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Sample records for willebrand factor interaction

  1. Polyphosphate binds to human von Willebrand factor in vivo and modulates its interaction with glycoprotein Ib.

    Science.gov (United States)

    Montilla, M; Hernández-Ruiz, L; García-Cozar, F J; Alvarez-Laderas, I; Rodríguez-Martorell, J; Ruiz, F A

    2012-11-01

    Polyphosphate, a phosphate polymer released by activated platelets, has recently been described as a potent modulator of blood coagulation and fibrinolysis. In blood plasma, polyphosphate binds to and alters the biological functions of factor XII, fibrin(ogen), thrombin and factor VII activating protease. The aim of the present study is to investigate whether polyphosphate also binds to von Willebrand factor (VWF) and alters some of its activities. When studying patients with type 1 von Willebrand disease (VWD) and their healthy relatives, we discovered a significant correlation between von Willebrand factor (VWF) and platelet polyphosphate levels. We have also found polyphosphate in preparations of VWF isolated from normal platelets and plasma. Surface plasmon resonance and electrophoretic mobility assays indicated that polyphosphate interacts with VWF in a dose- and time-dependent manner. Treatment of normal plasma with active exopolyphosphatase decreased the VWF ristocetin cofactor (VWF:RCo) activity, a functional measure of VWF binding to platelet glycoprotein receptor Ib. VWF collagen binding and multimerization were unaltered after polyphosphate depletion. Moreover, addition of polyphosphate increased the deficient VWF:RCo activity presented by plasma from patients with type 1 VWD. Our results reveal that a new role is played by polyphosphate in hemostasis by its interaction with VWF, and suggest that this polymer may be effective in the treatment of some types of VWD. © 2012 International Society on Thrombosis and Haemostasis.

  2. Active Von Willebrand Factor, thrombocytopenia and thrombosis

    NARCIS (Netherlands)

    Hulstein, J.J.J.

    2006-01-01

    Platelets and von Willebrand factor (VWF) are unable to interact in circulation. To induce an interaction, a conversion of VWF to a platelet-binding conformation is required. At higher shear stresses, the first step in thrombus formation is binding of VWF to the subendothelium. This results in

  3. Von Willebrand factor and aging.

    Science.gov (United States)

    Konkle, Barbara A

    2014-09-01

    von Willebrand factor (VWF) plays critical roles in initiating primary hemostasis and extending the half-life of coagulation factor VIII in circulation. VWF levels increase with age and elevated levels are associated with an increased risk of venous thromboembolism and cardiovascular disease (CVD). Patients with von Willebrand disease (VWD) due to a deficiency or dysfunction of VWF may have symptoms that ameliorate with aging or may have exacerbation of their disease. Bleeding sites of particular challenge in the aging patient include gastrointestinal bleeding and hematuria. Some medications used to treat VWD should be used with special precaution in older patients, including desmopressin and VWF-containing factor concentrates. Patients with VWD may have some protection from CVD, but in those patients who develop CVD, management is very challenging, given the role of antiplatelet therapy as the mainstay of treatment. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  4. Role of 14-3-3ζ in Platelet Glycoprotein Ibα-von Willebrand Factor Interaction-Induced Signaling

    Directory of Open Access Journals (Sweden)

    Kesheng Dai

    2012-05-01

    Full Text Available The interaction of platelet glycoprotein (GP Ib-IX with von Willebrand factor (VWF exposed at the injured vessel wall or atherosclerotic plaque rupture initiates platelet transient adhesion to the injured vessel wall, which triggers intracellular signaling cascades leading to platelet activation and thrombus formation. 14-3-3ζ has been verified to regulate the VWF binding function of GPIb-IX by interacting with the cytoplasmic domains of GPIb-IX. However, the data regarding the role of 14-3-3ζ in GPIb-IX-VWF interaction-induced signaling still remain controversial. In the present study, the data indicate that the S609A mutation replacing Ser609 of GPIbα with alanine (S609A significantly prevented the association of 14-3-3ζ with GPIbα before and after the VWF binding to GPIbα. GPIb-IX-VWF interaction-induced activations of Src family kinases and protein kinase C were clearly reduced in S609A mutation. Furthermore, S609A mutation significantly inhibited GPIb-IX-VWF interaction-induced elevation of cytoplasmic Ca2+ levels in flow cytometry analysis. Taken together, these data indicate that the association of 14-3-3ζ with the cytoplasmic domain of GPIbα plays an important role in GPIb-IX-VWF interaction-induced signaling.

  5. von Willebrand disease phenotype and von Willebrand factor marker genotype in Doberman Pinschers.

    Science.gov (United States)

    Brooks, M B; Erb, H N; Foureman, P A; Ray, K

    2001-03-01

    To define the relationship between clinical expression of a type-1 von Willebrand disease phenotype and genotype at 2 von Willebrand factor marker loci in Doberman Pinschers. 102 client-owned Doberman Pinschers. Dogs were recruited on the basis of plasma von Willebrand factor concentration, clinical history, and pedigree. Blood samples and response to a history questionnaire were obtained for each dog. Plasma von Willebrand factor concentration was measured by use of an ELISA, and genotyping was performed via polymerase chain reaction for 1 intragenic and 1 extragenic von Willebrand factor marker. Amplification product size was determined by use of polyacrylamide gel electrophoresis (intragenic marker) or automated sequence analysis (extragenic marker). Western blots were prepared from a subset of dogs with low plasma von Willebrand factor concentration to evaluate multimer distribution. Strong associations were detected between plasma von Willebrand factor concentration and von Willebrand factor marker genotype. Twenty-five dogs had substantial reduction in plasma von Willebrand factor concentration and multiple hemorrhagic events. All were homozygous for a 157-base-pair intragenic marker allele and homozygous or compound heterozygous for 1 of 4 extragenic marker alleles. These marker genotypes were exclusively detected in dogs with low plasma von Willebrand factor concentration, although some dogs with these genotypes did not have abnormal bleeding. Type-1 von Willebrand disease in Doberman Pinschers is associated with the von Willebrand factor gene locus; however, the expression pattern in this breed appears more complex than that of a simple recessive trait.

  6. An ELISA for the quantitation of von Willebrand Factor

    DEFF Research Database (Denmark)

    Vinholt, Pernille Just; Overgaard, Martin; Diederichsen, Axel Cosmus Pyndt

    2013-01-01

    BACKGROUND: Von Willebrand factor (VWF) is pivotal in arterial thrombosis, and osteoprotegerin (OPG) is besides being a bone protein also related to cardiovascular diseases. OPG can bind VWF, but the significance of this interaction is not known. OBJECTIVES: The aim was to develop an assay...... for measurement of von Willebrand factor-osteoprotegerin complex (VWF:OPG) in human plasma. Furthermore, the significance of VWF:OPG complex as a marker of cardiovascular disease (CVD) was evaluated. PATIENTS/METHODS: A sandwich ELISA for quantification of VWF:OPG was developed using a polyclonal rabbit anti...

  7. Molecular mechanisms of von Willebrand Factor mechanoregulation

    NARCIS (Netherlands)

    Jakobi, A.J.|info:eu-repo/dai/nl/311489621

    2012-01-01

    Von Willebrand factor (VWF) multimers mediate primary adhesion and aggregation of platelets. The potency to recruit platelets critically depends on the size of VWF multimers, which is regulated by a feedback mechanism involving shear-induced unfolding of the A2 domain in VWF and cleavage by the

  8. Laboratory Testing for Von Willebrand Factor Multimers.

    Science.gov (United States)

    Oliver, Susan; Lau, Kun Kan Edwin; Chapman, Kent; Favaloro, Emmanuel J

    2017-01-01

    Von Willebrand disease (VWD) is reportedly the most common inherited bleeding disorder and can also arise as an acquired syndrome (AVWS). These disorders develop due to defects and/or deficiency of the plasma protein von Willebrand factor (VWF). Laboratory testing for the VWF-related disorders requires assessment of both VWF level and VWF activity, the latter requiring multiple assays because of the many functions carried out by VWF to help prevent bleeding. As an additional step, an evaluation of VWF structural features by multimer analysis is useful in selective investigations. The current paper therefore describes a protocol for assessment of VWF multimers by gel electrophoresis, thus enabling identification of protein bands that represent differently sized multimers. The sample protocol described in this chapter is the methodology developed by Sebia.

  9. Comparison of automated von Willebrand factor activity assays

    DEFF Research Database (Denmark)

    Timm, Annette; Hillarp, Andreas; Philips, Malou

    2015-01-01

    INTRODUCTION: Von Willebrand Disease (VWD) is the most common inherited bleeding disorder. Measurement of von Willebrand factor (VWF) activity in plasma is often based on platelet agglutination stimulated by the ristocetin cofactor activity. Novel assays, based on latex beads with recombinant...

  10. Flow-induced elongation of von Willebrand factor precedes tension-dependent activation.

    Science.gov (United States)

    Fu, Hongxia; Jiang, Yan; Yang, Darren; Scheiflinger, Friedrich; Wong, Wesley P; Springer, Timothy A

    2017-08-23

    Von Willebrand factor, an ultralarge concatemeric blood protein, must bind to platelet GPIbα during bleeding to mediate hemostasis, but not in the normal circulation to avoid thrombosis. Von Willebrand factor is proposed to be mechanically activated by flow, but the mechanism remains unclear. Using microfluidics with single-molecule imaging, we simultaneously monitored reversible Von Willebrand factor extension and binding to GPIbα under flow. We show that Von Willebrand factor is activated through a two-step conformational transition: first, elongation from compact to linear form, and subsequently, a tension-dependent local transition to a state with high affinity for GPIbα. High-affinity sites develop only in upstream regions of VWF where tension exceeds ~21 pN and depend upon electrostatic interactions. Re-compaction of Von Willebrand factor is accelerated by intramolecular interactions and increases GPIbα dissociation rate. This mechanism enables VWF to be locally activated by hydrodynamic force in hemorrhage and rapidly deactivated downstream, providing a paradigm for hierarchical mechano-regulation of receptor-ligand binding.Von Willebrand factor (VWF) is a blood protein involved in clotting and is proposed to be activated by flow, but the mechanism is unknown. Here the authors show that VWF is first converted from a compact to linear form by flow, and is subsequently activated to bind GPIbα in a tension-dependent manner.

  11. SNAP23 Regulates Endothelial Exocytosis of von Willebrand Factor.

    Science.gov (United States)

    Zhu, Qiuyu Martin; Zhu, Qiuyu; Yamakuchi, Munekazu; Lowenstein, Charles J

    2015-01-01

    Endothelial exocytosis regulates vascular thrombosis and inflammation. The trafficking and release of endothelial vesicles is mediated by SNARE (Soluble NSF Attachment protein REceptors) molecules, but the exact identity of endothelial SNAREs has been unclear. Three SNARE molecules form a ternary complex, including isoforms of the syntaxin (STX), vesicle-associated membrane protein (VAMP), and synaptosomal-associated protein (SNAP) families. We now identify SNAP23 as the predominant endothelial SNAP isoform that mediates endothelial exocytosis of von Willebrand Factor (VWF). SNAP23 was localized to the plasma membrane. Knockdown of SNAP23 decreased endothelial exocytosis, suggesting it is important for endothelial exocytosis. SNAP23 interacted with the endothelial exocytic machinery, and formed complexes with other known endothelial SNARE molecules. Taken together, these data suggest that SNAP23 is a key component of the endothelial SNARE machinery that mediates endothelial exocytosis.

  12. Diurnal variation of von Willebrand factor in plasma

    DEFF Research Database (Denmark)

    Timm, Annette; Fahrenkrug, Jan; Jørgensen, Henrik L

    2014-01-01

    BACKGROUND: Quantitation of von Willebrand factor (VWF) in plasma is a central element in assessing von Willebrand disease (VWD). VWF activity is known to vary, which has partly been ascribed to biological and preanalytical variation. However, a possible diurnal expression of VWF has not been...... of light and 9 h of darkness); the plasma concentration of melatonin was used as an internal control to confirm the normal 24-h rhythms of the individual participants. RESULTS: The data, analyzed by rhythmometric statistics, revealed a significant variation (P = 0.02) and total amplitude of 22.6% in VWF...... and VWF and (ii) VWF propeptide and VWF was determined. Taken together, the data suggest changes in release and not in clearance. CONCLUSIONS: Diurnal variation in von Willebrand antigen and activity in plasma represents an important aspect of the biological variation. Standardized time-of-day plasma...

  13. Molecular characterization of exon 28 of von Willebrand's factor ...

    African Journals Online (AJOL)

    Background: Polymorphisms in von Willebrand factor (VWF) gene are an important contributor to the expression of VWF gene and differences in ethnic distribution of these single nucleotide polymorphisms (SNPs) exists. Aims: Our objective was to molecularly characterize the exon 28 of the VWF gene in the three major ...

  14. Molecular characterization of exon 28 of von Willebrand's factor ...

    African Journals Online (AJOL)

    2016-05-12

    May 12, 2016 ... two probable cases among 95 patients with hemophilia A and 11 with hemophilia B between 1980 and 1986, but full investigation and family studies were not performed. In. Nigeria, we have been unable to find documented cases of. Molecular characterization of exon 28 of von Willebrand's factor gene in ...

  15. Cooperation within von Willebrand factors enhances adsorption mechanism.

    Science.gov (United States)

    Heidari, Maziar; Mehrbod, Mehrdad; Ejtehadi, Mohammad Reza; Mofrad, Mohammad R K

    2015-08-06

    von Willebrand factor (VWF) is a naturally collapsed protein that participates in primary haemostasis and coagulation events. The clotting process is triggered by the adsorption and conformational changes of the plasma VWFs localized to the collagen fibres found near the site of injury. We develop coarse-grained models to simulate the adsorption dynamics of VWF flowing near the adhesive collagen fibres at different shear rates and investigate the effect of factors such as interaction and cooperativity of VWFs on the success of adsorption events. The adsorption probability of a flowing VWF confined to the receptor field is enhanced when it encounters an adhered VWF in proximity to the collagen receptors. This enhancement is observed within a wide range of shear rates and is mostly controlled by the attractive van der Waals interactions rather than the hydrodynamic interactions among VWF monomers. The cooperativity between the VWFs acts as an effective mechanism for enhancing VWF adsorption to the collagen fibres. Additionally, this implies that the adsorption of such molecules is nonlinearly dependent on the density of flowing VWFs. These findings are important for studies of primary haemostasis as well as general adsorption dynamics processes in polymer physics. © 2015 The Author(s).

  16. Polymorphism in the promoter region of von Willebrand factor gene and von Willebrand disease type 1

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    Daniel Simon

    2003-12-01

    Full Text Available The -1185A/G polymorphism in the 5'-regulatory region of the von Willebrand factor (VWF gene was associated with VWF plasma levels in a normal population. This study was undertaken to evaluate whether there is a relationship between this polymorphism and type 1 von Willebrand disease (VWD, a disorder characterized by a quantitative deficiency of VWF. The association between this polymorphism and plasma VWF levels in normal Brazilian individuals was also analyzed. Control subjects (n = 460 and type 1 VWD patients (n = 41 were studied. Polymerase chain reaction (PCR amplification of the 864-bp VWF promoter region followed by AccII restriction-digestion was used to identify the -1185A/G genotypes. The -1185G allele frequency was 57% in normal individuals and 63% in type 1 VWD patients, this difference was not significant (p = 0.29. No significant association was observed between -1185A/G genotypes and VWF plasma levels in normal individuals, although VWF levels were in the same direction as those reported by another study, with subjects carrying the G allele having the lower levels. These results suggest that -1185A/G polymorphism is not associated with the partial deficiency of VWF in type 1 VWD patients.

  17. [Structure and function of the factor VIII/von Willebrand factor complex].

    Science.gov (United States)

    Müller, G

    1990-03-01

    In the blood plasma factor VIII is bound to the von Willebrand factor. The primary structure of the two proteins were clarified by gene clonation. Factor VIII descends from a precursor protein with 2,351 amino acids by splitting of 19 amino acid residues and is activated by partial proteolysis. In the blood coagulation factor VIII acts as co-factor for the activation of factor X by factor IX in the presence of phospholipids and Ca++ within the intrinsic coagulation system. The formation of the von Willebrand factor takes place by splitting of 22 and 741 amino acid residues, respectively, from pre-pro-von Willebrand factor via pro-von Willebrand factor. The subunits of the von Willebrand factor consist od 2,050 amino acid residues. In the blood plasma the von Willebrand factor is existing as a mixture of multimeres. Receptors of the von Willebrand factor on the thrombocytic membrane are the glycoproteins GPIb and GPIIb/GPIIIa, by means of which the adhesion of thrombocytes at the subendoethelium of the vascular wall and the aggregation of thrombocytes are mediated.

  18. CHANGES OF VON WILLEBRAND FACTOR DURING PREGNANCY IN WOMEN WITHOUT AND WITH VON WILLEBRAND DISEASE

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    Giancarlo Castaman

    2013-07-01

    Full Text Available Delivery in von Willebrand disease (VWD represents a significant hemostatic challenge because of the variable pattern of changes observed during pregnancy of von Willebrand factor (VWF  and factor VIII (FVIII, the protein carried by VWF. The wide heterogeneity of phenotypes and of the underlying pathophysiological mechanisms associated with this disorder prompt a careful evaluation of pregnant women with VWD to plan the most appropriate treatment at time of parturition. VWF and FVIII increase significantly during pregnancy in normal women, already within the first trimester, reaching levels by far > 100 U/dL by the time of parturition. In women with VWD, levels at baseline of VWF and FVIII > 30 U/dL are usually associated with a high likelihood to achieve normal levels at the end of pregnancy and specific anti-hemorrhagic prophylaxis is seldom required. Women with basal level < 20 U/dL usually have a poor increase since most of these women carry mutations associated with increased VWF clearance or are compound heterozygous for different VWF mutations which prevent the achievement of satisfactory hemostatic levels. While women with mutations associated with increased clearance show a full, albeit transitory correction of their hemostatic deficiency after desmopressin administration, compound heterozygous need replacement therapy because they do not respond well to this agent. Patients with abnormal VWF:RCo/VWF:Ag ratio at baseline (e.g. < 0.6, typically associated with type 2 VWD, maintain the abnormality throughout pregnancy and VWF:RCo usually does not attain safe levels ³ 50 U/dL. These women require replacement therapy with VWF-FVIII concentrates. Delayed post-partum bleeding may occur when replacement therapy is not continued for some days. Tranexamic acid may be useful at discharge to avoid excessive lochia.

  19. Von Willebrand factor for menorrhagia: a survey and literature review.

    Science.gov (United States)

    Ragni, M V; Machin, N; Malec, L M; James, A H; Kessler, C M; Konkle, B A; Kouides, P A; Neff, A T; Philipp, C S; Brambilla, D J

    2016-05-01

    von Willebrand disease (VWD) is the most common congenital bleeding disorder. In women, menorrhagia is the most common bleeding symptom, and is disabling with iron deficiency anaemia, high health cost and poor quality of life. Current hormonal and non-hormonal therapies are limited by ineffectiveness and intolerance. Few data exist regarding von Willebrand factor (VWF), typically prescribed when other treatments fail. The lack of effective therapy for menorrhagia remains the greatest unmet healthcare need in women with VWD. Better therapies are needed to treat women with menorrhagia. We conducted a survey of US haemophilia treatment centres (HTCs) and a literature review using medical subject heading (MeSH) search terms 'von Willebrand factor,' 'menorrhagia' and 'von Willebrand disease' to assess the use of VWF in menorrhagia. Analysis was by descriptive statistics. Of 83 surveys distributed to HTC MDs, 20 (24.1%) provided sufficient data for analysis. Of 1321 women with VWD seen during 2011-2014, 816 (61.8%) had menorrhagia, for which combined oral contraceptives, tranexamic acid and desmopressin were the most common first-line therapies for menorrhagia, whereas VWF was third-line therapy reported in 13 women (1.6%). Together with data from 88 women from six published studies, VWF safely reduced menorrhagia in 101 women at a dose of 33-100 IU kg(-1) on day 1-6 of menstrual cycle. This represents the largest VWD menorrhagia treatment experience to date. VWF safely and effectively reduces menorrhagia in women with VWD. A prospective clinical trial is planned to confirm these findings. © 2016 John Wiley & Sons Ltd.

  20. Organization of von Willebrand factor on surface-activated platelets.

    Science.gov (United States)

    Escolar, G; White, J G

    1993-12-01

    The distribution and organization of von Willebrand factor (vWF) multimers on platelets after surface activation have not been fully characterized. In the present study, washed human platelets were allowed to interact with Formvar-coated, electron microscope grids for 20 minutes at 37 degrees C and then fixed. After fixation, cells were washed and then incubated with buffer alone, human plasma, human plasma preincubated with ristocetin (1.2 mg/mL), purified human vWF plus ristocetin, or bovine plasma. Macromolecular complexes were revealed by ultrastructural immunocytochemistry employing a polyclonal antibody against vWF and protein A-gold (PAG) as the electron-dense probe. vWF multimers were not present in discoid platelets but appeared on the central zone of dendritic cells and over larger central areas of fully spread platelets. Exposure to human plasma alone did not affect the distribution of electron-dense probes for vWF in central regions of surface-activated cells. Incubation of spread platelets with ristocetin-activated human plasma or bovine plasma resulted in the appearance of randomly dispersed, mottled areas of increased density covering the surface from edge to edge. Exposure to vWF antibody and PAG resulted in specific labeling of the dense areas in a serpentine, linear array. The gold-probe distribution suggested that the vWF multimers were not superimposed and were distributed in a random, irregular manner from edge to edge with label-free, clear areas between them. The results extend previous observations demonstrating that glycoprotein Ib-IX receptors are not spontaneously cleared from the plasma membranes of surface-activated platelets by showing that the receptor function of glycoprotein Ib-IX complex remains unchanged.

  1. von Willebrand factor, Jedi knight of the bloodstream.

