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https://www.readbyqxmd.com/read/28069606/proteolytic-properties-of-single-chain-factor-xii-a-mechanism-for-triggering-contact-activation
#1
Ivan Ivanov, Anton Matafonov, Mao-Fu Sun, Qiufang Cheng, S Kent Dickeson, Ingrid M Verhamme, Jonas Emsley, David Gailani
When blood is exposed to variety of artificial surfaces and biologic substances, the plasma proteins factor XII (FXII) and prekallikrein undergo reciprocal proteolytic conversion to the proteases αFXIIa and α-kallikrein by a process called contact activation. These enzymes contribute to host-defense responses including coagulation, inflammation, and fibrinolysis. The initiating event in contact activation is debated. To test the hypothesis that single-chain FXII expresses activity that could initiate contact activation, we prepared human FXII variants lacking the Arg353 cleavage site required for conversion to αFXIIa (FXII-R353A), or lacking the three known cleavage sites at Arg334, Arg343, and Arg353 (FXII-T, for "triple" mutant), and compared their properties to wild type αFXIIa...
January 9, 2017: Blood
https://www.readbyqxmd.com/read/28067447/importance-of-eif2%C3%AE-phosphorylation-as-a-protective-mechanism-against-heat-stress-in-mouse-male-germ-cells
#2
Jungbin Yoon, Kyosun Park, Deog Su Hwang, Kunsoo Rhee
Mammalian male germ cells are exceptionally labile to heat stress. A temporal arrest of translation is one immediate response to heat, which involves heat-induced phosphorylation of eukaryotic initiation factor 2α (eIF2α) to block the formation of the translational initiation complex. Here, we investigated the protective mechanisms against heat stress in mouse male germ cells. All known eIF2α kinases were expressed in lineage- and developmental stage-specific manners in the testis; noteworthy was the presence of Gcn2 (General control nonderepressible 2 kinase) in spermatocytes of all seminiferous tubules...
January 9, 2017: Molecular Reproduction and Development
https://www.readbyqxmd.com/read/28049643/polyphosphate-nanoparticles-on-the-platelet-surface-trigger-contact-system-activation
#3
Johan J F Verhoef, Arjan D Barendrecht, Katrin F Nickel, Kim Dijkxhoorn, Ellinor Kenne, Linda Labberton, Owen J T McCarty, Raymond Schiffelers, Harry F Heijnen, Antoni P Hendrickx, Huub Schellekens, Marcel H Fens, Steven de Maat, Thomas Renné, Coen Maas
Polyphosphate is an inorganic polymer that can potentiate several interactions in the blood coagulation system. Blood platelets contain polyphosphate, and the secretion of platelet-derived polyphosphate has been associated with increased thrombus formation and activation of coagulation factor XII. However, the small polymer size of secreted platelet polyphosphate limits its capacity to activate factor XII in vitro. Thus, the mechanism by which platelet polyphosphate contributes to thrombus formation remains unclear...
January 3, 2017: Blood
https://www.readbyqxmd.com/read/28045547/peptide-macrocycle-inhibitor-of-coagulation-factor-xii-with-subnanomolar-affinity-and-high-target-selectivity
#4
Simon Jan Middendorp, Jonas Wilbs, Claudia Quarroz, Sara Calzavarini, Anne Angelillo-Scherrer, Christian Heinis
Factor XII (FXII) is a plasma protease that has emerged in recent years as a potential target to treat or prevent pathological thrombosis, to inhibit contact activation in extracorporeal circulation, and to treat the swelling disorder hereditary angioedema. While several protein based inhibitors with high affinity for activated FXII (FXIIa) were developed, the generation of small molecule inhibitors has been challenging. In this work, we have generated a potent and selective FXIIa inhibitor by optimizing a peptide macrocycle that was recently evolved by phage display (Ki = 0...
January 3, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28035006/factor-xiia-as-a-novel-target-for-thrombosis-target-engagement-requirement-and-efficacy-in-a-rabbit-model-of-microembolic-signals
#5
Christopher M Barbieri, Xinkang Wang, Weizhen Wu, Xueping Zhou, Aimie M Ogawa, Kim O'Neill, Donald Chu, Gino Castriota, Dietmar A Seiffert, David E Gutstein, Zhu Chen
Coagulation Factor XII (FXII) plays a critical role in thrombosis. What is unclear is the level of enzyme occupancy of FXIIa needed for efficacy, and impact of FXIIa inhibition on cerebral embolism. A selective FXIIa inhibitor, recombinant human albumin-tagged mutant Infestin4 (rHA-Mut-inf), was generated to address these questions. rHA-Mut-inf displayed potency comparable to the original wild-type HA-Infestin4 (rHA-WT-inf) (human FXIIa KI = 0.07 and 0.12 nM, respectively), with markedly improved selectivity against FXa and plasmin...
