scholarly journals Oxidized Phospholipids Promote NETosis and Arterial Thrombosis in LNK(SH2B3) Deficiency

Circulation ◽  
2021 ◽  
Author(s):  
Huijuan Dou ◽  
Andriana Kotini ◽  
Wenli Liu ◽  
Trevor Fidler ◽  
Kaori Endo−Umeda ◽  
...  
Keyword(s):  
Arterial Thrombosis ◽  
Induced Pluripotent Stem Cell ◽  
Human Platelets ◽  
Neutrophil Extracellular Trap ◽  
Human Populations ◽  
Oxidized Phospholipids ◽  
Single Chain ◽  
Using Data ◽  
Deficient Mice

Background: LNK/SH2B3 inhibits JAK/STAT signaling by hematopoietic cytokine receptors. GWAS have shown association of a common SNP in LNK (R262W, T allele) with neutrophilia, thrombocytosis and coronary artery disease (CAD). We have shown that LNK(TT) reduces LNK function and that LNK deficient mice display prominent platelet−neutrophil aggregates, accelerated atherosclerosis and thrombosis. Platelet−neutrophil interactions can promote neutrophil extracellular trap (NET) formation. The goals of this study were to assess the role of neutrophil extracellular traps (NETs) in atherosclerosis and thrombosis in mice with hematopoietic Lnk deficiency. Methods: We bred mice with combined deficiency of Lnk and the NETosis-essential enzyme peptidylarginine deiminase4 (PAD4) and transplanted their bone marrow into Ldlr −/− mice. We evaluated the role of LNK in atherothrombosis in humans and mice bearing a gain of function variant in JAK2 (JAK2 V617F ). Results: Lnk deficient mice displayed accelerated carotid artery thrombosis with prominent NETosis that was completely reversed by PAD4 deficiency. Thrombin-activated Lnk −/− platelets promoted increased NETosis when incubated with Lnk −/− neutrophils compared to WT platelets or WT neutrophils. This involved increased surface exposure and release of oxidized phospholipids (OxPL) from Lnk −/− platelets, as well as increased priming and response of Lnk −/− neutrophils to OxPL. To counteract the effects of OxPL, we introduced a transgene expressing the single-chain variable fragment of E06 (E06−scFv). E06−scFv reversed accelerated NETosis, atherosclerosis and thrombosis in Lnk −/− mice. We also showed increased NETosis when human induced pluripotent stem cell (iPSC) derived LNK(TT) neutrophils were incubated with LNK(TT) platelet/megakaryocytes, but not in isogenic LNK(CC) controls, confirming human relevance. Using data from UK Biobank we found that individuals with the JAK2 VF mutation only showed increased CAD when also carrying the LNK R262W allele. Mice with hematopoietic Lnk +/- and Jak2 VF clonal hematopoiesis, showed accelerated arterial thrombosis but not atherosclerosis compared to Jak2VFLnk +/+ controls. Conclusions: Hematopoietic Lnk deficiency promotes NETosis and arterial thrombosis in an OxPL-dependent fashion. LNK(R262W) reduces LNK function in human platelets and neutrophils promoting NETosis, and increases CAD risk in humans carrying JAK2 VF mutations. Therapies targeting OxPL may be beneficial for CAD in genetically defined human populations.

scholarly journals Vascular smooth muscle–derived tissue factor is critical for arterial thrombosis after ferric chloride–induced injury

Blood ◽  
2009 ◽  
Vol 113 (3) ◽  
pp. 705-713 ◽  
Author(s):  
Li Wang ◽  
Christine Miller ◽  
Robert F. Swarthout ◽  
Mohan Rao ◽  
Nigel Mackman ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Tissue Factor ◽  
Ferric Chloride ◽  
Arterial Thrombosis ◽  
Critical Role ◽  
Arterial Injury ◽  
Aortic Media ◽  
Deficient Mice

Abstract Tissue factor (TF) initiates coagulation, regulates hemostasis, and plays a critical role in mediating arterial thrombosis. TF is up-regulated in vascular smooth muscle cells (VSMCs) in atherosclerosis and arterial injury. To examine the biologic role of VSMC-derived TF, we crossed TFflox/flox mice with SM22αCre+/− mice. TF mRNA and activity were decreased in the aortic media of TF-deficient mice by 96% and 94.8%, respectively. There were no differences in TF activity measured in plasma or concentrated microparticles. TF-deficient mice were generated with the expected frequency, showed no evidence of bleeding or increased mortality, and had similar activated partial thromboplastin and tail vein bleeding times. Thrombus-mediated flow reduction in response to ferric chloride injury of the carotid arteries was significantly attenuated in VSMC-specific TF-deficient. Stable occlusion was seen in 11 of 12 wild-type mice, but in only 6 of 16 VSMC-specific TF-deficient mice (P = .001). These data suggest that VSMC-derived TF is critical in a macrovascular model of arterial thrombosis. This mouse model should be valuable in determining the contribution of VSMC-derived TF in other TF-mediated phenomena, such as restenosis.