    Science.gov (United States)

    Springer, Timothy A

    2014-08-28

    When blood vessels are cut, the forces in the bloodstream increase and change character. The dark side of these forces causes hemorrhage and death. However, von Willebrand factor (VWF), with help from our circulatory system and platelets, harnesses the same forces to form a hemostatic plug. Force and VWF function are so closely intertwined that, like members of the Jedi Order in the movie Star Wars who learn to use "the Force" to do good, VWF may be considered the Jedi knight of the bloodstream. The long length of VWF enables responsiveness to flow. The shape of VWF is predicted to alter from irregularly coiled to extended thread-like in the transition from shear to elongational flow at sites of hemostasis and thrombosis. Elongational force propagated through the length of VWF in its thread-like shape exposes its monomers for multimeric binding to platelets and subendothelium and likely also increases affinity of the A1 domain for platelets. Specialized domains concatenate and compact VWF during biosynthesis. A2 domain unfolding by hydrodynamic force enables postsecretion regulation of VWF length. Mutations in VWF in von Willebrand disease contribute to and are illuminated by VWF biology. I attempt to integrate classic studies on the physiology of hemostatic plug formation into modern molecular understanding, and point out what remains to be learned. © 2014 by The American Society of Hematology.

  2. Clinical measurement of von Willebrand factor by fluorescence correlation spectroscopy.

    Science.gov (United States)

    Torres, Richard; Genzen, Jonathan R; Levene, Michael J

    2012-06-01

    Identification of von Willebrand factor (vWF) abnormalities in a variety of conditions is hampered by the limitations of currently available diagnostic tests. Although direct multimer visualization by immunoelectrophoresis is a commonly used method, it is impractical as a routine clinical test. In this study, we used a biophysical analysis tool, fluorescence correlation spectroscopy (FCS), to measure vWF distributions. The goals were to develop a method that is quicker and simpler than vWF gel electrophoresis and to evaluate the potential of FCS as a clinical diagnostic technique. We analyzed plasma from 12 patients with type 1 von Willebrand disease (vWD), 14 patients with type 2 vWD, and 10 healthy controls using a fluctuation-based immunoassay approach. FCS enabled identification and proper classification of type 1 and type 2 vWD, producing quantitative results that correspond to qualitative gel multimer patterns. FCS required minimal sample preparation and only a 5-min analysis time. This study represents the first implementation of FCS for clinical diagnostics directly on human plasma. The technique shows potential for further vWF studies and as a generally applicable laboratory test method.

  3. The effect of exercise on von Willebrand factor and ADAMTS-13 in individuals with type 1 and type 2B von Willebrand disease

    NARCIS (Netherlands)

    Stakiw, J.; Bowman, M.; Hegadorn, C.; Pruss, C.; Notley, C.; Groot, E.; Lenting, P. J.; Rapson, D.; Lillicrap, D.; James, P.

    Background: The effect of exercise on von Willebrand factor (VWF) and ADAMTS-13 levels in individuals with von Willebrand disease (VWD) has never been reported. Objectives: The aim was to quantify the effect of a standardized exercise protocol on individuals with type 1 and type 2B VWD.

  4. Is the activated partial thromboplastin time suitable to screen for von Willebrand factor deficiencies?

    Science.gov (United States)

    Lippi, Giuseppe; Franchini, Massimo; Poli, Giovanni; Salvagno, Gian Luca; Montagnana, Martina; Guidi, Gian Cesare

    2007-06-01

    The diagnostic approach to von Willebrand factor deficiencies is challenging and requires discretionary use of laboratory resources. Although extensive preoperative testing is not recommended, the activated partial thromboplastin time may be useful, especially in selected categories of patients. To establish the diagnostic sensitivity of this test to identify isolate von Willebrand factor deficiencies, 204 consecutive patients underwent a routine preoperative screening consisting of activated partial thromboplastin time, von Willebrand factor antigen, intrinsic pathway clotting factors activity, lupus anticoagulants and thrombin time. Thirty-seven patients were diagnosed with haemostasis disturbances other than von Willebrand factor deficiencies and were excluded from the evaluation. Isolated von Willebrand factor deficiency was diagnosed in 11 of the remaining 167 patients. A significant correlation was observed between von Willebrand factor antigen and activated partial thromboplastin time. Receiver operating characteristic curve analysis showed an area under the curve of 0.982 (95% confidence interval: 0.972-0.992; P thromboplastin time, sensitivity and specificity were 100 and 85%, respectively, with negative and positive predictive values of 100 and 31%, respectively. These results demonstrate that activated partial thromboplastin time has an excellent diagnostic sensitivity and a satisfactory specificity for identifying isolated von Willebrand factor deficiencies.

  5. Value of Von Willebrand Factor as a Predictor for Osteoporosis Development in Women with Hypothyroidism

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    I.V. Pankiv

    2015-08-01

    Full Text Available The paper presents the study of the value of von Willebrand factor as a marker of endothelial dysfunction for osteoporosis development and for prediction of risk of its formation in women with hypothyroidism. Postmenopausal women with hypothyroidism have significant increase of von Willebrand factor at lumbar osteopenia. High concentrations of von Willebrand factor in women with hypothyroidism follows to consider it as a predictor for osteoporosis development. Increased level of С-reactive protein belongs to the unfavorable prognostic signs in relation to the decline of bone mineral density for patients with primary hypothyroidism.

  6. Differential localization of P-selectin and von Willebrand factor during megakaryocyte maturation

    DEFF Research Database (Denmark)

    Zingariello, M; Fabucci, M E; Bosco, D

    2010-01-01

    Willebrand factor are two proteins present in the alpha-granules that recognize P-selectin glycoprotein ligand on neutrophils and collagen in the subendothelial matrix. These proteins may play an important role in determining the differential release of the alpha-granule contents in response to external....... These observations support the hypothesis that P-selectin and von Willebrand factor may ensure differential release of the alpha-granule content in response to external stimuli....

  7. Von Willebrand factor in patients on mechanical circulatory support - a double-edged sword between bleeding and thrombosis.

    Science.gov (United States)

    Hudzik, Bartosz; Kaczmarski, Jacek; Pacholewicz, Jerzy; Zakliczynski, Michal; Gasior, Mariusz; Zembala, Marian

    2015-09-01

    Mechanical circulatory support (MCS) is an umbrella term describing the various technologies used in both short- and long-term management of patients with either end-stage chronic heart failure (HF) or acute HF. Most often, MCS has emerged as a bridge to transplantation, but more recently it is also used as a destination therapy. Mechanical circulatory support includes left ventricular assist device (LVAD) or bi-ventricular assist device (Bi-VAD). Currently, 2- to 3-year survival in carefully selected patients is much better than with medical therapy. However, MCS therapy is hampered by sometimes life-threatening complications including bleeding and device thrombosis. Von Willebrand factor (vWF) has two major functions in haemostasis. First, it plays a crucial role in platelet-subendothelium adhesion and platelet-platelet interactions (aggregation). Second, it is the carrier of factor VIII (FVIII) in plasma. Von Willebrand factor prolongs FVIII half-time by protecting it from proteolytic degradation. It delivers FVIII to the site of vascular injury thus enhancing haemostatic process. On one hand, high plasma levels of vWF have been associated with an increased risk of thrombosis. On the other, defects or deficiencies of vWF underlie the inherited von Willebrand disease or acquired von Willebrand syndrome. Here we review the pathophysiology of thrombosis and bleeding associated with vWF.

  8. Modeling Shear Induced Von Willebrand Factor Binding to Collagen

    Science.gov (United States)

    Dong, Chuqiao; Wei, Wei; Morabito, Michael; Webb, Edmund; Oztekin, Alparslan; Zhang, Xiaohui; Cheng, Xuanhong

    2017-11-01

    Von Willebrand factor (vWF) is a blood glycoprotein that binds with platelets and collagen on injured vessel surfaces to form clots. VWF bioactivity is shear flow induced: at low shear, binding between VWF and other biological entities is suppressed; for high shear rate conditions - as are found near arterial injury sites - VWF elongates, activating its binding with platelets and collagen. Based on parameters derived from single molecule force spectroscopy experiments, we developed a coarse-grain molecular model to simulate bond formation probability as a function of shear rate. By introducing a binding criterion that depends on the conformation of a sub-monomer molecular feature of our model, the model predicts shear-induced binding, even for conditions where binding is highly energetically favorable. We further investigate the influence of various model parameters on the ability to predict shear-induced binding (vWF length, collagen site density and distribution, binding energy landscape, and slip/catch bond length) and demonstrate parameter ranges where the model provides good agreement with existing experimental data. Our results may be important for understanding vWF activity and also for achieving targeted drug therapy via biomimetic synthetic molecules. National Science Foundation (NSF),Division of Mathematical Sciences (DMS).

  9. Von Willebrand Factor Gene Variants Associate with Herpes simplex Encephalitis.

    Directory of Open Access Journals (Sweden)

    Nada Abdelmagid

    Full Text Available Herpes simplex encephalitis (HSE is a rare complication of Herpes simplex virus type-1 infection. It results in severe parenchymal damage in the brain. Although viral latency in neurons is very common in the population, it remains unclear why certain individuals develop HSE. Here we explore potential host genetic variants predisposing to HSE. In order to investigate this we used a rat HSE model comparing the HSE susceptible SHR (Spontaneously Hypertensive Rats with the asymptomatic infection of BN (Brown Norway. Notably, both strains have HSV-1 spread to the CNS at four days after infection. A genome wide linkage analysis of 29 infected HXB/BXH RILs (recombinant inbred lines-generated from the prior two strains, displayed variable susceptibility to HSE enabling the definition of a significant QTL (quantitative trait locus named Hse6 towards the end of chromosome 4 (160.89-174Mb containing the Vwf (von Willebrand factor gene. This was the only gene in the QTL with both cis-regulation in the brain and included several non-synonymous SNPs (single nucleotide polymorphism. Intriguingly, in human chromosome 12 several SNPs within the intronic region between exon 43 and 44 of the VWF gene were associated with human HSE pathogenesis. In particular, rs917859 is nominally associated with an odds ratio of 1.5 (95% CI 1.11-2.02; p-value = 0.008 after genotyping in 115 HSE cases and 428 controls. Although there are possibly several genetic and environmental factors involved in development of HSE, our study identifies variants of the VWF gene as candidates for susceptibility in experimental and human HSE.

  10. Regulation of plasma von Willebrand factor [version 1; referees: 3 approved

    Directory of Open Access Journals (Sweden)

    Karl C Desch

    2018-01-01

    Full Text Available Von Willebrand factor (VWF is a multimeric plasma glycoprotein that plays a central role in the initiation of blood coagulation. Through interactions between its specific functional domains, the vascular wall, coagulation factor VIII, and platelet receptors, VWF maintains hemostasis by binding to platelets and delivering factor VIII to the sites of vascular injury. In the healthy human population, plasma VWF levels vary widely. The important role of VWF is illustrated by individuals at the extremes of the normal distribution of plasma VWF concentrations where individuals with low VWF levels are more likely to present with mucocutaneous bleeding. Conversely, people with high VWF levels are at higher risk for venous thromboembolic disease, stroke, and coronary artery disease. This report will summarize recent advances in our understanding of environmental influences and the genetic control of VWF plasma variation in healthy and symptomatic populations and will also highlight the unanswered questions that are currently driving this field of study.

  11. The impact of von Willebrand factor on factor VIII memory immune responses

    OpenAIRE

    Chen, Juan; Schroeder, Jocelyn A.; Luo, Xiaofeng; Shi, Qizhen

    2017-01-01

    Immune tolerance induction (ITI) with aggressive infusion of factor VIII (FVIII) is the current strategy used to eradicate FVIII inhibitors and restore normal FVIII pharmacokinetics in inhibitor patients. Whether the use of FVIII products containing von Willebrand factor (VWF) will affect the efficacy of ITI is still controversial. In this study, we explored the impact of VWF on FVIII memory immune responses in hemophilia A (HA) mice. A T-cell proliferation assay and cytokine profile analysis...

  12. Differential proteolytic activation of factor VIII-von Willebrand factor complex by thrombin

    Energy Technology Data Exchange (ETDEWEB)

    Hill-Eubanks, D.C.; Parker, C.G.; Lollar, P. (Univ. of Vermont, Burlington (USA))

    1989-09-01

    Blood coagulation factor VIII (fVIII) is a plasma protein that is decreased or absent in hemophilia A. It is isolated as a mixture of heterodimers that contain a variably sized heavy chain and a common light chain. Thrombin catalyzes the activation of fVIII in a reaction that is associated with cleavages in both types of chain. The authors isolated a serine protease from Bothrops jararacussu snake venom that catalyzes thrombin-like heavy-chain cleavage but not light-chain cleavage in porcine fVIII as judged by NaDodSO{sub 4}/PAGE and N-terminal sequence analysis. Using a plasma-free assay of the ability of activated {sup 125}I-fVIII to function as a cofactor in the activation of factor X by factor IXa, they found that fVIII is activated by the venom enzyme. The venom enzyme-activated fVIII was isolated in stable form by cation-exchange HPLC. von Willebrand factor inhibited venom enzyme-activated fVIII but not thrombin-activated fVIII. These results suggest that the binding of fVIII to von Willebrand factor depends on the presence of an intact light chain and that activated fVIII must dissociate from von Willebrand factor to exert its cofactor effect. Thus, proteolytic activation of fVIII-von Willebrand factor complex appears to be differentially regulated by light-chain cleavage to dissociate the complex and heavy-chain cleavage to activate the cofactor function.

  13. Towards improved diagnosis of von Willebrand disease: comparative evaluations of several automated von Willebrand factor antigen and activity assays.

    Science.gov (United States)

    Favaloro, Emmanuel J; Mohammed, Soma

    2014-12-01

    von Willebrand disease (VWD) is reportedly the most common bleeding disorder and arises from deficiency and/or defects of von Willebrand factor (VWF). Laboratory diagnosis and typing has important management implications and requires a wide range of tests, including VWF activity and antigen, and involves differential identification of qualitative vs quantitative defects. We have assessed several VWF antigen and activity assays (collagen binding [VWF:CB], ristocetin cofactor [VWF:RCo] and the new Siemens INNOVANCE assay [VWF:Ac], employing latex particles and gain of function recombinant glycoprotein Ib to facilitate VWF binding and agglutination without need for ristocetin) using different instrumentation, including the new Sysmex CS-5100, with a large sample test set (n=600). We included retrospective plus prospective study designs, and also evaluated desmopressin responsiveness plus differential sensitivity to high molecular weight VWF. VWF:Ag and VWF:RCo results from different methods were respectively largely comparable, although some notable differences were evident, including one high false normal VWF:Ag value (105 U/dL) on a type 3 VWD sample, possibly due to heterophile antibody interference in the latex-based CS-5100 methodology. VWF:Ac was largely comparable to VWF:RCo, but VWF:CB showed discrepant findings to both VWF:RCo and VWF:Ac with some patients, most notably patients with type 2M VWD. (a) VWF:Ag on different platforms are largely interchangeable, as are VWF:RCo on different platforms, except for occasional (some potentially important) differences, and manufacturer recommended methods may otherwise require some assay optimization; (b) VWF:RCo and VWF:Ac are largely interchangeable, except for occasional differences that may also relate to assay design (differing optimizations); (c) VWF:CB provides an additional activity to supplement VWF:RCo or VWF:Ac activity assays, and is not interchangeable with either. Crown Copyright © 2014. Published by

  14. Diagnostic Differentiation of von Willebrand Disease Types 1 and 2 by von Willebrand Factor Multimer Analysis and DDAVP Challenge Test.

    Science.gov (United States)

    Michiels, Jan Jacques; Smejkal, Petr; Penka, Miroslav; Batorova, Angelika; Pricangova, Tatiana; Budde, Ulrich; Vangenechten, Inge; Gadisseur, Alain

    2017-09-01

    The European Clinical Laboratory and Molecular (ECLM) classification of von Willebrand disease (vWD) is based on the splitting approach which uses sensitive and specific von Willebrand factor (vWF) assays with regard to the updated molecular data on structure and function of vWF gene and protein defects. A complete set of FVIII:C and vWF ristocetine cofactor, collagen binding, and antigen, vWF multimeric analysis in low- and medium-resolution gels, and responses to desmopressin (DDAVP) of FVIII:C and vWF parameters are mandatory. The ECLM classification distinguishes recessive types 1 and 3 vWD from recessive vWD 2C due to mutations in the D1 and D2 domains and vWD 2N due to mutations in the D'-FVIII-binding domain of vWF. The ECLM classification differentiates between mild vWD type 1 with variable penetrance of bleedings from symptomatic dominant type 1 vWD secretion defect and/or clearance defect with normal vWF multimers versus vWD 1M and 2M with normal or smeary vWF multimers in low- and medium-resolution gels. High-quality multimeric analysis of vWF in medium-resolution gels based on a DDAVP challenge test clearly delineates and distinguishes each of the dominant type 2 vWDs 1/2E, 2M, 2B, 2A, and 2D caused by vWF gene mutations in the D3 multimerization domain, loss or gain-of-function mutations in the glycoprotein Ib receptor A1 domain, gene mutations in the A2 proteolytic domain, and the C-terminal dimerization domain, respectively.

  15. von Willebrand Factor and Prekallikrein in Plasma Are Associated With Thrombus Volume in Abdominal Aortic Aneurysms

    DEFF Research Database (Denmark)

    Ghulam, Qasam M; Bredahl, Kim; Gram, Jørgen Brodersen

    2016-01-01

    was consecutively obtained from 38 patients with asymptomatic infrarenal abdominal aortic aneurysm. von Willebrand factor activity, thrombin generation time, factor XII, and prekallikrein concentration were measured in plasma on automated and in-house platforms. In total, 8 patients were excluded due to ongoing...

  16. Von Willebrand factor, a key protein in the exposure of CD62P on platelets.

    Science.gov (United States)

    Broberg, M; Nygren, H

    2001-09-01

    When a biomaterial is introduced into the body water, electrolytes, and proteins adsorb to the surface. Platelets are then the first cells to interact with the surface adsorbed protein layer. We have studied the role of von Willebrand factor (vWF) for platelet-protein interaction by measuring different platelet responses to protein- and plasma-coated hydrophobic glass surfaces. A high exposure of CD62P on the platelet surface was seen after 10 min of incubation on platelets interacting with vWF and normal plasma-coated surfaces (79 and 67%, respectively). On the surfaces coated with albumin and factor VIII deficient plasma, the exposure was low (11 and 27%, respectively). A higher formation of filipodial extensions on the platelets was seen on the surfaces coated with vWF and normal plasma than on the surfaces coated with albumin or factor VIII deficient plasma. No significant differences were seen between the surfaces regarding the platelet release of PF4, ATP, or phospholipids. As shown by these results, vWF is a specific regulator of the exposure of CD62P by platelets and hence important for the interaction between platelets and later arriving neutrophils at biomaterial surfaces.

  17. Detailed von Willebrand factor multimer analysis in patients with von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 von Willebrand disease (MCMDM-1VWD)

    DEFF Research Database (Denmark)

    Budde, U.; Schneppenheim, R.; Eikenboom, J.

    2008-01-01

    BACKGROUND: Type 1 von Willebrand disease (VWD) is a congenital bleeding disorder characterized by a partial quantitative deficiency of plasma von Willebrand factor (VWF) in the absence of structural and/or functional VWF defects. Accurate assessment of the quantity and quality of plasma VWF...... is difficult but is a prerequisite for correct classification. OBJECTIVE: To evaluate the proportion of misclassification of patients historically diagnosed with type 1 VWD using detailed analysis of the VWF multimer structure. Patients and methods: Previously diagnosed type 1 VWD families and healthy controls...

  18. Immunoprotective effect of von Willebrand factor towards therapeutic factor VIII in experimental haemophilia A.

    Science.gov (United States)

    Delignat, S; Repessé, Y; Navarrete, A-M; Meslier, Y; Gupta, N; Christophe, O D; Kaveri, S V; Lacroix-Desmazes, S

    2012-03-01

    The development of inhibitory anti-factor VIII (FVIII) antibodies in patients with haemophilia A following replacement therapy is associated with several types of risk factors. Among these, the purity of FVIII concentrates, and in particular the presence of von Willebrand factor (VWF), was controversially proposed to influence the immunogenicity of exogenous FVIII. We re-assessed in vivo and in vitro the immuno-protective effect of VWF towards FVIII. The immuno-protective effect of VWF towards FVIII was investigated in vivo, in a model of haemophilia A. We studied the endocytosis of FVIII by murine bone marrow-derived dendritic cells and evaluated the capacity of VWF to block the internalization of FVIII. We characterized the relevance of VWF for the accumulation of FVIII in the marginal zone of the spleen, a secondary lymphoid organ where the immune response to therapeutically administered FVIII initiates. Our results confirm that VWF reduces the immunogenicity of FVIII in FVIII-deficient mice. Paradoxically, VWF is important for the accumulation of FVIII in the marginal zone of the spleen. We propose that VWF exerts at least two non-mutually exclusive immunoprotective roles towards FVIII in haemophilic mice: VWF prevents the endocytosis of FVIII by professional antigen-presenting cells by blocking the interaction of FVIII with as yet unidentified endocytic receptor(s). Hypothetically, VWF, by virtue of increasing the half-life of FVIII in the circulation, may allow an increased contact time with tolerogenic marginal zone B cells in the spleen. © 2011 Blackwell Publishing Ltd.

  19. Small GTP-binding protein Ral modulates regulated exocytosis of von Willebrand factor by endothelial cells

    NARCIS (Netherlands)

    de Leeuw, H. P.; Fernandez-Borja, M.; Reits, E. A.; Romani de Wit, T.; Wijers-Koster, P. M.; Hordijk, P. L.; Neefjes, J.; van Mourik, J. A.; Voorberg, J.

    2001-01-01

    Weibel-Palade bodies are endothelial cell-specific organelles, which contain von Willebrand factor (vWF), P-selectin, and several other proteins. Recently, we found that the small GTP-binding protein Ral is present in a subcellular fraction containing Weibel-Palade bodies. In the present study, we

  20. Efficiency of von Willebrand factor-mediated targeting of interleukin-8 into Weibel-Palade bodies

    NARCIS (Netherlands)

    Bierings, R.; van den Biggelaar, M.; Kragt, A.; Mertens, K.; Voorberg, J.; van Mourik, J. A.

