An adaptive algorithm for n-body field expansions
Weinberg, Martin D.
1998-05-28
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The small GTPase Rap1 is highly expressed in human neutrophils,
but its function is largely unknown. Using the Rap1-
binding domain of RalGDS (RalGDS-RBD) as an activationspecific
probe for Rap1, we have investigated the regulation
of Rap1 activity in primary human neutrophils. We found
that a variety of stimuli involved in neutrophil activation,
including fMet-Leu-Phe (fMLP), platelet-activating factor
(PAF), granulocyte-macrophage colony-stimulating factor
(GM-CSF), and IgG-coated particles, induce a rapid and
transient Rap1 activation. In addition, we found that Rap1 is
normally activated in neutrophils from chronic granulomatous
disease patients that lack cytochrome b558 or p47phox
and have a defective NADPH oxidase system. From these
results we conclude that in neutrophils Rap1 is activated
independently of respiratory burst induc...
High-affinity receptors for interleukin-3 (IL-3), IL-5, and granu-locyte-
macrophage colony-stimulating factor (GM-CSF) are
composed of two distinct subunits, a ligand-specific a chain
and a common ß chain (ßc). Whereas the mouse has two
homologous ß subunits (ßc and bIL-3), in humans, only a
single ß chain is identified. We describe here the isolation
and characterization of the gene encoding the human IL-3/IL-5/
GM-CSF receptor ß subunit. The gene spans about 25 kb
and is divided into 14 exons, a structure very similar to that
of the murine ßc/ßIL-3 genes. Surprisingly, we also found
the remnants of a second ßc chain gene directly downstream
of ßc. We identified a functional promoter that is active in the
myeloid cell lines U937 and HL-60, but not in HeLa cells. The
proximal promoter region, located from -103 to +33 bp,
contains two ...
Eosinophil-derived neurotoxin (EDN) found in the granules
of human eosinophils is a cationic ribonuclease toxin. Expression
of the EDN gene (RNS2) in eosinophils is dependent on
proximal promoter sequences in combination with an enhancer
located in the first intron. We further define here the
active region of the intron using transfections in differentiated
eosinophilic HL60 cells. We show that a region containing
a tandem PU.I binding site is important for intronic
enhancer activity. This region binds multiple forms of transcription
factor PU.I as judged by gel-shift analysis and DNA
affinity precipitation. Importantly, introducing point mutations
in the PU.I site drastically reduces the intronic enhancer
activity, showing the importance of PU.I for expression
of EDN in cells of the eosinophilic lineage.
The receptor for interleukin-5 (IL-5R) is composed of a
unique a chain (IL-5Ra) expressed on eosinophils and
basophils, associated with a bc subunit, which is shared
by the receptors for IL-3 and granulocyte macrophagecolony
stimulating factor. One of the molecular events
activated via the IL-5R is the JAK/STAT signaling pathway.
Recent reports have shown that IL-5 induces tyrosine
phosphorylation of JAK2 followed by the subsequent
cell type-specific activation of either STAT1a or
STAT5. To identify additional STAT proteins activated
by IL-5, we co-transfected the IL-5R with STAT cDNAs in
COS cells. We found that IL-5 induces binding of STAT3
to the intercellular adhesion molecule-1 pIRE, and activates
STAT3-dependent transcription. Moreover, endogenous
STAT3 was tyrosine phosphorylated and activated
in human IL-5-stimulated BaF3 cells...
Detachment of the rear of the cell from its substratum is an important aspect of locomotion. The
signaling routes involved in this adhesive release are largely unknown. One of the few candidate
proteins to play a role is RhoA, because activation of RhoA in many cell types leads to contraction,
a mechanism probably involved in detachment. To study the role of RhoA in detachment
regulation, we analyzed several subsets of expert migratory leukocytes by video microscopy. In
contrast to fast-migrating neutrophils, eosinophils do not detach the rear of the cell unless
stimulated with serum. When measuring the amount of active RhoA, with the use of a GSTRhotekin
pulldown assay, we found that serum is an excellent activator of RhoA in granulocytes.
Inhibition of RhoA or one of Rhos target proteins, the kinase ROCK, in neutrophils leads to the...
The multistep model of leukocyte adhesion reveals that selectins mediate rolling interactions and that integrins mediate firm
adhesion processes. In this study, the interaction between eosinophils and TNF-a-activated HUVEC (second or third passage) was
studied under flow conditions (0.8 and 3.2 dynes/cm 2 ). Especially the role of a4 integrins on eosinophils and E-selectin on HUVEC
was studied. Inhibition of the integrin a4 chain on eosinophils reduced the number of firmly adhered resting eosinophils to
TNF-a-stimulated endothelium by 43% whereas the percentage rolling cells increased 2.2-fold compared with untreated control
eosinophils. Blocking of E-selectin on the endothelium reduced the number of adherent eosinophils by only 23% and 16%. In this
situation, however, hardly any rolling adhesion was observed, and the few rolling cells...