December 29, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28034743/discovery-of-host-targeted-covalent-inhibitors-of-dengue-virus
#6
Mélissanne de Wispelaere, Margot Carocci, Yanke Liang, Qingsong Liu, Eileen Sun, Michael L Vetter, Jinhua Wang, Nathanael S Gray, Priscilla L Yang
We report here on an approach targeting the host reactive cysteinome to identify inhibitors of host factors required for the infectious cycle of Flaviviruses and other viruses. We used two parallel cellular phenotypic screens to identify a series of covalent inhibitors, exemplified by QL-XII-47, that are active against dengue virus. We show that the compounds effectively block viral protein expression and that this inhibition is associated with repression of downstream processes of the infectious cycle, and thus significantly contributes to the potent antiviral activity of these compounds...
December 26, 2016: Antiviral Research
https://www.readbyqxmd.com/read/28011710/identification-of-novel-loci-affecting-circulating-chromogranins-and-related-peptides
#7
Beben Benyamin, Adam X Maihofer, Andrew J Schork, Bruce A Hamilton, Fangwen Rao, Geert W Schmid-SchÖnbein, Kuixing Zhang, Manjula Mahata, Mats Stridsberg, Nicholas J Schork, Nilima Biswas, Vivian Y Hook, Zhiyun Wei, Grant W Montgomery, Nicholas G Martin, Caroline M Nievergelt, John B Whitfield, Daniel T O'Connor
Chromogranins are pro-hormone secretory proteins released from neuroendocrine cells, with effects on control of blood pressure. We conducted a genome-wide association study for plasma catestatin, the catecholamine release inhibitory peptide derived from chromogranin A (CHGA), and other CHGA- or chromogranin B (CHGB)-related peptides, in 545 US and 1252 Australian subjects. This identified loci on chromosomes 4q35 and 5q34 affecting catestatin concentration (p=3.40 x 10(-30) for rs4253311 and 1.85 x 10(-19) for rs2731672, respectively)...
December 22, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/28007010/genetic-analysis-of-a-hereditary-factor-xii-deficiency-pedigree-of-a-consanguineous-marriage-due-to-a-homozygous-f12-gene-mutation-gly341arg
#8
Xiaoli Cheng, Lihong Yang, Guoyong Huang, Yanhui Jin, Xiuping Hao, Mingshan Wang
OBJECTIVE AND IMPORTANCE: To study the gene mutations of factor XII (FXII) in a Chinese family of consanguineous marriage with FXII deficiency and illuminate the possible molecular pathogenic mechanism. It will contribute to our comprehension of the pathogenesis of the disease. CLINICAL PRESENTATION: The proband was a 26-year-old Chinese pregnant woman who was discovered, in a pregnancy test, with a prolonged activated partial thromboplastin time (APTT) at 61.6s (reference range, 29...
December 22, 2016: Hematology (Amsterdam, Netherlands)
https://www.readbyqxmd.com/read/27942517/troubleshooting-an-isolate-prolongation-of-activated-partial-thromboplastin-time-in-a-patient-with-acute-myocardial-infarction-a-paradigmatic-case-report
#9
Giovanni Poli, Piero Castiglioni, Martina Montagnana, Emmanuel J Favaloro, Giuseppe Lippi
We describe here the case of a 46-year-old man admitted to the emergency department (ED) and diagnosed with a non-ST elevation myocardial infarction. Before referring the patient to the coronary care unit and initiating antiplatelet and anticoagulant therapy, a highly prolonged activated partial thromboplastin time (APTT) was observed among results of laboratory testing. Results of mixing test showed complete correction of APTT, thus ruling out the presence of inhibitors of blood coagulation. On the following day, second line coagulation testing revealed normal activity of all clotting factors except factor XII, the concentration of which was found to be 1...