    2007-01-01

    Background: After de novo synthesis in endothelial cells, the chemokine interleukin-8 (IL-8) is targeted to endothelial cell-specific storage vesicles, the Weibel-Palade bodies (WPBs), where it colocalizes with von Willebrand factor (VWF). Objective: In this study we investigated a putative

  1. Binding of von Willebrand factor and plasma proteins to the eggshell of Schistosoma mansoni

    NARCIS (Netherlands)

    Dewalick, Saskia; Hensbergen, Paul J; Bexkens, Michiel L; Grosserichter-Wagener, Christina; Hokke, Cornelis H; Deelder, André M; de Groot, Philip G; Tielens, Aloysius G M; van Hellemond, Jaap J

    Schistosoma mansoni eggs have to cross the endothelium and intestinal wall to leave the host and continue the life cycle. Mechanisms involved in this essential step are largely unknown. Here we describe direct binding to the S. mansoni eggshell of von Willebrand factor and other plasma proteins

  2. Altered glycosylation of platelet-derived von Willebrand factor confers resistance to ADAMTS13 proteolysis

    NARCIS (Netherlands)

    McGrath, Rachel T.; van den Biggelaar, Maartje; Byrne, Barry; O'Sullivan, Jamie M.; Rawley, Orla; O'Kennedy, Richard; Voorberg, Jan; Preston, Roger J. S.; O'Donnell, James S.

    2013-01-01

    Platelet-von Willebrand factor (VWF) is stored within α-granules and accounts for ∼20% of total VWF in platelet-rich plasma. This platelet-VWF pool is distinct from plasma-VWF and is enriched in high molecular weight multimers (HMWM). Previous studies have described significant functional

  3. ADAMTS-13 and von Willebrand factor predict venous thromboembolism in patients with cancer

    NARCIS (Netherlands)

    Pepin, M.; Kleinjan, A.; Hajage, D.; Buller, H. R.; Di Nisio, M.; Kamphuisen, P. W.; Salomon, L.; Veyradier, A.; Stepanian, A.; Mahe, I.

    Essentials Cancer patients are at high risk of venous thromboembolism (VTE). In this study, cases and controls were cancer patients who did or did not develop VTE. von Willebrand factor (VWF) levels were higher if compared with controls and correlated with cancer stage. VWF and ADAMTS-13 are

  4. Mutant botrocetin-2 inhibits von Willebrand factor-induced platelet agglutination.

    Science.gov (United States)

    Matsui, T; Hori, A; Hamako, J; Matsushita, F; Ozeki, Y; Sakurai, Y; Hayakawa, M; Matsumoto, M; Fujimura, Y

    2017-03-01

    Essentials Botrocetin-2 (Bot2) binds to von Willebrand factor (VWF) and induces platelet agglutination. We identified Bot2 residues that are required for binding to VWF and glycoprotein (GP) Ib. We produced a mutant Bot2 that binds to VWF but inhibits platelet agglutination. Mutant Bot2 could be used as a potential anti-thrombotic reagent to block VWF-GPIb interaction. Background Botrocetin-2 (Bot2) is a botrocetin-like protein composed of α and β subunits that have been cloned from the snake Bothrops jararaca. Bot2 binds specifically to von Willebrand factor (VWF), and the complex induces glycoprotein (GP) Ib-dependent platelet agglutination. Objectives To exploit Bot2's VWF-binding capacity in order to attempt to create a mutant Bot2 that binds to VWF but inhibits platelet agglutination. Methods and Results Several point mutations were introduced into Bot2 cDNA, and the recombinant protein (recombinant Bot2 [rBot2]) was purified on an anti-botrocetin column. The mutant rBot2 with either Ala at Asp70 in the β subunit (Aspβ70Ala), or Argβ115Ala and Lysβ117Ala, showed reduced platelet agglutination-inducing activity. rBot2 with Aspβ70Ala showed little binding activity towards immobilized VWF on an ELISA plate, whereas rBot2 with Argβ115Ala/Lysβ117Ala showed reduced binding activity towards GPIb (glycocalicin) after forming a complex with VWF. rBot2 point-mutated to oppositely charged Glu at both Argβ115 and Lysβ117 showed normal binding activity towards VWF but no platelet-agglutinating activity. Furthermore, this doubly mutated protein inhibited ristocetin-induced or high shear stress-induced platelet aggregation, and restrained thrombus formation under flow conditions. Conclusions Asp70 in the β subunit of botrocetin is important for VWF binding, and Arg115 and Lys117 in the β subunit are essential for interaction with GPIb. Doubly mutated rBot2, with Argβ115Glu and Lysβ117Glu, repels GPIb and might have potential as an antithrombotic reagent that

  5. Storage of factor VIII variants with impaired von Willebrand factor binding in Weibel-Palade bodies in endothelial cells

    NARCIS (Netherlands)

    van den Biggelaar, Maartje; Bouwens, Eveline A. M.; Voorberg, Jan; Mertens, Koen

    2011-01-01

    Point mutations resulting in reduced factor VIII (FVIII) binding to von Willebrand factor (VWF) are an important cause of mild/moderate hemophilia A. Treatment includes desmopressin infusion, which concomitantly increases VWF and FVIII plasma levels, apparently from storage pools containing both

  6. Requirements for cellular co-trafficking of factor VIII and von Willebrand factor to Weibel-Palade bodies

    NARCIS (Netherlands)

    van den Biggelaar, M.; Bierings, R.; Storm, G.; Voorberg, J.; Mertens, K.

    2007-01-01

    von Willebrand factor (VWF) serves a critical role as a carrier of factor (F)VIII in circulation. While it is generally believed that FVIII and VWF assemble in circulation after secretion from different cells, an alternative view is that cells should exist that co-express FVIII and VWF. In this

  7. Exercise induced hypercoagulability, increased von Willebrand factor and decreased thyroid hormone concentrations in sled dogs

    DEFF Research Database (Denmark)

    Krogh, Anne Kirstine Havnsøe; Legind, Pernille; Kjelgaard-Hansen, Mads

    2014-01-01

    Sled dogs performing endurance races have been reported to have a high incidence of gastric erosions or ulcerations and an increased risk of gastro intestinal bleeding leading to death in some cases. In addition, these dogs also become hypothyroid during training and exercise. Canine hypothyroidi......, activated partial thromboplastin time (aPTT), prothrombin time (PT), fibrinogen, von Willebrand factor (vWf), D-dimer, platelet number, thyroid hormones, hematocrit and C-reactive protein (CRP)....

  8. Assembly of multimeric von Willebrand factor directs sorting of P-selectin

    NARCIS (Netherlands)

    Hop, C.; Guilliatt, A.; Daly, M.; de Leeuw, H. P.; Brinkman, H. J.; Peake, I. R.; van Mourik, J. A.; Pannekoek, H.

    2000-01-01

    We designed a model system to study the role of von Willebrand factor (vWF) in the sorting of P-selectin and the biogenesis of Weibel-Palade body (WPB)-like organelles. For that purpose, a human epithelial cell line (T24) that synthesizes P-selectin mRNA, but which is devoid of vWF mRNA synthesis

  9. Factor VIII alters tubular organization and functional properties of von Willebrand factor stored in Weibel-Palade bodies

    NARCIS (Netherlands)

    Bouwens, Eveline A. M.; Mourik, Marjon J.; van den Biggelaar, Maartje; Eikenboom, Jeroen C. J.; Voorberg, Jan; Valentijn, Karine M.; Mertens, Koen

    2011-01-01

    In endothelial cells, von Willebrand factor (VWF) multimers are packaged into tubules that direct biogenesis of elongated Weibel-Palade bodies (WPBs). WPB release results in unfurling of VWF tubules and assembly into strings that serve to recruit platelets. By confocal microscopy, we have previously

  10. Heritability of plasma von Willebrand factor antigen concentration in German Wirehaired pointers.

    Science.gov (United States)

    Brooks, M B; Castillo-Juarez, H; Oltenacu, P

    2001-07-01

    We applied quantitative genetic analyses to a population of German Wirehaired pointer dogs affected with type 2 von Willebrand disease. Plasma von Willebrand factor (vWF) protein concentration measured as vWF antigen (vWF:Ag), clinical history, and pedigree data were compiled for 331 dogs over a 5-year test period. Eight dogs had histories of abnormal bleeding and had markedly decreased plasma vWF:Ag concentrations (dogs were inbred, with an average inbreeding of 2.52%. The estimated heritability of plasma vWF concentration was 0.52. We found a major gene effect on vWF concentration. Using a single gene locus model and two different prediction methods, the upper threshold value for the aa genotype was less than 1% vWF:Ag, and the optimal threshold value for discrimination between the AA and Aa genotypes was between 68% and 72% vWF:Ag. Our analyses indicate that phenotype, assigned on the basis of a single vWF:Ag determination, is heritable and can be applied for selective breeding in a von Willebrand disease test programme.

  11. Homocisteína plasmática total e fator von Willebrand no diabete melito experimental Total plasmatic homocysteine and von Willebrand factor in experimental diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Renato Delascio Lopes

    2007-04-01

    Full Text Available OBJETIVOS: Determinar os valores plasmáticos de homocisteína e fator von Willebrand, como marcador de disfunção endotelial, em ratos com diabete melito induzido por estreptozotocina. MÉTODOS: Trinta e cinco ratos (rattus norvegicus albinus, machos, adultos (180-200 g, randomizados em três grupos: controle (n=10 não receberam agente ou veículo; sham (n=10 receberam solução veículo da estreptozotocina; e diabético (n=15 receberam estreptozotocina. Após oito semanas de indução do diabete melito, os animais foram pesados, anestesiados e tiveram sangue colhido da aorta abdominal para determinação dos valores de homocisteína plasmática total, fator von Willebrand e glicemia. RESULTADOS: O modelo experimental foi reprodutível em 100% dos animais. A média das concentrações plasmáticas de homocisteína foi: 7,9 µmol/l (controle; 8,6 µmol/l (sham e 6,1 µmol/l (diabético, com diferença entre os grupos (pOBJECTIVES: To determine the plasma homocysteine and von Willebrand factor levels as markers of endothelial dysfunction in rats with diabetes mellitus induced by streptozotocin. METHODS: Thirty-five adult male rats (Rattus norvegicus albinus (weight between 180-200g were randomized into three groups: control group (n=10, which received no drugs or vehicles; sham group (n=10, which received streptozotocin solution; and diabetic group (n=15, which received streptozotocin. Eight weeks after diabetes mellitus induction, the animals were weighed and anesthesized; blood samples were collected from abdominal aorta for plasma total homocysteine, von Willebrand factor and glucose levels. RESULTS: The experimental model was reproducible in 100% of animals. The mean plasma homocysteine levels were: 7.9 µmol/l (control, 8.6µmol/l (sham and 6.1µmol/l (diabetic, with difference among the groups (p<0.01. Multiple comparison analysis among the groups showed that values in the diabetic group were lower than in the sham group (p<0.01. The mean

  12. Thrombin-dependent Incorporation of von Willebrand Factor into a Fibrin Network*

    Science.gov (United States)

    Miszta, Adam; Pelkmans, Leonie; Lindhout, Theo; Krishnamoorthy, Ganeshram; de Groot, Philip G.; Hemker, Coenraad H.; Heemskerk, Johan W. M.; Kelchtermans, Hilde; de Laat, Bas

    2014-01-01

    Attachment of platelets from the circulation onto a growing thrombus is a process involving multiple platelet receptors, endothelial matrix components, and coagulation factors. It has been indicated previously that during a transglutaminase reaction activated factor XIII (FXIIIa) covalently cross-links von Willebrand factor (VWF) to polymerizing fibrin. Bound VWF further recruits and activates platelets via interactions with the platelet receptor complex glycoprotein Ib (GPIb). In the present study we found proof for binding of VWF to a fibrin monomer layer during the process of fibrinogen-to-fibrin conversion in the presence of thrombin, arvin, or a snake venom from Crotalus atrox. Using a domain deletion mutant we demonstrated the involvement of the C domains of VWF in this binding. Substantial binding of VWF to fibrin monomers persisted in the presence of the FXIIIa inhibitor K9-DON, illustrating that cross-linking via factor XIII is not essential for this phenomenon and suggesting the identification of a second mechanism through which VWF multimers incorporate into a fibrin network. Under high shear conditions, platelets were shown to adhere to fibrin only if VWF had been incorporated. In conclusion, our experiments show that the C domains of VWF and the E domain of fibrin monomers are involved in the incorporation of VWF during the polymerization of fibrin and that this incorporation fosters binding and activation of platelets. Fibrin thus is not an inert end product but partakes in further thrombus growth. Our findings help to elucidate the mechanism of thrombus growth and platelet adhesion under conditions of arterial shear rate. PMID:25381443

  13. Interference from lupus anticoagulant on von Willebrand factor measurement in splenic marginal zone lymphoma

    DEFF Research Database (Denmark)

    Vinholt, Pernille J; Nybo, Mads

    2015-01-01

    We present a case concerning a patient with splenic marginal zone lymphoma (SMZL) and isolated prolonged activated partial thromboplastin time (aPTT) caused by lupus anticoagulant. Von Willebrand factor (VWF) activity and antigen were immeasurable by latex particle immunoturbidimetric assays......, and several coagulation factor levels were decreased. However, VWF activity and antigen were normal when analyzed by other methods. Also, coagulation factor levels were normal if an aPTT reagent with low lupus anticoagulant sensitivity or a chromogenic method was applied. Altogether, the initial findings were...

  14. Aging and ABO blood type influence von Willebrand factor and factor VIII levels through interrelated mechanisms.

    Science.gov (United States)

    Albánez, S; Ogiwara, K; Michels, A; Hopman, W; Grabell, J; James, P; Lillicrap, D

    2016-05-01

    Essentials von Willebrand factor (VWF) and factor VIII (FVIII) levels are modulated by age and ABO status. The effect of aging and ABO blood type on VWF and FVIII was assessed in 207 normal individuals. Aging and ABO blood type showed combined and bidirectional influences on VWF and FVIII levels. Aging and ABO blood type influence VWF levels through both secretion and clearance mechanisms. Background The effect of aging and ABO blood type on plasma levels of von Willebrand factor (VWF) and factor VIII (FVIII) have been widely reported; however, a comprehensive analysis of their combined effect has not been performed and the mechanisms responsible for the age-related changes have not been determined. Objectives To assess the influence of aging and ABO blood type on VWF and FVIII levels, and to evaluate the contribution of VWF secretion and clearance to the age-related changes. Methods A cross-sectional observational study was performed in a cohort of 207 normal individuals, whose levels of VWF, FVIII, VWF propeptide (VWFpp), VWFpp/VWF:Ag ratio and blood type A antigen content on VWF (A-VWF) were quantified. Results Aging and ABO blood type exerted interrelated effects on VWF and FVIII plasma levels, because the age-related increase in both proteins was significantly higher in type non-O individuals (β = 0.011 vs. 0.005). This increase with age in non-O subjects drove the differences between blood types in VWF levels, as the mean difference increased from 0.13 U/mL in the young to 0.57 U/mL in the old. Moreover, A-VWF was associated with both VWF antigen (β = 0.29; 95% confidence interval [CI], 0.09, 0.50) and VWF clearance (β = -0.15; 95% CI, -0.25, -0.06). We also documented an effect of ABO blood type on VWF secretion with aging, as old individuals with blood type non-O showed higher levels of VWFpp (mean difference 0.29 U/mL). Conclusions Aging and ABO blood type have an interrelated effect on VWF and FVIII levels, where the effect of one is significantly

  15. Plasmatic ADAMTS-13 metalloprotease and von Willebrand factor in children with cyanotic congenital heart disease

    Energy Technology Data Exchange (ETDEWEB)

    Soares, R.P.S. [Fundação Pró-Sangue Hemocentro de São Paulo, São Paulo, SP (Brazil); Bydlowski, S.P.; Nascimento, N.M. [Laboratório de Investigação Médica-31, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Thomaz, A.M.; Bastos, E.N.M.; Lopes, A.A. [Faculdade de Medicina, Instituto do Coração, Universidade de São Paulo, São Paulo, SP (Brazil)

    2013-04-05

    Changes in plasma von Willebrand factor concentration (VWF:Ag) and ADAMTS-13 activity (the metalloprotease that cleaves VWF physiologically) have been reported in several cardiovascular disorders with prognostic implications. We therefore determined the level of these proteins in the plasma of children with cyanotic congenital heart disease (CCHD) undergoing surgical treatment. Forty-eight children were enrolled (age 0.83 to 7.58 years). Measurements were performed at baseline and 48 h after surgery. ELISA, collagen-binding assays and Western blotting were used to estimate antigenic and biological activities, and proteolysis of VWF multimers. Preoperatively, VWF:Ag and ADAMTS-13 activity were decreased (65 and 71% of normal levels considered as 113 (105-129) U/dL and 91 ± 24% respectively, P < 0.003) and correlated (r = 0.39, P = 0.0064). High molecular weight VWF multimers were not related, suggesting an interaction of VWF with cell membranes, followed by proteolytic cleavage. A low preoperative ADAMTS-13 activity, a longer activated partial thromboplastin time and the need for cardiopulmonary bypass correlated with postoperative bleeding (P < 0.05). Postoperatively, ADAMTS-13 activity increased but less extensively than VWF:Ag (respectively, 2.23 and 2.83 times baseline, P < 0.0001), resulting in an increased VWF:Ag/ADAMTS-13 activity ratio (1.20 to 1.54, respectively, pre- and postoperative median values, P = 0.0029). ADAMTS-13 consumption was further confirmed by decreased ADAMTS-13 antigenic concentration (0.91 ± 0.30 to 0.70 ± 0.25 µg/mL, P < 0.0001) and persistent proteolysis of VWF multimers. We conclude that, in pediatric CCHD, changes in circulating ADAMTS-13 suggest enzyme consumption, associated with abnormal structure and function of VWF.

  16. Conventional rapid latex agglutination in estimation of von Willebrand factor: method revisited and potential clinical applications.

    Science.gov (United States)

    Mahat, Marianor; Abdullah, Wan Zaidah; Hussin, Che Maraina Che

    2014-01-01

    Measurement of von Willebrand factor antigen (VWF : Ag) levels is usually performed in a specialised laboratory which limits its application in routine clinical practice. So far, no commercial rapid test kit is available for VWF : Ag estimation. This paper discusses the technical aspect of latex agglutination method which was established to suit the purpose of estimating von Willebrand factor (VWF) levels in the plasma sample. The latex agglutination test can be performed qualitatively and semiquantitatively. Reproducibility, stability, linearity, limit of detection, interference, and method comparison studies were conducted to evaluate the performance of this test. Semiquantitative latex agglutination test was strongly correlated with the reference immunoturbidimetric assay (Spearman's rho = 0.946, P agglutination test and the reference assay. Using the scoring system for the rapid latex test, no agglutination is with 0% VWF : Ag (control negative), 1+ reaction is equivalent to 150% VWF : Ag (when comparing with immunoturbidimetric assay). The findings from evaluation studies suggest that latex agglutination method is suitable to be used as a rapid test kit for the estimation of VWF : Ag levels in various clinical conditions associated with high levels and low levels of VWF : Ag.

  17. Functional variation in the arginine vasopressin 2 receptor as a modifier of human plasma von Willebrand factor levels

    DEFF Research Database (Denmark)

    Nossent, Anne Yaël; Robben, J H; Deen, P M T

    2010-01-01

    SUMMARY OBJECTIVES: Stimulation of arginine vasopressin 2 receptor (V2R) with arginine vasopressin (AVP) results in a rise in von Willebrand factor (VWF) and factor VIII plasma levels. We hypothesized that gain-of-function variations in the V2R gene (AVPR2) would lead to higher plasma levels of V...

  18. Molecular characterization of exon 28 of von Willebrand's factor gene in Nigerian population.

    Science.gov (United States)

    Ezigbo, E D; Ukaejiofo, E O; Nwagha, T U

    2017-02-01

    Polymorphisms in von Willebrand factor (VWF) gene are an important contributor to the expression of VWF gene and differences in ethnic distribution of these single nucleotide polymorphisms (SNPs) exists. Our objective was to molecularly characterize the exon 28 of the VWF gene in the three major ethnic groups of Nigeria. We recruited 90 subjects, 45 had a history of bleeding. Questions included those used in the Zimmerman Program for the Molecular and Clinical Biology of von Willebrand disease (VWD), and the bleeding scores were calculated using the Molecular and Clinical Markers for the Diagnosis and Management of type 1 VWD scoring system. Full blood count, coagulation profile, VWF:antigen level and VWF:collagen-binding activities were carried out. Data were analyzed using GraphPad Prism (5.03). GraphPad Software, Inc USA. The BigDye terminator chemistry was used to determine the nucleotide sequences of VWF gene (exon 28). Eight SNPs were identified, rs 216310 (T1547), rs 1800385 (V1565L), rs1800384 (A1515), rs1800383 (D1472H), rs 1800386 (Y1584C), rs 216311 (T1381A), rs 216312 (intronic) and rs 1800381 (P1337). The SNPs rs 216311, rs 1800383 and rs 1800386 associated significantly with bleeding in study subjects. rs1800386 occurred in all with bleeding history, no ethnic variations were noted.

  19. Characterization of Zebrafish von Willebrand Factor Reveals Conservation of Domain Structure, Multimerization, and Intracellular Storage

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    Arunima Ghosh

    2012-01-01

    Full Text Available von Willebrand disease (VWD is the most common inherited human bleeding disorder and is caused by quantitative or qualitative defects in von Willebrand factor (VWF. VWF is a secreted glycoprotein that circulates as large multimers. While reduced VWF is associated with bleeding, elevations in overall level or multimer size are implicated in thrombosis. The zebrafish is a powerful genetic model in which the hemostatic system is well conserved with mammals. The ability of this organism to generate thousands of offspring and its optical transparency make it unique and complementary to mammalian models of hemostasis. Previously, partial clones of zebrafish vwf have been identified, and some functional conservation has been demonstrated. In this paper we clone the complete zebrafish vwf cDNA and show that there is conservation of domain structure. Recombinant zebrafish Vwf forms large multimers and pseudo-Weibel-Palade bodies (WPBs in cell culture. Larval expression is in the pharyngeal arches, yolk sac, and intestinal epithelium. These results provide a foundation for continued study of zebrafish Vwf that may further our understanding of the mechanisms of VWD.

  20. Storage of factor VIII variants with impaired von Willebrand factor binding in Weibel-Palade bodies in endothelial cells.

