C1-Inactivator as a Determining Factor in Contact Activation of Fibrinolysis

1975 ◽  
Author(s):  
C. Kluft
Keyword(s):  
Fibrinolytic Activity ◽  
Slow Rate ◽  
Contact Activation ◽  
Activation Rate ◽  
Activity Generation ◽  
High Level ◽  
Fletcher Factor ◽  
Determining Factor

The rate of contact activation of fibrinolysis is considered to reflect the activation rate of proactivator and Hageman factor. This study was undertaken to determine the role of Cl-inactivator in this process.Contact activation of fibrinolysis was performed according to Ogston et al. (1969), J. Clin. Invest. 48, 1786-1801. The rate of activity generation was measured in plasma with various levels of Cl-inactivator and appeared to be dependent on that level; i.e., a high level of Cl-inactivator corresponds with a slow rate of activity generation.It has recently been demonstrated that the fibrinolytic activity of euglobulin fractions is strongly inhibited by Cl-inactivator also present in this fraction. The activity generation of contact activation is found to be accompanied by a gradual decrease in functional Cl-inactivator in the euglobulin fraction. The fibrinolytic activity is set free by this disappearance of inhibition.It is concluded that the rate of contact activation of fibrinolysis must be interpreted in terms of the inactivation of Cl-inactivator rather than of the activation of proenzymes. All enzymes capable of inactivating Cl-inactivator can contribute to the process of contact activation of fibrinolysis. This mechanism might account for the observed defects in fibrinolysis in vitro in Fletcher Factor deficient patients.

scholarly journals Politeness of Vietnamese Students in Writing Request Email in English: a Course-based and Socio-pragmatic Study

2020 ◽  
Vol 2 (2) ◽  
pp. 109-128
Author(s):  
Thi Minh Trang Pham ◽  
Aiden Yeh
Keyword(s):  
Critical Discourse Analysis ◽  
Cultural Awareness ◽  
Critical Discourse ◽  
Linguistic Knowledge ◽  
Learning And Teaching ◽  
Politeness Strategies ◽  
High Level ◽  
Pragmatic Knowledge ◽  
Determining Factor

This exploratory study investigates politeness strategies employed by Vietnamese EFL learners when writing English request emails sent to foreign and Vietnamese professors and school staff. A corpus-based critical discourse analysis is used to analyze sub-elements of politeness including the degree of imposition, terms of address, request-giving strategy and lexicon-syntactic modifier. The results support the assumption that Vietnamese language pragmatic knowledge is deeply ingrained and has tremendous influence on students’ L2 email writing skills. The study also reveals that Vietnamese students applied a high level of imposition with formal term of address and salutation, directness strategies with the overuse of “please” and other hedges. While gender is not a determining factor, the inflexible adoption of fixed phrases and syntactic-lexical devices were attributed to the lack of sociopragmatic competence. Thus, apart from linguistic knowledge, the role of cultural awareness and socio-pragmatic knowledge should be highlighted in communicative English learning and teaching.

THE PROTECTIVE EFFECT OF ACYLATI0N ON THE STABILITY OF EMINASE (APSAC) IN HUMAN PLASMA

1987 ◽  
Author(s):  
R Fears ◽  
H Ferres ◽  
R Standring
Keyword(s):  
Protective Effect ◽  
Human Plasma ◽  
Fibrinolytic Activity ◽  
Animal Studies ◽  
Active Form ◽  
Α2 Macroglobulin ◽  
The Stability ◽  
High Level ◽  
Activator Complex

Clinical and animal studies indicate that APSAC (anisoylated plasminogen.streptokinase activator complex, Eminase) circulates longer in the bloodstream in an active form than the other thrombolytics. In the present studies in vitro u/e have found that functional activity of APSAC is maintained in human plasma longer than that of SK.plasmin(ogen): the relative stability half-lives are similar to the plasma clearance haif-lives in patients. Some of the loss of activity of SK at early times can be attributed to neutralisation by inhibitors. Thus, the survival of fibrinolytically-active SK was promoted in plasma depleted in α2-antiplasmin (α2AP) and α2AP-SK.plasmin complexes (detected by immunoblotting) formed rapidly in normal plasma. Corresponding studies with α2 macroglobulin-depleted plasma suggested a slight, late influence on SK activity but the inhibitor complex has not been detected unequivocally. In addition, loss of SK activity can be attributed, in part, to. rapid degradation to low molecular products. The degradation of SK in APSAC was much slower. In other comparative studies, the stability of APSAC was found to be similar to the stability of prourokinase and much superior to that of SK which is similar to UK; t-PA is intermediate in stability.Maintenance of fibrinolytic activity vivo depends on the stability of the thrombolytic, its rate of clearance and mode of administration. The protective effect of acylation, demonstrated in these experiments, explains why the objective of maintaining a high level of fibrinolytic activity after intravenous bolus injection of APSAC is less compromised by opposing inactivation processes.

