Common variation in the C-terminal region of the fibrinogen β-chain: effects on fibrin structure, fibrinolysis and clot rigidity

Blood ◽  
2008 ◽  
Vol 111 (2) ◽  
pp. 643-650 ◽  
Author(s):  
Ramzi Ajjan ◽  
Bernard C. B. Lim ◽  
Kristina F. Standeven ◽  
Robert Harrand ◽  
Sarah Dolling ◽  
...  
Keyword(s):  
Fibrin Clot ◽  
Magnetic Tweezers ◽  
Phenotypic Effect ◽  
Compact Structure ◽  
Novel Method ◽  
Artery Disease ◽  
Clot Structure ◽  
First Time ◽  
Protein Variants ◽  
Β Chain

Fibrinogen BβArg448Lys is a common polymorphism, positioned within the carboxyl terminus of the Bβ-chain of the molecule. Studies suggest that it is associated with severity of coronary artery disease and development of stroke. The effects of the amino acid substitution on clot structure remains controversial, and the aim of this study was to investigate the effect(s) of this polymorphism on fibrin clot structure using recombinant techniques. Permeation, turbidity, and scanning electron microscopy showed that recombinant Lys448 fibrin had a significantly more compact structure, with thin fibers and small pores, compared with Arg448. Clot stiffness, measured by means of a novel method using magnetic tweezers, was significantly higher for the Lys448 compared with the Arg448 variant. Clots made from recombinant protein variants had similar lysis rates outside the plasma environment, but when added to fibrinogen-depleted plasma, the fibrinolysis rates for Lys448 were significantly slower compared with Arg448. This study demonstrates for the first time that clots made from recombinant BβLys448 fibrinogen are characterized by thin fibers and small pores, show increased stiffness, and appear more resistant to fibrinolysis. Fibrinogen BβArg448Lys is a primary example of common genetic variation with a significant phenotypic effect at the molecular level.

scholarly journals Altered Fibrin Clot Structure in the Healthy Relatives of Patients With Premature Coronary Artery Disease

Circulation ◽  
2002 ◽  
Vol 106 (15) ◽  
pp. 1938-1942 ◽  
Author(s):  
Joseph D. Mills ◽  
Robert A.S. Ariëns ◽  
Michael W. Mansfield ◽  
Peter J. Grant
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Fibrin Clot ◽  
Premature Coronary Artery Disease ◽  
Artery Disease ◽  
Clot Structure

Platelet count, platelet turnover and fibrin clot structure in patients with coronary artery disease

2014 ◽  
Vol 133 (6) ◽  
pp. 1161-1163 ◽  
Author(s):  
Søs Neergaard-Petersen ◽  
Anne-Mette Hvas ◽  
Ramzi Ajjan ◽  
Sanne Bøjet Larsen ◽  
Morten Würtz ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Platelet Count ◽  
Coronary Artery ◽  
Fibrin Clot ◽  
Artery Disease ◽  
Clot Structure

Organic Reactivity Control by Means of Neighboring Groups and Organometallics. A Personal Account

1994 ◽  
Vol 59 (1) ◽  
pp. 1-74 ◽  
Author(s):  
Pavel Kočovský
Keyword(s):  
Transition Metals ◽  
Cyclopropane Ring ◽  
Allylic Substitutions ◽  
Recent Developments ◽  
Cardioactive Drug ◽  
Novel Method ◽  
Metal Catalyzed ◽  
Electrophilic Additions ◽  
Near Future ◽  
First Time

This review summarizes the main topics of our research and covers the period of the last 15 years. The prime interest is focused on various ways of controlling the regio- and stereoselectivity of selected organic reactions, in particular electrophilic additions, cleavage of cyclopropane rings, and allylic substitutions by means of neighboring groups and/or transition and non-transition metals. In the first part, the factors governing the course of electrophilic additions are assessed, culminating in the formulation of selection rules for the reactivity of cyclohexene systems, and in a concise synthesis of the natural cardioactive drug, strophanthidin. These studies also contribute to a better understanding of the mechanisms of electrophilic additions. The second part describes recent developments in the stereo- and regiocontrolled cleavage of cyclopropane rings by non-transition metals (Tl and Hg), and the reactivity and transmetalation (with Pd) of the primary products. This methodology has resulted in novel routes to unique polycyclic structures, and will have synthetic applications in the near future. Evidence for the stereospecific "corner" cleavage of the cyclopropane ring has been provided for the first time for Tl and later for Hg. The third part deals with transition metal-catalyzed allylic substitution. Evidence for a new "syn" mechanism for the formation of the intermediate (π-allyl)palladium complex has been provided, which runs counter to the generally accepted "anti" mechanism. A novel method for a Pd-catalyzed allylic oxidation has been developed and employed in the synthesis of natural sesquiterpenes. The increasing importance of transition and non-transition metals for synthetic organic chemistry is demonstrated by their unique reactivity in a number of the papers included in this review.