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    Maartje van den Biggelaar

    Full Text Available BACKGROUND: Point mutations resulting in reduced factor VIII (FVIII binding to von Willebrand factor (VWF are an important cause of mild/moderate hemophilia A. Treatment includes desmopressin infusion, which concomitantly increases VWF and FVIII plasma levels, apparently from storage pools containing both proteins. The source of these VWF/FVIII co-storage pools and the mechanism of granule biogenesis are not fully understood. METHODOLOGY/PRINCIPAL FINDINGS: We studied intracellular trafficking of FVIII variants implicated in mild/moderate hemophilia A together with VWF in HEK293 cells and primary endothelial cells. The role of VWF binding was addressed using FVIII variants displaying reduced VWF interaction. Binding studies using purified FVIII proteins revealed moderate (Arg2150His, Del2201, Pro2300Ser to severe (Tyr1680Phe, Ser2119Tyr VWF binding defects. Expression studies in HEK293 cells and primary endothelial cells revealed that all FVIII variants were present within VWF-containing organelles. Quantitative studies showed that the relative amount of FVIII storage was independent of various mutations. Substantial amounts of FVIII variants are co-stored in VWF-containing storage organelles, presumably by virtue of their ability to interact with VWF at low pH. CONCLUSIONS: Our data suggest that the potential of FVIII co-storage with VWF is not affected in mild/moderate hemophilia A caused by reduced FVIII/VWF interaction in the circulation. These data support the hypothesis that Weibel-Palade bodies comprise the desmopressin-releasable FVIII storage pool in vivo.

  1. Von Willebrand factor availability in platelet concentrates stored for 5 days.

    Science.gov (United States)

    Cesar, J M; García-Avello, A; Monteagudo, J; Espinosa, J I; Lodos, J C; Castillo, R; Navarro, J L

    1994-02-01

    Von Willebrand factor (vWF) availability was assessed in platelet concentrates (PCs). After 5 days of storage, 82 +/- 9% of basal levels of ristocetin cofactor activity (vWF:RCo) remained in PCs. vWF antigen (vWF:Ag) increased up to 166 +/- 38% (P < 0.05) in the same period. Autoradiograph pattern of vW:Ag showed an increase in low molecular weight multimers, and fast migrating multimeric forms were visualized by crossed immunoelectrophoresis on day 5. Studies carried out in platelet free plasma stored as PCs showed similar changes in vWF:RCo but increments in vWF:Ag were not detected. These data indicate that PCs maintain vWF:RCo levels of clinical value even after 5 days of storage and suggest that vWF comes out from platelets to plasma during storage.

  2. Novel antiplatelet agents: ALX-0081, a Nanobody directed towards von Willebrand factor.

    Science.gov (United States)

    Bartunek, Jozef; Barbato, Emanuele; Heyndrickx, Guy; Vanderheyden, Marc; Wijns, William; Holz, Josefin-Beate

    2013-06-01

    This manuscript reviews the studies performed with ALX-0081 (INN: caplacizumab), a Nanobody targeting von Willebrand factor, in the context of current antithrombotic therapy in coronary artery disease. ALX-0081 specifically inhibits platelet adhesion to the vessel wall, and may control platelet aggregation and subsequent clot formation without increasing bleeding risk. A substantial number of antithrombotics are aimed at this cascade; however, their generally indiscriminative mode of action can result in a narrow therapeutic window, defined by the risk for bleeding complications, and thrombotic events. Nonclinically, ALX-0081 compared favorably to several antithrombotics. In Phase I studies in healthy subjects and stable angina patients undergoing percutaneous coronary intervention (PCI), ALX-0081 was well tolerated, and effectively inhibited pharmacodynamic markers. Following these results, a phase II study was initiated in high-risk acute coronary syndrome patients undergoing PCI. Based on its mechanism of action, ALX-0081 is also being developed for acquired thrombotic thrombocytopenic purpura.

  3. A comparative evaluation of a new automated assay for von Willebrand factor activity.

    Science.gov (United States)

    Lawrie, A S; Stufano, F; Canciani, M T; Mackie, I J; Machin, S J; Peyvandi, F

    2013-03-01

    The ristocetin cofactor assay (VWF:RCo) is the reference method for assessing von Willebrand factor (VWF) activity in the diagnosis of von Willebrand's Disease (VWD). However, the assay suffers from poor reproducibility and sensitivity at low levels of VWF and is labour intensive. We have undertaken an evaluation of a new immunoturbidimetric VWF activity (VWF:Ac) assay (INNOVANCE(®) VWF Ac. Siemens Healthcare Diagnostics, Marburg, Germany) relative to an established platelet-based VWF:RCo method. Samples from 50 healthy normal subjects, 80 patients with VWD and 50 samples that exhibited 'HIL' (i.e. Haemolysis, Icterus or Lipaemia) were studied. VWF:Ac, VWF:RCo and VWF:Ag were performed on a CS-analyser (Sysmex UK Ltd, Milton Keynes, UK), all reagents were from Siemens Healthcare Diagnostics. The VWF:Ac assay, gave low intra- and inter-assay imprecision (over a 31-day period, n = 200 replicate readings) using commercial normal (Mean 96.2 IU dL(-1), CV < 3.0%) and pathological (Mean 36.1 IU dL(-1), CV < 3.5%) control plasmas. The normal and clinical samples exhibited good correlation between VWF:RCo (range 3-753 IU dL(-1)) and VWF:Ac (rs = 0.97, P < 0.0001), with a mean bias of 5.6 IU dL(-1). Ratios of VWF:Ac and VWF:RCo to VWF:Ag in the VWD samples were comparable, although VWF:Ac had a superior lower level of detection to that of VWF:RCo (3% and 5% respectively). A subset (n = 97) of VWD and HIL samples were analysed for VWF:Ac at two different dilutions to assess the effect on relative potency, no significant difference was observed (P = 0.111). The INNOVANCE(®) VWF Ac assay was shown to be reliable and precise. © 2012 Blackwell Publishing Ltd.

  4. PROTEOLYTIC PROCESSING OF VON WILLEBRAND FACTOR BY ADAMTS13 AND LEUKOCYTE PROTEASES

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    Stefano Lancellotti

    2013-09-01

    Full Text Available ADAMTS13 is a 190 kDa zinc protease encoded by a gene located on chromosome 9q34.   This protease specifically hydrolyzes von Willebrand factor (VWF multimers, thus causing VWF size reduction. ADAMTS13 belongs to the A Disintegrin And Metalloprotease with ThromboSpondin type 1 repeats (ADAMTS family, involved in proteolytic processing of many matrix proteins. ADAMTS13 consists of numerous domains including a metalloprotease domain, a disintegrin domain, several thrombospondin type 1 (TSP1 repeats, a cysteine-rich domain, a spacer domain and 2 CUB (Complement c1r/c1s, sea Urchin epidermal growth factor, and Bone morphogenetic protein domains. ADAMTS13 cleaves a single peptide bond (Tyr1605-Met1606 in the central A2 domain of the VWF molecule. This proteolytic cleavage is essential to reduce the size of ultra-large VWF polymers, which, when exposed to high shear stress in the microcirculation, are prone to form with platelets clumps, which cause severe syndromes called thrombotic microangiopathies (TMAs. In this review, we a discuss the current knowledge of structure-function aspects of ADAMTS13 and its involvement in the pathogenesis of TMAs, b address the recent findings concerning proteolytic processing of VWF multimers by different proteases, such as the leukocyte-derived serine and metallo-proteases and c indicate the direction of future investigations

  5. The membrane-proximal intermolecular disulfide bonds in glycoprotein Ib influence receptor binding to von Willebrand factor.

    Science.gov (United States)

    Mo, X; Luo, S-Z; Munday, A D; Sun, W; Berndt, M C; López, J A; Dong, J-F; Li, R

    2008-10-01

    In the platelet glycoprotein (GP)Ib-IX complex, the binding site for its ligand von Willebrand factor (VWF) is restricted to the N-terminal domain of the GPIbalpha subunit. How the other subunits in the complex, GPIbbeta and GPIX, regulate the GPIbalpha-VWF interaction is not clear. As GPIbalpha connects with two GPIbbeta subunits via disulfide bonds, we tested whether these intersubunit covalent links were important to the proper VWF-binding activity of the GPIb-IX complex by characterizing the structure and VWF-binding activity of a mutant GPIb-IX complex that lacked the GPIbalpha-GPIbbeta disulfide bonds. Mutating both Cys484 and Cys485 of GPIbalpha to serine prevents GPIbalpha from forming covalent disulfide bonds with GPIbbeta, while maintaining the integrity of the complex in the membrane. The mutations cause two GPIbbeta subunits to form a disulfide bond between themselves. As compared to Chinese hamster ovary (CHO) cells stably expressing the wild-type GPIb-IX complex at a comparable level, CHO cells stably expressing the mutant GPIb-IX complex bind to significantly less soluble VWF in the presence of ristocetin and roll on the immobilized VWF under flow at a higher velocity. The disulfide bonds between GPIbalpha and GPIbbeta are necessary for optimal GPIbalpha binding to VWF. The structural plasticity around the disulfide bonds may also help to shed light on the inside-out mechanism underlying GPIbbeta modulation of VWF binding.

  6. Space and Time Resolved Detection of Platelet Activation and von Willebrand Factor Conformational Changes in Deep Suspensions.

    Science.gov (United States)

    Biasetti, Jacopo; Sampath, Kaushik; Cortez, Angel; Azhir, Alaleh; Gilad, Assaf A; Kickler, Thomas S; Obser, Tobias; Ruggeri, Zaverio M; Katz, Joseph

    2017-01-01

    Tracking cells and proteins' phenotypic changes in deep suspensions is critical for the direct imaging of blood-related phenomena in in vitro replica of cardiovascular systems and blood-handling devices. This paper introduces fluorescence imaging techniques for space and time resolved detection of platelet activation, von Willebrand factor (VWF) conformational changes, and VWF-platelet interaction in deep suspensions. Labeled VWF, platelets, and VWF-platelet strands are suspended in deep cuvettes, illuminated, and imaged with a high-sensitivity EM-CCD camera, allowing detection using an exposure time of 1 ms. In-house postprocessing algorithms identify and track the moving signals. Recombinant VWF-eGFP (rVWF-eGFP) and VWF labeled with an FITC-conjugated polyclonal antibody are employed. Anti-P-Selectin FITC-conjugated antibodies and the calcium-sensitive probe Indo-1 are used to detect activated platelets. A positive correlation between the mean number of platelets detected per image and the percentage of activated platelets determined through flow cytometry is obtained, validating the technique. An increase in the number of rVWF-eGFP signals upon exposure to shear stress demonstrates the technique's ability to detect breakup of self-aggregates. VWF globular and unfolded conformations and self-aggregation are also observed. The ability to track the size and shape of VWF-platelet strands in space and time provides means to detect pro- and antithrombotic processes.

  7. von Willebrand Factor and Oxidative Stress Parameters in Acute Coronary Syndromes

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    Zoran Koprivica

    2011-01-01

    Full Text Available Considering the role of von Willebrand factor (vWf in hemostasis, and the role of oxidative stress in the development of endothelial dysfunction and atherosclerotic disease, the aim of our study was to investigate the relationship between vWf, parameters of oxidative stress and different types of acute coronary syndromes (ACS. Levels of vWf activity (vWfAct, vWf antigen (vWfAg, nitric oxide (estimated through nitrites–NO2 −, superoxide anion radical (O2 −, hydrogen peroxide (H2O2, index of lipid peroxidation (estimated through thiobarbituric acid reactive substances–TBARS, superoxide dismutase (SOD and catalase (CAT activity of 115 patients were compared with those of 40 healthy controls. ACS patients had significantly higher vWfAct and vWfAg levels, as well as TBARS levels, while their levels of NO2 −, H2O2, SOD and CAT activities were lower than controls'. vWfAg showed high specificity and sensitivity as a test to reveal healthy or diseased subjects. Multivariant logistic regression marked only vWfAg and TBARS as parameters that were under independent effect of ACS type. The results of our study support the implementation of vWf in clinical rutine and into therapeutic targets, and suggest that ACS patients are in need of antioxidant supplementation to improve their impaired antioxidant defence.

  8. Secretion of von Willebrand factor by endothelial cells links sodium to hypercoagulability and thrombosis.

    Science.gov (United States)

    Dmitrieva, Natalia I; Burg, Maurice B

    2014-04-29

    Hypercoagulability increases risk of thrombi that cause cardiovascular events. Here we identify plasma sodium concentration as a factor that modulates blood coagulability by affecting the production of von Willebrand factor (vWF), a key initiator of the clotting cascade. We find that elevation of salt over a range from the lower end of what is normal in blood to the level of severe hypernatremia reversibly increases vWF mRNA in endothelial cells in culture and the rate of vWF secretion from them. The high NaCl increases expression of tonicity-regulated transcription factor NFAT5 and its binding to promoter of vWF gene, suggesting involvement of hypertonic signaling in vWF up-regulation. To elevate NaCl in vivo, we modeled mild dehydration, subjecting mice to water restriction (WR) by feeding them with gel food containing 30% water. Such WR elevates blood sodium from 145.1 ± 0.5 to 150.2 ± 1.3 mmol/L and activates hypertonic signaling, evidenced from increased expression of NFAT5 in tissues. WR increases vWF mRNA in liver and lung and raises vWF protein in blood. Immunostaining of liver revealed increased production of vWF protein by endothelium and increased number of microthrombi inside capillaries. WR also increases blood level of D-dimer, indicative of ongoing coagulation and thrombolysis. Multivariate regression analysis of clinical data from the Atherosclerosis Risk in Communities Study demonstrated that serum sodium significantly contributes to prediction of plasma vWF and risk of stroke. The results indicate that elevation of extracellular sodium within the physiological range raises vWF sufficiently to increase coagulability and risk of thrombosis.

  9. Complex changes in von Willebrand factor-associated parameters are acquired during uncomplicated pregnancy.

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    Danielle N Drury-Stewart

    Full Text Available The coagulation protein von Willebrand Factor (VWF is known to be elevated in pregnancy. However, the timing and nature of changes in VWF and associated parameters throughout pregnancy are not well understood.To better understand the changes in VWF provoked by pregnancy, we studied VWF-associated parameters in samples collected over the course of healthy pregnancies.We measured VWF antigen (VWF:Ag, VWF propeptide (VWFpp, Factor VIII (FVIII, and ADAMTS13 activity in samples collected from 46 women during pregnancy and at non-pregnant baseline. We also characterized pregnant vs. non-pregnant VWF multimer structure in 21 pregnancies, and performed isoelectric focusing (IEF of VWF in two pregnancies which had samples from multiple trimesters.VWF:Ag and FVIII levels were significantly increased during pregnancy. ADAMTS13 activity was unchanged. VWFpp levels increased much later in pregnancy than VWF:Ag, resulting in a progressive decrease in VWFpp:Ag ratios. FVIII:VWF ratios also decreased in pregnancy. Most pregnancies exhibited a clear loss of larger VWF multimers and altered VWF triplet structure. Further evidence of acquired VWF qualitative changes in pregnancy was found in progressive, reversible shifts in VWF IEF patterns over gestation.These data support a new view of pregnancy in which VWF can acquire qualitative changes associated with advancing gestational age. Modeling supports a scenario in which both increased VWF production and doubling of the VWF half-life would account for the data observed. We propose that gestation induces a prolongation in VWF survival, which likely contributes to increased total VWF levels and altered VWF structure.

  10. Plasmatic ADAMTS-13 metalloprotease and von Willebrand factor in children with cyanotic congenital heart disease.

    Science.gov (United States)

    Soares, R P S; Bydlowski, S P; Nascimento, N M; Thomaz, A M; Bastos, E N M; Lopes, A A

    2013-04-01

    Changes in plasma von Willebrand factor concentration (VWF:Ag) and ADAMTS-13 activity (the metalloprotease that cleaves VWF physiologically) have been reported in several cardiovascular disorders with prognostic implications. We therefore determined the level of these proteins in the plasma of children with cyanotic congenital heart disease (CCHD) undergoing surgical treatment. Forty-eight children were enrolled (age 0.83 to 7.58 years). Measurements were performed at baseline and 48 h after surgery. ELISA, collagen-binding assays and Western blotting were used to estimate antigenic and biological activities, and proteolysis of VWF multimers. Preoperatively, VWF:Ag and ADAMTS-13 activity were decreased (65 and 71% of normal levels considered as 113 (105-129) U/dL and 91 ± 24% respectively, P membranes, followed by proteolytic cleavage. A low preoperative ADAMTS-13 activity, a longer activated partial thromboplastin time and the need for cardiopulmonary bypass correlated with postoperative bleeding (P < 0.05). Postoperatively, ADAMTS-13 activity increased but less extensively than VWF:Ag (respectively, 2.23 and 2.83 times baseline, P < 0.0001), resulting in an increased VWF:Ag/ADAMTS-13 activity ratio (1.20 to 1.54, respectively, pre- and postoperative median values, P = 0.0029). ADAMTS-13 consumption was further confirmed by decreased ADAMTS-13 antigenic concentration (0.91 ± 0.30 to 0.70 ± 0.25 µg/mL, P < 0.0001) and persistent proteolysis of VWF multimers. We conclude that, in pediatric CCHD, changes in circulating ADAMTS-13 suggest enzyme consumption, associated with abnormal structure and function of VWF.

  11. Allelic associations of two polymorphic microsatellites in intron 40 of the human von Willebrand factor gene

    Energy Technology Data Exchange (ETDEWEB)

    Pena, S.D.J.; De Souza, K.T. (Nucleo de Genetica Medica de Minas Gerais, Belo Horizonte (Brazil)); De Andrade, M.; Chakraborty, R. (Univ. of Texas Graduate School of Biomedical Sciences, Houston, TX (United States))

    1994-01-18

    At intron 40 of the von Willebrand factor (vWF) gene, two GATA-repeat polymorphic sites exist that are physically separated by 212 bp. At the first site (vWF1 locus), seven segregating repeat alleles were observed in a Brazilian Caucasian population, and at the second (vWF2 locus) there were eight alleles, detected through PCR amplifications of this DNA region. Haplotype analysis of individuals revealed 36 different haplotypes in a sample of 338 chromosomes examined. Allele frequencies between generations and gender at each locus were not significantly different, and the genotype frequencies were consistent with their Hardy-Weinberg expectations. Linkage disequilibrium between loci is highly significant with positive allele size association; that is, large alleles at the loci tend to occur together, and so do the same alleles. Variability at each locus appeared to have arisen in a stepwise fashion, suggesting replication slippage as a possible mechanism of production of new alleles. However, the authors observed an increased number of haplotypes, in contrast with the predictions of a stepwise production of variation in the entire region, suggesting some form of cooperative changes between loci that could be due to either gene conversion, or a common control mechanism of production of new variation at these repeat polymorphism sites. The high degree of polymorphism (gene diversity values of 72% and 78% at vWF1 and vWF2, respectively, and of 93% at the haplotype level) makes these markers informative for paternity testing, genetic counseling, and individual-identification purposes.

  12. von Willebrand factor deficiency leads to impaired blood flow recovery after ischaemia in mice.

    Science.gov (United States)

    de Vries, Margreet R; Peters, Erna A B; Quax, Paul H A; Nossent, A Yaël

    2017-06-28

    Neovascularisation, i. e. arteriogenesis and angiogenesis, is an inflammatory process. Therefore attraction and extravasation of leukocytes is essential for effective blood flow recovery after ischaemia. Previous studies have shown that von Willebrand factor (VWF) is a negative regulator of angiogenesis. However, it has also been shown that VWF facilitates leukocyte attraction and extravasation. We aimed to investigate the role of VWF in arteriogenesis and angiogenesis during post-ischaemic neovascularisation. Wild-type (WT) and VWF deficient (VWF -/- ) C57BL/6 mice were subjected to hindlimb ischaemia via double ligation of the left femoral artery, and blood flow recovery was followed over time, using Laser Doppler Perfusion Imaging. Blood flow recovery was impaired in VWF -/- mice. After 10 days, VWF -/- mice showed a 43 ± 5 % recovery versus 68 ± 5 % in WT. Immunohistochemistry revealed that both arteriogenesis in the adductor muscles and angiogenesis in the gastrocnemius muscles were reduced in VWF -/- mice. Furthermore, leukocyte infiltration in the affected adductor muscles was reduced in VWF -/- mice. Residual paw perfusion directly after artery ligation was also reduced in VWF -/- mice, indicating a decrease in pre-existing collateral arteriole density. When we quantified collateral arterioles, we observed a 31 % decrease in the average number of collateral arterioles in the pia mater compared to WT mice (57 ± 3 in WT vs 40 ± 4 pial collaterals in VWF -/- ). We conclude that VWF facilitates blood flow recovery in mice. VWF deficiency hampers both arteriogenesis and angiogenesis in a hindlimb ischaemia model. This is associated with impaired leukocytes recruitment and decreased pre-existing collateral density in the absence of VWF.

  13. Increased deposition of von Willebrand factor in the rat heart after local ionizing irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Boerma, M.; Loenen, M.M. van; Klein, H.R.; Bart, C.I.; Wondergem, J. [Dept. of Clinical Oncology (K1-P), Leiden Univ. Medical Center (Netherlands); Kruse, J.J.C.M. [Dept. of Clinical Oncology (K1-P), Leiden Univ. Medical Center (Netherlands); Dept. of Experimental Therapy (H6), Netherlands Cancer Inst., Amsterdam (Netherlands); Zurcher, C. [Dept. of Clinical Oncology (K1-P), Leiden Univ. Medical Center (Netherlands); Dept. of Pathology, Faculty of Veterinary Medicine, Univ. of Utrecht (Netherlands)

    2004-02-01

    Background and purpose: von willebrand factor (vWf), a glycoprotein involved in blood coagulation, is synthesized by endothelial cells. Increased amounts of vWf in blood plasma or tissue samples are indicative of damaged endothelium. In the present study, mRNA expression and localization of vWf were determined in irradiated rat heart tissue. Material and methods: sprague-dawley rats received local heart irradiation with a single dose of 0, 15, or 20 Gy. Hearts were dissected at different time points (up to 16 months) after irradiation. In a second experiment, rats were injected with the radioprotector amifostine (160 mg/kg, i.p.) 15-20 min before irradiation and sacrificed after 6 months. Immunohistochemistry was performed using a polyclonal anti-vWf antibody. Serial sections were subjected to a general rat endothelial cell immunostaining (RECA-1) or a collagen staining (picrosirius red). mRNA expression was determined by using PCR. Results: in control tissue, all endothelial cells lining the lumen of the endocardium and coronary arteries, but not capillary endothelial cells, were stained for vWf. 1 month after irradiation with both 15 and 20 Gy, myocardial capillaries became immunoreactive. From 3 months onward, staining was observed also within the extracellular matrix (ECM) of fibrotic areas. At mRNA level, no changes in vWf could be observed at all time points after irradiation, suggesting that vWf deposition was not due to increased biosynthesis of the protein. In sections of amifostine-treated rat hearts, vWf staining was increased to a lesser extent. Conclusion: these dose- and time-dependent increases in deposition of vWf indicate the presence of damaged endothelium in the irradiated rat heart. These increases in vWf accumulation precede development of fibrosis in the subendocardial layer and myocardium of the left ventricles, right ventricles, and atria. (orig.)