scholarly journals Reducing the Native Tropism of Adenovirus Vectors Requires Removal of both CAR and Integrin Interactions

2001 ◽  
Vol 75 (23) ◽  
pp. 11284-11291 ◽  
Author(s):  
David A. Einfeld ◽  
Rosanna Schroeder ◽  
Peter W. Roelvink ◽  
Alena Lizonova ◽  
C. Richter King ◽  
...  
Keyword(s):  
Adenovirus Type ◽  
Wild Type ◽  
Base Modification ◽  
Model Following ◽  
Vector Distribution ◽  
High Level ◽  
Adenovirus Type 5

ABSTRACT The development of tissue-selective virus-based vectors requires a better understanding of the role of receptors in gene transfer in vivo, both to rid the vectors of their native tropism and to introduce new specificity. CAR and αv integrins have been identified as the primary cell surface components that interact with adenovirus type 5 (Ad5)-based vectors during in vitro transduction. We have constructed a set of four vectors, which individually retain the wild-type cell interactions, lack CAR binding, lack αv integrin binding, or lack both CAR and αv integrin binding. These vectors have been used to examine the roles of CAR and αv integrin in determining the tropism of Ad vectors in a mouse model following intrajugular or intramuscular injection. CAR was found to play a significant role in liver transduction. The absence of CAR binding alone, however, had little effect on the low level of expression from Ad in other tissues. Binding of αv integrins appeared to have more influence than did binding of CAR in promoting the expression in these tissues and was also found to be important in liver transduction by Ad vectors. An effect of the penton base modification was a reduction in the number of vector genomes that could be detected in several tissues. In the liver, where CAR binding is important, combining defects in CAR and αv integrin binding was essential to effectively reduce the high level of expression from Ad vectors. While there may be differences in Ad vector tropism among species, our results indicate that both CAR and αv integrins can impact vector distribution in vivo. Disruption of both CAR and αv integrin interactions may be critical for effectively reducing native tropism and enhancing the efficacy of specific targeting ligands in redirecting Ad vectors to target tissues.

scholarly journals The Association of Aberrant Expression of FGF1 and mTOR-S6K1 in Colorectal Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Tinghui Duan ◽  
Diyuan Zhou ◽  
Yizhou Yao ◽  
Xinyu Shao
Keyword(s):  
Colorectal Cancer ◽  
Malignant Neoplasms ◽  
Aberrant Expression ◽  
Protein Levels ◽  
And Migration ◽  
High Level ◽  
Proliferation And Migration

Colorectal cancer (CRC) is one of the most frequent malignant neoplasms worldwide, and the effect of treatments is limited. Fibroblast growth factor 1 (FGF1) has been involved in a wide variety of several malignant diseases and takes part in the tumorigenesis of CRC. However, the function and mechanism of FGF1 in CRC remains elusive. In this study, the results indicated that FGF1 is elevated in CRC tissues and linked with poor prognosis (P < 0.001). In subgroup analysis of FGF1 in CRC, regardless of any clinic-factors except gender, high level FGF1 expression was associated with markedly shorter survival (P < 0.05). In addition, the expression of p-S6K1 and FGF1 was not associated in normal tissue (P = 0.781), but their expression was closely related in tumor tissue (P = 0.010). The oncogenic role of FGF1 was determined using in vitro and in vivo functional assays. FGF1 depletion inhibited the proliferation and migration of CRC cells in vitro and vivo. FGF1 was also significantly correlated with mTOR-S6K1 pathway on the gene and protein levels (P < 0.05). In conclusion, FGF1 acts as a tumor activator in CRC, and against FGF1 may provide a new visual field on treating CRC, especially for mTORC1-targeted resistant patients.

Factor XII Contact Activation

2017 ◽  
Vol 43 (08) ◽  
pp. 814-826 ◽  
Author(s):  
Clément Naudin ◽  
Elena Burillo ◽  
Stefan Blankenberg ◽  
Lynn Butler ◽  
Thomas Renné
Keyword(s):  
Critical Role ◽  
Factor Xii ◽  
Contact Activation ◽  
Kinin System ◽  
Disease States ◽  
Charged Surfaces ◽  
Mechanistic Basis ◽  
Kallikrein Kinin System

AbstractContact activation is the surface-induced conversion of factor XII (FXII) zymogen to the serine protease FXIIa. Blood-circulating FXII binds to negatively charged surfaces and this contact to surfaces triggers a conformational change in the zymogen inducing autoactivation. Several surfaces that have the capacity for initiating FXII contact activation have been identified, including misfolded protein aggregates, collagen, nucleic acids, and platelet and microbial polyphosphate. Activated FXII initiates the proinflammatory kallikrein-kinin system and the intrinsic coagulation pathway, leading to formation of bradykinin and thrombin, respectively. FXII contact activation is well characterized in vitro and provides the mechanistic basis for the diagnostic clotting assay, activated partial thromboplastin time. However, only in the past decade has the critical role of FXII contact activation in pathological thrombosis been appreciated. While defective FXII contact activation provides thromboprotection, excess activation underlies the swelling disorder hereditary angioedema type III. This review provides an overview of the molecular basis of FXII contact activation and FXII contact activation–associated disease states.

