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.

Political attention has increasingly focused on limiting warming to 2êC. However, to date the only mitigation commitments accompanying this target are the so-called Copenhagen pledges, and these pledges appear to be inconsistent with the 2êC objective. Diverging opinions on whether this inconsistency can or should be resolved have been expressed. This paper clarifies the alternative assumptions underlying these diverging view points and explicits their implications. It first gives simple visualizations of the challenge posed by the 2êC target. It then proposes a decision tree, linking different beliefs on climate change, the achievability of different policies, and current international policy dynamics to various options to move forward on climate change.

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.

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

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. ; Sí

Asma Boujenna – Universidad AbdelMalek Essâadi – Tetuan, Marruecos - 0000-0002-0023-7759 ; Vanessa Martos Núñez – Universidad de Granada - 0000-0001-6442-7968 ; Belén García del Moral Garrido – Universidad de Almería - 0000-0001-9803-9939 ; Luis F. Garcia del Moral – Universidad de Granada - 0000-0002-0533-2915 ; Recepción: 08.04.2022 | Aceptado: 18.04.2022 ; Correspondencia a través de ORCID: Luis F. García del Moral - 0000-0002-0533-2915 ; El punto de compensación para el CO2 (ΓCO2) es el límite mínimo de CO2 atmosférico necesario para una asimilación fotosintética positiva. Por debajo de este límite los procesos respiratorios predominan sobre los fotosintéticos, la fotosíntesis neta tiene valores negativos y el crecimiento se detiene, con consecuencias negativas sobre el rendimiento y la productividad. Las diferencias en ΓCO2, se han utilizado para seleccionar genotipos con una mayor capacidad de captación de CO2 y con mejor productividad. El objetivo de este trabajo es contribuir al conocimiento práctico, por parte del alumnado de una asignatura de Ecofisiología Vegetal, de cómo se puede calcular el valor del ΓCO2 y su interés para evaluar la eficiencia en la captación de CO2 por plantas con metabolismo fotosintético C3 o C4. Abstract: The compensation point for CO2 (ΓCO2) is the minimum limit of atmospheric CO2 necessary for positive photosynthetic assimilation. Below this limit, respiratory processes predominate over photosynthetic ones, net photosynthesis has negative values and growth stops, with negative consequences on yield and productivity. Differences in ΓCO2 have been used to select genotypes with a higher CO2 uptake capacity and better productivity. The objective of this work is to contribute to the practical knowledge, by students of a Plant Ecophysiology course, of how the value of ΓCO2 can be calculated and its interest in evaluating the efficiency of CO2 uptake by plants with C3 or C4 photosynthetic metabolism. ; Financiación: Grupo de investigación AGR123 de la Junta de Andalucía y proyecto "SUSTAINABLE" funded by the European Union's Horizon 2020 Project H2020-MSCA-RISE-2020, Grant Agreement 101007702.

Surface temperatures of synthetic turf have become a factor of growing interest and concern, particularly in warmer regions like Australia. However, it is unclear which components of the synthetic turf system contribute to surface temperature. The aim of this paper was to compare the surface temperature of 34 different synthetic turf products that were exposed to the same environmental conditions to ascertain which components of the synthetic turf system and which environmental factors contributed to increased surface temperature. A total of 6,120 observations were taken on the 34 products over the summer months, giving 30 observations for each of the variables on each product. An analysis of covariance (ANCOVA) indicated that the type of infill and shockpad had small-medium, but significant, effects on surface temperature (p<0.001 and p=0.003, respectively), and the interaction between shockpad and tuft gauge was also significant (p=0.047). Level of solar radiation, ambient temperature and relative humidity (p<0.001 in all instances) were the only environmental variables that significantly influenced surface temperature. These findings confirm that both the composition of the synthetic turf system and environmental factors contribute to synthetic turf surface temperature, thus providing important information for synthetic turf manufacturers developing new cool climate products, or for local government authorities selecting products and/or informing safe play for end-users. ; E1

The number of patients with multimorbidity has been steadily increasing in the modern aging societies. The European C3-Cloud project provides a multidisciplinary and patient-centered "Collaborative Care and Cure-system" for the management of elderly with multimorbidity, enabling continuous coordination of care activities between multidisciplinary care teams (MDTs), patients and informal caregivers (ICG). In this study various components of the infrastructure were tested to fulfill the functional requirements and the entire system was subjected to an early application testing involving different groups of end-users. MDTs from participating European regions were involved in requirement elicitation and test formulation, resulting in 57 questions, distributed via an internet platform to 48 test participants (22 MDTs, 26 patients) from three pilot sites. The results indicate a high level of satisfaction with all components. Early testing also provided feedback for technical improvement of the entire system, and the paper points out useful evaluation methods.