Time trends in use of cardioprotective medication in patients with peripheral artery disease between 1997 and 2016: a nationwide study

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Kamil ◽  
T.S.G Sehested ◽  
K Houlind ◽  
J.F Lassen ◽  
G Gislason ◽  
...  
Keyword(s):  
Peripheral Artery Disease ◽  
Ace Inhibitors ◽  
Lifestyle Modification ◽  
Temporal Trends ◽  
Peripheral Artery ◽  
Nationwide Study ◽  
History Of ◽  
Artery Disease ◽  
First Time ◽  
Time Diagnosis

Abstract Background Peripheral artery disease (PAD) is associated with increased cardiovascular (CV) morbidity and mortality. Aggressive management of risk factors and lifestyle modification may improve outcomes for patients with PAD. The present study aims to investigate changes in use of cardioprotective medication after the incident diagnosis of PAD between 1997 and 2016. Methods By using Danish national healthcare registries, we identified all patients with first-time diagnosis of PAD between 1997 and 2016. These patients were classified into 2 main groups: PAD-all (n=167,762) that includes all PAD patients with or without a history of CVD, including myocardial infarction (MI), atrial fibrillation (AF), and stroke (n=167,761) and PAD-only (n=87,935) that comprise patients with PAD without a history of AF, MI, and stroke. We calculated temporal trends and assessed comparative use of cardioprotective medication in the first 12 months after the incident diagnosis of PAD. Results Our results showed an improved use of cardioprotective medication temporally in both groups. However, PAD-all were marginally better treated (Aspirin, 3.5% - 48.4%; Clopidogrel, 0% - 17.6%; VKA 0.9% - 7.8%; NOACs 0.0% - 10.1%; Statins, 1.9%- 58.1%; ACE-inhibitors, 1.2% - 20.6%), compared to PAD-only (Aspirin, 2.9% - 54.4%; Clopidogrel, 0% - 11.9%; VKA 0.9% - 2.4%; NOACs 0.0% - 3.4%; Statins, 1.5%- 56.9%; ACE-inhibitors, 0.9% - 17.2%), respectively. Proportion of PAD patients treated with any cardioprotective medication was greater among those with a history of MI or stroke. Whereas, PAD patients with a history of AF were substantially better treated with VKA and NOACs. Conclusion In this nationwide study, use of cardioprotective medication increased considerably with time, but there remains an underuse of guideline-recommended therapy in patients with PAD. Funding Acknowledgement Type of funding source: None

Ionized AGN outflows are less powerful than assumed: A multi-wavelength census of outflows in type II AGN

2019 ◽  
Vol 15 (S356) ◽  
pp. 225-225
Author(s):  
Dalya Baron
Keyword(s):  
Optical Emission ◽  
Infrared Emission ◽  
Type Ii ◽  
Ionized Gas ◽  
Kinetic Coupling ◽  
Mass Outflow ◽  
Multi Wavelength ◽  
Novel Method ◽  
First Time ◽  
Ionization Parameter

AbstractIn this talk I will show that multi-wavelength observations can provide novel constraints on the properties of ionized gas outflows in AGN. I will present evidence that the infrared emission in active galaxies includes a contribution from dust which is mixed with the outflow and is heated by the AGN. We detect this infrared component in thousands of AGN for the first time, and use it to constrain the outflow location. By combining this with optical emission lines, we constrain the mass outflow rates and energetics in a sample of 234 type II AGN, the largest such sample to date. The key ingredient of our new outflow measurements is a novel method to estimate the electron density using the ionization parameter and location of the flow. The inferred electron densities, ∼104.5 cm−3, are two orders of magnitude larger than found in most other cases of ionized outflows. We argue that the discrepancy is due to the fact that the commonly-used [SII]-based method underestimates the true density by a large factor. As a result, the inferred mass outflow rates and kinetic coupling efficiencies are 1–2 orders of magnitude lower than previous estimates, and 3–4 orders of magnitude lower than the typical requirement in hydrodynamic cosmological simulations. These results have significant implications for the relative importance of ionized outflows feedback in this population.