scholarly journals Endocarditis Caused by Highly Penicillin-Resistant Viridans Group Streptococci: Still Room for Vancomycin-Based Regimens

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Juan M. Pericàs ◽  
Ruvandhi Nathavitharana ◽  
Cristina Garcia-de-la-Mària ◽  
Carles Falces ◽  
Juan Ambrosioni ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Treatment Options ◽  
Content Type ◽  
High Level ◽  
Viridans Group Streptococci ◽  
Time Kill

ABSTRACT Optimal treatment options remain unknown for infective endocarditis (IE) caused by penicillin-resistant (PEN-R) viridans group streptococcal (VGS) strains. The aims of this study were to report two cases of highly PEN-R VGS IE, perform a literature review, and evaluate various antibiotic combinations in vitro and in vivo. The following combinations were tested by time-kill studies and in the rabbit experimental endocarditis (EE) model: PEN-gentamicin, ceftriaxone-gentamicin, vancomycin-gentamicin, daptomycin-gentamicin, and daptomycin-ampicillin. Case 1 was caused by Streptococcus parasanguinis (PEN MIC, 4 μg/ml) and was treated with vancomycin plus cardiac surgery. Case 2 was caused by Streptococcus mitis (PEN MIC, 8 μg/ml) and was treated with 4 weeks of vancomycin plus gentamicin, followed by 2 weeks of vancomycin alone. Both patients were alive and relapse-free after ≥6 months follow-up. For the in vitro studies, except for daptomycin-ampicillin, all combinations demonstrated both synergy and bactericidal activity against the S. parasanguinis isolate. Only PEN-gentamicin, daptomycin-gentamicin, and daptomycin-ampicillin demonstrated both synergy and bactericidal activity against the S. mitis strain. Both strains developed high-level daptomycin resistance (HLDR) during daptomycin in vitro passage. In the EE studies, PEN alone failed to clear S. mitis from vegetations, while ceftriaxone and vancomycin were significantly more effective (P < 0.001). The combination of gentamicin with PEN or vancomycin increased bacterial eradication compared to that with the respective monotherapies. In summary, two patients with highly PEN-R VGS IE were cured using vancomycin-based therapy. In vivo, regimens of gentamicin plus either β-lactams or vancomycin were more active than their respective monotherapies. Further clinical studies are needed to confirm the role of vancomycin-based regimens for highly PEN-R VGS IE. The emergence of HLDR among these strains warrants caution in the use of daptomycin therapy for VGS IE.

Sperm-derived factors enhance the in vitro developmental potential of haploid parthenotes

Zygote ◽  
2017 ◽  
Vol 25 (6) ◽  
pp. 697-710 ◽  
Author(s):  
Ramya Nair ◽  
Shahin Aboobacker ◽  
Srinivas Mutalik ◽  
Guruprasad Kalthur ◽  
Satish Kumar Adiga
Keyword(s):  
Strontium Chloride ◽  
Cortical Granules ◽  
Cell Stage ◽  
Developmental Potential ◽  
Activation Rate ◽  
Paternal Factors ◽  
Artificial Activation ◽  
Cortical Distribution

SummaryParthenotes are characterized by poor in vitro developmental potential either due to the ploidy status or the absence of paternal factors. In the present study, we demonstrate the beneficial role of sperm-derived factors (SDF) on the in vitro development of mouse parthenotes. Mature (MII) oocytes collected from superovulated Swiss albino mice were activated using strontium chloride (SrCl2) in the presence or absence of various concentrations of SDF in M16 medium. The presence of SDF in activation medium did not have any significant influence on the activation rate. However, a significant increase in the developmental potential of the embryos and increased blastocyst rate (P < 0.01) was observed at 50 µg/ml concentration. Furthermore, the activated oocytes from this group exhibited early cleavage and cortical distribution of cortical granules that was similar to that of normally fertilized zygotes. Culturing 2-cell stage parthenotes in the presence of SDF significantly improved the developmental potential (P < 0.05) indicating that they also play a significant role in embryo development. In conclusion, artificial activation of oocytes with SDF can improve the developmental potential of parthenotes in vitro.