November 2016: Annals of Translational Medicine
https://www.readbyqxmd.com/read/27933406/differential-roles-for-the-coagulation-factors-xi-and-xii-in-regulating-the-physical-biology-of-fibrin
#10
Joanna L Sylman, Uranbileg Daalkhaijav, Ying Zhang, Elliot M Gray, Parsa A Farhang, Tiffany T Chu, Jevgenia Zilberman-Rudenko, Cristina Puy, Erik I Tucker, Stephanie A Smith, James H Morrissey, Travis W Walker, Xiaolin L Nan, András Gruber, Owen J T McCarty
In the contact activation pathway of the coagulation, zymogen factor XII (FXII) is converted to FXIIa, which triggers activation of FXI leading to the activation of FIX and subsequent thrombin generation and fibrin formation. Feedback activation of FXI by thrombin has been shown to promote thrombin generation in a FXII-independent manner and FXIIa can bypass FXI to directly activate FX and prothrombin in the presence of highly negatively charged molecules, such as long-chain polyphosphates (LC polyP). We sought to determine whether activation of FXII or FXI differentially regulate the physical biology of fibrin formation...
December 8, 2016: Annals of Biomedical Engineering
https://www.readbyqxmd.com/read/27927771/propagation-of-thrombosis-by-neutrophils-and-extracellular-nucleosome-networks
#11
Susanne Pfeiler, Konstantin Stark, Steffen Massberg, Bernd Engelmann
Neutrophils, early mediators of innate immune defense, are recruited to developing thrombi in different types of thrombosis. They amplify intravascular coagulation by stimulating the tissue factor-dependent extrinsic pathway via inactivation of endogenous anticoagulants, enhancing factor XII activation or decreasing plasmin generation. Neutrophil-dependent prothrombotic mechanisms are supported by the externalization of decondensed nucleosomes and granule proteins that together form neutrophil extracellular traps...
December 7, 2016: Haematologica
https://www.readbyqxmd.com/read/27913422/factor-xi-deficiency-enhances-the-pulmonary-allergic-response-to-house-dust-mite-in-mice-independent-of-factor-xii
#12
Ingrid Stroo, Jack Yang, Johannes Daan de Boer, Joris J T H Roelofs, Cornelis van 't Veer, Francis J Castellino, Sacha Zeerleder, Tom van der Poll
Asthma is associated with activation of coagulation in the airways. The coagulation system can be initiated via the extrinsic tissue factor dependent pathway or via the intrinsic pathway, in which the central player factor XI (FXI) can be either activated via active factor XII (FXIIa) or via thrombin. We aimed to determine the role of the intrinsic coagulation system, and its possible route of activation, in allergic lung inflammation induced by the clinically relevant human allergen house dust mite (HDM). Wild-type (WT), FXI knockout (KO) and FXII KO mice were subjected to repeated exposure to HDM via the airways, and inflammatory responses were compared...
December 2, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/27888641/carotid-artery-and-lower-cranial-nerve-exposure-with-increasing-surgical-complexity-to-the-parapharyngeal-space
#13
Ana M Lemos-Rodriguez, Satyan B Sreenath, Rounak B Rawal, Lewis J Overton, Zainab Farzal, Adam M Zanation
OBJECTIVES/HYPOTHESIS: To investigate the extent of carotid artery exposure attained, including the identification of the external carotid branches and lower cranial nerves in five sequential external approaches to the parapharyngeal space, and to provide an anatomical algorithm. STUDY DESIGN: Anatomical study. METHODS: Six latex-injected adult cadaver heads were dissected in five consecutive approaches: transcervical approach with submandibular gland removal, posterior extension of the transcervical approach, transcervical approach with parotidectomy, parotidectomy with lateral mandibulotomy, and parotidectomy with mandibulectomy...
November 26, 2016: Laryngoscope
https://www.readbyqxmd.com/read/27867935/processing-of-factor-xii-during-inflammatory-reactions
#14
REVIEW
Bernard Nico Jukema, Steven de Maat, Coen Maas
The contact system was originally identified as an obsolete part of the coagulation system, but it has been repeatedly implicated in inflammatory states, such as infection, as well as in allergic- and chronic inflammatory disease. Under these conditions, there is surprisingly little evidence that factor XII (FXII) acts as a coagulation factor, and its activity appears to be mainly directed toward activation of the kallikrein-kinin system. The contact system factors interact with pathogens as well as cells of the (innate) immune system on several levels...
