scholarly journals Endothelial O-Glycoproteins Cooperate with Platelet CLEC-2 Signaling to Maintain Cerebrovascular Integrity during Mouse Development

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 76-76
Author(s):  
Jianxin Fu ◽  
Jianhua Song ◽  
Lijun Xia
Keyword(s):  
Conflicts Of Interest ◽  
Critical Role ◽  
Protein Glycosylation ◽  
Developing Brain ◽  
Mouse Development ◽  
Vascular Integrity ◽  
Platelet Receptor ◽  
Fatal Hemorrhage ◽  
Platelet Release ◽  
Cerebral Vascular

Abstract Protein glycosylation plays vital roles in many biological processes. We previously discovered that embryos with global deficiencies of mucin-type O-glycans (i.e. C1galt1-/- mice) develop fatal brain hemorrhage during embryogenesis. However, mice lacking endothelial cell O-glycans exhibit blood-lymphatic mixing with no brain bleeding phenotype, whereas mice lacking either O-glycoprotein podoplanin or its receptor CLEC-2 develop similar spontaneous bleeding in developing brain. To further investigate whether endothelial O-glycans contribute to cerebrovascular barrier development and/or maintenance, we generated two independent transgenic mouse lines, in which the expression of C1galt1 is under the control of endothelial-specific Tie2 promoter/enhancer (EC-C1galt1 Tg mice). When breeding the EC-C1galt1 Tg mice into C1galt1-/- background, we found that the embryonic lethality of C1galt1-/- mice was completely rescued, supporting a critical role of endothelial O-glycans in governing the cerebral vascular integrity during embryogenesis. Platelets have been identified as one of the key players for vascular integrity under physiological and pathological conditions although the underlying mechanisms remain elusive. Based on the existing knowledge, we hypothesize that endothelial O-glycoproteins cooperate with neural podoplanin, an O-glycoprotein highly expressed on neural progenitor cells in early developing brain, through activating its platelet receptor CLEC-2, to maintain cerebral vascular integrity during active sprouting angiogenesis. To test the hypothesis, we generated mice with compound deficiencies of endothelial O-glycans and podoplanin. Interestingly, double knockout mice faithfully phenocopied the global C1galt1-/- mice, including a full penetration of fatal hemorrhage. These results strongly support a cooperative role between endothelial O-glycans and neural podoplanin. Mechanistically, we demonstrated that loss of podoplanin or CLEC-2 in vivo leads to an impaired expression of VE-cadherin, a major endothelial intercellular junctional protein. Moreover, in vitro cell-based analysis showed that podoplanin-CLEC-2 interaction and subsequent platelet release counteracts the effects of VEGF on VE-cadherin expression and endothelial permeability, indicating that podoplanin-dependent activation of platelet CLEC-2 signaling is critical for the stability of newly formed fragile vessels in the early developing brain by promoting endothelial junctions via platelet release. Taken together, our results provide a new model for the maintenance of cerebrovascular integrity during early brain development, in which the interactions between endothelial cells, neural cells and platelets are essential for the brain vascular homeostasis. These findings not only provide new insights into the regulation of cerebrovascular development, but could also allow us to test new therapies for hemorrhagic disorders with pathway-targeted drugs. Disclosures No relevant conflicts of interest to declare.

KAUTILYA ON THE SCOPE AND METHODOLOGY OF ACCOUNTING, ORGANIZATIONAL DESIGN AND THE ROLE OF ETHICS IN ANCIENT INDIA

2004 ◽  
Vol 31 (2) ◽  
pp. 125-148 ◽  
Author(s):  
Balbir S. Sihag
Keyword(s):  
Economic Development ◽  
Economic Performance ◽  
Organizational Design ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
Ethical Values ◽  
Allocation Of Resources ◽  
Economic Data ◽  
Ancient India

