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Red Blood Cell and Platelet Mechanics
Published in Michel R. Labrosse, Cardiovascular Mechanics, 2018
The activating platelet collagen receptor, GPVI, is a megakaryocyte-/platelet-specific transmembrane receptor; it is noncovalently associated with the FcR γ chain, which contains an immunoreceptor tyrosine-based activation motif. On ligand-induced GPVI clustering, this motif becomes tyrosine phosphorylated and initiates a series of phosphorylation events, finally resulting in full cellular activation (Figure 8.11) (Berlanga et al. 2007, Dutting et al. 2012). GPVI has been estimated to be expressed at 4000–6000 copies (Berlanga et al. 2007). Multiple studies have shown that only the dimeric form of the receptor binds exposed subendothelial collagen with high affinity (Miura et al. 2002). A few patients with GPVI-related defects (Arthur et al. 2007, Dumont et al. 2009, Hermans et al. 2009, Matus et al. 2013) have been reported so far, suffering merely from a mild bleeding tendency, but their platelets are unresponsive to collagen. It was revealed that GPVI is largely dispensable for normal hemostasis but has a predominant role in the formation of (experimental) arterial thrombi in vivo (Dutting et al. 2012).
Characterization of Biosimilar Biologics
Published in Laszlo Endrenyi, Paul Jules Declerck, Shein-Chung Chow, Biosimilar Drug Product Development, 2017
All FcγR are transmembrane molecules, with the exception of FcγRIIIb which is glycosylphosphatidylinositol (GPI)-anchored within the membrane of neutrophils. FcγRI and FcγRIIIa are members of the multichain immune recognition receptor (MIRR) family and are present in the membrane as heterooligomeric complexes comprised of an α and a γ chain: an IgG/antigen complex binds the α chain to initiate signaling through the γ chain; the FcγRIIIa α chain of NK cells is also associated with a signaling ζ chain. FcγRIIa and FcγRIIb molecules are composed of an α chain only (Gillis et al., 2014; Lux et al., 2013; van de Winkel, 2010). The FcγR α chains show a high degree of sequence homology in their extracellular domains (70%–98%) but differ significantly in their cytoplasmic domains. The cytoplasmic domains of γ chains and the FcγRIIa α chain express the immunoreceptor tyrosine-based activation motif (ITAM) that is involved in the early stages of intracellular signal generation. By contrast, the FcγRIIb receptor α chain expresses an immunoreceptor tyrosine-based inhibition motif (ITIM) (Deisenhofer, 1981; Gillis et al., 2014; Jefferis, 2012; Lux et al., 2013; Stanfield and Wilson, 2014). Cellular activation may be dependent on the balance between the relative levels of expression of these two isoforms and hence the balance of signals generated through the ITAM and ITIM motifs (Gillis et al., 2014; Lux et al., 2013).
Benzo[a]pyrene osteotoxicity and the regulatory roles of genetic and epigenetic factors: A review
Published in Critical Reviews in Environmental Science and Technology, 2022
Jiezhang Mo, Doris Wai-Ting Au, Jiahua Guo, Christoph Winkler, Richard Yuen-Chong Kong, Frauke Seemann
OCs, which are derived from hematopoietic stem cells (HSCs), are responsible for bone resorption. Stimulated by the macrophage colony-stimulating factor (M-CSF), HSCs first differentiate into mononuclear precursor cells (MPCs) (Boyle et al., 2003). Thereafter, M-CSF and RANKL induce MPCs to further differentiate into osteoclast progenitors (OCPs) which ultimately become functional multinuclear osteoclasts (MOCs) following fusion and polarization (Figure 6) (Crockett et al., 2011; Tang et al., 2014). OC differentiation initially depends on signaling via colony-stimulating factor 1 receptor (CSF1R) − the receptor for M-CSF − in MPCs to upregulate the expression of RANK. Its ligand, RANKL (RANK competes with a decoy receptor, OPG, for RANKL), is expressed in OBs and stromal cells in response to PTH and stimulation by the active dihydroxy form of vitamin D3 (1,25 Vit D3) (Crockett et al., 2011; Hrdlicka et al., 2019). Upon binding of RANK to RANKL, tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) forms a complex with transforming growth factor-β-activated kinase 1 (TAK1) and TGF-β activated kinase 1 binding protein 1 (TAB1). They subsequently recruit SMAD3 and facilitate the downstream ubiquitination and degradation of IκBα, the inhibitor of transcription factors nuclear factor κB (NF-κB). The free NF-κB then translocates from the cytosol to the nucleus and promotes the transcription of the nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) (Hrdlicka et al., 2019; Lozano et al., 2019). Alternatively, together with the immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptors, DNAX-activating protein of 12 kDa (DAP12) and Fc receptor γ chain (FcRγ), binding of RANKL to RANK activates NF-κB, activator protein 1 (AP-1, composed of C-FOS and C-JUN) and NFATc1 (Lozano et al., 2019). All of these transcription factors induce the expression of key OC genes, which include dendritic cell-specific transmembrane protein (DC-STAMP), tartrate-resistant acid phosphatase (TRAcP), cathepsin K (CTSK), matrix metalloproteinases (MMPs), and β3 integrin in MOCs (Crockett et al., 2011; Hrdlicka et al., 2019).