An improved concept of the best analogs method is used to reconstruct the climate of the last glacial maximum from pollen data in Europe. In order to deal with the lack of perfect analogs of fossil assemblages and therefore to obtain a more accurate climate reconstruction, we used a combination of pollen types grouped according to plant phenology and present climate constraints rather than pollen percentages for each individual taxon. The distribution of pollen taxa into plant functional types (PFTs) is aimed to reflect the vegetation in terms of biomes which have a wider distribution than a species. The climatic variables are then calibrated on these PFTs using an artificial neural network technique. The use of PFTs allowed us to deal with situations where pollen assemblages have only partial modern analogs. The method is applied to the glacial steppic vegetation in Europe, using 15 pollen records. North of the Pyrenees–Alps line, the reconstructed temperatures were lower than today: −30 ± 10°C for the temperature of the coldest month ( Tc) and −12 ± 3°C for the annual mean ( Tann). South of that line, Tc and Tann anomalies were respectively, −15 ± 5°C and −10 ± 5°C. The available moisture index and annual precipitation were also lower than present: −60 ± 20% north of Mediterranean Sea, (−800 ± 100 mm for precipitation). In Italy and Greece, the available moisture was 20% lower, with a precipitation anomaly of ca. −600 ± 200 mm. Southward, the moisture index was close to that at present (±20%), and precipitation was lower (−300 ± 300 mm).

Pollen data from 18,000 14 C yr bp were compiled in order to reconstruct biome distributions at the last glacial maximum in southern Europe and Africa. Biome reconstructions were made using the objective biomization method applied to pollen counts using a complete list of dryland taxa wherever possible. Consistent and major differences from present-day biomes are shown.Forest and xerophytic woods/scrub were replaced by steppe, both in the Mediterranean region and in southern Africa, except in south-western Cape Province where fynbos (xerophytic scrub) persisted.Sites in the tropical highlands, characterized today by evergreen forest, were dominated by steppe and/or xerophytic vegetation (cf. today's Ericaceous belt and Afroalpine grassland) at the last glacial maximum.Available data from the tropical lowlands are sparse but suggest that the modern tropical rain forest was largely replaced by tropical seasonal forest while the modern seasonal or dry forests were encroached on by savanna or steppe. Montane forest elements descended to lower elevations than today.

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Vascular endothelial growth factor (VEGF ), an endothelial cell mitogen, is a potent angiogenic factor produced by several cell types. Whether human neutrophils are potential producers of VEGF has not yet been described. The present work shows that phorbol-12-myristate 13-acetate (PMA), fMet-Leu-Phe, and tumor necrosis factor-α (TNF-α) triggered a time-dependent secretion of VEGF by human neutrophils. Cells incubated with 50 ng/mL of PMA released significant amounts of VEGF after 15 minutes. Because the extracellular content of VEGF in human neutrophils supernatants remained constant over a period of 2 to 24 hours and because PMA is a potent inducer of human neutrophil degranulation, the PMA-induced secretion of VEGF may be due to a pre-existing intracellular pool of this molecule. This hypothesis was reinforced by the absence of cycloheximide effect on the PMA-induced secretion of VEGF. The existence of an intracellular pool of VEGF was confirmed by measuring the intracellular content of VEGF in resting neutrophils. A dosedependent inhibition of PMA-induced VEGF secretion was observed when the cells were incubated in the presence of pentoxifylline, a methylxanthine known to inhibit neutrophil degranulation. To confirm the implication of neutrophil degranulation in VEGF release, the effects of two inducers of physiologic degranulation, fMet-Leu-Phe and TNF-α, were determined. Both agonists induced a release of VEGF in the absence of cytochalasin B, confirming the involvement of neutrophil degranulation and suggesting the intracellular localization of VEGF in the specific granule fraction. In addition, the kinetics of fMet-Leu-Phe– and TNF-α–induced secretion of lactoferrin were similar to those of VEGF release induced by these two both agonists. The subcellular fractionation of human neutrophils showed a granule-specific distribution of the intracellular pool of VEGF in resting neutrophils. The finding that human neutrophils contain an intracellular pool of VEGF, secreted in the extracellular space under PMA-, fMet-Leu-Phe–, and TNF-α–induced degranulation, suggests a role for human neutrophils as cellular effectors of physiologic as well as pathologic angiogenesis.