Kautilya, a 4th century B.C.E. economist, recognized the importance of accounting methods in economic enterprises. He realized that a proper measurement of economic performance was absolutely essential for efficient allocation of resources, which was considered an important source of economic development. He viewed philosophy and political science as separate disciplines but considered accounting an integral part of economics. He specified a very broad scope for accounting and considered explanation and prediction as its proper objectives. Kautilya developed bookkeeping rules to record and classify economic data, emphasized the critical role of independent periodic audits and proposed the establishment of two important but separate offices - the Treasurer and Comptroller-Auditor, to increase accountability, specialization, and above all to reduce the scope for conflicts of interest. He also linked the successful enforcement of rules and regulations to their clarity, consistency and completeness. Kautilya believed that such measures were necessary but not sufficient to eliminate fraudulent accounting. He also emphasized the role of ethics, considering ethical values as the glue which binds society and promotes economic development.

scholarly journals Dosage-Dependent Effects of Akt1/Protein Kinase Bα (PKBα) and Akt3/PKBγ on Thymus, Skin, and Cardiovascular and Nervous System Development in Mice

2005 ◽  
Vol 25 (23) ◽  
pp. 10407-10418 ◽  
Author(s):  
Zhong-Zhou Yang ◽  
Oliver Tschopp ◽  
Nicolas Di-Poï ◽  
Elisabeth Bruder ◽  
Anne Baudry ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cell Cycle Progression ◽  
System Development ◽  
Critical Role ◽  
Nervous System Development ◽  
Mouse Development ◽  
Double Knockout ◽  
Developmental Defects ◽  
Regulation Of Metabolism ◽  
Survival And Development

ABSTRACT Akt/protein kinase B (PKB) plays a critical role in the regulation of metabolism, transcription, cell migration, cell cycle progression, and cell survival. The existence of viable knockout mice for each of the three isoforms suggests functional redundancy. We generated mice with combined mutant alleles of Akt1 and Akt3 to study their effects on mouse development. Here we show that Akt1 − / − Akt3 +/ − mice display multiple defects in the thymus, heart, and skin and die within several days after birth, while Akt1 +/ − Akt3 − / − mice survive normally. Double knockout (Akt1 − / − Akt3 − / −) causes embryonic lethality at around embryonic days 11 and 12, with more severe developmental defects in the cardiovascular and nervous systems. Increased apoptosis was found in the developing brain of double mutant embryos. These data indicate that the Akt1 gene is more essential than Akt3 for embryonic development and survival but that both are required for embryo development. Our results indicate isoform-specific and dosage-dependent effects of Akt on animal survival and development.

scholarly journals Platelet CLEC-2 protects against lung injury via effects of its ligand podoplanin on inflammatory alveolar macrophages in the mouse

2017 ◽  
Vol 313 (6) ◽  
pp. L1016-L1029 ◽  
Author(s):  
Siân Lax ◽  
Julie Rayes ◽  
Surasak Wichaiyo ◽  
Elizabeth J. Haining ◽  
Kate Lowe ◽  
...  
Keyword(s):  
Alveolar Macrophages ◽  
Therapeutic Intervention ◽  
Arterial Oxygen Saturation ◽  
Arterial Oxygen ◽  
Type I ◽  
Vascular Integrity ◽  
Platelet Receptor ◽  
Patients At Risk ◽  
Novel Target ◽  
Deficient Mice