  14. In vivo analysis of the role of O-glycosylations of von Willebrand factor.

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    Idinath Badirou

    Full Text Available The objective of this project was to study the function of O-glycosylations in von Willebrand factor (VWF life cycle. In total, 14 different murine Vwf cDNAs mutated on one or several O-glycosylations sites were generated: 9 individual mutants, 2 doublets, 2 clusters and 1 mutant with all 9 murine glycosylation sites mutated (Del-O-Gly. We expressed each mutated cDNA in VWF deficient-mice by hydrodynamic injection. An immunosorbent assay with Peanut Agglutinin (PNA was used to verify the O-glycosylation status. Wild-type (WT VWF expressed by hepatocytes after hydrodynamic injection was able to bind PNA with slightly higher affinity than endothelial-derived VWF. In contrast, the Del-O-Gly VWF mutant did not bind PNA, demonstrating removal of O-linked glycans. All mutants displayed a normal multimeric pattern. Two mutants, Del-O-Gly and T1255A/T1256A, led to expression levels 50% lower than those induced by WT VWF and their half-life in vivo was significantly reduced. When testing the capacity of each mutant to correct the bleeding time of VWF-deficient mice, we found that S1486A, T1255A, T1256A and the doublet T1255A/T1256A were unable to do so. In conclusion we have shown that O-glycosylations are dispensable for normal VWF multimerization and biosynthesis. It also appears that some O-glycosylation sites, particularly the T1255 and T1256 residues, are involved in the maintenance of VWF plasma levels and are essential for normal haemostasis. As for the S1486 residue, it seems to be important for platelet binding as demonstrated in vitro using perfusion experiments.

  15. Genome-wide linkage analysis of von Willebrand factor plasma levels: results from the GAIT project.

    Science.gov (United States)

    Souto, Juan Carlos; Almasy, Laura; Soria, Jose Manuel; Buil, Alfonso; Stone, William; Lathrop, Mark; Blangero, John; Fontcuberta, Jordi

    2003-03-01

    High plasma levels of von Willebrand factor (vWF) have been associated with the risk of thromboembolic disease. As a complex trait, this phenotype must be influenced by genetic and environmental factors. Among the genetic factors, only the ABO gene located on chromosome 9q34 has been clearly linked to the plasma levels of vWF. This locus explains about 30-40% of the genetic variability. Therefore, the source of the majority of the genetic component remains to be identified. To search for these unknown loci, we conducted a genomewide linkage screen for genes affecting normal variation in vWF levels in 21 Spanish families as part of the GAIT (Genetic Analysis of Idiopathic Thrombophilia) Project. The results showed that the strongest linkage signal (LOD =3.46, p = 0.00003) for vWF was found on chromosome 9q34 at the DNA marker D9S290, where the ABO gene is located. Additional suggestive linkage signals were found on chromosomes 2q23.2 (LOD = 1.65, p = 0.003) and 1p36.13 (LOD =1.32, p = 0.007). After refining the linkage analysis, conditional to the ABO genotype, three additional loci on chromosomes 5, 6 and 22 showed LOD scores higher than 1, suggesting the presence of other genes linked to vWF levels. Curiously, no linkage signals were detected in other chromosome regions previously associated with vWF levels (like the structural VWF gene on 12p13.2 or Lewis blood group gene on 19q13). These results indicate that these loci are not important genetic determinants of the normal variation of vWF levels. Our results indicate that the ABO locus is the major genetic determinant of the plasma levels of the vWF in Spanish population. It is possible that there are other potential regions on chromosomes 1, 2, 5, 6 and 22 that influence this thrombosis risk factor. However, the structural vWF gene itself has a very low influence (if any) on the plasma levels of vWF.

  16. A model for the conformational activation of the structurally quiescent metalloprotease ADAMTS13 by von willebrand factor

    Science.gov (United States)

    South, Kieron; Freitas, Marta O.; Lane, David A.

    2017-01-01

    Blood loss is prevented by the multidomain glycoprotein von Willebrand factor (VWF), which binds exposed collagen at damaged vessels and captures platelets. VWF is regulated by the metalloprotease ADAMTS13, which in turn is conformationally activated by VWF. To delineate the structural requirements for VWF-mediated conformational activation of ADAMTS13, we performed binding and functional studies with a panel of truncated ADAMTS13 variants. We demonstrate that both the isolated CUB1 and CUB2 domains in ADAMTS13 bind to the spacer domain exosite of a truncated ADAMTS13 variant, MDTCS (KD of 135 ± 1 0.1 nm and 86.9 ± 9.0 nm, respectively). However, only the CUB1 domain inhibited proteolytic activity of MDTCS. Moreover, ADAMTS13ΔCUB2, unlike ADAMTS13ΔCUB1-2, exhibited activity similar to wild-type ADAMTS13 and could be activated by VWF D4-CK. The CUB2 domain is, therefore, not essential for maintaining the inactive conformation of ADAMTS13. Both CUB domains could bind to the VWF D4-CK domain fragment (KD of 53.7 ± 2.1 nm and 84.3 ± 2.0 nm, respectively). However, deletion of both CUB domains did not prevent VWF D4-CK binding, suggesting that competition for CUB-domain binding to the spacer domain is not the dominant mechanism behind the conformational activation. ADAMTS13ΔTSP8-CUB2 could no longer bind to VWF D4-CK, and deletion of TSP8 abrogated ADAMTS13 conformational activation. These findings support an ADAMTS13 activation model in which VWF D4-CK engages the TSP8-CUB2 domains, inducing the conformational change that disrupts the CUB1-spacer domain interaction and thereby activates ADAMTS13. PMID:28209710

  17. Comparative analysis of von Willebrand factor profiles after implantation of left ventricular assist device and total artificial heart.

    Science.gov (United States)

    Reich, H J; Morgan, J; Arabia, F; Czer, L; Moriguchi, J; Ramzy, D; Esmailian, F; Lam, L; Dunhill, J; Volod, O

    2017-08-01

    Essentials Bleeding is a major source of morbidity during mechanical circulatory support. von Willebrand factor (VWF) multimer loss may contribute to bleeding. Different patterns of VWF multimer loss were seen with the two device types. This is the first report of total artificial heart associated VWF multimer loss. Background Bleeding remains a challenge during mechanical circulatory support and underlying mechanisms are incompletely understood. Functional von Willebrand factor (VWF) impairment because of loss of high-molecular-weight multimers (MWMs) produces acquired von Willebrand disease (VWD) after left ventricular assist device (LVAD). Little is known about VWF multimers with total artificial hearts (TAHs). Here, VWF profiles with LVADs and TAHs are compared using a VWD panel. Methods VWD evaluations for patients with LVAD or TAH (2013-14) were retrospectively analyzed and included: VWF activity (ristocetin cofactor, VWF:RCo), VWF antigen (VWF:Ag), ratio of VWF:RCo to VWF:Ag, and quantitative VWF multimeric analysis. Results Twelve patients with LVADs and 12 with TAHs underwent VWD evaluation. All had either normal (47.8%) or elevated (52.2%) VWF:RCo, normal (26.1%) or elevated (73.9%) VWF:Ag and 50.0% were disproportional (ratio ≤ 0.7). Multimeric analysis showed abnormal patterns in all patients with LVADs: seven with high MWM loss; five with highest MWM loss. With TAH, 10/12 patients had abnormal patterns: all with highest MWM loss. High MWM loss correlated with presence of LVAD and highest MWM loss with TAH. Increased low MWMs were detected in 22/24. Conclusion Using VWF multimeric analysis, abnormalities after LVAD or TAH were detected that would be missed with measurements of VWF level alone: loss of high MWM predominantly in LVAD, loss of highest MWM in TAH, and elevated levels of low MWM in both. This is the first study to describe TAH-associated highest MWM loss, which may contribute to bleeding. © 2017 International Society on Thrombosis and

  18. Alterations in hemostatic parameters during hemodialysis with dialyzers of different membrane composition and flow design. Platelet activation and factor VIII-related von Willebrand factor during hemodialysis.

    Science.gov (United States)

    Schmitt, G W; Moake, J L; Rudy, C K; Vicks, S L; Hamburger, R J

    1987-09-01

    The effect of dialyzer membrane and design on hemostatic parameters during hemodialysis were evaluated in a prospective controlled study. This study demonstrated that hemodialysis is associated with significant platelet activation and loss, which are influenced by both dialyzer configuration and membrane composition. In addition, use of the cuprophan membrane is associated with greater perturbations of the vascular endothelium, as reflected in changes in factor VIII-related von Willebrand factor and 6-keto-prostaglandin F1 alpha concentrations not seen with the polyacrylonitrile membrane. Of the dialyzers studied, the polyacrylonitrile membrane in a hollow-fiber configuration appears to minimize platelet loss and activation, and to minimize increases in factor VIII-related von Willebrand factor and 6-keto-prostaglandin F1 alpha.

  19. Insights into the mechanism(s) of von Willebrand factor degradation during mechanical circulatory support.

    Science.gov (United States)

    Bartoli, Carlo R; Dassanayaka, Sujith; Brittian, Kenneth R; Luckett, Andrew; Sithu, Srinivas; Siess, Thorsten; Raess, Daniel H; Spence, Paul A; Koenig, Steven C; Dowling, Robert D; D'Souza, Stanley E

    2014-05-01

    Left ventricular assist device support produces a bleeding diathesis. Evidence suggests a major role for von Willebrand factor (vWF). We examined vWF metabolism in a preclinical model of short-term mechanical circulatory support. In 25 calves (weight, 80-110 kg), the inflow/outflow graft of the Symphony Heart Assist System was sewn end-to-side to the carotid artery. Support was initiated (acute, n = 4; 1 week, n = 16; 2 weeks, n = 5). Acutely, carotid artery pressure and flow were measured to evaluate the hemodynamic changes near the anastomosis. At baseline and after ≤2 weeks of support, platelet aggregometry with adenosine 5'-diphosphate, collagen, and ristocetin was performed. Gel electrophoresis and wet immunoblotting qualitatively evaluated vWF multimers and quantified plasma ADAMTS-13, the vWF-cleaving protease. Carotid arterial rings near the anastomosis were studied with immunohistochemical staining for ADAMTS-13 and were cultured to quantify endothelial ADAMTS-13 production. Fluorescent resonance energy transfer was used to evaluate the enzymatic activity of ADAMTS-13 in the plasma and in supernatant from cultured carotid arterial rings. Plasma interleukin-6, which inhibits ADAMTS-13 activity, was measured using an enzyme-linked immunosorbent assay. During support, statistically significant (P < .05) changes in the carotid endothelium arterial hemodynamics were observed. The highest molecular weight vWF multimers were absent, and the vWF-ristocetin platelet aggregation pathway was significantly impaired. A modest but significant increase in plasma ADAMTS-13 protein and activity was observed. ADAMTS-13 decreased significantly in the carotid near the anastomosis but increased significantly in supernatant from cultured carotid arterial rings. The plasma interleukin-6 levels did not change significantly. Hemodynamic activation of vWF and increased plasma ADAMTS-13 activity may have reduced high-molecular-weight vWF multimers and thereby impaired the

  20. Homocisteína plasmática total e fator von Willebrand no diabete melito experimental Total plasmatic homocysteine and von Willebrand factor in experimental diabetes mellitus

    OpenAIRE

    Renato Delascio Lopes; Lindalva Batista Neves; Vânia D'Almeida; Gleice Margarete de Souza Conceição; Alexandre Gabriel Junior

    2007-01-01

    OBJETIVOS: Determinar os valores plasmáticos de homocisteína e fator von Willebrand, como marcador de disfunção endotelial, em ratos com diabete melito induzido por estreptozotocina. MÉTODOS: Trinta e cinco ratos (rattus norvegicus albinus), machos, adultos (180-200 g), randomizados em três grupos: controle (n=10) não receberam agente ou veículo; sham (n=10) receberam solução veículo da estreptozotocina; e diabético (n=15) receberam estreptozotocina. Após oito semanas de indução do diabete me...

  1. Structural specializations of A2, a force-sensing domain in the ultralarge vascular protein von Willebrand factor

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Qing; Zhou, Yan-Feng; Zhang, Cheng-Zhong; Zhang, Xiaohui; Lu, Chafen; Springer, Timothy A.; Harvard-Med

    2009-06-30

    The lengths of von Willebrand factor (VWF) concatamers correlate with hemostatic potency. After secretion in plasma, length is regulated by hydrodynamic shear force-dependent unfolding of the A2 domain, which is then cleaved by a specific protease. The 1.9-{angstrom} crystal structure of the A2 domain demonstrates evolutionary adaptations to this shear sensor function. Unique among VWF A (VWA) domains, A2 contains a loop in place of the {alpha}4 helix, and a cis-proline. The central {beta}4-strand is poorly packed, with multiple side-chain rotamers. The Tyr-Met cleavage site is buried in the {beta}4-strand in the central hydrophobic core, and the Tyr structurally links to the C-terminal {alpha}6-helix. The {alpha}6-helix ends in 2 Cys residues that are linked by an unusual vicinal disulfide bond that is buried in a hydrophobic pocket. These features may narrow the force range over which unfolding occurs and may also slow refolding. Von Willebrand disease mutations, which presumably lower the force at which A2 unfolds, are illuminated by the structure.

  2. Cerebral venous thrombosis and plasma concentrations of factor VIII and von Willebrand factor: a case control study.

    Science.gov (United States)

    Bugnicourt, Jean-Marc; Roussel, Bertrand; Tramier, Blaise; Lamy, Chantal; Godefroy, Olivier

    2007-07-01

    High plasma concentrations of factor VIII (FVIII) and von Willebrand factor (VWF) have been recently associated with a moderately increased risk of venous thrombosis, but their roles in cerebral sinus and venous thrombosis (CSVT) have not been addressed. To determine whether elevation of FVIII and VWF is more frequent in CSVT, we analysed plasma levels of FVIII and VWF in a case control study. The study population consisted of 25 consecutive patients (of whom nine were excluded) admitted for CSVT to the Department of Neurology, Amiens University Hospital, France, from January 1997 to December 2002, for a general screening for thrombophilia. Sixty-four healthy subjects matched for age and sex formed the group control. Mean FVIII (CSVT: 167.3 (SD 48.8) IU/dl; control group: 117.9 (39.8) IU/dl; p = 0.001) and VWF levels (CSVT: 165.4 (76.5)%; control group: 108.5 (27.8)%; p = 0.01) were significantly higher in the CSVT group. Using the 95th percentile of the control group as the cut off value, elevated FVIII (>190 IU/dl) occurred in 25% (4/16) (p = 0.005) and elevated VWF (>168%) in 37.5% (6/16) of patients with CSVT (p150 IU/dl or >150%) showed the same results (FVIII: p = 0.005; VWF: p = 0.009). Our study suggests that elevation of plasma factor VIII levels is the most common prothrombotic risk factor for CSVT. Elevation of VWF is also associated with an increased risk of CSVT but its effect seems to be partly mediated through FVIII.

  3. ADAMTS13 deficiency with elevated levels of ultra-large and active von Willebrand factor in P. falciparum and P. vivax malaria.

    NARCIS (Netherlands)

    Mast, Q. de; Groot, E. de; Asih, P.B.; Syafruddin, D.; Oosting, M.; Sebastian, S.; Ferwerda, B.; Netea, M.G.; Groot, P.G. de; Ven, A.J.A.M. van der; Fijnheer, R.

    2009-01-01

    A deficiency in ADAMTS13 (a von Willebrand factor [VWF] cleaving protease) is associated with accumulation of prothrombogenic unusually large VWF multimers (UL-VWF) in plasma. We studied VWF release and proteolysis in patients with symptomatic Plasmodium falciparum or P. vivax malaria on the

  4. Dogs with hearth diseases causing turbulent high-velocity blood flow have changes in patelet function and von Willebrand factor multimer distribution

    DEFF Research Database (Denmark)

    Tarnow, Inge; Kristensen, Annemarie Thuri; Olsen, Lisbeth Høier

    2005-01-01

    The purpose of this prospective study was to investigate platelet function using in vitro tests based on both high and low shear rates and von Willebrand factor (vWf) multimeric composition in dogs with cardiac disease and turbulent high-velocity blood flow. Client-owned asymptomatic, untreated d...

  5. Factor VIII and von Willebrand factor co-delivery by endothelial cells

    NARCIS (Netherlands)

    Bouwens, E.A.M.

    2011-01-01

    A defect in coagulation factor VIII (FVIII) results in the inherited bleeding disorder hemophilia A. Current treatment of hemophilia A is hampered by the need of frequent administration of costly FVIII products. Therefore gene therapy is an attractive alternative for protein replacement to treat

  6. von Willebrand Factor-Rich Platelet Thrombi in the Liver Cause Sinusoidal Obstruction Syndrome following Oxaliplatin-Based Chemotherapy.

    Directory of Open Access Journals (Sweden)

    Naoto Nishigori

    Full Text Available Oxaliplatin-based chemotherapy is widely used to treat advanced colorectal cancer (CRC. Sinusoidal obstruction syndrome (SOS due to oxaliplatin is a serious type of chemotherapy-associated liver injury (CALI in CRC patients. SOS is thought to be caused by the sinusoidal endothelial cell damage, which results in the release of unusually-large von Willebrand factor multimers (UL-VWFMs from endothelial cells. To investigate the pathophysiology of CALI after oxaliplatin-based chemotherapy, we analyzed plasma concentration of von Willebrand factor (VWF and the distribution of VWFMs in CRC patients. Twenty-three patients with advanced CRC who received oxaliplatin-based chemotherapy with (n = 6 and without (n = 17 bevacizumab were analyzed. CALI (n = 6 and splenomegaly (n = 9 were found only in patients who did not treated with bevacizumab. Plasma VWF antigen (VWF:Ag and serum aspartate aminotransferase (AST levels increased after chemotherapy only in patients without bevacizumab. VWFM analysis in patients who did not receive bevacizumab showed the presence of UL-VWFMs and absence of high molecular weight VWFMs during chemotherapy, especially in those with CALI. In addition, plasma VWF:Ag and AST levels increased after chemotherapy in patients with splenomegaly (n = 9, but not in patients without splenomegaly (n = 14. Histological findings in the liver tissue of patients who did not receive bevacizumab included sinusoidal dilatation and microthrombi in the sinusoids. Many microthrombi were positive for both anti-IIb/IIIa and anti-VWF antibodies. Plasma UL-VWFM levels might be increased by damage to endothelial cells as a result of oxaliplatin-based chemotherapy. Bevacizumab could prevent CALI and splenomegaly through inhibition of VWF-rich platelet thrombus formation.

  7. Evaluation of von Willebrand factor phenotypes and genotypes in Hemophilia A patients with and without identified F8 mutations.

    Science.gov (United States)

    Boylan, B; Rice, A S; De Staercke, C; Eyster, M E; Yaish, H M; Knoll, C M; Bean, C J; Miller, C H

    2015-06-01

    Hemophilia A (HA) is an X-linked bleeding disorder caused by a deficiency in factor VIII (FVIII). von Willebrand disease (VWD) is characterized by a quantitative or qualitative defect in von Willebrand factor (VWF). Patients with VWD with severely low VWF or VWD Type 2N (VWD2N), a VWD subtype distinguished by defective VWF binding to FVIII, may have reduced FVIII levels secondary to their VWD. These patients superficially resemble patients with HA and pose a potential for misdiagnosis. To investigate the unexplained cause of bleeding in HA patients without known FVIII mutations by assessing plasma VWF antigen (VWF:Ag), FVIII binding capacities and VWF genotypes. Thirty-seven of 1027 patients with HA studied as part of the Hemophilia Inhibitor Research Study lacked identifiable F8 mutations. These patients (cases) and 73 patients with identified F8 mutations (controls) were evaluated for VWF:Ag, a patient's VWF capacity to bind FVIII (VWF:FVIIIB) and VWF sequence. Four cases had VWF:Ag < 3 IU dL(-1) and VWF mutations consistent with Type 3 VWD. Six cases and one control were heterozygous for mutations previously reported to cause Type 1 VWD (VWD1) (n = five cases and one control) or predicted to be deleterious by Polyphen2 and SIFT prediction tools (n = 1 case). One control had VWF:Ag < 30 IU dL(-1) and seven patients (four cases and three controls), including two cases who were heterozygous for a known VWD2N mutation, had reduced VWF:FVIIIB. These data emphasize that some patients diagnosed with HA require VWF assessments in order to achieve a comprehensive diagnosis and an optimal treatment strategy. © 2015 International Society on Thrombosis and Haemostasis.

  8. Differential proteolytic activation of factor VIII-von Willebrand factor complex by thrombin.

    OpenAIRE

    Hill-Eubanks, D C; Parker, C G; Lollar, P

    1989-01-01

    Blood coagulation factor VIII (fVIII) is a plasma protein that is decreased or absent in hemophilia A. It is isolated as a mixture of heterodimers that contain a variably sized heavy chain and a common light chain. Thrombin catalyzes the activation of fVIII in a reaction that is associated with cleavages in both types of chain. We isolated a serine protease from Bothrops jararacussu snake venom that catalyzes thrombin-like heavy-chain cleavage but not light-chain cleavage in porcine fVIII as ...