Hepatocyte growth factor (HGF), a heparin-binding factor, is synthesized as a single-chain inactive precursor (pro-HGF), which is converted by proteolysis to an active heterodimer (mature HGF). HGF has pleiotropic activities and has been implicated in the regulation of mitogenesis, motogenesis, and morphogenesis of epithelial and endothelial cells. As polymorphonuclear neutrophils (PMNs) secrete numerous cytokines involved in the modulation of local inflammation, we investigated their ability to produce HGF. We found that HGF was stored in secretory vesicles and in gelatinase/specific granules. This intracellular stock was rapidly mobilized by degranulation when neutrophils were stimulated with phorbol myristate acetate or N-formylmethionylleucyl-phenylalanine. Cycloheximide did not affect the release of HGF. Moreover, HGF messenger RNA and protein expression was found in bone marrow myeloid cells, suggesting that HGF synthesis likely occurs during PMN maturation. In mature circulating PMNs, intracellular HGF was in the pro-HGF form, whereas the HGF secreted by degranulation was the mature form. Furthermore, PMNs pretreated with diisopropyl fluorophosphate only released the pro-HGF form, suggesting that PMN-derived serine protease(s) are involved in the proteolytic process. We also obtained evidence that secreted mature HGF binds PMN-derived glycosaminoglycans (probably heparan sulfate). These findings suggest that PMNs infiltrating damaged tissues may modulate local wound healing and repair through the production of HGF, a major mediator of tissue regeneration. IntroductionHepatocyte growth factor (HGF), a heparin-binding factor, was originally described as a potent mitogen for the growth of hepatocytes in vitro and was subsequently purified from rat platelets, 1 plasma of a patient with fulminant hepatic failure, 2 and normal human plasma. 3 HGF has mitogenic, motogenic, and morphogenic effects on various epithelial and endothelial cell types. 4,5 Many studies have demonstrated that embryogenesis, angiogenesis, hematopoiesis, as well as wound healing and organ regeneration, are critically controlled by HGF. [5][6][7] HGF is secreted as a 92-kd single-chain pro-HGF that requires endoproteolytic processing. This processing is mediated by a serine protease. The HGF activator, 8 blood coagulation factor XII, 9 urokinase, 10 and tissue-type plasminogen activator 11 are reported to activate HGF. Processing of HGF results in a bioactive form (mature HGF) consisting of a disulfide-linked 69-kd ␣ chain and a 32-kd ␤ chain. 12 The biologic effects of HGF are mediated by the activation of its high-affinity binding site known as the tyrosine kinase receptor c-met. 13 Besides c-met, HGF possesses lower-affinity/highcapacity binding sites corresponding to extracellular matrix molecules (glycosaminoglycans or collagen) or to cell surfaceassociated heparan sulfate 14,15 ; this correspondence creates a molecular reservoir of HGF on the cell surface, whereas HGF transfer to c-met initiates the cellular response. 16 The broad r...

Mouse bone marrow erythropoiesis is homeostatic, whereas after acute anemia, bone morphogenetic protein 4 (BMP4)-dependent stress erythropoiesis develops in the spleen. The aim of this work was to compare spleen stress erythropoiesis and bone marrow erythropoiesis in a mouse model of zymosan-induced generalized inflammation, which induces longlasting anemia and to evaluate the ability of erythropoietin (Epo) injections to correct anemia in this setting. The effects of zymosan and/or Epo injections on erythroid precursor maturation and apoptosis, serum interferon-␥ levels, hematologic parameters, and spleen BMP4 expression were analyzed, as well as the effect of zymosan on red blood cell halflife. We found that bone marrow erythropoiesis is suppressed by inflammation and does not respond to Epo administration, despite repression of erythroblast apoptosis. On the contrary, a robust erythropoietic response takes place in the spleen after Epo injections in both control and zymosan-induced generalized in-

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