Complement alternative pathway plays an important, but not clearly understood, role in neutrophil-mediated diseases. We here show that neutrophils themselves activate complement when stimulated by cytokines or coagulation-derived factors. In whole blood, tumor necrosis factor/ formyl-methionyl-leucyl-phenylalanine or phorbol myristate acetate resulted in C3 fragments binding on neutrophils and monocytes, but not on T cells. Neutrophils, stimulated by tumor necrosis factor, triggered the alternative pathway on their surface in normal and C2-depleted, but not in factor B-depleted serum and on incubation with purified C3, factors B and D. This occurred independently of neutrophil proteases, oxidants, or apoptosis. Neutrophil-secreted properdin was detected on the cell surface and could focus "in situ" the alternative pathway activation. Importantly, complement, in turn, led to further activation of neutrophils, with enhanced CD11b expression and oxidative burst. Complement-induced neutrophil activation involved mostly C5a and possibly C5b-9 complexes, detected on tumor necrosis factor-and serum-acti- IntroductionNeutrophils and the complement alternative pathway (AP) are major effectors of cell-mediated and humoral innate immunity. The analysis of complement knockout mice, in experimental inflammatory diseases, shed new light on the participation of complement AP in neutrophil-mediated diseases, such as rheumatoid arthritis, 1 membranoproliferative glomerulonephritis, 2 ischemia-reperfusion injury, 3 and, more recently, antineutrophil cytoplasmic autoantibody (ANCA)-associated small-vessel vasculitis. 4 In an experimental model of ANCA-associated small-vessel vasculitis, the unexpected observation that factor B-deficient mice were protected from the disease, whereas C4-deficient mice were not, 4 revealed the alternative complement pathway as a new partner of this neutrophilmediated disease. It was thus reasonable to propose that neutrophils could participate in the activation of complement AP.If the activation of neutrophils by complement fragments, such as C3a or C5a, is well known, data on complement triggering by neutrophils are scarce. Neutrophil proteases and oxidants have been reported to activate complement in cell-free systems, 5-7 and supernatants of ANCA-activated neutrophils were shown to release unknown complement activating factors. 4 We investigated the ability of the neutrophil surface to activate complement and deposit active complement fragments on their plasma membrane.Complement activation on blood cells is kept under control by fluid phase regulators (ie, plasma factor H and C4b-binding protein) and by cell membrane regulators (ie, decay accelerating factor DAF [CD55] and membrane cofactor protein MCP [CD46]). These regulators prevent the formation and accelerate the decay of C3bBb and C4b2a alternative and classic C3-convertases and act as cofactors for factor I-mediated C3b and C4b proteolysis. Neutrophils also express CR1 (CD35), which is the only cofactor allowing factor I to fully degrade ...

Atypical hemolytic uremic syndrome (aHUS) is a rare renal thrombotic microangiopathy commonly associated with rare genetic variants in complement system genes, unique to each patient/family. Here, we report 14 sporadic aHUS patients carrying the same mutation, R139W, in the complement C3 gene. The clinical presentation was with a rapid progression to end-stage renal disease (6 of 14) and an unusually high frequency of cardiac (8 of 14) and/or neurologic (5 of 14) events. Although resting glomerular endothelial cells (GEnCs) remained unaffected by R139W-C3 sera, the incubation of those sera with GEnC preactivated with proinflammatory stimuli led to increased C3 deposition, C5a release, and procoagulant tissue-factor expression. This functional consequence of R139W-C3 resulted from the formation of a hyperactive C3 convertase. Mutant C3 showed an increased affinity for factor B and a reduced binding to membrane cofactor protein (MCP; CD46), but a normal regulation by factor H (FH). In addition, the frequency of at-risk FH and MCP haplotypes was significantly higher in the R139W-aHUS patients, compared with normal donors or to healthy carriers. These genetic background differences could explain the R139W-aHUS incomplete penetrance. These results demonstrate that this C3 mutation, especially when associated with an at-risk FH and/or MCP haplotypes, becomes pathogenic following an inflammatory endothelium-damaging event. (Blood. 2012;119(18):4182-4191)

Mossadegh-Keller et al. show distinct origin of two different testicular macrophage populations during the postnatal development. Embryonic precursors give rise exclusively to the interstitial macrophage population, whereas peritubular macrophages derive from bone marrow progenitors only postnatally. Surprisingly, both macrophage populations display a remarkable long life span.