  9. Platelet function analyser (PFA-100) results and von Willebrand factor deficiency: a 16-year 'real-world' experience.

    Science.gov (United States)

    Ardillon, L; Ternisien, C; Fouassier, M; Sigaud, M; Lefrançois, A; Pacault, M; Ribeyrol, O; Fressinaud, E; Boisseau, P; Trossaërt, M

    2015-09-01

    The platelet function analyser (PFA-100) is a biological tool designed to explore primary haemostasis. This system has thus been widely demonstrated as reliable in detecting von Willebrand factor (VWF) deficiency. However, most studies were based on patients benefitting from regular medical care and accurate diagnosis, and it would seem probable that the results were somewhat optimistic, and do not reflect its performances in 'real-world' situations. We have chosen to study the reliability of PFA-100 for screening VWF ristocetin cofactor (VWF:RCo) deficiency. We retrospectively analysed the results (n = 6431) of 4027 patients referred to our centre between October 1997 and June 2013 and in whom PFA-Epi, PFA-ADP, and VWF:RCo activity had been evaluated. We studied the influence of blood group on the results and the performances of each method in a subgroup of 213 patients with genetically confirmed von Willebrand disease. We have shown that the PFA-100 system, in our experience, constitutes an excellent screening test for detecting VWF:RCo deficiency, whatever the clinical situation, in 'real-world' conditions. The negative predictive value (NPV), the positive predictive value, the sensitivity and the specificity were respectively: 0.98, 0.51, 0.98 and 0.40. When values adjusted for blood group are used, NPV and sensitivity are inferior to those using normal values which have not been adjusted for blood group. We have shown the PFA-100 method to be more efficient in screening for VWF deficiency than the VWF:RCo technique. © 2015 John Wiley & Sons Ltd.

  10. Distinct roles of Ser-764 and Lys-773 at the N terminus of von Willebrand factor in complex assembly with coagulation factor VIII.

    Science.gov (United States)

    Castro-Núñez, Lydia; Bloem, Esther; Boon-Spijker, Mariëtte G; van der Zwaan, Carmen; van den Biggelaar, Maartje; Mertens, Koen; Meijer, Alexander B

    2013-01-04

    Complex formation between coagulation factor VIII (FVIII) and von Willebrand factor (VWF) is of critical importance to protect FVIII from rapid in vivo clearance and degradation. We have now employed a chemical footprinting approach to identify regions on VWF involved in FVIII binding. To this end, lysine amino acid residues of VWF were chemically modified in the presence of FVIII or activated FVIII, which does not bind VWF. Nano-LC-MS analysis showed that the lysine residues of almost all identified VWF peptides were not differentially modified upon incubation of VWF with FVIII or activated FVIII. However, Lys-773 of peptide Ser-766-Leu-774 was protected from chemical modification in the presence of FVIII. In addition, peptide Ser-764-Arg-782, which comprises the first 19 amino acid residues of mature VWF, showed a differential modification of both Lys-773 and the α-amino group of Ser-764. To verify the role of Lys-773 and the N-terminal Ser-764 in FVIII binding, we employed VWF variants in which either Lys-773 or Ser-764 was replaced with Ala. Surface plasmon resonance analysis and competition studies revealed that VWF(K773A) exhibited reduced binding to FVIII and the FVIII light chain, which harbors the VWF-binding site. In contrast, VWF(S764A) revealed more effective binding to FVIII and the FVIII light chain compared with WT VWF. The results of our study show that the N terminus of VWF is critical for the interaction with FVIII and that Ser-764 and Lys-773 have opposite roles in the binding mechanism.

  11. Elevated preoperative von Willebrand factor is associated with perioperative thrombosis in infants and neonates with congenital heart disease.

    Science.gov (United States)

    Hunt, R; Hoffman, C M; Emani, S; Trenor, C C; Emani, S M; Faraoni, D; Kimchi-Sarfaty, C; Ibla, J C

    2017-12-01

    Essentials Perioperative thrombosis is a major cause of morbidity and mortality in congenital heart disease. Neonates and infants undergoing repair of congenital heart lesions were prospectively followed. Elevated von Willebrand factor (VWF) to ADAMTS-13 activity ratios typified the postoperative period. Thrombosis was associated with preoperative VWF activity and cryoprecipitate transfusion SUMMARY: Background The surgical repair of congenital heart malformations is frequently complicated by perioperative thrombosis of unclear etiology. An imbalance between von Willebrand factor (VWF) and ADAMTS-13 is an emerging variable in thrombosis. Objectives To describe perioperative changes to VWF, ADAMTS-13 and NETosis, and evaluate clinical and biochemical associations with postoperative thrombosis. Methods Neonates and infants undergoing palliation or definitive surgical repair of congenital heart malformations were recruited (n = 133). Preoperative and postoperative plasma levels of VWF, ADAMTS-13 and markers of NETosis were determined. Patients were followed for up to 30 days for the occurrence of thrombosis. Univariate and multivariate logistic regression analyses were conducted to identify variables associated with thrombosis. Results We identified significant postoperative increases in VWF activity, VWF level, DNA-histone complexes and cell-free DNA with an overall decrease in ADAMTS-13 activity. Patients experiencing postoperative thrombotic events (9%) were characterized by surgery performed at a lower intraoperative temperature, higher preoperative lactic acid levels, and higher preoperative VWF activity and level. A multivariate logistic regression model identified preoperative VWF activity (odds ratio (OR) 8.39 per IU mL-1 , 95% confidence interval [CI] 1.73-40.55) and transfusion of cryoprecipitate (OR 1.10 per mL kg-1 , 95% CI 1.03-1.17) as being associated with thrombosis. Conclusions Pediatric patients undergoing surgical repair of congenital

  12. Time course of soluble P-selectin and von Willebrand factor levels in trauma patients: a prospective observational study.

    Science.gov (United States)

    Tang, Ning; Yin, Shiyu; Sun, Ziyong; Pan, Yingying

    2013-09-14

    Coagulopathy often develops in patients with serious trauma and is correlated with the clinical outcome. The contribution of platelet activity and endothelial dysfunction to trauma-induced coagulopathy remain to be defined. The purpose of this study was to investigate the time courses of soluble P-selectin (sPsel, an index of platelet activation) and von Willebrand factor (VWF, an index of endothelial dysfunction) in trauma patients and elucidate their relationship to coagulation parameter levels, the presence of coagulopathy, and patient outcome. This prospective observational study, which took place in a university hospital intensive care unit (ICU), included 82 severely injured trauma patients. The sPsel, VWF antigen, protein C, and factor VII levels were measured and routine coagulation tests were performed upon admission to ICU and daily within the first week. The 30-day mortality rate was also determined. Thirty-seven (45.1%) patients developed coagulopathy upon admission to the ICU, and the 30-day mortality rate was 20.7% (n = 17). Both the admission sPsel and VWF levels were lower in patients with coagulopathy than in those without (p trauma patients in the ICU, lower levels of sPsel and VWF on admission were associated with the presence of coagulopathy and might not predict a better outcome. An increase in the VWF level at the end of the first week after admission to ICU was associated with increased 30-day mortality.

  13. Von Willebrand factor and fibrinolytic parameters during the desmopressin test in patients with Cushing's disease

    Science.gov (United States)

    Giraldi, Francesca Pecori; Ambrogio, Alberto G; Fatti, Letizia M; Rubini, Valentina; Cozzi, Giovanna; Scacchi, Massimo; Federici, Augusto B; Cavagnini, Francesco

    2011-01-01

    AIMS Desmopressin, a vasopressin analogue, is used for various clinical purposes, including haemostasis and, in recent times, the diagnostic work-up of patients with Cushing's syndrome, a condition associated with a known prothrombotic profile. We decided to evaluate whether and to what extent a diagnostic dose of desmopressin induces significant changes in endothelial parameters in patients with Cushing's disease (CD) and obese and normal weight controls. METHODS Twelve patients with CD, 10 obese and five normal weight controls were studied. Von Willebrand antigen (VWF : Ag), tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) were measured at baseline and up to 4 h after 10 µg desmopressin i.v. RESULTS Desmopressin 10 µg transiently increased VWF : Ag and t-PA and decreased PAI-1 in all subjects. The magnitude of the VWF : Ag and t-PA increases after desmopressin was comparable in the three groups (VWF : Ag peak-to-basal ratio 1.9 ± 0.17, 1.5 ± 0.11 and 1.8 ± 0.13 and t-PA peak-to-basal ratio 1.6 ± 0.18, 1.6 ± 0.20 and 1.8 ± 0.24 for CD, obese and controls, respectively, all NS). The PAI-1 decrease observed in patients with CD was comparable with obese (0.7 ± 0.07 and 0.6 ± 0.09, NS) and controls (0.7 ± 0.07 vs. 0.4 ± 0.09, P = 0.08). CONCLUSIONS Administration of desmopressin to patients with CD for diagnostic purposes induces a transitory increase in VWF : Ag counterbalanced by a decrease in PAI-1 and increase in t-PA. The magnitude of these changes is largely comparable with that observed in obese and normal weight controls. Our data show that testing with desmopressin does not induce disease-specific changes in endothelial markers in patients with CD. PMID:21143510

  14. Associations Between Diabetic Retinopathy and Plasma Levels of High-sensitive C-reactive Protein or Von Willebrand Factor in Long-term Type 1 Diabetic Patients

    DEFF Research Database (Denmark)

    Laursen, Jonas Vejvad Nørskov; Hoffmann, Stine Skovbo; Green, Anders

    2013-01-01

    a population-based cohort from Fyn County, Denmark. Plasma levels of hs-CRP and von Willebrand factor antigen were measured and related to the level of diabetic retinopathy (DR) as evaluated by dilated nine-field 45 degree monoscopic fundus photos captured by Topcon TRC-NWS6 and graded according to the Early...... Treatment Diabetic Retinopathy Study (ETDRS) adaptation of the modified Airlie House classification of DR. Results: Median age and duration of diabetes were 58.7 and 43 years, respectively. Median levels (10th-90th percentile) of hs-CRP and von Willebrand factor antigen were 1.31 mg/l (0.37-13.3 mg/l) and 1......Purpose: To evaluate high-sensitive C-reactive protein (hs-CRP) and von Willebrand factor as possible plasma markers of diabetic retinopathy in a population-based cohort of type 1 diabetic patients. Materials and Methods: This was a cross-sectional study of 201 type 1 diabetic patients from...

  15. Adhesive Forces between A1 Domain of von Willebrand Factor and N-terminus Domain of Glycoprotein Ibα Measured by Atomic Force Microscopy.

    Science.gov (United States)

    Tobimatsu, Hiroaki; Nishibuchi, Yuichiro; Sudo, Ryo; Goto, Shinya; Tanishita, Kazuo

    2015-01-01

    von Willebrand factor (VWF) plays an important role in the regulation of hemostasis and thrombosis formation, particularly under a high shear rate. However, the adhesive force due to the molecular interaction between VWF and glycoprotein Ibα (GPIbα) has not been fully explored. Thus, we employed atomic force microscopy to directly measure the adhesive force between VWF and GPIbα. We measured the adhesive force between VWF and GPIbα at the molecular level using an atomic force microscope (AFM). An AFM cantilever was coated with recombinant N-terminus VWF binding site of GPIbα, whereas a cover glass was coated with native VWF. The adhesive force at the molecular level was measured using an AFM. In the presence of 1 μg/mL VWF, the adhesion force was nearly 200 pN. As per the Gaussian fit analysis, the adhesive force of a single bond could have been 54 or 107 pN. Our consideration with the Gaussian fit analysis proposed that the adhesive force of a single bond could be 54 pN, which is very close to that obtained by optical tweezers (50 pN).

  16. A Novel Single-Domain Antibody Against von Willebrand Factor A1 Domain Resolves Leukocyte Recruitment and Vascular Leakage During Inflammation-Brief Report.

    Science.gov (United States)

    Aymé, Gabriel; Adam, Frédéric; Legendre, Paulette; Bazaa, Amine; Proulle, Valérie; Denis, Cécile V; Christophe, Olivier D; Lenting, Peter J

    2017-09-01

    von Willebrand factor (VWF) is crucial to hemostasis, but also plays a role in inflammatory processes. Unfortunately, no proper monoclonal antibodies to study VWF function in mice are currently available. We therefore aimed to generate single-domain antibodies (sdAbs) recognizing murine VWF and blocking its function in vivo. Llama-derived sdAbs recognizing both human and murine VWF were isolated via phage display technology. One of them (designated KB-VWF-006) recognized the VWF A1 domain with picomolar affinity. This sdAb avidity was strongly enhanced via dimerization using a triple Ala linker (KB-VWF-006bi). When administered in vivo to wild-type mice, KB-VWF-006bi dose dependently induced bleeding in a tail clip model. In 2 distinct models of inflammation, KB-VWF-006bi efficiently interfered with leukocyte recruitment and vascular leakage. KB-VWF-006bi is an sdAb recognizing the A1 domain of human VWF and murine VWF that interferes with VWF-platelet interactions in vivo. By using this sdAb, we now also show that the A1 domain is pertinent to the participation of VWF in the inflammatory response. © 2017 American Heart Association, Inc.

  17. Distribution of von Willebrand factor levels in young women with and without bleeding symptoms: influence of ABO blood group and promoter haplotypes

    DEFF Research Database (Denmark)

    Lethagen, S.; Hillarp, A.; Ekholm, C.

    2008-01-01

    The normal distribution of von Willebrand factor (VWF) levels is wide. Low levels are associated with bleeding symptoms and von Willebrand disease (VWD). We have recently described a high prevalence of bleeding symptoms in a whole age group of young females (n = 1,019) from Malmo, Sweden....... It was the objective of the present study to evaluate the distribution of VWF levels in young females with or without bleeding symptoms in this population, and the influence of ABO blood group and promoter haplotypes on VWF levels and to identify a possible increased prevalence of VWD in females with bleeding symptoms....... A random selection of the female age group (n = 246), into a study group (n = 176) with, and a control group (n = 70) without bleeding symptoms, was evaluated. Eighteen girls had VWF:RCo below the reference range, of which 17 belonged to the study group (17/176, 9.7%), and one to the control group (1/70, 1...

  18. Mechanism and functional impact of CD40 ligand-induced von Willebrand factor release from endothelial cells.

    Science.gov (United States)

    Möller, Kerstin; Adolph, Oliver; Grünow, Jennifer; Elrod, Julia; Popa, Miruna; Ghosh, Subhajit; Schwarz, Manuel; Schwale, Chrysovalandis; Grässle, Sandra; Huck, Volker; Bruehl, Claus; Wieland, Thomas; Schneider, Stefan W; Nobiling, Rainer; Wagner, Andreas H; Hecker, Markus

    2015-05-01

    Co-stimulation via CD154 binding to CD40, pivotal for both innate and adaptive immunity, may also link haemostasis to vascular remodelling. Here we demonstrate that human platelet-bound or recombinant soluble CD154 (sCD154) elicit the release from and tethering of ultra-large (UL) von Willebrand factor (vWF) multimers to the surface of human cultured endothelial cells (ECs) exposed to shear stress. This CD40-mediated ULVWF multimer release from the Weibel-Palade bodies was triggered by consecutive activation of TRAF6, the tyrosine kinase c-Src and phospholipase Cγ1 followed by inositol-1,4,5 trisphosphate-mediated calcium mobilisation. Subsequent exposure to human washed platelets caused ULVWF multimer-platelet string formation on the EC surface in a shear stress-dependent manner. Platelets tethered to these ULVWF multimers exhibited P-selectin on their surface and captured labelled monocytes from the superfusate. When exposed to shear stress and sCD154, native ECs from wild-type but not CD40 or vWF-deficient mice revealed a comparable release of ULVWF multimers to which murine washed platelets rapidly adhered, turning P-selectin-positive and subsequently capturing monocytes from the perfusate. This novel CD154-provoked ULVWF multimer-platelet string formation at normal to fast flow may contribute to vascular remodelling processes requiring the perivascular or intravascular accumulation of pro-inflammatory macrophages such as arteriogenesis or atherosclerosis.

  19. Subclinical Atherosclerosis in Patients with Rheumatoid Arthritis and Low Cardiovascular Risk: The Role of von Willebrand Factor Activity.

    Science.gov (United States)

    Ristić, Gorica G; Subota, Vesna; Lepić, Toplica; Stanisavljević, Dejana; Glišić, Branislava; Ristić, Arsen D; Petronijević, Milan; Stefanović, Dušan Z

    2015-01-01

    To evaluate association between von Willebrand factor (vWF) activity, inflammation markers, disease activity, and subclinical atherosclerosis in patients with rheumatoid arthritis (RA) and low cardiovascular risk. Above mentioned parameters were determined in blood samples of 74 non-diabetic, normotensive, female subjects, with no dyslipidemia(42 patients, 32 matched healthy controls, age 45.3±10.0 vs. 45.2±9.8 years). Intima-media thickness (IMT) was measured bilaterally, at common carotid, bifurcation, and internal carotid arteries. Subclinical atherosclerosis was defined as IMT>IMTmean+2SD in controlsat each carotid level and atherosclerotic plaque as IMT>1.5 mm. Majority of RA patients were on methotrexate (83.3%), none on steroids >10 mg/day or biologic drugs. All findings were analysed in the entire study population and in RA group separately. RA patients with subclinical atherosclerosis had higher vWF activity than those without (133.5±69.3% vs. 95.3±36.8%, psubclinical atherosclerosis was confirmed by logistic regression. vWF activity correlated significantly with erythrocyte sedimentation rate, fibrinogen, modified disease activity scores (mDAS28-ESR, mDAS28-CRP), modified Health Assessment Questionnaire (psubclinical atherosclerosis (130±68% vs. 97±38%, psubclinical atherosclerosis in low-risk RA patients as well as its correlation with inflammation markers, all parameters of disease activity, and seropositivity. Therefore, vWF might be a valuable marker of early atherosclerosis in RA patients.

  20. Analysis of von Willebrand factor A domain-related protein (WARP polymorphism in temperate and tropical Plasmodium vivax field isolates

    Directory of Open Access Journals (Sweden)

    Zakeri Sedigheh

    2009-06-01

    Full Text Available Abstract Background The identification of key molecules is crucial for designing transmission-blocking vaccines (TBVs, among those ookinete micronemal proteins are candidate as a general class of malaria transmission-blocking targets. Here, the sequence analysis of an extra-cellular malaria protein expressed in ookinetes, named von Willebrand factor A domain-related protein (WARP, is reported in 91 Plasmodium vivax isolates circulating in different regions of Iran. Methods Clinical isolates were collected from north temperate and southern tropical regions in Iran. Primers have been designed based on P. vivax sequence (ctg_6991 which amplified a fragment of about 1044 bp with no size variation. Direct sequencing of PCR products was used to determine polymorphism and further bioinformatics analysis in P. vivax sexual stage antigen, pvwarp. Results Amplified pvwarp gene showed 886 bp in size, with no intron. BLAST analysis showed a similarity of 98–100% to P. vivax Sal-I strain; however, Iranian isolates had 2 bp mismatches in 247 and 531 positions that were non-synonymous substitution [T (ACT to A (GCT and R (AGA to S (AGT] in comparison with the Sal-I sequence. Conclusion This study presents the first large-scale survey on pvwarp polymorphism in the world, which provides baseline data for developing WARP-based TBV against both temperate and tropical P. vivax isolates.

  1. Expression of von Willebrand factor, pulmonary intravascular macrophages, and Toll-like receptors in lungs of septic foals

    Science.gov (United States)

    Harrison, Jacqueline M. E.; Quanstrom, Leah M.; Robinson, Alex R.; Wobeser, Bruce; Anderson, Stacy L.

    2017-01-01

    Sepsis causes significant mortality in neonatal foals; however, there is little data describing the cellular and molecular pathways of lung inflammation in septic foals. This study was conducted to characterize lung inflammation in septic foals. Lung tissue sections from control (n = 6) and septic (n = 17) foals were compared using histology and immunohistology. Blinded pathologic scoring of hematoxylin and eosin stained samples revealed increased features of lung inflammation such as thickened alveolar septa and sequestered inflammatory cells in septic foals. Septic foal lungs showed increased expression of von Willebrand factor in blood vessels, demonstrating vascular inflammation. Use of MAC387 antibody to detect calprotectin as a reflection of mononuclear cell infiltration revealed a significant increase in their numbers in alveolar septa of lungs from septic foals compared to those from control foals. The mononuclear cells appeared to be mature macrophages and were located in the septal capillaries, suggesting they were pulmonary intravascular macrophages (PIMs). Finally, lungs from septic foals showed increased expression of Toll-like receptor 4 and 9 in mononuclear cells relative to the control. Taken together, this study is the first to show the expression of inflammatory molecules and an increase in PIMs in lungs from foals that died from sepsis. PMID:27297419

  2. Von Willebrand Factor, ADAMTS13 and D-Dimer Are Correlated with Different Levels of Nephropathy in Type 1 Diabetes Mellitus.

    Directory of Open Access Journals (Sweden)

    Caroline Pereira Domingueti

    Full Text Available We have investigated whether von Willebrand factor, ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13, and D-Dimer were associated with different levels of renal function in patients with type 1 diabetes. Patients were classified according to level of renal function through estimated glomerular filtration rate: ≥90 and <130mL/min/1,73m2, n=52 (control group, ≥60 and <90mL/min/1,73m2, n=29 (mild renal dysfunction group, <60mL/min/1,73m2, n=28 (severe renal dysfunction group; and through urinary albumin excretion: normoalbuminuria, microalbuminuria and macroalbuminuria. Von Willebrand factor, ADAMTS13, and D-Dimer plasma levels were determined by enzyme-linked immunosorbent assay. ADAMTS13 activity was determined by fluorescence resonance energy transfer assay. Von Willebrand factor levels were increased in patients with mild (P=0.001 and severe (P<0.001 renal dysfunction as compared to the control group. ADAMTS13 levels were also increased in mild (P=0.029 and severe (P=0.002 renal dysfunction groups in comparison to the control group, while ADAMTS13 activity was increased only in the severe renal dysfunction group as compared to the control group (P=0.006. No significant differences were observed among the groups regarding von Willebrand factor/ADAMTS13 ratio. ADAMTS13 activity/ADAMTS13 levels ratio was reduced in patients with mild (P=0.013 and severe (P=0.015 renal dysfunction as compared to the control group. D-Dimer levels were increased in patients with mild (P=0.006 and severe (P<0.001 renal dysfunction as compared to the control group; it was also higher in patients with severe renal dysfunction as compared to the mild renal dysfunction group (P=0.019. Similar results were found for albuminuria classification. Increased von Willebrand factor, ADAMTS13, and D-Dimer levels and decreased ADAMTS13 activity/ADAMTS13 levels ratio are associated with renal dysfunction in patients with type 1 diabetes

  3. Safety of a pasteurized plasma-derived Factor VIII and von Willebrand factor concentrate: analysis of 33 years of pharmacovigilance data.

