortical actin cytoskeleton network and modulates its dynamics in response to PDGF signaling via interaction with the Nherf2/ezrin complex. Its implication in proteinuric diseases remains to be further investigated.
MARCO is a trimeric class A scavenger receptor of macrophages and dendritic cells that recognizes polyanionic particles and pathogens. The distal, scavenger receptor cysteine-rich (SRCR) domain of ...the extracellular part of this receptor has been implicated in ligand binding. To provide a structural basis for understanding the ligand-binding mechanisms of MARCO, we have determined the crystal structure of the mouse MARCO SRCR domain. The recombinant SRCR domain purified as monomeric and dimeric forms, and their structures were determined at 1.78 and 1.77Å resolution, respectively. The monomer has a compact globular fold with a twisted five-stranded antiparallel β-sheet and a long loop covering a single α-helix, whereas the dimer is formed via β-strand swapping of two monomers, thus containing a large eight-stranded β-sheet. Calculation of the surface electrostatic potential revealed that the β-sheet region with several arginines forms a basic cluster. Unexpectedly, an acidic cluster was found in the long loop region. In the monomer, the acidic cluster is involved in metal ion binding. Studies with cells expressing various SRCR domain mutants showed that all of the arginines of the basic cluster are involved in ligand binding, suggesting a cooperative binding mechanism. Ligand binding is also dependent on the acidic cluster and Ca2+ ions whose depletion appears to affect ligand binding at least by modulating the electrostatic potential or relative domain orientation. We propose that the SRCR domain dimerization can contribute to the recognition of large ligands by providing a means for the MARCO receptor oligomerization.
Recognition of microbial components by TLR, key sensors of infection, leads to induction of inflammatory responses. We found that, in vivo, TLR4 engagement by LPS induces up-regulation of the class A ...scavenger receptors (SR) macrophage receptor with a collagenous structure (MARCO) and SR-A, which occurs, at least in the case of MARCO, via both MyD88-dependent and -independent pathways. When challenging mice with a low dose of LPS followed by a high dose, class A SR-deficient mice showed a higher survival rate than WT mice. This was paired with increased production of IL-10 and anti-LPS Ab, as well as increased activation status of marginal zone B cells. However, the receptors were not crucial for survival when challenging mice i.p. with Neisseria meningitidis or Listeria monocytogenes, but they were found to contribute to microbial capture and clearance. This indicates physiological significance for the up-regulation of class A SR during early stages of bacterial infection. Thus, we believe that we have revealed a mechanism where SR regulate the activation status of the immune system and are involved in balancing a proper immune response to infection. This regulation could also be important in maintaining tolerance since these receptors have been shown to be involved in regulation of self-reactivity.
We study the properties of structured and unstructured Pc1 pulsations at a high-latitude station (Sodankylä;
L=5.1) and a mid-latitude station (Nurmijärvi;
L=3.3) during 18 storms occurring in low ...solar activity years. The storms were divided into two groups according to their intensity as measured by the minimum value of the
D
st index. Pc1 activity was studied from the day of the storm sudden commencement onwards during six consecutive days. Having recently published the average results for all 18 storms Kerttula et al., J. Geophys. Res. (2000) in press, we concentrate here on the effect of magnetic storm intensity on wave properties. The source of structured Pc1s was found to be at lower latitudes during intense storms, in agreement with the lower latitude of the ring current during intense storms. Also, the source of unstructured Pc1s, the plasmasheet ions, was found to shift to lower latitudes during intense storms but this change was only observed in the early recovery phase. The great depletion of structured Pc1s on ground during the storm main and early recovery phase, which is in apparent disagreement with space observations and model calculations, is even more dramatic for intense storms. This further emphasizes the significance of the ionospheric conditions for wave observations on ground, and suggests that the depletion is due to deterioration of the ionospheric Alfvén resonator during the storm main phase. Moreover, the results support the idea Kerttula et al., J. Geophys. Res. 62 (2000) 299–309 that Pc1 occurrence maximum during late recovery phase is related to the improved ionospheric amplification and propagation conditions, rather than the outward expansion of the plasmapause.