scholarly journals Direct observation of a coil-to-helix contraction triggered by vinculin binding to talin

2020 ◽  
Vol 6 (21) ◽  
pp. eaaz4707 ◽  
Author(s):  
Rafael Tapia-Rojo ◽  
Alvaro Alonso-Caballero ◽  
Julio M. Fernandez
Keyword(s):  
Focal Adhesions ◽  
Interaction Force ◽  
Magnetic Tweezers ◽  
Feedback Mechanism ◽  
Force Transmission ◽  
Mechanical Coupling ◽  
Negative Feedback Mechanism ◽  
The Reformation ◽  
Energy Penalty ◽  
First Time

Vinculin binds unfolded talin domains in focal adhesions, which recruits actin filaments to reinforce the mechanical coupling of this organelle. However, it remains unknown how this interaction is regulated and its impact on the force transmission properties of this mechanotransduction pathway. Here, we use magnetic tweezers to measure the interaction between vinculin head and the talin R3 domain under physiological forces. For the first time, we resolve individual binding events as a short contraction of the unfolded talin polypeptide caused by the reformation of the vinculin-binding site helices, which dictates a biphasic mechanism that regulates this interaction. Force favors vinculin binding by unfolding talin and exposing the vinculin-binding sites; however, the coil-to-helix contraction introduces an energy penalty that increases with force, defining an optimal binding regime. This mechanism implies that the talin-vinculin-actin association could operate as a negative feedback mechanism to stabilize force on focal adhesions.

Altered fibrin clot structure/function in patients with antiphospholipid syndrome: association with thrombotic manifestation

2014 ◽  
Vol 112 (08) ◽  
pp. 287-296 ◽  
Author(s):  
Magdalena Celińska-Löwenhoff ◽  
Teresa Iwaniec ◽  
Agnieszka Padjas ◽  
Jacek Musiał ◽  
Anetta Undas
Keyword(s):  
Structure Function ◽  
Antiphospholipid Syndrome ◽  
Thrombotic Event ◽  
Fibrin Clot ◽  
Clot Lysis ◽  
Lag Phase ◽  
Lysis Time ◽  
Clot Structure ◽  
Clot Lysis Time ◽  
D Dimer

SummaryWe tested the hypothesis that plasma fibrin clot structure/function is unfavourably altered in patients with antiphospholipid syndrome (APS). Ex vivo plasma clot permeability, turbidity and susceptibility to lysis were determined in 126 consecutive patients with APS enrolled five months or more since thrombotic event vs 105 controls. Patients with both primary and secondary APS were characterised by 11% lower clot permeability (p<0.001), 4.8% shorter lag phase (p<0.001), 10% longer clot lysis time (p<0.001), and 4.7% higher maximum level of D-dimer released from clots (p=0.02) as compared to the controls. Scanning electron microscopy images confirmed denser fibrin networks composed of thinner fibres in APS. Clots from patients with “triple-antibody positivity” were formed after shorter lag phase (p=0.019) and were lysed at a slower rate (p=0.004) than in the remainder. Clots from APS patients who experienced stroke and/or myocardial infarction were 8% less permeable (p=0.01) and susceptible to lysis (10.4% longer clot lysis time [p=0.006] and 4.5% slower release of D-dimer from clots [p=0.01]) compared with those following venous thromboembolism alone. Multivariate analysis adjusted for potential confounders showed that in APS patients, lupus anticoagulant and “triple-positivity” were the independent predictors of clot permeability, while “triple-positivity” predicted lysis time. We conclude that APS is associated with prothrombotic plasma fibrin clot phenotype, with more pronounced abnormalities in arterial thrombosis. Molecular background for this novel prothrombotic mechanism in APS remains to be established.

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