Suchergebnisse

Tortajada, Agustín et alt. ; C3 glomerulopathies (C3G) are a group of severe renal diseases with distinct patterns of glomerular inflammation and C3 deposition caused by complement dysregulation. Here we report the identification of a familial C3G-associated genomic mutation in the gene complement factor H-related 1 (CFHR1), which encodes FHR1. The mutation resulted in the duplication of the N-terminal short consensus repeats (SCRs) that are conserved in FHR2 and FHR5. We determined that native FHR1, FHR2, and FHR5 circulate in plasma as homo- and hetero-oligomeric complexes, the formation of which is likely mediated by the conserved N-terminal domain. In mutant FHR1, duplication of the N-terminal domain resulted in the formation of unusually large multimeric FHR complexes that exhibited increased avidity for the FHR1 ligands C3b, iC3b, and C3dg and enhanced competition with complement factor H (FH) in surface plasmon resonance (SPR) studies and hemolytic assays. These data revealed that FHR1, FHR2, and FHR5 organize a combinatorial repertoire of oligomeric complexes and demonstrated that changes in FHR oligomerization influence the regulation of complement activation. In summary, our identification and characterization of a unique CFHR1 mutation provides insights into the biology of the FHRs and contributes to our understanding of the pathogenic mechanisms underlying C3G. Copyright © 2013, American Society for Clinical Investigation. ; Work in this report was funded by the Spanish Ministerio de Economía y Competitividad (SAF2011-26583), the Fundación Renal Iñigo Alvarez de Toledo and the 7FP European Union project EURenOmics to S. Rodríguez de Córdoba; the "Ramón Areces" Foundation, the Spanish Ministerio de Economía y Competitividad (SAF2011-22988), and the "Red Temática de Investigación Cooperativa en Cáncer(RTICC)" (RD06/0020/1001) to O. Llorca; the Spanish "Ministerio de Economía y Competitividad" (PI0900268) to P. Sánchez-Corral; the MRC UK (G0701298) to C.L. Harris; and the Spanish "Ministerio de Economía y Competitividad" (PS09/00122) to M. López Trascasa. In addition, this work was supported by a grant from the Autonomous Region of Madrid (S2010/BMD-2316) to S. Rodríguez de Córdoba, O. Llorca, M. López Trascasa, and P. Sánchez-Corral. M.C. Pickering is a Wellcome Trust Senior Fellow in Clinical Science (WT098476MA). H. Yébenes was supported by a postdoctoral contract by the RTICC, and C. Abarrategui-Garrido was supported by the "Fundación de Investigación Biomédica del Hospital Universitario La Paz." ; Peer reviewed

33 p.-4 fig.-2 fig. supl. ; Complement is an essential component of innate immunity. Its activation results in the assembly of unstable protease complexes, denominated C3/C5 convertases, leading to inflammation and lysis. Regulatory proteins inactivate C3/C5 convertases on host surfaces to avoid collateral tissue damage. On pathogen surfaces, properdin stabilizes C3/C5 convertases to efficiently fight infection. How properdin performs this function is, however, unclear. Using electron microscopy we show that the N-and C-terminal ends of adjacent monomers in properdin oligomers conform a curly vertex that holds together the AP convertase, interacting with both the C345C and vWA domains of C3b and Bb, respectively. Properdin also promotes a large displacement of the TED (thioestercontaining domain) and CUB (complement protein subcomponents C1r/C1s, urchin embryonic growth factor and bone morphogenetic protein 1) domains of C3b, which likely impairs C3-convertase inactivation by regulatory proteins. The combined effect of molecular cross-linking and structural reorganization increases stability of the C3 convertase and facilitates recruitment of fluid-phase C3 convertase to the cell surfaces. Our model explains how properdin mediates the assembly of stabilized C3/C5-convertase clusters, which helps to localize complement amplification to pathogen surfaces. ; This work was funded by the Autonomous Region of Madrid (S2010/BMD-2316 to S.R.d.C. and O.L.), the Ramón Areces Foundation (O.L.), and the Spanish government (SAF2011-22988 to O.L. and SAF2011-26583 to S.R.d.C.). O.L. is additionally supported by Red Temática de Investigación Cooperativa en Cáncer (RD06/0020/1001), and S.R.d.C. is also supported by the Fundación Renal Iñigo Alvarez de Toledo and the Seventh Framework Programme European Union Project EURenOmics (European Consortium for High-Throughput Research in Rare Kidney Diseases-305608). ; Peer Reviewed