Fine structure and properties of defects in naturally occurring silicates and oxides

1990 ◽  
Vol 48 (4) ◽  
pp. 460-461
Author(s):  
David R. Veblen
Keyword(s):  
Chemical Reactions ◽  
High Resolution Electron Microscopy ◽  
Extended Defects ◽  
Single Chain ◽  
Naturally Occurring ◽  
Resolution Electron ◽  
Fine Structures ◽  
Image Simulations ◽  
Similar Crystal Structure

Extended defects and interfaces control many processes in rock-forming minerals, from chemical reactions to rock deformation. In many cases, it is not the average structure of a defect or interface that is most important, but rather the structure of defect terminations or offsets in an interface. One of the major thrusts of high-resolution electron microscopy in the earth sciences has been to identify the role of defect fine structures in reactions and to determine the structures of such features. This paper will review studies using HREM and image simulations to determine the structures of defects in silicate and oxide minerals and present several examples of the role of defects in mineral chemical reactions. In some cases, the geological occurrence can be used to constrain the diffusional properties of defects.The simplest reactions in minerals involve exsolution (precipitation) of one mineral from another with a similar crystal structure, and pyroxenes (single-chain silicates) provide a good example. Although conventional TEM studies have led to a basic understanding of this sort of phase separation in pyroxenes via spinodal decomposition or nucleation and growth, HREM has provided a much more detailed appreciation of the processes involved.

Collagen-Induced Platelet Aggregation: -Evidence Against the Essential Role of Platelet Adenosine Diphosphate

1979 ◽  
Vol 42 (04) ◽  
pp. 1193-1206 ◽  
Author(s):  
Barbara Nunn
Keyword(s):  
Platelet Aggregation ◽  
Time Course ◽  
Essential Role ◽  
Atp Release ◽  
Adenosine Diphosphate ◽  
Human Platelets ◽  
High Doses ◽  
Induced Aggregation

SummaryThe hypothesis that platelet ADP is responsible for collagen-induced aggregation has been re-examined. It was found that the concentration of ADP obtaining in human PRP at the onset of aggregation was not sufficient to account for that aggregation. Furthermore, the time-course of collagen-induced release in human PRP was the same as that in sheep PRP where ADP does not cause release. These findings are not consistent with claims that ADP alone perpetuates a collagen-initiated release-aggregation-release sequence. The effects of high doses of collagen, which released 4-5 μM ADP, were not inhibited by 500 pM adenosine, a concentration that greatly reduced the effect of 300 μM ADP. Collagen caused aggregation in ADP-refractory PRP and in platelet suspensions unresponsive to 1 mM ADP. Thus human platelets can aggregate in response to collagen under circumstances in which they cannot respond to ADP. Apyrase inhibited aggregation and ATP release in platelet suspensions but not in human PRP. Evidence is presented that the means currently used to examine the role of ADP in aggregation require investigation.

The Role of the Low-Density Lipoprotein Receptor-Related Protein (LRP) in the Plasma Clearance and Liver Uptake of Recombinant Single-chain Urokinase-type Plasminogen Activator in Rats

1997 ◽  
Vol 77 (04) ◽  
pp. 710-717 ◽  
Author(s):  
Marieke E van der Kaaden ◽  
Dingeman C Rijken ◽  
J Kar Kruijt ◽  
Theo J C van Berkel ◽  
Johan Kuiper
Keyword(s):  
Plasminogen Activator ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Single Chain ◽  
Liver Uptake ◽  
Type Plasminogen Activator ◽  
Parenchymal Liver ◽  
Urokinase Type Plasminogen Activator ◽  
Density Lipoprotein Receptor

SummaryUrokinase-type plasminogen activator (u-PA) is used as a thrombolytic agent in the treatment of acute myocardial infarction. In vitro, recombinant single-chain u-PA (rscu-PA) expressed in E.coli is recognized by the Low-Density Lipoprotein Receptor-related Protein (LRP) on rat parenchymal liver cells. In this study we investigated the role of LRP in the liver uptake and plasma clearance of rscu-PA in rats. A preinjection of the LRP inhibitor GST-RAP reduced the maximal liver uptake of 125I-rscu-PA at 5 min after injection from 50 to 30% of the injected dose and decreased the clearance of rscu-PA from 2.37 ml/min to 1.58 ml/min. Parenchymal, Kupffer and endothelial cells were responsible for 40, 50 and 10% of the liver uptake, respectively. The reduction in liver uptake of rscu-PA by the preinjection of GST-RAP was caused by a 91 % and 62% reduction in the uptake by parenchymal and Kupffer cells, respectively. In order to investigate the part of rscu-PA that accounted for the interaction with LRP, experiments were performed with a mutant of rscu-PA lacking residues 11-135 (= deltal25- rscu-PA). Deletion of residues 11-135 resulted in a 80% reduction in liver uptake and a 2.4 times slower clearance (0.97 ml/min). The parenchymal, Kupffer and endothelial cells were responsible for respectively 60, 33 and 7% of the liver uptake of 125I-deltal25-rscu-PA. Preinjection of GST-RAP completely reduced the liver uptake of delta 125-rscu-PA and reduced its clearance to 0.79 ml/min. Treatment of isolated Kupffer cells with PI-PLC reduced the binding of rscu-PA by 40%, suggesting the involvement of the urokinase-type Plasminogen Activator Receptor (u-PAR) in the recognition of rscu-PA. Our results demonstrate that in vivo LRP is responsible for more than 90% of the parenchymal liver cell mediated uptake of rscu-PA and for 60% of the Kupffer cell interaction. It is also suggested that u-PAR is involved in the Kupffer cell recognition of rscu-PA.