There is no therapeutic intervention proven to prevent acute respiratory distress syndrome (ARDS). Novel mechanistic insights into the pathophysiology of ARDS are therefore required. Platelets are implicated in regulating many of the pathogenic processes that occur during ARDS; however, the mechanisms remain elusive. The platelet receptor CLEC-2 has been shown to regulate vascular integrity at sites of acute inflammation. Therefore the purpose of this study was to establish the role of CLEC-2 and its ligand podoplanin in a mouse model of ARDS. Platelet-specific CLEC-2-deficient, as well as alveolar epithelial type I cell (AECI)-specific or hematopoietic-specific podoplanin deficient, mice were established using cre-loxP strategies. Combining these with intratracheal (IT) instillations of lipopolysaccharide (LPS), we demonstrate that arterial oxygen saturation decline in response to IT-LPS in platelet-specific CLEC-2-deficient mice is significantly augmented. An increase in bronchoalveolar lavage (BAL) neutrophils and protein was also observed 48 h post-IT-LPS, with significant increases in pro-inflammatory chemokines detected in BAL of platelet-specific CLEC-2-deficient animals. Deletion of podoplanin from hematopoietic cells but not AECIs also reduces lung function and increases pro-inflammatory chemokine expression following IT-LPS. Furthermore, we demonstrate that following IT-LPS, platelets are present in BAL in aggregates with neutrophils, which allows for CLEC-2 interaction with podoplanin expressed on BAL inflammatory alveolar macrophages. Taken together, these data suggest that the platelet CLEC-2-podoplanin signaling axis regulates the severity of lung inflammation in mice and is a possible novel target for therapeutic intervention in patients at risk of developing ARDS.

scholarly journals My D88-Dependent Interplay Between Myeloid and Endothelial Cells in the Initiation and Progression of Obesity-Associated Inflammatory Diseases

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. SCI-44-SCI-44
Author(s):  
Xiaoxia Li
Keyword(s):  
Insulin Resistance ◽  
Endothelial Cells ◽  
Adipose Tissue ◽  
Systemic Inflammation ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Low Grade

Abstract Low-grade systemic inflammation is often associated with metabolic syndrome, which plays a critical role in the development of the obesity-associated inflammatory diseases, including insulin resistance and atherosclerosis. Here, we investigate how Toll-like receptor-MyD88 signaling in myeloid and endothelial cells coordinately participates in the initiation and progression of high fat diet-induced systemic inflammation and metabolic inflammatory diseases. MyD88 deficiency in myeloid cells inhibits macrophage recruitment to adipose tissue and their switch to an M1-like phenotype. This is accompanied by substantially reduced diet-induced systemic inflammation, insulin resistance, and atherosclerosis. MyD88 deficiency in endothelial cells results in a moderate reduction in diet-induced adipose macrophage infiltration and M1 polarization, selective insulin sensitivity in adipose tissue, and amelioration of spontaneous atherosclerosis. Both in vivo and ex vivo studies suggest that MyD88-dependent GM-CSF production from the endothelial cells might play a critical role in the initiation of obesity-associated inflammation and development of atherosclerosis by priming the monocytes in the adipose and arterial tissues to differentiate into M1-like inflammatory macrophages. Collectively, these results implicate a critical MyD88-dependent interplay between myeloid and endothelial cells in the initiation and progression of obesity-associated inflammatory diseases. Disclosures No relevant conflicts of interest to declare.

Values, Other-Interest, and Ethical Behavior: The Critical Role of Moral Emotions

2020 ◽  
Author(s):  
Jason Kautz ◽  
M. Audrey Korsgaard ◽  
Sophia So Young Jeong
Keyword(s):  
Conflicts Of Interest ◽  
Critical Role ◽  
Moral Values ◽  
Moral Emotions ◽  
The Self ◽  
Collective Rationality ◽  
Ethical Challenges ◽  
Self Interest ◽  
Organizational Stakeholders ◽  
Rational Reasoning