Purpose Dysregulation of the complement cascade contributes to a variety of retinal dystrophies, including age-related macular degeneration (AMD). The central component of complement, C3, is expressed in abundance by macrophages in the outer retina, and its ablation suppresses photoreceptor death in experimental photo-oxidative damage. Whether this also influences macrophage reactivity in this model system, however, is unknown. We investigate the effect of C3 ablation on macrophage activity and phagocytosis by outer retinal macrophages during photo-oxidative damage. Methods Age-matched C3 knockout (KO) mice and wild-type (WT) C57/Bl6 mice were subjected to photo-oxidative damage. Measurements of the outer nuclear layer (ONL) thickness and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to assess pathology and photoreceptor apoptosis, respectively. Macrophage abundance and phagocytosis were assessed with immunolabeling for pan-macrophage and phagocytic markers, in conjunction with TUNEL staining in cohorts of C3 KO and WT mice. Results The C3 KO mice exhibited protection against photoreceptor cell death following photo-oxidative damage, which was associated with a reduction in immunoreactivity for the stress-related factor GFAP. In conjunction, there was a reduction in IBA1-positive macrophages in the outer retina compared to the WT mice and a decrease in the number of CD68-positive cells in the outer nuclear layer and the subretinal space. In addition, the engulfment of TUNEL-positive and -negative photoreceptors by macrophages was significantly lower in the C3 KO mice cohort following photo-oxidative damage compared to the WT cohort. Conclusions The results show that the absence of C3 mitigates the phagocytosis of photoreceptors by macrophages in the outer retina, and the net impact of C3 depletion is neuroprotective in the context of photo-oxidative damage. These data improve our understanding of the impact of C3 inhibition in subretinal inflammation and inform the development of treatments for targeting complement activation in diseases such as AMD. ; This study was supported by project grants from the National Health and Medical Research Council (APP1165599; APP1127705), Australian National University Translational Fellowship and Australian Government Research Training Program Scholarship.

5 p.-2 fig. ; [Background] Glomerulonephritis is one of the most severe complications of lupus, a systemic disease with multi-organ involvement, with tissue damage produced mainly by complement activation. As a result of this activation, patients with active lupus present hypocomplementemia during disease flares, but C3 and C4 levels are recovered between episodes. ; [Case presentation] We present a patient who suffered two lupus nephritis episodes in 5 years, achieving complete remission with treatment after both of them, but with C3 levels persistently below normal range. Genetic study revealed that the patient carried a mutation in heterozygosis in the C3 gene. Serial sera samples were analyzed, and autoantibodies to complement alternative pathway proteins (Factor I, Factor B, C3 and Properdin) were found. Functional assays showed that these autoantibodies cause alternative pathway activation. ; [Conclusion] This case is the first reported of a heterozygous C3 mutation associated with lupus nephritis and autoantibodies against complement alternative pathway proteins (Factor I, Factor B, C3 and Properdin).These autoantibodies cause activation of this pathway and this fact could explain that the tissue damage is restricted to the kidney. ; This work was funded by Spanish government, Ministerio de Economía y Competitividad (grant SAF2012-38636), Autonomous region of Madrid (S2010/BMD-2316 to SRdeC y MLT) and Sociedad Española de Nefrología Fundación Senefro to MLT. ; Peer reviewed

Le problème principal de l'économie de l'environnement peut donc être défini à la fois comme la recherche d'un nouveau mode de croissance et la transformation d'un consensus moral sur les fins en moyens d'action politique. L'Union européenne est aujourd'hui le lieu où le consensus moral est le mieux partagé et où les moyens politiques de l'action collective sont les plus puissants. L'Union européenne, à travers la Communauté européenne de l'environnement, de l'énergie et de la recherche, est donc l'échelle pertinente qui peut rendre opératoire une nouvelle croissance " écogène ", à condition d'en préciser le cadre d'analyse et le contexte institutionnel.