INOVASI PEMBELAJARAN AKIDAH AKHLAK MENGGUNAKAN METODE ROLE PLAY DALAM MENINGKATKAN PRESTASI BELAJAR SISWA

2018 ◽  
Vol 2 (1) ◽  
pp. 52-63
Author(s):  
Ansori Ansori
Keyword(s):  
Data Reduction ◽  
Role Play ◽  
Learning Goals ◽  
New Paradigm ◽  
Learning Materials ◽  
Analysis Technique ◽  
Flexible Schedule ◽  
Using Data ◽  
Real Action

The use of various methods will greatly help students in achieving learning goals. As role play method is one way mastery of learning materials through the development of imagination and appreciation of students on learning materials. Data collection techniques in this study are observation, interviews, and documentation. To analyze the data in this research using data analysis technique of Miles and Huberman model that is data reduction (Data Reduction), data presentation (Data Display) and conclusion (Conclution Drawing / verification) The findings in this research is innovation of role play method can change paradigm to the new paradigm so that the role of the teacher is more as a facilitator, counselor, consultant, and comrade study Flexible schedule, open as needed Learning directed by students themselves Problem-based, project, real world, real action, and reflection Design and investigation. Computers as tools, and dynamic media presentations.

Adiabatic large polarons in anisotropic molecular crystals

2011 ◽  
Vol 35 (1) ◽  
pp. 15-27
Author(s):  
Zoran Ivić ◽  
Željko Pržulj
Keyword(s):  
Energy Transfer ◽  
Effective Mass ◽  
Molecular Crystals ◽  
Single Chain ◽  
Proper Understanding ◽  
One Dimensional ◽  
Interchain Coupling ◽  
Large Polaron ◽  
The One

Adiabatic large polarons in anisotropic molecular crystals We study the large polaron whose motion is confined to a single chain in a system composed of the collection of parallel molecular chains embedded in threedimensional lattice. It is found that the interchain coupling has a significant impact on the large polaron characteristics. In particular, its radius is quite larger while its effective mass is considerably lighter than that estimated within the one-dimensional models. We believe that our findings should be taken into account for the proper understanding of the possible role of large polarons in the charge and energy transfer in quasi-one-dimensional substances.

The role of corporate investment in social responsible practices in the promotion of employees’ organizational citizenship behaviour

2014 ◽  
Author(s):  
Ana Patrícia Duarte ◽  
José Gonçalves das Neves
Keyword(s):  
Job Satisfaction ◽  
Organizational Citizenship ◽  
Economic Uncertainty ◽  
Socially Responsible ◽  
Organizational Survival ◽  
Current Scenario ◽  
Reducing Costs ◽  
Using Data ◽  
Airline Company

In the current scenario of economic uncertainty, where many organizations struggle harder for reducing costs while improving their competitiveness, employees’ organizational citizenship behaviours might have an enhanced importance for organizational survival and success. A model proposing that corporate engagement in internal socially responsible practices enhances employees’ job satisfaction and consequently increases employees’ extra-role behaviours was tested. Using data obtained from a sample of employees from an airline company (n=133), the model was examined and supported. We have therefore concluded that organizations may foster employees’ extra-role behaviours by investing in corporate socially responsible practices that signal corporate concern with employees and promote job satisfaction.

Peranan Ketua Pengurus dan Manajer Dalam Penyusunan dan Penerapan Laporan Keuangan Berbasis SAK ETAP Pada Koperasi di Kota Palembang

2019 ◽  
Vol 14 (2) ◽  
pp. 119
Author(s):  
Riza Syahputera ◽  
Martha Rianty
Keyword(s):  
Data Analysis ◽  
Sampling Technique ◽  
Financial Statements ◽  
Significant Positive Effect ◽  
Analysis Technique ◽  
Regression Test ◽  
Using Data ◽  
The City ◽  
Positive Effect

AbstractThis study aims to determine the effect of the role of the Chairperson and Cooperative Manager in the preparation and application of Financial Statements based on SAK ETAP in cooperatives in the city of Palembang. This research is a quantitative study using data obtained from questionnaires and measured using a Likert scale. The sampling technique used is purposive sampling. The sample used in this study was the Chairperson of the cooperative and the manager of the cooperative in the city of Palembang. The cooperatives studied were 203 cooperatives. The data analysis technique used is multiple linear regression test. The results showed that the role of cooperative leaders and managers had a significant positive effect on the preparation and application of SAK ETAP-based financial statements.Keywords : chairman, manager, SAK ETAP, cooperative

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