The aim of this work is to produce highly porous and stable alkali-activated material (AAM) prepared from two combinations of sodium (Na)- and potassium (K)-based alkali solutions (NaOH/Na2SiO3 and ...KOH/K2SiO3). The reactive metakaolin as precursor and AAM were characterized using X-ray diffraction spectroscopy (XRD), X-ray fluorescence spectroscopy (XRF), aluminum nuclear magnetic resonance spectroscopy (27Al MS-NMR), diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), field emission scanning electron microscopy (FESEM), compressive strength measurement and Brunauer–Emmett–Teller (BET) surface analysis. The porosity of the AAMs were increased by using hydrogen peroxide and sodium percarbonate as foaming agents. Characterization results showed the viscosity of the K-AAM paste was 70% lower than that of the Na-AAM paste. However, the volume of the Na-AAM paste in an air-tight plastic tube was three times higher than that of K-AAM, but the specific surface area (SSA) of K-AAM were 30% higher than those of Na-AAM. In terms of compressive strength, the blank AAM (foaming agent-free) demonstrated the highest strength values: 6.1 MPa for K-AAM and 9.0 MPa for Na-AAM. When the concentration of the foaming agent was increased, the compressive strength of both the materials decreased but were still around 1.0 MPa. The FESEM images of the Na-AAM and K-AAM produced with H2O2 indicated the high porosity of materials which were also observed in SSA values of AAM. Furthermore, the XRD data showed that the Na-AAM contained water in hydrate form (halloysite) compared with the K-AAM, suggesting the different polymerization reaction route and speed between these AAM.
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•Metakaolin precursor and produced materials was characterized by multiple methods.•Viscosity of the potassium-based paste was 70% lower than sodium-based.•Volume of sodium-based paste was three times higher than potassium-based.•Potassium-based specific surface area values were 30% higher than sodium-based.•Curing at 60 °C gave two to four times higher compressive strength values than 105 °C.
Podocytes serve as an important constituent of the glomerular filtration barrier. Recently, we and others identified Myo1e as a key molecular component of the podocyte cytoskeleton.
Myo1e mRNA and ...protein was expressed in human and mouse kidney sections as determined by Northern blot and reverse transcriptase PCR, and its expression was more evident in podocytes by immunofluorescence. By specific knock-down of MYO1E in zebrafish, the injected larvae exhibited pericardial edema and pronephric cysts, consistent with the appearance of protein in condensed incubation supernate. Furthermore, specific inhibition of Myo1e expression in a conditionally immortalized podocyte cell line induced morphological changes, actin cytoskeleton rearrangement, and dysfunction in cell proliferation, migration, endocytosis, and adhesion with the glomerular basement membrane.
Our results revealed that Myo1e is a key component contributing to the functional integrity of podocytes. Its impairment may cause actin cytoskeleton re-organization, alteration of cell shape, and membrane transport, and podocyte drop-out from the glomerular basement membrane, which might eventually lead to an impaired glomerular filtration barrier and proteinuria.
Carbon capture and storage is a concept to reduce greenhouse gas emissions of energy production from fossil fuels. In oxy‐fuel combustion, the fuel is burned in a mixture of oxygen and recycled flue ...gas. This generates CO2‐rich flue gas from which the CO2 is easily separated and compressed. Foster Wheeler Power Group is developing the existing design tools and process models of air‐fired circulating fluidized bed boilers to implement specific features of oxycombustion. The validation data is produced from bench‐scale and pilot‐scale experiments at the VTT, Technical Research Centre of Finland. A three‐dimensional circulating fluidized bed (CFB) furnace model is developed and applied by Lappeenranta University of Technology for predicting the effects of oxycombustion in full scale units. This paper presents concept studies and initial 3D modeling results based on a 460 MWe supercritical CFB power plant at Lagisza, and pilot‐scale studies with flue gas recirculation demonstrating real oxygen combustion conditions.
Conversion of a supercritical circulating fluidized bed boiler to oxycombustion is studied using a boiler design model and three‐dimensional modeling of the furnace process. Oxy‐CFB pilot tests with flue gas recirculation are presented, showing the sulfur capture possibilities in oxycombustion.
We report the isolation and characterization of six overlapping cDNA clones that provide the first and complete amino acid sequence of the human laminin B1 chain. The cDNA clones cover 5613 ...nucleotides with 5358 nucleotides in an open reading frame encoding 1786 amino acids, including a 21-residue signal peptide-like sequence. Sequence analysis demonstrated the presence of two types of internal homology repeats that were found in clusters within the polypeptide chain. The type A repeats contain about 50 amino acids of which 8 are cysteine. These repeats are present in two clusters toward the NH2-terminal end of the chain and are separated from each other by about 220 amino acids. The two clusters contain five and eight consecutive repeats each. There are two copies of consecutive type B repeats of about 40 amino acids close to the COOH-terminal end. Computer analysis of the amino acid sequence of the B1 chain revealed the presence of structurally distinct domains that contain cysteine-rich repeats, globular regions, and helical structures. Using somatic cell hybrid methodology and in situ hybridization to metaphase chromosomes it was established that the human laminin B1 gene (LAMB1) is located in the q22 region of chromosome 7.
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