Spectrins are ubiquitous scaffolding components of the membrane skeleton that organize and stabilize microdomains on both the plasma membrane and the intracellular organelles. By way of their numerous interactions with diverse protein families, they are implicated in various cellular functions. Using small interfering RNA strategy in the WM-266 cell line derived from human melanoma, we found that ␣II-spectrin deficiency is associated with a defect in cell proliferation, which is related to a cell cycle arrest at the G 1 phase (first gap phase), as evaluated by DNA analysis and Rb phosphorylation. These observations coincided with elevated expression of the cyclin-dependent kinase inhibitor, p21 Cip . Concomitantly, spectrin loss impaired cell adhesion and spreading. These cell adhesion defects were associated with modifications of the actin cytoskeleton, such as loss of stress fibers, alterations of focal adhesions, and modified expression of some integrins. Our results provide novel insights into spectrin functions by demonstrating the involvement of ␣II-spectrin in cell cycle regulation and actin organization.First identified at the intracellular surface of the erythrocyte plasma membrane, the spectrin-based skeleton is considered as a nearly ubiquitous and complex spectrin-actin network in metazoan cells (1).Spectrins are giant extended flexible molecules composed of two subunits (␣ and ␤) that intertwine to form ␣␤ heterodimers. Spectrin is normally considered to exist as tetramers resulting from self-association of ␣␤ dimers. Spectrin tetramers constitute the filaments of the lattice, the nodes of which are cross-linked by actin filaments. This spectrin-based skeleton is bound to various transmembrane proteins either directly, or more frequently through two connecting proteins, ankyrin and protein 4.1. In mammals, the spectrin family currently includes seven genes encoding for two ␣-subunits (␣I and ␣II), four "conventional" ␤-subunits (␤I to ␤IV) and one ␤ heavy subunit (␤V), as well as multiple alternatively spliced variants, each of these species presenting its specific cellular expression pattern. For example, whereas ␣I-spectrin is essentially expressed in the mature erythrocyte, ␣II-spectrin is the most common form in nucleated cells.The functions clearly determined up to date for the spectrin network emerge from human mutations associated with diseases as well as from animal models. Numerous studies on red cells, particularly those in hereditary hemolytic anemia, have clearly established its importance for supporting cell shape and for maintaining cell membrane integrity and stability (2, 3). In nucleated cells, the spectrin-based skeleton has been shown to participate in the stabilization or activation of several specialized membrane proteins, as recently reported for the TRCP channels (4). The direct interaction between TRCP4 channel and spectrin is involved in the regulation of the channel surface expression and activation. One consistent feature observed when spectrin or its binding partner ankyr...

The rainfall variability of subequatorial South America and Africa is poorly documented owing to the scarcity of data. We present a new land-only data set of monthly precipitation from 1951 to 1990, focusing on subequatorial South America and Africa, which improves the knowledge of rainfall variability and allows comparisons with GCM outputs. The results of multivariate analyses are compared with those performed on the best actual global rainfall data set developed by Mike Hulme.The main modes of bimonthly rainfall variability are not located in the major rain-forest basins of Za'ke and Amazonia, but rather on the tropical margins, such as Venezuela or Sudan, and near-coastal equatorial areas, such as Guyana, Nordeste, Guinea, and Gabon. A regionalization into 13 homogeneous areas selected from the multivariate analyses is proposed. The statistical links between the rainfall variability and the four main sea-surface temperature modes indicate a strong influence of the El NiHeSouthem Oscillation (ENSO) phenomenon upon South America (lesslmore rainfall during an El Niiio/La NiHa event) and a weaker impact, modulated by the Atlantic thermal state, upon Africa. The impact of ENSO events seems stronger since 1965 than before.