2016: Frontiers in Medicine
https://www.readbyqxmd.com/read/27862752/improving-the-binding-affinity-of-in-vitro-evolved-cyclic-peptides-by-inserting-atoms-into-the-macrocycle-backbone
#15
Jonas Wilbs, Simon J Middendorp, Christian Heinis
Cyclic peptides binding to targets of interest can be generated efficiently with powerful in vitro display techniques, such as phage display or mRNA display. The cyclic peptide libraries screened with these methods are generated by altering in a combinatorial fashion the amino acid sequence of the peptides, the number of amino acids in the macrocycle rings, and the cyclization chemistry. A structural element that cannot easily be varied in the cyclic peptides is the backbone, which is built from amino acids, each of which contributes three atoms to the macrocyclic ring structure...
December 14, 2016: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/27848184/the-initiation-and-effects-of-plasma-contact-activation-an-overview
#16
Lisha Lin, Mingyi Wu, Jinhua Zhao
The plasma contact system sits atop the intrinsic coagulation cascade and plasma kallikrein-kinin pathway, and in vivo its activation contributes, respectively, to coagulation and inflammation mainly via two downstream pathways. This system has been widely investigated, its activation mechanisms by negatively charged surfaces and the interactions within its components, factor XII, prekallikrein and high molecular weight kininogen are well understood at the biochemical level. However, as most of the activators that have been discovered by in vitro experiments are exogenous, the physiological activators and roles of the contact system have remained unclear and controversial...
November 15, 2016: International Journal of Hematology
https://www.readbyqxmd.com/read/27836023/coagulation-factor-abnormalities-related-to-discordance-between-anti-factor-xa-and-activated-partial-thromboplastin-time-in-patients-supported-with-continuous-flow-left-ventricular-assist-devices
#17
Sirtaz Adatya, Roy Sunny, Megan J Fitzpatrick, Monica Colvin, Thennapan Thennapan, Ranjit John, Nicole Dodge Zantek, Marc Pritzker, Peter Eckman, Nir Uriel
BACKGROUND: High levels of discordance between activated partial thromboplastin time (aPTT) and anti-factor Xa (anti-FXa) have been reported in patients with continuous-flow left ventricular assist devices (CF-LVADs). We sought to determine the biochemical basis for discordance by simultaneous measurement of coagulation factors with aPTT and anti-FXa. METHODS: Consecutive CF-LVAD patients admitted for intravenous unfractionated heparin (IV-UFH) therapy were studied...
November 2016: Journal of Heart and Lung Transplantation
https://www.readbyqxmd.com/read/27834692/factor-xii-as-a-therapeutic-target-in-thromboembolic-and-inflammatory-diseases
#18
Katrin F Nickel, Andy T Long, Tobias A Fuchs, Lynn M Butler, Thomas Renné
Coagulation factor XII (FXII, Hageman factor) is a plasma protease that in its active form (FXIIa) initiates the procoagulant and proinflammatory contact system. This name arises from FXII's unique mechanism of activation that is induced by binding (contact) to negatively charged surfaces. Various substances have the capacity to trigger FXII contact-activation in vivo including mast cell-derived heparin, misfolded protein aggregates, collagen, nucleic acids, and polyphosphate. FXII deficiency is not associated with bleeding, and for decades, the factor was considered to be dispensable for coagulation in vivo...
January 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/27829580/inhibitory-effect-of-ethinylestradiol-on-coagulation-factors-in-rats
#19
Yanira Franco-Murillo, Ruth Jaimez
Epidemiological and experimental data have indicated the beneficial and adverse effects of estrogenic replacement therapy. In the present study, we explored the effect of ethinylestradiol (EE) and 17β-estradiol (E2) on screening tests, prothrombin time (PT) and activated partial thromboplastin time (APTT), as well as the activity of coagulation factors (FVII, FX, FXI, and FXII) in male Wistar rats. Animals were injected subcutaneously during three consecutive days with EE or E2 (1, 3, 10, and 30 mg/kg) and propylene glycol (0...
November 9, 2016: Experimental Animals
https://www.readbyqxmd.com/read/27829262/-upper-airway-stimulation-in-osa
#20
B Bender
Anatomical basis of obstructive sleep apnea (OSA) is the collapse of the pharynx during sleep. It is considered as a result of complex interactions of structural and neuromuscular factors. Depth of sleep and body position have modulating effects. Although different areas of obstruction were identified, studies show that the sleep-mediated obstruction frequently occurs in the base of tongue area.Continuous positive airway pressure (CPAP) is the standard treatment for obstructive sleep apnea syndrome (OSAS) since more than 30 years...
November 2016: Laryngo- Rhino- Otologie
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