    Science.gov (United States)

    Kouides, Peter; Wawra-Hehenberger, Kathrin; Sajan, Anna; Mead, Henry; Simon, Toby

    2017-10-01

    Haemate-P/Humate-P (Humate-P) is a pasteurized human plasma-derived concentrate containing both Factor VIII and von Willebrand factor for treatment of hemophilia A and von Willebrand disease (VWD). We analyzed the safety of Humate-P based on more than 33 years of postmarketing pharmacovigilance data, representing an estimated exposure of approximately 25,000 patient-years. The analysis comprises reports of potential adverse drug reactions (ADRs) from all sources, reported as part of routine pharmacovigilance at CSL Behring. ADRs considered clinically relevant or potential risks of Humate-P were identified based on defined and standardized Medical Dictionary for Regulatory Activities queries. Recognizing the limitations of spontaneous reporting, we also reviewed the literature, including clinical trials with mandatory reporting. From 1982 to 2015, a total of 670 postmarketing cases had been reported via pharmacovigilance, for an overall reporting rate of approximately one ADR per 3900 administered standard doses. Of these cases, 343 involved ADRs considered clinically relevant risks (33 thromboembolic complications, 97 inhibitor formation, 110 hypersensitivity or allergic reactions) or potential risks (103 suspected virus transmissions) for Humate-P. Most thromboembolic complications occurred in patients undergoing surgery or with other known risk factors. Inhibitor formation occurred mostly in patients with hemophilia A (24 cases were high titer). Most patients with hypersensitivity or allergic reactions had VWD. None of the reported suspected virus transmission cases were confirmed to be associated with Humate-P. Reported results of company-sponsored studies showed a low incidence of adverse events possibly or probably related to Humate-P. More than 33 years of pharmacovigilance data continue to support the safety of Humate-P. © 2017 The Authors. Transfusion published by Wiley Periodicals, Inc. on behalf of AABB.

  4. Von Willebrand factor and alkaline phosphatase predict re-transplantation-free survival after the first liver transplantation.

    Science.gov (United States)

    Wannhoff, Andreas; Rauber, Conrad; Friedrich, Kilian; Rupp, Christian; Stremmel, Wolfgang; Weiss, Karl Heinz; Schemmer, Peter; Gotthardt, Daniel N

    2017-02-01

    After liver transplantation (LT), there are liver-related, infectious and cardiovascular complications that contribute to reduced graft survival. These conditions are associated with an increase in the Von Willebrand factor antigen (VWF-Ag), which was previously correlated with survival in cirrhotic patients. Evaluate VWF-Ag as a predictive marker of re-transplantation-free survival in patients after LT. We measured VWF-Ag in patients after first LT and then followed them prospectively with regard to the primary endpoint, namely re-transplantation-free survival. There were 6 out of 80 patients who died or received re-LT during follow-up. In these patients, the median VWF-Ag was 510.6%, which was significantly higher (p = 0.001) than in the patients who were alive at the end of follow-up (with a median VWF-Ag = 186.8%). At a cut-off of 286.8%, VWF-Ag was significantly correlated with re-transplantation-free survival (p alkaline phosphatase (ALP), but not the model of end-stage liver disease (MELD) score, donor age, nor cold ischemia time. A score combining VWF-Ag and ALP showed an impressive capability in the receiver operating characteristic (ROC) analysis (with area under the curve (AUC) = 0.958) to distinguish between patients with regard to the primary endpoint. VWF-Ag is a non-invasive marker that can predict outcome in patients after LT. Its diagnostic performance increased when combined with ALP in a newly developed scoring system.

  5. Neutrophil Protease Cleavage of Von Willebrand Factor in Glomeruli - An Anti-thrombotic Mechanism in the Kidney.

    Science.gov (United States)

    Tati, Ramesh; Kristoffersson, Ann-Charlotte; Manea Hedström, Minola; Mörgelin, Matthias; Wieslander, Jörgen; van Kooten, Cees; Karpman, Diana

    2017-02-01

    Adequate cleavage of von Willebrand factor (VWF) prevents formation of thrombi. ADAMTS13 is the main VWF-cleaving protease and its deficiency results in development of thrombotic microangiopathy. Besides ADAMTS13 other proteases may also possess VWF-cleaving activity, but their physiological importance in preventing thrombus formation is unknown. This study investigated if, and which, proteases could cleave VWF in the glomerulus. The content of the glomerular basement membrane (GBM) was studied as a reflection of processes occurring in the subendothelial glomerular space. VWF was incubated with human GBMs and VWF cleavage was assessed by multimer structure analysis, immunoblotting and mass spectrometry. VWF was cleaved into the smallest multimers by the GBM, which contained ADAMTS13 as well as neutrophil proteases, elastase, proteinase 3 (PR3), cathepsin-G and matrix-metalloproteinase 9. The most potent components of the GBM capable of VWF cleavage were in the serine protease or metalloprotease category, but not ADAMTS13. Neutralization of neutrophil serine proteases inhibited GBM-mediated VWF-cleaving activity, demonstrating a marked contribution of elastase and/or PR3. VWF-platelet strings formed on the surface of primary glomerular endothelial cells, in a perfusion system, were cleaved by both elastase and the GBM, a process blocked by elastase inhibitor. Ultramorphological studies of the human kidney demonstrated neutrophils releasing elastase into the GBM. Neutrophil proteases may contribute to VWF cleavage within the subendothelium, adjacent to the GBM, and thus regulate thrombus size. This anti-thrombotic mechanism would protect the normal kidney during inflammation and could also explain why most patients with ADAMTS13 deficiency do not develop severe kidney failure. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

  6. Contrast ultrasound imaging of the aorta alters vascular morphology and circulating von Willebrand factor in hypercholesterolemic rabbits.

    Science.gov (United States)

    Smith, Brendon W; Simpson, Douglas G; Sarwate, Sandhya; Miller, Rita J; Blue, James P; Haak, Alexander; O'Brien, William D; Erdman, John W

    2012-05-01

    Ultrasound contrast agents (UCAs) are intravenously infused microbubbles that add definition to ultrasonic images. Ultrasound contrast agents continue to show clinical promise in cardiovascular imaging, but their biological effects are not known with confidence. We used a cholesterol-fed rabbit model to evaluate these effects when used in conjunction with ultrasound (US) to image the descending aorta. Male New Zealand White rabbits (n = 41) were weaned onto an atherogenic diet containing 1% cholesterol, 10% fat, and 0.11% magnesium. At 21 days, rabbits were exposed to contrast US at 1 of 4 pressure levels using either the UCA Definity (Lantheus Medical Imaging, Inc, North Billerica, MA) or a saline control (n = 5 per group). Blood samples were collected and analyzed for lipids and von Willebrand factor (vWF), a marker of endothelial function. Animals were euthanized at 42 days, and tissues were collected for histologic analysis. After adjustment for pre-exposure vWF, high-level US (in situ [at the aorta] peak rarefactional pressure of 1.4 or 2.1 MPa) resulted in significantly lower vWF 1 hour post exposure (P = .0127; P(adj) < .0762). This difference disappeared within 24 hours. Atheroma thickness in the descending aorta was lower in animals receiving the UCA compared to animals receiving saline. Contrast US affected the descending aorta, as evidenced by two separate outcome measures. These results may be a first step in elucidating a previously unknown biological effect of UCAs. Further research is warranted to characterize the effects of this procedure.

  7. The study of the effect of splicing mutations in von Willebrand factor using RNA isolated from patients' platelets and leukocytes.

    Science.gov (United States)

    Corrales, I; Ramírez, L; Altisent, C; Parra, R; Vidal, F

    2011-04-01

    In von Willebrand factor (VWF) the effect of mutations potentially affecting mRNA processing or splicing is less predictable than that of other mutations (e.g. nonsense or missense substitutions). Bioinformatic tools can provide a valuable means to determine the consequences of potential splice site mutations (PSSM), but functional studies are mandatory to elucidate the true effect of the variation detected. After identification of PSSM in VWD patients, we began a systematic study of their in vivo effect in RNA extracted from the patients' platelets and leukocytes. Thirteen pairs of primers were designed for full amplification of VWF mRNA by RT-PCR that, after sequencing of aberrant products, enabled elucidation of the PSSM consequences for mRNA processing. This procedure was used to study seven different PSSM identified in four patients demonstrating diverse molecular mechanisms such as exon skipping (c.533-2A>G and c.8155+3G>C) and the activation of a cryptic splice site (c.7730-1G>C). No visible effect was evident for c.1533+15G>A and c.5170+10C>T and the consequence of c.[546G>A;7082-2A>G] was hidden by nonsense-mediated mRNA decay (NMD). Results were compared with in silico predictions of four splice-site analysis tools. We demonstrate selective degradation of VWF mRNA bearing PSSM by NMD for several mutations, which suggests that NMD represents a general mechanism for truncating mutations in VWF. Furthermore, because NMD efficiency varies between cell types, use of RNA from both platelets and leukocytes for in vivo study of VWF PSSM offers complementary results, particularly in cases in which NMD occurs in the allele carrying the mutation. © 2011 International Society on Thrombosis and Haemostasis.

  8. The spider hemolymph clot proteome reveals high concentrations of hemocyanin and von Willebrand factor-like proteins.

    Science.gov (United States)

    Sanggaard, Kristian W; Dyrlund, Thomas F; Bechsgaard, Jesper S; Scavenius, Carsten; Wang, Tobias; Bilde, Trine; Enghild, Jan J

    2016-02-01

    Arthropods include chelicerates, crustaceans, and insects that all have open circulation systems and thus require different properties of their coagulation system than vertebrates. Although the clotting reaction in the chelicerate horseshoe crab (Family: Limulidae) has been described in details, the overall protein composition of the resulting clot has not been analyzed for any of the chelicerates. The largest class among the chelicerates is the arachnids, which includes spiders, ticks, mites, and scorpions. Here, we use a mass spectrometry-based approach to characterize the spider hemolymph clot proteome from the Brazilian whiteknee tarantula, Acanthoscurria geniculata. We focused on the insoluble part of the clot and demonstrated high concentrations of proteins homologous to the hemostasis-related and multimerization-prone von Willebrand factor. These proteins, which include hemolectins and vitellogenin homologous, were previously identified as essential components of the hemolymph clot in crustaceans and insects. Their presence in the spider hemolymph clot suggests that the origin of these proteins' function in coagulation predates the split between chelicerates and mandibulata. The clot proteome reveals that the major proteinaceous component is the oxygen-transporting and phenoloxidase-displaying abundant hemolymph protein hemocyanin, suggesting that this protein also plays a role in clot biology. Furthermore, quantification of the peptidome after coagulation revealed the simultaneous activation of both the innate immune system and the coagulation system. In general, many of the identified clot-proteins are related to the innate immune system, and our results support the previously suggested crosstalk between immunity and coagulation in arthropods. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Insulin resistance is accompanied by increased von Willebrand factor levels in nondiabetic women: a study of offspring of type 2 diabetic subjects compared to offspring of nondiabetic subjects

    DEFF Research Database (Denmark)

    Foss, Anne-Catherine; Vestbo, Else; Frøland, Anders

    2002-01-01

    : We compared vWF, fibrinogen and fibronectin in 88 nondiabetic offspring of type 2 diabetic subjects (relatives) and 103 offspring of nondiabetic subjects (controls). Other measurements included urinary albumin excretion rate, blood pressure, lipid profile and insulin resistance using homeostasis......OBJECTIVES: To examine whether levels of von Willebrand factor (vWF), fibrinogen and fibronectin are related to a parental history of type 2 diabetes and to determine possible explanatory factors for high versus low vWF and fibrinogen. DESIGN: Cross-sectional study. SUBJECTS, MAIN OUTCOME MEASURES...

  10. Plasma concentration of von Willebrand factor predicts mortality in patients on chronic renal replacement therapy

    NARCIS (Netherlands)

    Péquériaux, Nathalie C.; Fijnheer, Rob; Gemen, Eugenie F.; Barendrecht, Arjan D.; Dekker, Friedo W.; Krediet, Raymond T.; Beutler, Jaap J.; Boeschoten, Elisabeth W.; Roest, Mark

    2012-01-01

    Background. Traditional cardiovascular risk factors do not explain the high incidence of cardiovascular mortality and morbidity in patients with end-stage renal disease. A prothrombotic state could accelerate the process of vascular disease in these patients. Methods. In this study, four platelet

  11. The markers of platelet functions and Von Willebrand factor serum content from patients with type 2 diabetes mellitus and ishemic stroke

    Directory of Open Access Journals (Sweden)

    Tetiana Tsarenko

    2016-03-01

    Full Text Available Introduction: The est and #1110;mated number of people with diabetes worldwide in 2015 is 415 million persons, up to 91% of adults hadtype 2 diabetes and the crude incidence of stroke among patients with diabetes of the 2ndtype can be more than 3 times that in the general population. It is known platelet activation and aggregation are critical in the pathogenesis of acute ischemic cerebrovascular diseases. Thus to examine the evidence of platelet functioning such as platelet count,aggregation in response to ADP, coagulation von Willebrand factor and serotonin content, monoamine oxidase (MAO activity in the blood of patients with ischemic stroke and with ischemic stroke complicated with the 2ndtype diabetes are the aim of the present study. Methods: The platelet aggregation was assayed for photo-optical aggregometer, von Willebrand factor was determined by Elisa, serotonin determination included ion-exchange chromatography and fluorescence spectrophotometry. Determination of monoamine-oxidase serum activity was spectophotometry. Results: The investigation has shown an increase of serotonin and Von Willebrand factor blood content in both groups of patients with ischemic stroke andtype 2 diabetes and stroke alone compared with the values of the control group. The monoamine oxidase activity and platelet count were reduced in blood of patients with diabetes of the 2ndtype with ischemic stroke against to the values from the group of healthy donors. Platelet aggregation in response to ADP increased under the investigated pathologies. Conclusions: These obtained data suggested a significant imbalance in vascular platelet element of hemostasis under the ischemic stroke and amplification of negative changes under the stroke with the 2ndtype diabetes. [Biomed Res Ther 2016; 3(3.000: 542-547

  12. Elevated levels of plasma von Willebrand factor and the risk of macro- and microvascular disease in type 2 diabetic patients with microalbuminuria

    DEFF Research Database (Denmark)

    Gaede, P; Vedel, P; Parving, H H

    2001-01-01

    according to baseline plasma von Willebrand factor levels below or above the median. The main outcome was cardiovascular disease (cardiovascular mortality, non-fatal stroke, non-fatal myocardial infarction, coronary artery bypass graft and revascularization or amputation of legs), progression to diabetic...... nephropathy or progression in diabetic retinopathy. RESULTS: At baseline the two groups were comparable for HbA(1c), fasting levels of s-total-cholesterol, s-HDL-cholesterol and s-triglycerides, systolic and diastolic blood pressure, gender, known diabetes duration, smoking habits, previous cardiovascular...

  13. Subclinical Atherosclerosis in Patients with Rheumatoid Arthritis and Low Cardiovascular Risk: The Role of von Willebrand Factor Activity.

    Directory of Open Access Journals (Sweden)

    Gorica G Ristić

    Full Text Available To evaluate association between von Willebrand factor (vWF activity, inflammation markers, disease activity, and subclinical atherosclerosis in patients with rheumatoid arthritis (RA and low cardiovascular risk.Above mentioned parameters were determined in blood samples of 74 non-diabetic, normotensive, female subjects, with no dyslipidemia(42 patients, 32 matched healthy controls, age 45.3±10.0 vs. 45.2±9.8 years. Intima-media thickness (IMT was measured bilaterally, at common carotid, bifurcation, and internal carotid arteries. Subclinical atherosclerosis was defined as IMT>IMTmean+2SD in controlsat each carotid level and atherosclerotic plaque as IMT>1.5 mm. Majority of RA patients were on methotrexate (83.3%, none on steroids >10 mg/day or biologic drugs. All findings were analysed in the entire study population and in RA group separately.RA patients with subclinical atherosclerosis had higher vWF activity than those without (133.5±69.3% vs. 95.3±36.8%, p<0.05. Predictive value of vWF activity for subclinical atherosclerosis was confirmed by logistic regression. vWF activity correlated significantly with erythrocyte sedimentation rate, fibrinogen, modified disease activity scores (mDAS28-ESR, mDAS28-CRP, modified Health Assessment Questionnaire (p<0.01 for all, duration of smoking, number of cigarettes/day, rheumatoid factor concentration (p<0.05 for all, and anti-CCP antibodies (p<0.01. In the entire study population, vWF activity was higher in participants with subclinical atherosclerosis (130±68% vs. 97±38%, p<0.05 or atherosclerotic plaques (123±57% vs. 99±45%, p<0.05 than in those without. Duration of smoking was significantly associated with vWF activity (β 0.026, p = 0.039.We demonstrated association of vWF activity and subclinical atherosclerosis in low-risk RA patients as well as its correlation with inflammation markers, all parameters of disease activity, and seropositivity. Therefore, vWF might be a valuable marker of

  14. von Willebrand Disease

    Science.gov (United States)

    ... the condition. For example, the school nurse, teacher, daycare provider, coach, or any leader of afterschool activities ... MedlinePlus) Von Willebrand Disease (MedlinePlus) Building 31 31 Center Drive Bethesda, MD 20892 Learn more about getting ...

  15. von Willebrand Disease

    Science.gov (United States)

    ... for type 1 von Willebrand disease is called desmopressin. It causes a temporary increase in the von ... injection or by being sniffed into the nose. Desmopressin may also help some people with type 2 ...

  16. Successful immune tolerance induction consisting of high-dose factor VIII rich in von Willebrand factor and pulsed intravenous immunoglobulin: a case report

    Directory of Open Access Journals (Sweden)

    Kubisz Peter

    2012-10-01

    Full Text Available Abstract Introduction The development of factor VIII inhibitors is a serious complication of replacement therapy in patients with congenital hemophilia A. Immune tolerance induction has been accepted as the only clinically proven treatment allowing antigen-specific tolerance to factor VIII. However, some of its issues, such as patient selection, timing, factor VIII dosing, use of immunosuppressive or immunomodulatory procedures, still remain the subject of debate. Case presentation A case of a 3-year-old Caucasian boy with severe congenital hemophilia A, intron 22 inversion of the F8 gene and high-titer inhibitor, who underwent an immune tolerance induction according to the modified Bonn regimen (high doses of plasma-derived factor VIII rich in von Willebrand factor and pulsed intravenous immunoglobulin is presented. The treatment lasted for 13 months and led to the eradication of inhibitor. Conclusion Addition of intravenous immunoglobulin did not negatively affect the course of immune tolerance induction and led to the rapid eradication of factor VIII inhibitor.

  17. Factor VIII/V C-domain swaps reveal discrete C-domain roles in factor VIII function and intracellular trafficking

    OpenAIRE

    Ebberink, Eduard H T M; Bouwens, Eveline A. M.; Bloem, Esther; Boon-Spijker, Mariëtte; van den Biggelaar, Maartje; Voorberg, Jan; Alexander B. Meijer; Mertens, Koen

    2017-01-01

    Factor VIII C-domains are believed to have specific functions in cofactor activity and in interactions with von Willebrand factor. We have previously shown that factor VIII is co-targeted with von Willebrand factor to the Weibel-Palade bodies in blood outgrowth endothelial cells, even when factor VIII carries mutations in the light chain that are associated with defective von Willebrand factor binding. In this study, we addressed the contribution of individual factor VIII C-domains in intrace...

  18. von Willebrand disease and aging : an evolving phenotype

    NARCIS (Netherlands)

    Sanders, Y. V.; Giezenaar, M. A.; Laros-van Gorkom, B. A. P.; Meijer, K.; van der Bom, J. G.; Cnossen, M. H.; Nijziel, M. R.; Ypma, P. F.; Fijnvandraat, K.; Eikenboom, J.; Mauser-Bunschoten, E. P.; Leebeek, F. W. G.

    Background: Because the number of elderly von Willebrand disease (VWD) patients is increasing, the pathophysiology of aging in VWD has become increasingly relevant. Objectives: To assess age-related changes in von Willebrand factor (VWF) and factor VIII (FVIII) levels and to compare age-related

  19. Function of von Willebrand factor in children with diarrhea-associated hemolytic-uremic syndrome (D+ HUS).

    Science.gov (United States)

    Sutor, A H; Thomas, K B; Prüfer, F H; Grohmann, A; Brandis, M; Zimmerhackl, L B

    2001-06-01

    Reports on von Willebrand factor (vWF) in hemolytic-uremic syndrome (HUS) are not unequivocal. Because of potential pathogenic implications, we examined the ability of vWF to bind to collagen in vitro, which reflects its function. Plasma vWF antigen (vWF:Ag) and collagen-binding activity (vWF:CBA) were measured by enzyme-linked immunosorbent assay in children with (1) diarrhea-associated (D+) HUS (n = 27), (2) chronic renal insufficiency (CRI) (n = 8), (3) gastroenteritis (GE) not associated with HUS (n = 15), (4) immune thrombocytopenia (ITP) (n = 40) and from controls (n = 35). Structural vWF was evaluated by multimer analysis. Children with D+ HUS had vWF:Ag of 2.53 and vWF:CBA of 1.98 U/mL. The corresponding values for patients with ITP were 1.35 and 1.82 U/mL, with CRI 1.55 and 1.55 U/mL, and with GE 1.68 and 2.10 U/mL; all values were higher than in controls (1.04 and 1.16 U/mL). The mean ratio of vWF:CBA to vWF:Ag ratio in controls was 1.13; only children with HUS had a dysfunctional vWF, as indicated by a low ratio of 0.78; the ratio was elevated in children with ITP (1.36) and GE (1.27) and was normal in those with CRI (1.06). No ultralarge molecular multimers of vWF were detected in any group, including HUS. The very high concentration of plasma vWF:Ag in HUS probably reflects endothelial cell damage or irritation. In contrast to all other groups, only children with HUS had a dysfunctional vWF, caused either by a primary (due to enterohemorrhagic Escherichia coli) or secondary (due to consumption of functionally active vWF) process. This abnormality was not obvious as structural anomaly by multimer analysis.

  20. von Willebrand Factor Test

    Science.gov (United States)

    ... Hormone Binding Globulin (SHBG) Shiga toxin-producing Escherichia coli Sickle Cell Tests Sirolimus Smooth Muscle Antibody (SMA) ... Ratio Valproic Acid Vancomycin Vanillylmandelic Acid (VMA) VAP Vitamin A Vitamin B12 and Folate Vitamin D Tests ...