ON THE RELEVANCE OF THE CORE HELIX ALPHA 6 TO KINESIN ACTIVITY GENERATION

2009 ◽  
Vol 04 (01n02) ◽  
pp. 63-75 ◽  
Author(s):  
NIKOLINA KALCHISHKOVA ◽  
KONRAD J. BÖHM
Keyword(s):  
Structural Organization ◽  
Atp Hydrolysis ◽  
Catalytic Core ◽  
Microtubule Binding ◽  
The Core ◽  
Activity Generation ◽  
Core Elements ◽  
High Level ◽  
Β Sheet

KIF5A and Eg5 are plus-end directed motor proteins with conserved motor domains. The catalytic cores of both motors comprise a central β-sheet consisting of eight β-strands surrounded by six α-helices. Notwithstanding the high level of similarity in their structural organization, Eg5 moves significantly slower than KIF5A. Recently, we reported that neck linker and neck elements of KIF5A and Eg5 contribute to velocity regulation. As the neck linker of both motors is known to be connected to the catalytic core via helix α6, the question arises if also helix α6 and strand β8 as the last core elements might be involved in velocity regulation. To elucidate the role these structures in kinesin activity generation we constructed KIF5A- and Eg5-based chimeras in which the β8 strand, helix α6, the neck linker, and the neck were interchanged. Additionally, we studied the role of α6 and β8 in ATP hydrolysis and microtubule binding by expression of truncated KIF5A and Eg5 constructs lacking both strand β8 and helix α6, or α6 only. The results obtained suggest that strand β8 and helix α6 are not involved in microtubule-binding, but α6 is an obligate and kinesin type-specific structure required to generate ATPase activity.

scholarly journals Regulation of ATP-induced calcium release in COS-7 cells by calcineurin

2000 ◽  
Vol 348 (1) ◽  
pp. 173-181 ◽  
Author(s):  
Arun BANDYOPADHYAY ◽  
Dong-Wook SHIN ◽  
Do Han KIM
Keyword(s):  
Mammalian Cells ◽  
Calcium Release ◽  
Calcineurin Inhibitors ◽  
Dependent Manner ◽  
Transfected Cells ◽  
High Level ◽  
Dose Dependent ◽  
Constitutively Active

Experiments were conducted to examine the role of calcineurin in regulating Ca2+ fluxes in mammalian cells. In COS-7 cells, increasing concentrations (1-10 μM) of ATP triggered intracellular Ca2+ release in a dose-dependent manner. Treatment of the cells with calcineurin inhibitors such as cyclosporin A (CsA), deltamethrin and FK506 resulted in an enhancement of ATP-induced intracellular Ca2+ release. Measurement of calcineurin-specific phosphatase activity in vitro demonstrated a high level of endogenous calcineurin activities in COS-7 cells, which was effectively inhibited by the addition of deltamethrin or CsA. The expression of constitutively active calcineurin (CnA∆CaMAI) inhibited the ATP-induced increase in intracellular Ca2+ concentration ([Ca2+]i), in both the presence and the absence of extracellular Ca2+. These results suggest that the constitutively active calcineurin prevented Ca2+ release from the intracellular stores. In the calcineurin-transfected cells, treatment with CsA restored the calcineurin-mediated inhibition of intracellular Ca2+ release. Protein kinase C-mediated phosphorylation of Ins(1,4,5)P3 receptor [Ins(1,4,5)P3R] was partly inhibited by the extracts prepared from the vector-transfected cells and completely inhibited by those from cells co-transfected with CnA∆CaMAI and calcineurin B. On the addition of 10 μM CsA, the inhibited phosphorylation of Ins(1,4,5)P3R was restored in both the vector-transfected cells and the calcineurin-transfected cells. These results show direct evidence that Ca2+ release through Ins(1,4,5)P3R in COS-7 cells is regulated by calcineurin-mediated dephosphorylation.

scholarly journals MicroRNA-491-5p inhibit gastric cancer development by targeting EMT, cell adhesion genes and IFITM2

2020 ◽  
Author(s):  
Zhijian Wei ◽  
Lixiang Zhang ◽  
Angqing Li ◽  
Chuanhong Li ◽  
Wenxiu Han ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Adhesion ◽  
Tumor Suppressor ◽  
Tumor Development ◽  
Migration And Invasion ◽  
Different Types ◽  
High Level

Abstract Gastric cancer (GC) is one of the deadliest cancers in China. And, it can be regulated by MicroRNAs (miRNAs) generally. miR-491-5p function as a tumor suppressor in different types of cancer, but we still don’t know the role of miR-491-5p in gastric cancer. In this study, we found that high level of miR-491-5p caused a weak cell proliferation, migration and invasion abilities. In order to explore the role of miR-491-5p in vivo, we set a xenograft mouse model, and also found that high level of miR-491-5p suppressed tumor growth. Moreover, we found that miR-491-5p regulate the tumor development thought regulate the expression of EMT, cell adhesion genes and IFITM2. These data show that miR-491-5p function as a tumor suppressor in GC both in vitro and in vivo .

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