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991.
Lara-Pezzi E Felkin LE Birks EJ Sarathchandra P Panse KD George R Hall JL Yacoub MH Rosenthal N Barton PJ 《Endocrinology》2008,149(11):5822-5827
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Papadaki HA Eliopoulos DG Ponticoglou C Eliopoulos GD 《International journal of hematology》2001,73(3):339-345
This study describes the frequency of monoclonal gammopathy of undetermined significance (MGUS) and the changes in some inflammation-related serum proteins in 157 patients with nonimmune chronic idiopathic neutropenia syndrome (NI-CINS). Of these patients, 42 had pronounced neutropenia with neutrophil counts < 1500/microL, and 115 had mild neutropenia with neutrophil counts ranging from 1500 to 2499/microL. Sixty-six volunteers served as healthy control subjects and 157 age- and sex-matched patients hospitalized for nonmalignant diseases served as patient control subjects. We found that 28.6% of patients with pronounced neutropenia and 14.8% of patients with mild neutropenia had increased serum gamma globulins (above the 95% confidence limit of values of the control subjects). In the group of patients with pronounced neutropenia, 30.9% had increased immunoglobulin (Ig)G values and 23.8% had increased IgA values. In the group of patients with mild neutropenia, 17.4% had increased IgG values and 21.7% had increased IgA values. IgG and IgA values strongly correlated with the neutrophil count. No changes in serum IgM were found. Three of 42 patients with pronounced neutropenia (7.14%) and 3 of 115 patients with mild neutropenia (2.61%) had serum immunofixation tests which showed a small monoclonal spike--4 were IgG-kappa type, 1 was IgG-lambda type, and 1 was IgA-kappa type. None of the healthy or patient control subjects had any evidence of MGUS. No significant changes in the amount of monoclonal spikes were documented during an 18- to 143-month follow-up (median, 58 months). Except for significantly increased alpha1-antitrypsin levels, there were no significant differences in the levels of acute-phase proteins studied between the study patients and the control subjects. These findings are consistent with our previous report suggesting the possible existence of an unrecognized low-grade chronic inflammation in patients with NI-CINS, which may be involved in the pathogenesis of neutropenia in the affected subjects. 相似文献
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Differential hippocampal gene expression and pathway analysis in an etiology‐based mouse model of major depressive disorder 下载免费PDF全文
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Peter Geon Kim Haruko Nakano Partha P. Das Michael J. Chen R. Grant Rowe Stephanie S. Chou Samantha J. Ross Kathleen M. Sakamoto Leonard I. Zon Thorsten M. Schlaeger Stuart H. Orkin Atsushi Nakano George Q. Daley 《The Journal of experimental medicine》2015,212(5):633-648
Fluid shear stress promotes the emergence of hematopoietic stem cells (HSCs) in the aorta–gonad–mesonephros (AGM) of the developing mouse embryo. We determined that the AGM is enriched for expression of targets of protein kinase A (PKA)–cAMP response element-binding protein (CREB), a pathway activated by fluid shear stress. By analyzing CREB genomic occupancy from chromatin-immunoprecipitation sequencing (ChIP-seq) data, we identified the bone morphogenetic protein (BMP) pathway as a potential regulator of CREB. By chemical modulation of the PKA–CREB and BMP pathways in isolated AGM VE-cadherin+ cells from mid-gestation embryos, we demonstrate that PKA–CREB regulates hematopoietic engraftment and clonogenicity of hematopoietic progenitors, and is dependent on secreted BMP ligands through the type I BMP receptor. Finally, we observed blunting of this signaling axis using Ncx1-null embryos, which lack a heartbeat and intravascular flow. Collectively, we have identified a novel PKA–CREB–BMP signaling pathway downstream of shear stress that regulates HSC emergence in the AGM via the endothelial-to-hematopoietic transition.Embryonic hematopoietic development in the mouse proceeds through defined stages. The first hematopoietic cells of the erythroid lineage develop in the extraembryonic yolk sac at embryonic day 7.5 (E7.5; Moore and Metcalf, 1970). At E9, hematopoietic stem cell (HSC) activity from the yolk sac and paraaortic