Le problème principal de l'économie de l'environnement peut donc être défini à la fois comme la recherche d'un nouveau mode de croissance et la transformation d'un consensus moral sur les fins en moyens d'action politique. L'Union européenne est aujourd'hui le lieu où le consensus moral est le mieux partagé et où les moyens politiques de l'action collective sont les plus puissants. L'Union européenne, à travers la Communauté européenne de l'environnement, de l'énergie et de la recherche, est donc l'échelle pertinente qui peut rendre opératoire une nouvelle croissance " écogène ", à condition d'en préciser le cadre d'analyse et le contexte institutionnel.

Telegram from Mr. G. Inclán, President of the Pedro C. Colorado Radical Club of Cunduacán, to Gen. Alvaro Obregón, welcoming him to the state of Tabasco. / Telegrama del Sr. G. Inclán, Presidente del Club Radical Cunduacanense Pedro C. Colorado al Gral. Alvaro Obregón enviándole un saludo de bienvenida por su arribo al estado de Tabasco.

Mr. G. Furlong's telegram to Gen. Alvaro Obregón, informing of being stranded in Mazatlán due to bad weather, but having been warmly welcomed by the Democratic Party. / Telegrama del Sr. G. Furlong al Gral. Alvaro Obregón, informando estar detenido en Mazatlán por mal tiempo y haber sido recibido con mucho entusiasmo por el Partido Democrático.

Letter from Mr. G. Vizcarra to Engr. Elías Torres on a power of attorney granted by Gen. Francisco Villa to claim checks on his behalf. File. V-26 / Carta del Sr. G. Vizcarra al Ing. Elías Torres sobre carta poder que le otorgó el Gral. Francisco Villa para reclamar cheques en su nombre. Exp. V-26

Telegram from Mr. G. Gaona to Gen. Alvaro Obregón, requesting to be sent the name of his representative and indicating that said representative must be in Jalapa, Veracruz on October 10th. / Telegrama del Sr. G. Gaona al Gral. Alvaro Obregón, solicitando le envíe el nombre de su representante e informando que el mismo debe estar en Jalapa, Ver. el 10 de octubre.

Telegram from Mr. G. Vizcárraga, President of the Finance and Publications Committee of the National Cooperative Party, to Gen. Alvaro Obregón, asking him when he will visit the city of Puebla. Mr. Vizcárraga also requests a meeting. / Telegrama del Sr. G. Vizcárraga, Presidente del Comité de Hacienda y Publicaciones del Partido Cooperatista Nacional al Gral. Alvaro Obregón, preguntándole cuándo visitará la ciudad de Puebla y solicitando una audiencia.

