Alternatively activated macrophages, generated in a T-helper 2 environment, have demonstrated roles in wound repair and tissue remodeling in addition to being charged with immune tasks. Because the hydrolytic chemistries of the phagosomal lumen are central to many of these functions, we investigated their modification after alternative activation with IL-4 and IL-13. Most significantly, we found striking up-regulation of the proteolytic levels within the phagosome of IL-4-activated macrophages. Two synergistic mechanisms were determined to underlie this up-regulation. First, IL-4-activated macrophages displayed increased expression of cathepsin S and L, providing greater proteolytic machinery to the phagosome despite unchanged rates of lysosomal contribution. Secondly, decreased phagosomal NADPH oxidase (NOX2) activity, at least partially resulting from decreased expression of the NOX2 subunit gp91 phox , resulted in a more reductive lumenal microenvironment, which in turn, enhanced activities of local cysteine cathepsins.Decreased NOX2 activity additionally increased the phagosome's ability to reduce disulfides, further enhancing the efficiency of the macrophage to degrade proteins containing disulfide bonds. Together, these changes initiated by IL-4 act synergistically to rapidly and dramatically enhance the macrophage's ability to degrade phagocytosed protein, which, we reason, better equips this cell for its roles in wound repair and tissue remodeling. IntroductionThe ability of the macrophage to dramatically remodel its cell biology in response to environmental cues and immune signals permits this ubiquitous cell lineage to function in a wide range of homeostatic and immune physiologies. Classic activation of the macrophage in response to microbial products and T-helper 1 cytokines has been long known to reprogram the macrophage's biology to enhance microbial killing and its ability to present antigen. [1][2][3] Modulation of the macrophage's key organelle, the phagosome, contributes to this functional reprogramming. [4][5][6] During the past 2 decades, alternative activation of macrophages by the T-helper 2 cytokines IL-4 and IL-13 has been shown to result in a unique phenotype that enables the macrophage to perform distinct physiologic functions. In addition to their demonstrated roles in helminthic infection, alternatively activated macrophages (AAMØs) are gaining considerable attention for their roles in tissue remodeling, wound repair, and control of inflammation. 7,8 Concomitant with these roles, several features of AAMØs have been identified that are consistent with the clearance of apoptotic cells and debris, such as up-regulation of certain phagocytic receptors and modification of endolysosomal dynamics. 7,[9][10][11][12] Hitherto changes to the functional chemistries within the phagosome that facilitate the AAMØ's function have not been elucidated.The lumenal chemistries of phagosomes play a central role in many macrophage functions. In addition to microbial killing and antigen processing, the ph...

No abstract

No abstract

A series of 1-H-pyrazole-3-carboxamide derivatives have been designed and synthesized that exhibit excellent FLT3 and CDK inhibition and antiproliferative activities. A structure-activity-relationship study illustrates that the incorporation of a pyrimidine-fused heterocycle at position 4 of the pyrazole is critical for FLT3 and CDK inhibition. Compound 50 (FN-1501), which possesses potent inhibitory activities against FLT3, CDK2, CDK4, and CDK6 with IC values in the nanomolar range, shows antiproliferative activities against MV4-11 cells (IC: 0.008 μM), which correlates with the suppression of retinoblastoma phosphorylation, FLT3, ERK, AKT, and STAT5 and the onset of apoptosis. Acute-toxicity studies in mice show that compound 50 (LD: 186 mg/kg) is safer than AT7519 (32 mg/kg). In MV4-11 xenografts in a nude-mouse model, compound 50 can induce tumor regression at the dose of 15 mg/kg, which is more efficient than cytarabine (50 mg/kg). Taken together, these results demonstrate the potential of this unique compound for further development into a drug applied in acute-myeloid-leukemia (AML) therapeutics.

No abstract

A B S T R A C TSoft-bottom bioturbators are ecosystem engineers in the sense that they can have considerable effects on sediment erodibility and resuspension. The common cockle Cerastoderma edule is a bioturbating filter feeder that is widespread along the European Atlantic coastline. Its presence and activity can decrease sediment erosion thresholds in cohesive sediments but little is known about its effect on non-cohesive sediments. Using controlled annular flume experiments, we investigated the relative effects of different cockle densities on sediment resuspension in cohesive vs. non-cohesive sediments by assessing the following: (i) the mud and sand burrowing behavior of cockles, (ii) critical erosion thresholds, (iii) the mass of eroded sediment and (iv) erosion rates. Our results show that cockles were more active in non-cohesive sediment compared with cohesive sediment. Despite their lower activity, the presence of cockles in cohesive sediment increased sediment erodibility by reducing the critical erosion threshold (U crit ) and increasing both the mass of eroded sediment and erosion rate. In contrast, cockles had no effect on erodibility in non-cohesive sediment, especially on the eroded sediment mass and erosion rate. The mass eroded was not significantly different between cohesive and non-cohesive sediments when cockles were present. Our experiments show that the increased erodibility of cohesive sediment due to the bioturbation by cockles is density dependent: higher cockle density results in stronger effects on erodibility. Moreover, this increase in cohesive sediment erosion due to cockle bioturbation was positively correlated with current velocity. In contrast, the erosion of non-cohesive sediment only depended on the current stress and was unaffected by cockle density. Considering the high abundance of C. edule, its widespread distribution and its extensive activities, the results of this study could be widely applicable to intertidal mud flats around the world.

Main conclusion This review will provide evidence for the indispensable function of these elements in regulating plant development and resistance to biotic and abiotic stresses, as well as their evolutionary role in facilitating plant adaptation.

No abstract