splanchnopleura (PSp) can be detected when transplanted into neonatal mice (Yoder et al., 1997; Arora et al., 2014). HSCs that engraft lethally irradiated adult recipients emerge in the aorta–gonad–mesonephros (AGM) region at E10-11 (Medvinsky and Dzierzak, 1996; North et al., 2002). These HSCs later colonize additional organs required for adult hematopoiesis and possess the ability to reconstitute multiple hematopoietic lineages.The development of the murine circulatory system at E8.5 coincides with the development of more definitive hematopoietic compartments, including HSCs and the lymphoid lineage. Accordingly, recent studies have linked biomechanical forces, such as blood flow–induced shear stress, to hematopoietic development (Adamo et al., 2009; North et al., 2009). In these studies, genetic mutants lacking intravascular circulation were used to demonstrate the reduction in hematopoietic emergence in the AGM and nitric oxide signaling was implicated in blood flow–dependent AGM hematopoiesis (Adamo et al., 2009; North et al., 2009; Wang et al., 2011). Although chimeric analysis demonstrated a cell autonomous requirement for nitric oxide signaling in zebrafish (North et al., 2009), whether this pathway directly promotes hematopoiesis remains an open question due to the vasodilatory effect of nitric oxide donors and their effects on smooth muscle. Apart from these observations, signaling pathways responsible for flow-dependent hematopoietic induction have not been characterized.Activation of protein kinase A (PKA) and its downstream target cAMP response element-binding protein (CREB) by exogenous shear stress has been observed in diverse cell types, including chondrocytes and osteocytes (Cherian et al., 2003; Ogawa et al., 2014). The classic mechanism of PKA activation involves the binding of a ligand to a G protein–coupled receptor and activation of adenylyl cyclase, which converts ATP into the second messenger cyclic AMP (cAMP). The binding of cAMP to PKA releases catalytic subunits that phosphorylate CREB in the nucleus. In differentiating mouse embryonic stem cells (mESCs), PKA–CREB has been linked to endothelial and hematopoietic differentiation via binding of CREB to the Etv2 promoter, which up-regulates pro-hematopoietic factors such as Gata2 and Scl/Tal1 (Yamamizu et al., 2012). Moreover, the PKA–CREB signaling pathway has been explored in the context of the prostaglandin E2 signaling pathway in zebrafish, where it promotes AGM hematopoiesis via activation of the Wnt pathway (Goessling et al., 2009). However, whether this pathway is conserved in the mouse is unclear, especially given conflicting reports on Wnt signaling in AGM hematopoiesis (Ruiz-Herguido et al., 2012; Chanda et al., 2013). Prostaglandin E2 also directly activates several pathways including PI3K–AKT and ERK–MAPK, which makes it difficult to conclude that PKA–CREB is the sole mediator of the pro-hematopoietic effects of this molecule (Alfranca et al., 2006). Given the shear-responsiveness of the PKA–CREB pathway and its implication in early embryonic hematopoiesis in other species, we investigated the possible role of shear stress–activated PKA–CREB signaling during AGM hematopoiesis in the mouse.We first verified that this pathway is activated by shear stress in VE-cadherin+ endothelial cells and present in the murine AGM, specifically in the cells lining the dorsal aorta. We then conducted a bioinformatics-based screen using microarray data on CREB overexpression and CREB chromatin immunoprecipitation-sequencing (ChIP-Seq) data using data available at Encyclopedia of DNA Elements (ENCODE) and elsewhere to identify regulators of CREB function in hematopoietic cells (Esparza et al., 2008; Jolma et al., 2010; Pencovich et al., 2011; Raney et al., 2011; Trompouki et al., 2011; Martens et al., 2012). Using insight gained from bioinformatics, we discover that the bone morphogenetic protein (BMP) signaling pathway acts downstream of PKA–CREB signaling in regulating AGM hematopoiesis. Finally, we show that this is a blood flow–dependent pathway by demonstrating the abrogation of PKA–CREB–BMP signaling axis in Ncx1-null embryos, which lack a heartbeat and intravascular flow. Our data thus document a blood-flow dependent pathway regulating hematopoietic development. 相似文献
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