Organizations and their agents regularly face ethical challenges as the interests of various constituents compete and conflict. The theory of other-orientation provides a useful framework for understanding how other concerns and modes of reasoning combined to produce different mindsets for approaching ethical challenges. To optimize outcomes across parties, individuals can engage in complex rational reasoning that addresses the interests of the self as well as others, a mindset referred to as collective rationality. But collective rationality is as difficult to sustain as it is cognitively taxing. Thus, individuals are apt to simplify their approach to complex conflicts of interest. One simplifying strategy is to reduce the relevant outcome set by focusing on self-interests to the neglect of other-interest. This approach, referred to as a rational self-interest mindset, is self-serving and can lead to actions that are deemed unethical. At the other extreme, individuals can abandon rational judgment in favor of choices based on heuristics, such as moral values that specify a given mode of prosocial behavior. Because this mindset, referred to as other-oriented, obviates consideration of outcome for the self and other, it can result in choices that harm the self as well as other possible organizational stakeholders. This raises the question: how does one maintain an other-interested focus while engaging in rational reasoning? The resolution of this question rests in the arousal of moral emotions. Moral emotions signal to the individual the opportunity to express, or the need to uphold, moral values. Given that moral values direct behavior that benefits others or society, they offset the tendency to focus on self-interest. At extreme levels of arousal, however, moral emotions may overwhelm cognitive resources and thus influence individuals to engage in heuristic rather than rational reasoning. The effect of moral emotions is bounded by attendant emotions, as individuals are likely to experience multiple hedonic and moral emotions in the same situation. Deontic justice predicts that the arousal of moral emotions will lead individuals to retaliate in response to injustice, regardless of whether they experience personal benefit. However, evidence suggests that individuals may instead engage in self-protecting behavior, such as withdrawal, or self-serving behaviors, such as the contagion of unjust behavior. These alternative responses may be due to strong hedonic emotions, such as fear or schadenfreude, the pleasure derived from others’ misfortunes, overpowering one’s moral emotions. Future research regarding the arousal levels of moral emotions and the complex interplay of emotions in the decision-making process may provide beneficial insight into managing the competing interests of organizational stakeholders.

scholarly journals Expression of c-kit and kit ligand proteins in normal human tissues.

1994 ◽  
Vol 42 (11) ◽  
pp. 1417-1425 ◽  
Author(s):  
A Lammie ◽  
M Drobnjak ◽  
W Gerald ◽  
A Saad ◽  
R Cote ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Critical Role ◽  
Regional Distribution ◽  
Cervix Uterus ◽  
Sweat Glands ◽  
Human Tissues ◽  
Mouse Development ◽  
Normal Tissues ◽  
The Central Nervous System

The c-kit receptor and its cognate ligand, KL, play a critical role in melanogenesis, gametogenesis, and hematopoiesis. Studies on the expression of c-kit and KL have been primarily focused on mouse development. We undertook the present study to characterize the pattern of expression of these molecules in normal adult human tissues. Using immunohistochemistry and consecutive tissue sections from the same block, we evaluated a variety of well-preserved normal tissues for c-kit and KL microanatomic distribution. c-kit protein was identified in tissue mast cells, melanocytes, glandular epithelial cells of breast, parotid, dermal sweat, and esophageal glands. Scattered c-kit immunoreactivity was also observed for testicular and ovarian interstitial cells. A striking regional distribution of c-kit was detected in the central nervous system, particularly in the cerebellum, hippocampus, and dorsal horn of the spinal cord. KL protein was identified in cells complementary to staining for the receptor, such as glandular myoepithelium of breast and sweat glands. Intense KL immunoreactivity was observed in smooth muscle cells of the bladder, cervix, uterus, and gastrointestinal tract, as well as in striated and cardiac muscle. Strong KL staining was also detected in prostate fibromuscular stroma cells. In the central nervous system, KL expression was confined to Golgi and Purkinje cells in the cerebellum. These results suggest a role for this receptor and its ligand in the maintenance of a variety of fully differentiated tissues.

P15 and P16 Promoters Methylation Status in APL Patients Treated by Arsenic Trioxide.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4682-4682
Author(s):  
Omid Yeganeh ◽  
Kamran Alimoghaddam ◽  
Seyed Hamidolah Ghaffari ◽  
Shahrbano Rostami ◽  
Mahdi Jalili ◽  
...  
Keyword(s):  
Arsenic Trioxide ◽  
Tumor Suppressor Genes ◽  
Promoter Region ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
Methylation Status ◽  
Early Mortality ◽  
Newly Diagnosed ◽  
Sodium Bisulphite ◽  
Disease Free