Cereal yield and grain quality may be impaired by environmental factors associated with climate change. Major factors, including elevated CO2 concentration ([CO2]), elevated temperature, and drought stress, have been identified as affecting C3 crop production and quality. A me-ta‐analysis of existing literature was performed to study the impact of these three environmental factors on the yield and nutritional traits of C3 cereals. Elevated [CO2] stimulates grain production (through larger grain numbers) and starch accumulation but negatively affects nutritional traits such as protein and mineral content. In contrast to [CO2], increased temperature and drought cause significant grain yield loss, with stronger effects observed from the latter. Elevated temperature decreases grain yield by decreasing the thousand grain weight (TGW). Nutritional quality is also negatively influenced by the changing climate, which will impact human health. Similar to drought, heat stress decreases starch content but increases grain protein and mineral concentra-tions. Despite the positive effect of elevated [CO2], increases to grain yield seem to be counterbal-anced by heat and drought stress. Regarding grain nutritional value and within the three environmental factors, the increase in [CO2] is possibly the more detrimental to face because it will affect cereal quality independently of the region. ; This work was supported by European Interest Group (EIG) CONCERT-Japan (IRUEC), the Spanish Ministry of Science and Innovation (Spanish MINECO projects PCIN-2017-007 and PID2019-110445RB-I00). Sinda Ben Mariem had a PhD grant from the Navarra Government

Following a request from European Commission, the Panel on Additives and Product or Substances used in Animal Feed (FEEDAP) was asked to deliver an opinion on the safety and efficacy of Biomin C3 when used in diets for chickens for fattening. The additive Biomin C3 is a preparation of strains of Enterococcus faecium, Bifidobacterium animalis subsp. animalis and Lactobacillus salivarius subsp. salivarius. The product is intended to improve the performance of chickens for fattening when added in their diets at a minimum content of 1 x 108 and a maximum content of 1 x 109 CFU/kg of complete feedingstuffs. It has not been previously authorised in the European Union. The identity of the strains B. animalis subsp. animalis, L. salivarius subsp. salivarius and E. faecium has been established and no antibiotic resistance detected. On the basis of a tolerance study in which chickens for fattening showed no effects in the presence of 100 times the maximum recommended dose, the additive is considered safe for the target species at doses up to 1 109 CFU/kg of complete feedingstuffs Two of the three strains, B. animalis subsp. animalis and L. salivarius subsp. salivarius, satisfy the requirements for the qualified presumption of safety approach to safety assessment, and thus are presumed safe for consumers. The third strain, E. faecium, was shown not to contain marker genes typical of hospital-associated isolates responsible for clinical infections and does not raise additional safety concerns. Consequently, the FEEDAP Panel considers the use of the Biomin C3 safe for consumers. The additive is not irritant to skin or eyes and is not a skin sensitiser. Biomin C3 should be treated as a potential respiratory sensitiser as a result of its proteinaceous nature. The three species are natural components of gut microbiota and their use as Biomin C3 in animal feeding would not be expected to pose any additional risk to the environment. In four of the five studies carried out in chickens for fattening, Biomin C3 showed the potential to improve the performance of birds at the minimum dose of 1 x 108 CFU/kg of complete feedingstuffs. This was supported by a meta-analysis which showed significant improvements in final weight across the five trials. The three strains are compatible with robenidine hydrochloride, maduramycin ammonium and diclazuril but not with monensin sodium and lasalocid A sodium.

Background: C3-Cloud is an integrated care ICT infrastructure offering seamless patient-centered approach to managing multimorbidity, deployed in three European pilot sites. Challenge: The digital delivery of best practice guidelines unified for multimorbidity, customized to local practice, offering the capability to improve patient personalization and benefit. Method: C3-Cloud has adopted a co-production approach to developing unified multimorbidity guidelines, by collating and reconciling best practice guidelines for each condition. Clinical and technical teams at pilot sites and the C3-Cloud consortium worked in tandem to create the specification and technical implementation. Results: C3-Cloud offers CDSS for diabetes, renal failure, depression and congenital heart failure, with over 300 rules and checks that deliver four best practice guidelines in parallel, customized for each pilot site. Conclusions: The process provided a traceable, maintainable and audited digitally delivered collated and reconciled guidelines.