An intercomparison of seven gridded rainfall products incorporating satellite data (ARC, CHIRPS, CMORPH, PERSIANN, TAPEER, TARCAT, TMPA) is carried out over Central Africa, by evaluating them against three observed datasets: (a) the WaTFor database, consisting of 293 (monthly records) and 154 (daily records) rain‐gauge stations collected from global datasets, national meteorological services and monitoring projects, (b) the WorldClim v2 gridded database, and (c) a set of stations expanded from the FAOCLIM network, these two latter sets describing climate normals. All products fairly well reproduce the mean rainfall regimes and the spatial patterns of mean annual rainfall, although with some discrepancies in the east–west gradient. A systematic positive bias is found in the CMORPH product. Despite its lower spatial resolution, TAPEER shows reasonable skills. When considering daily rainfall amounts, TMPA shows best skills, followed by CMORPH, but over the central part of the Democratic Republic of the Congo, TARCAT is amongst the best products. Skills ranking is however different at the interannual time‐scale, with CHIRPS and TMPA performing best, though PERSIANN has comparable skills when only fully independent stations are used as reference. A preliminary study of Southern Hemisphere dry season variability, from the example of Kinshasa, shows that it is a difficult variable to capture with satellite‐based rainfall products. Users should still be careful when using any product in the most data‐sparse regions, especially for trend assessment.

Comparisons between years of below average rainfall over West Africa, sea-surface temperatures (SST) over the Atlantic Ocean and the world ocean, and latitudinal positions of the Inter Tropical Convergence Zone (ITCZ) over the Atlantic Ocean show that the relationships depend mainly on the rainfall anomaly patterns. The well-known SST dipole (cold northern ocean and warm equatorial and southern ocean) is only apparent during those August months with below average Sudano-Sahelian rainfall and above average Guinean rainfall (rainfall type ' -/+') and an abnormal southward position of the ITCZ. In contrast, those August months that experience rainfall deficits over the whole of West Africa (rainfall type '-/-') are associated with warm SST anomalies over the eastern Pacific Ocean, cold persistant SST anomalies over the equatorial Atlantic Ocean and a more northward position of the ITCZ. Those patterns first appear in northern spring before the Sahelian rainy season.The composite SST differences for the '-/+' and '-/-' rainfall types computed with August or July-September amounts have a good resemblance with each other. Comparison of results related to the reverse July-September rainfall patterns (the '+/-' and '+/+' patterns) during the 1950s shows that the SST anomalies were globally colder when, on average, the Sahelian rainy seasons experienced significant excesses while the Guinean little dry seasons were more marked.

Rainfall thresholds under which forests grow in Central Africa are lower than those of Amazonia and southeast Asia. Attention is thus regularly paid to rainfall whose seasonality and interannual variability has been shown to control Central African forests' water balance and photosynthetic activity. Nonetheless, light availability is also recognized as a key factor to tropical forests. Therefore this study aims to explore the light conditions prevailing across Central Africa, and their potential impact on forests' traits. Using satellite estimates of hourly irradiance, we find first that the four main types of diurnal cycles of irradiance extracted translate into different levels of rainfall, evapotranspiration, direct and diffuse light. Then accounting for scale interactions between the diurnal and annual cycles, we show that the daily quantity and quality of light considerably vary across Central African forests during the annual cycle: the uniqueness of western Central Africa and Gabon in particular, with strongly lightdeficient climates especially during the main dry season, points out. Lastly, using an original map of terra firme forests, we also show that most of the evergreen forests are located in western Central Africa and Gabon. We postulate that despite mean annual precipitation below 2000 mm yr −1 , the lightdeficient climates of western Central Africa can harbour evergreen forests because of an extensive lowlevel cloudiness developing during the June-September main dry season, which strongly reduces the water demand and enhances the quality of light available for tree photosynthesis. These findings pave the way for further analyses of the past and future changes in the light-deficient climates of western Central Africa and the vulnerability of evergreen forests to these changes.