Abstract Abstract 4682 Introduction Inactivation of tumor suppressor genes P15 & P16 due to Hypermethylation has a critical role in progression of cancer. We analyzed the meltylation status of promoter region of these two genes and their correlation with patients survival in APL patients treated with ATO without chemotherapy and /or ATRA. Methods Patients treated by Arsenic Trioxide without ATRA or chemotherapy and 45 newly diagnosed and 5 relapsed were enrolled in our study. Whole blood DNA was extracted and modified by sodium bisulphite reaction. Then methylation status was studied by MS-PCR and gel electrophoresis. Also for newly diagnosed patients, early mortality, disease-free and overall survival compared between methylated or non-methylated groups. Results Of 45 new cases, 31patients(69%) had methylated P15 but no patient had methylated P16. Eighty percent of relapsed patients had methylated P15 too, and no relapsed patient had methylated P16. DFS and OS correlated significantly with methylation status of P15 ( P=0.05 and 0.04) for patients who achieve to CR after treatment but it has no correlation with early motility during treatment course. Actually methyaltion of P15 improve chance of DFS and OS. Conclusion P15 but not P16 is frequently methylated in APL. Although in some studies, methyaltion of P15 negatively affected prognosis of APL patients treated by ATRA but it has no adverse effect when Arsenic Trioxide used in induction and cosolidation. Disclosures: No relevant conflicts of interest to declare.

A Novel Platelet Small-Molecule Agonist Targeting Glycoprotein Ibalpha.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4010-4010
Author(s):  
Jianfeng Yang ◽  
Zhi Chen ◽  
Weiliang Zhu ◽  
Changgeng Ruan
Keyword(s):  
Monoclonal Antibody ◽  
Platelet Aggregation ◽  
Small Molecule ◽  
Platelet Adhesion ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
Structural Basis ◽  
Terminal Fragment ◽  
Von Willebrand

Abstract Abstract 4010 Poster Board III-946 Introduction Interaction of glycoprotein (GP) Ibα with Von Willebrand factor (VWF) plays a critical role in platelet adhesion and signal transduction for αIIbβ3 activation under condition of high shear stress. Methods Based on the crystal structure of platelet GPIbα (PDB:1P9A), virtual screening was employed to identify active compounds. Compounds in SPECS database were docked to VWF binding site on the surface of GPIbα. The screening was carried out with the DOCK4.0 program. The 150 highest-scoring compounds were obtained for further bioassay and those with inhibitory activity of VWF binding to GPIbα were investigated the effect on platelet activation and aggregation. Results We found one compound, designated it as YC148, blocked ristocetin-induced plasma VWF binding to recombinant N-terminal fragment GPIbα (H1-V289) by ELISA method. More interestingly, YC148 did not inhibit ristocetin-induced platelet aggregation, on the contrary, it induced platelet aggregation itself in the absence of exogenous modulators such as ristocetin and botrocetin. A VWF A1 blocking antibody could not block platelet aggregation induced by YC148 despite it completely inhibited ristocetin-induced platelet agglutination. And YC148 also stimulated washed platelet aggregation where VWF was absent in the resuspension buffer. These indicated that the aggregation stimulated by YC148 could not the result from VWF binding. Flow cytomety also showed that YC148 increased P-selectin expression on platelet membrane and promoted monoclonal antibody PAC-1 binding to platelet. The platelet aggregation stimulated by YC148 was inhibited by anti-GPIbα monoclonal antibody AN51 and 6D1. Conclusion A novel exogenous small-molecule agonist was found to activate platelet through binding to GPIbα. It provides us a new tool for investigating platelet GPIb outside-in signaling pathway in platelet adhesion and aggregation. Furthermore, the structure of YC148 may provide a structural basis for developing new hemostatic drugs based on the inhibition of VWF-GPIb interaction. The effect of YC148 on platelet from Bernard-Soulier syndrome or GPIbα N-terminal fragment deficient platelet after in vitro cleavage will be further investigated. Disclosures: No relevant conflicts of interest to declare.