Two types of photocatalysts, 1%Pt/Cd1−x Znx S/g-C3 N4 (x = 0.2–0.3) and Cd1−x Znx S/1% Pt/g-C3 N4 (x = 0.2–0.3), were synthesized by varying the deposition order of platinum, and a solid solution of cadmium and zinc sulfides onto the surface of g-C3 N4. The characterization of photo-catalysts showed that, for 1%Pt/Cd1−x Znx S/g-C3 N4, small platinum particles were deposited onto a solid solution of cadmium and zinc sulfides; in the case of Cd1−x Znx S/1%Pt/g-C3 N4, enlarged platinum clusters were located on the surface of graphitic carbon nitride. Based on the structure of the photocatalysts, we assumed that, in the first case, type II heterojunctions and, in the latter case, S-scheme heterojunctions were realized. The activity of the synthesized samples was tested in hydrogen evolution from triethanolamine (TEOA) basic solution under visible light (λ = 450 nm). A remarkable increase in hydrogen evolution rate compared to single-phase platinized 1%Pt/Cd1−x Znx S photocat-alysts was observed only in the case of ternary photocatalysts with platinum located on the g-C3 N4 surface, Cd1−x Znx S/1%Pt/g-C3 N4. Thus, we proved using kinetic experiments and characterization techniques that, for composite photocatalysts based on Cd1−x Znx S and g-C3 N4, the formation of the S-scheme mechanism is more favorable than that for type II heterojunction. The highest activity, 2.5 mmol H2 g−1 h−1, with an apparent quantum efficiency equal to 6.0% at a wavelength of 450 nm was achieved by sample 20% Cd0.8 Zn0.2 S/1% Pt/g-C3 N4. © 2021 by the authors. Licensee MDPI, Basel, Switzerland. ; Funding: This work was supported by the Ministry of Science and Higher Education of the Russian Federation within the governmental order for Boreskov Institute of Catalysis (project AAAA-A21-121011390009-1) and was also funded by the Russian Foundation for Basic Research (project No. 20-33-70086). A.S.V. and I.A.W. thank Minobrnauki research project FEUZ-2020-0059 for financial support.

"Big G" typically refers to aggregate government spending on a homogeneous good. In this paper, we open up this construct by analyzing the entire universe of procurement contracts of the US government and establish five facts. First, government spending is granular, that is, it is concentrated in relatively few firms and sectors. Second, relative to private expenditures its composition is biased. Third, procurement contracts are short-lived. Fourth, idiosyncratic variation dominates the fluctuation of spending. Last, government spending is concentrated in sectors with relatively sticky prices. Accounting for these facts within a stylized New Keynesian model offers new insights into the fiscal transmission mechanism: fiscal shocks hardly impact inflation, little crowding out of private expenditure exists, and the multiplier tends to be larger compared to a one-sector benchmark aligning the model with the empirical evidence.

Letter from Maj. Salvador G. Sotomayor to Gen. Alvaro Obregón requesting help for being wrongly accused of theft of assets of the Army / Carta del Mayor Salvador G. Sotomayor al Gral. Alvaro Obregón pidiéndole ayuda por haber sido acusado injustamente de robo de haberes del ejército.

41 p.-11 fig. ; C3 is the central component of the complement system. Upon activation, C3 sequentially generates various proteolytic fragments, C3a, C3b, iC3b, C3dg, each of them exposing novel surfaces, which are sites of interaction with other proteins. C3 and its fragments are therapeutic targets and markers of complement activation. We report the structural and functional characterization of four monoclonal antibodies (mAbs) generated by immunizing C3-deficient mice with a mixture of human C3b, iC3b and C3dg fragments, and discuss their potential applications. This collection includes three mAbs interacting with native C3 and inhibiting AP complement activation; two of them by blocking the cleavage of C3 by the AP C3-converase and one by impeding formation of the AP C3-convertase. The interaction sites of these mAbs in the target molecules were determined by resolving the structures of Fab fragments bound to C3b and/or iC3b using electron microscopy. A fourth mAb specifically recognizes the iC3b, C3dg, and C3d fragments. It binds to an evolutionary-conserved neoepitope generated after C3b cleavage by FI, detecting iC3b/C3dg deposition over opsonized surfaces by flow cytometry and immunohistochemistry in human and other species. Because well-characterized anti-complement mAbs are uncommon, the mAbs reported here may offer interesting therapeutic and diagnostic opportunities. ; Work in this report has been funded by the Spanish "Ministerio de Economía y Competitividad" (SAF2011-26583 and SAF2015-66287-R to SRdC and SAF2014- 52301-R to OL) and the Seventh Framework Programme European Union Project EURenOmics (305608) to SRdC. In addition, this work has been supported by a grant from the Autonomous Region of Madrid (S2010/BMD-2316) to SRdeC and OL. ; Peer reviewed