Fibrinogen Supports Colitis-Associated Adenoma Progression through a Mechanism Coupled to Engagement of the Leukocyte Integrin αMβ2.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 334-334
Author(s):  
Netanel Horowitz ◽  
Kris A. Steinbrecher ◽  
Maureen A. Shaw ◽  
Kelley A. Barney ◽  
Matthew Flick ◽  
...  
Keyword(s):  
Cell Function ◽  
Conflicts Of Interest ◽  
Thrombus Formation ◽  
Disease Process ◽  
Mutant Form ◽  
Short Term ◽  
Activation Markers ◽  
Vascular Integrity ◽  
Tumor Dissemination

Abstract Abstract 334 A growing body of evidence points to a crucial role for fibrinogen in both tumor dissemination and the regulation of inflammation. Given this dual importance, we hypothesized that fibrinogen plays an important role in the progression of inflammation-driven cancers. To test this hypothesis, we induced colitis-associated cancer (CAC) in fibrinogen-deficient mice and controls using a combination of azoxymethane (AOM) and dextran sodium sulfate (DSS). Fibrinogen deficiency resulted in a dramatic diminution in the number of adenomas formed after AOM/DSS challenge in spite of the fact that overt gastrointestinal bleeding appeared more severe in Fib- animals relative to controls. These results suggest that while fibrin deposition is crucial for the maintenance of vascular integrity and control of blood loss in colitis, fibrin(ogen) appears to drive colitis-associated adenoma development/outgrowth. Fibrin(ogen) could promote CAC through multiple mechanisms. One intriguing possibility is that fibrin(ogen) interactions with leukocytes through the integrin αMβ2 are an important determinant of inflammation-induced tumor progression. To test this hypothesis, we explored CAC development in control mice and animals expressing a mutant form of fibrinogen (Fibγ390-396A) that maintains full clotting function and supports thrombus formation normally in vivo, but does not support binding to αMβ2. Consistent with our hypothesis, Fibγ390-396A mice developed significantly fewer adenomas after AOM/DSS challenge. In fact, the majority of Fibγ390-396A mice had no discernable adenomas while the phenotypic penetrance of adenoma development was 100% in control animals. Detailed analyses revealed that one mechanism coupling fibrin(ogen)-mediated αMβ2 engagement to adenoma formation/outgrowth is by supporting inflammatory events during the antecedent colitis. Fibγ390-396A mice manifested a dramatic diminution in inflammatory cell infiltrates, colonic edema, crypt loss and epithelial ulceration relative to control mice after chronic DSS exposure. Analyses of short-term DSS exposure revealed an ∼10-fold diminution in Fibγ390-396A mice relative to controls in the elaboration of key cytokines known to promote CAC progression (i.e., IL-6, TNF-α, IL-1β, IFN-γ). Previous studies suggest that these cytokines promote CAC, at least in part, through changes in epithelial cell function. Consistent with this view, the number of colonic epithelial cells staining positive for established activation markers (i.e., phosphorylated cJun and RelA/p65) were significantly diminished in Fibγ390-396A animals relative to control animals after short-term DSS exposure. Taken together, these data strongly suggest that one mechanism coupling fibrin(ogen) to adenoma progression is through αMβ2-mediated proinflammatory events early in the disease process which lead to epithelial damage/turnover important in adenoma formation. However, the role of fibrin(ogen) in adenoma progression does not appear to be limited to these early inflammatory events. The adenomas harvested from Fibγ390-396A mice were significantly smaller than those from control mice and less proliferative based on mitotic indices, suggesting an additional role for fibrin(ogen) in the growth of established adenomas. These studies demonstrate, for the first time, a unique link between fibrin(ogen) and the development of inflammation-driven malignancy. Given the importance of antecedent inflammation in the progression of numerous cancers, these studies suggest that therapies targeting fibrin(ogen)-αMβ2 interactions may be useful in preventing and/or treating this important subset of malignancies. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document