  1. Characterization of recessive severe type 1 and 3 von willebrand disease (vwd), asymptomatic heterozygous carriers versus bloodgroup o-related von willebrand factor deficiency, and dominant type 1 VWD

    NARCIS (Netherlands)

    J.J. Michiels (Jan); Z. Berneman (Zwi); A. Gadisseur (Alain); M. van der Planken (Marc); W. Schroyens (Wilfried); A. van de Velde (Ann); H.H.D.M. van Vliet (Huib)

    2006-01-01

    textabstractRecessive type 3 von Willebrand disease (VWD) is caused by homozygosity or double heterozygosity for two non-sense mutations (null alleles). Type 3 VWD is easy to diagnose by the combination of a strongly prolonged bleeding time (BT), absence of ristocetine-induced platelet aggregation

  2. An external quality assessment program for von Willebrand factor laboratory analysis: an overview from the European concerted action on thrombosis and disabilities foundation.

    Science.gov (United States)

    Meijer, Piet; Haverkate, Frits

    2006-07-01

    The laboratory diagnosis of von Willebrand disease (vWD) is complex and requires a panel of different laboratory tests. Because of this complexity, a proper quality control process is necessary. Since 2003, the European Concerted Action on Thrombosis and Disabilities Foundation has provided an external quality control program for several laboratory tests included in the diagnosis of vWD. Currently, ~180 different laboratories participate in this program, of which the vast majority perform both von Willebrand factor (vWF):antigen (Ag) and activity tests. The lowest between-laboratory variation was observed for the vWF antigen assay (10 to 24%), with a better performance for the latex immunoassay (8 to 24%) than the enzyme immunoassay (13 to 25%). Both the ristocetin cofactor activity assay (RCo) and the collagen-binding assay showed a higher between-laboratory variation (20 to 40% and 17 to 29%, respectively). We have observed that the within-laboratory repeatability for normal samples ranged from 0 to 40% for the antigen assay and from 0 to 86% for the ristocetin cofactor activity assay. Normal samples were interpreted correctly by the majority of the participants. However, type 1 vWD samples were wrongly interpreted by 20 to 40% of the participants, which was mainly caused by a discordance in the vWF:RCo/vWF:Ag ratio. It can be concluded that further improvement in the laboratory diagnosis of vWD is necessary.

  3. Doença de von Willebrand e anestesia Enfermedad de von Willebrand y anestesia Von Willebrand's disease and anesthesia

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    Fabiano Timbó Barbosa

    2007-06-01

    Full Text Available JUSTIFICATIVA E OBJETIVOS: A doença de von Willebrand ocorre devido à mutação no cromossomo 12 e é caracterizada por deficiência qualitativa ou quantitativa do fator de von Willebrand. A diversidade de mutações leva ao aparecimento das mais variadas manifestações clínicas possibilitando a divisão dos pacientes em vários tipos e subtipos clínicos. A coagulopatia se manifesta basicamente através da disfunção plaquetária associada à diminuição dos níveis séricos do fator VIII coagulante. O objetivo dessa revisão foi mostrar os cuidados relacionados aos pacientes portadores da doença de von Willebrand durante o período perioperatório. CONTEÚDO: Foram definidas as características da doença de von Willebrand quanto à fisiopatologia, à classificação, ao diagnóstico laboratorial, ao tratamento atual e aos cuidados com o manuseio do paciente no período perioperatório. CONCLUSÕES: A doença de von Willebrand é o distúrbio hemorrágico hereditário mais comum, porém ela é subdiagnosticada pela complexidade da própria doença. A correta classificação do paciente, o uso apropriado da desmopressina e a transfusão do fator de von Willebrand são medidas fundamentais para a realização do procedimento anestésico bem-sucedido.JUSTIFICATIVA Y OBJETIVOS: La enfermedad de von Willebrand ocurre debido a la mutación en el cromosoma 12 y se caracteriza por la deficiencia cualitativa o cuantitativa del factor de von Willebrand. La diversidad de mutaciones conlleva al aparecimiento de las más variadas manifestaciones clínicas posibilitando la división de los pacientes en varios tipos y subtipos clínicos. La coagulopatía se manifiesta básicamente a través de la disfunción plaquetaria asociada con la disminución de los niveles séricos del factor VIII coagulante. El objetivo de esa revisión fue mostrar los cuidados relacionados con las pacientes portadoras de la enfermedad de von Willebrand durante el per

  4. VON WILLEBRAND DISEASE: DIAGNOSIS AND TREATMENT

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    Majda Benedik Dolničar

    2004-12-01

    Full Text Available Background. Von Willebrand disease (VWD is a most frequently inborn bleeding disorder caused by quantitative or qualitative defects of von Willebrand factor (VWF. VWF promotes platelet-vessel wall (adhesion and plateletplatelet interaction (aggregation. It is also the carrier for factor VIII (F VIII in plasma. A deficiency of VWF may results in impairment of both, primary and secondary haemostasis. Therefore, patients with VWD can have bleeding symptoms typical fot the defect in primary haemostasis (mucocutaneous haemorrhages. In severe deficiency of VWF there are also haemarthroses and haematomas typical for patients with coagulation defects. Several types and subtypes of VWD have been described. The diagnosis is based on measurements of VWF concentration and activity and F VIII activity in plasma. The tests identifying VWD subtypes are ristocetin induced platelet agglutination (RIPA, multimeric analysis of VWF and measurement of the binding of VWF to F VIII.Conclusions. Due to heterogeneity of VWF defects, the correct diagnosis of types and subtypes is sometimes difficult but is important for appropriate treatment. There are two main therapeutic options for patients with VWD: desmopressin and blood derived concentrates of F VIII/VWF. In certain cases antifibrinolytics and hormones can be suitable treatment. Desmopressin is the treatment of choice in patients with type 1 VWD. It raises endogenous F VIII and VWF and thereby corrects the intrinsic coagulation defect as well as the prolonged bleeding time (BT or closure time (CT-PFA100 in most type 1 VWD patients. In type 3 and in the majority of type 2 patients desmopressin is not effective and it is necessary to use concentrates containing F VIII and VWF. These are always effective in raising of F VIII activity, whereas the BT/CT may not be completely corrected, but the normalisation of the BT/CT is not always necessary.

  5. Endothelial markers in malignant vascular tumours of the liver: superiority of QB-END/10 over von Willebrand factor and Ulex europaeus agglutinin 1.

    Science.gov (United States)

    Anthony, P P; Ramani, P

    1991-01-01

    A new monoclonal antibody, QB-END/10, raised against the CD34 antigen in human endothelial cell membranes and haemopoietic progenitor cells, was studied for its usefulness as a marker of neoplastic vascular cells in 21 angiosarcomas and seven malignant haemangioendotheliomas of the liver. QB-END/10 was both more sensitive and more specific than Von Willebrand factor (VWF) and Ulex europaeus 1 agglutinin (UEA-1) in labelling endothelial cells and it did not cross react with epithelia as UEA-1 often does. Staining was uniformly strong and clear in all histological variants of these two tumours. QB-END/10 should prove particularly useful in the differential diagnosis of malignant vascular tumours of the liver. Images PMID:1705261

  6. Influences of ABO blood group, age and gender on plasma coagulation factor VIII, fibrinogen, von Willebrand factor and ADAMTS13 levels in a Chinese population

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    Zongkui Wang

    2017-03-01

    Full Text Available Background ABO blood group is a hereditary factor of plasma levels of coagulation factor VIII (FVIII and von Willebrand factor (VWF. Age and gender have been shown to influence FVIII, VWF, fibrinogen (Fbg, and ADAMTS13 (A disintegrin and metalloprotease with thrombospondin type 1 motif, 13. We investigated the effects of ABO type, age, and gender on plasma levels of FVIII, Fbg, VWF, and ADAMTS13 in a Chinese population. Methods A total of 290 healthy volunteers were eligible for this study. ABO blood group was determined by indirect technique. FVIII:C and Fbg were measured by clotting assays. VWF antigen (VWF:Ag, collagen-binding activity (VWF:CBA, and ADAMTS13 antigen were assessed by ELISA, whereas VWF ristocetin cofactor activity (VWF:Rcof was performed by agglutination of platelets with ristocetin. Results Mean FVIII:C and VWF levels (VWF:Ag, VWF:CBA, and VWF:Rcof were significantly higher in non-O than in O type subjects (p < 0.05 for all comparison. ADAMTS13 antigen decreased with increasing age, whereas the other parameters increased. Other than ADAMTS13 (p < 0.01, no gender-related variations were observed in the other parameters. Moreover, FVIII:C, Fbg, VWF:Ag, VWF:CBA, and VWF:Rcof showed significant and positive relationships with age (r = 0.421, 0.445, 0.410, 0.401, and 0.589, resp.; all p < 0.001, whereas a negative relationship was observed for ADAMTS13 antigen (r = 0.306; p = 0.006. Furthermore, FVIII:C were strongly correlated with VWF:Ag, VWF:CBA, and VWF:Rcof (r = 0.746, r = 0.746, and r = 0.576, resp.; p < 0.0001. VWF parameters were also strongly correlated with each other (r = 0.0.847 for VWF:Ag and VWF:CBA; r = 0.722 for VWF:Ag and VWF:Rcof; p < 0.0001. Conclusions ABO blood group, age, and gender showed different effects on plasma levels of FVIII:C, Fbg, VWF:Ag, VWF:CBA, VWF:Rcof, and ADAMTS13 antigen. These new data on a Chinese population are quite helpful to compare with other ethnic groups.

  7. Revascularization Operation for Moyamoya Disease with Concurrent von Willebrand Disease.

    Science.gov (United States)

    Miki, Kenji; Arimura, Koichi; Nishimura, Ataru; Yoshimoto, Koji; Sayama, Tetsuro; Iihara, Koji

    2017-12-01

    Although extracranial-intracranial (EC-IC) bypass is an effective treatment strategy for symptomatic moyamoya disease, surgeons need to be cautious regarding the possibility of postoperative hemorrhagic complications in patients with a concurrent coagulation disorder. Here, we describe a case of EC-IC bypass for moyamoya disease concurrent with von Willebrand disease type 1. Following perioperative replacement of the von Willebrand factor, the patient showed an uneventful and uncomplicated clinical course. This is the first reported case of EC-IC bypass being performed for moyamoya disease in a patient with concurrent von Willebrand disease. We emphasize the importance of appropriate management with replacement of the von Willebrand factor during the perioperative period to avoid hemorrhagic complications. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Von Willebrand factor antigen predicts response to double dose of aspirin and clopidogrel by PFA-100 in patients undergoing primary angioplasty for ST elevation myocardial infarction.

    Science.gov (United States)

    Gianetti, Jacopo; Parri, Maria Serena; Della Pina, Francesca; Marchi, Federica; Koni, Endrin; De Caterina, Alberto; Maffei, Stefano; Berti, Sergio

    2013-01-01

    Von Willebrand factor (VWF) is an emerging risk factor in acute coronary syndromes. Platelet Function Analyzer (PFA-100) with Collagen/Epinephrine (CEPI) is sensitive to functional alterations of VWF and also identifies patients with high on-treatment platelet reactivity (HPR). The objective of this study was to verify the effect of double dose (DD) of aspirin and clopidogrel on HPR detected by PFA-100 and its relation to VWF and to its regulatory metalloprotease ADAMTS-13. Between 2009 and 2011 we enrolled 116 consecutive patients with ST elevation myocardial infarction undergoing primary PCI with HPR at day 5 after PCI. Patients recruited were then randomized between a standard dose (SD, n = 58) or DD of aspirin and clopidogrel (DD, n = 58), maintained for 6 months follow-up. Blood samples for PFA-100, light transmittance aggregometry, and VWF/ADAMTS-13 analysis were collected after 5, 30, and 180 days (Times 0, 1, and 2). At Times 1 and 2 we observed a significantly higher CEPI closure times (CT) in DD as compared to SD (P myocardial infarction is reversible by DD of aspirin and clopidogrel; the response is predicted by basal levels of VWF and ADAMTS-13. PFA-100 may be a useful tool to risk stratification in acute coronary syndromes given its sensitivity to VWF.

  9. Immunohistochemial study on the expression of von Willebrand factor (vWF) after onlay autogenous iliac grafts for lateral alveolar ridge augmentation

    Science.gov (United States)

    2013-01-01

    Introduction The main problems of autogenous bone transplants are their unpredictable atrophy and their loss of structure. One key factor lies in the poor revascularization of simple onlay grafts. The the aim of this study was to evaluate the revascularization processes in autogenous bone grafts from the iliac crest to the alveolar ridge. Methods In a sheep model, autogenous bone grafts were harvested from the iliac crest. A combination of a resorbable collagen membrane (CM) and deproteinized bovine bone material (DBBM) was used to modify the bone graft (experiment 2). This was compared with a simple onlay bone graft (control group, experiment 1). The amount of vessels in bone and connective tissue (CT), and the amount of CT were analyzed. The expression of von Willebrand factor (vWF) was compared between the two experimental groups using immunohistochemical analysis. Results The ratio of the amount of vessels in bone and CT changed over time, and more vessels could be detected in bone at 12–16 weeks of graft healing. The number of vessels were significantly higher in experiment 2 than in experiment 1. More CT was found in experiment 1, whereas the amount of CT in both experiments decreased over time. Conclusion This study shows a more intensive and extensive revascularization in experiment 2, as significantly more vessels were detected. The decreased amount of CT in experiment 2 clarifies its clinical superiority. PMID:24330606

  10. Gender and age peculiarities of content changes of protein C, von Willebrand factor, vascular cell adhesion molecules sVCAM-1 in patients with acute left ventricle Q-wave myocardial infarction

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    S. M. Kyselov

    2015-04-01

    Full Text Available Markers of hemostasis have an influence on the state of postinfarction remodeling processes. Aim. In order to study the gender and age peculiarities, to determine the predictive value of the protein C, von Willebrand factor and vascular cell adhesion molecules sVCAM-1 concentration, we examined 76 patients with acute Q-wave myocardial infarction. Methods and results. On the 1st day of the disease, higher concentrations of protein C were detected in young women, vascular cell adhesion molecules sVCAM-1 - in men of any age. On the 10th day of the disease, both in men and women increase in the content of protein C, reducing the concentration of von Willebrand factor and vascular cell adhesion molecules sVCAM-1 were detected. Conclusion. Protein C has the highest prognostic potential in relation to the formation of heart aneurysm after Q-wave myocardial infarction in women of young age, and von Willebrand factor and vascular cell adhesion molecules sVCAM-1 - in older men.

  11. Plasma fibrinolysis is related to the degree of organ dysfunction but not to the concentration of von Willebrand Factor in critically ill patients

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    Vincent Jean-Louis

    2009-06-01

    Full Text Available Abstract Background Endothelial cell dysfunction, by promoting fibrin deposition, has been implicated in the development of multiple organ failure. Altered fibrinolysis during inflammation may participate in microvascular alterations. We sought to determine whether plasma fibrinolysis was related to the severity of organ dysfunction and/or to the levels of von Willebrand factor (vWF antigen, as a marker of endothelium dysfunction, in critically ill patients. Methods Forty-nine consecutive patients admitted to an adult medico-surgical intensive care unit (ICU with (18 or without sepsis (31 were included. C-reactive protein and vWF levels were measured on ICU admission and plasma fibrinolysis was assessed by the Euglobulin Clot Lysis Time (ECLT. The sequential organ failure assessment (SOFA score and the simplified acute physiology score (SAPS II were calculated on admission. Results ECLT was significantly longer in septic than in non-septic patients [1033 min (871–1372 versus 665 min (551–862, p = 0.001]. There were significant correlations between ECLT and C-reactive protein (CRP concentrations (r = 0.78, p Conclusion ECLT measurement at admission could be a marker of organ dysfunction and a prognostic indicator in critically ill patients.

  12. The cooperative activity between the carboxyl-terminal TSP1 repeats and the CUB domains of ADAMTS13 is crucial for recognition of von Willebrand factor under flow.

    Science.gov (United States)

    Zhang, Ping; Pan, Weilan; Rux, Ann H; Sachais, Bruce S; Zheng, X Long

    2007-09-15

    ADAMTS13 cleaves von Willebrand factor (VWF) between Tyr(1605) and Met(1606) residues at the central A2 subunit. The amino-terminus of ADAMTS13 protease appears to be sufficient to bind and cleave VWF under static and denatured condition. However, the role of the carboxyl-terminus of ADAMTS13 in substrate recognition remains controversial. Present study demonstrates that ADAMTS13 cleaves VWF in a rotation speed- and protease concentration-dependent manner on a mini vortexer. Removal of the CUB domains (delCUB) or truncation after the spacer domain (MDTCS) significantly impairs its ability to cleave VWF under the same condition. ADAMTS13 and delCUB (but not MDTCS) bind VWF under flow with dissociation constants (K(D)) of about 50 nM and about 274 nM, respectively. The isolated CUB domains are neither sufficient to bind VWF detectably nor capable of inhibiting proteolytic cleavage of VWF by ADAMTS13 under flow. Addition of the TSP1 5-8 (T5-8CUB) or TSP1 2-8 repeats (T2-8CUB) to the CUB domains restores the binding affinity toward VWF and the inhibitory effect on cleavage of VWF by ADAMTS13 under flow. These data demonstrate directly and quantitatively that the cooperative activity between the middle carboxyl-terminal TSP1 repeats and the distal carboxyl-terminal CUB domains may be crucial for recognition and cleavage of VWF under flow.

  13. Characterization of an entomopathogenic fungi target integument protein, Bombyx mori single domain von Willebrand factor type C, in the silkworm, Bombyx mori.

    Science.gov (United States)

    Han, F; Lu, A; Yuan, Y; Huang, W; Beerntsen, B T; Huang, J; Ling, E

    2017-06-01

    The insect cuticle works as the first line of defence to protect insects from pathogenic infections and water evaporation. However, the old cuticle must be shed in order to enter the next developmental stage. During each ecdysis, moulting fluids are produced and secreted into the area among the old and new cuticles. In a previous study, the protein Bombyx mori single domain von Willebrand factor type C (BmSVWC; BGIBMGA011399) was identified in the moulting fluids of Bo. mori and demonstrated to regulate ecdysis. In this study we show that in Bo. mori larvae, BmSVWC primarily locates to the integument (epidermal cells and cuticle), wing discs and head. During the moulting stage, BmSVWC is released into the moulting fluids, and is then produced again by epidermal cells after ecdysis. Fungal infection was shown to decrease the amount of BmSVWC in the cuticle, which indicates that BmSVWC is a target protein of entomopathogenic fungi. Thus, BmSVWC is mainly involved in maintaining the integrity of the integument structure, which serves to protect insects from physical damage and pathogenic infection. © 2017 The Royal Entomological Society.

  14. Treatment of patients with von Willebrand disease

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    Tuohy E

    2011-04-01

    Full Text Available Emma Tuohy1, Emma Litt1, Raza Alikhan1,21Department of Haematology, University Hospital of Wales, Cardiff, UK; 2Haemophilia and Thrombosis Centre, University Hospital of Wales, Cardiff, UKAbstract: Von Willebrand disease (vWD is the most common hereditary bleeding disorder. The aim of therapy is to correct the dual hemostatic defect, due to defective platelet adhesion-aggregation and abnormal coagulation due to Factor VIII (FVIII deficiency. The choice of treatment depends on a number of factors, including the severity of the bleed, the procedure planned, the subtype and severity of the disease and the age and morbidity of the patient. Desmopressin (DDAVP is the treatment of choice for type 1 vWD as it increases endogenous release of FVIII and von Willebrand factor (vWF and is also used in some subtypes of type 2 vWD. In those patients in whom DDAVP is ineffective or contraindicated, levels can be restored by infusing vWF:FVIII concentrates. The role of antifibrinolytic treatment is an important adjunct to replacement therapy during minor or major surgery involving mucosal surfaces. The dosing and timing of vWF:FVIII concentrates is important depending on the nature of the surgical procedure. The role of secondary prophylaxis needs to be further defined.Keywords: von Willebrand disease, treatment, DDAVP 

  15. Assembly and activation of alternative complement components on endothelial cell-anchored ultra-large von Willebrand factor links complement and hemostasis-thrombosis.

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    Nancy A Turner

    Full Text Available Vascular endothelial cells (ECs express and release protein components of the complement pathways, as well as secreting and anchoring ultra-large von Willebrand factor (ULVWF multimers in long string-like structures that initiate platelet adhesion during hemostasis and thrombosis. The alternative complement pathway (AP is an important non-antibody-requiring host defense system. Thrombotic microangiopathies can be associated with defective regulation of the AP (atypical hemolytic-uremic syndrome or with inadequate cleavage by ADAMTS-13 of ULVWF multimeric strings secreted by/anchored to ECs (thrombotic thrombocytopenic purpura. Our goal was to determine if EC-anchored ULVWF strings caused the assembly and activation of AP components, thereby linking two essential defense mechanisms.We quantified gene expression of these complement components in cultured human umbilical vein endothelial cells (HUVECs by real-time PCR: C3 and C5; complement factor (CF B, CFD, CFP, CFH and CFI of the AP; and C4 of the classical and lectin (but not alternative complement pathways. We used fluorescent microscopy, monospecific antibodies against complement components, fluorescent secondary antibodies, and the analysis of >150 images to quantify the attachment of HUVEC-released complement proteins to ULVWF strings secreted by, and anchored to, the HUVECs (under conditions of ADAMTS-13 inhibition. We found that HUVEC-released C4 did not attach to ULVWF strings, ruling out activation of the classical and lectin pathways by the strings. In contrast, C3, FB, FD, FP and C5, FH and FI attached to ULVWF strings in quantitative patterns consistent with assembly of the AP components into active complexes. This was verified when non-functional FB blocked the formation of AP C3 convertase complexes (C3bBb on ULVWF strings.AP components are assembled and activated on EC-secreted/anchored ULVWF multimeric strings. Our findings provide one possible molecular mechanism for clinical

  16. Platelets, inflammatory cells, von Willebrand factor, syndecan-1, fibrin, fibronectin, and bacteria co-localize in the liver thrombi of Bacillus anthracis-infected mice.

    Science.gov (United States)

    Popova, Taissia G; Millis, Bryan; Bailey, Charles; Popov, Serguei G

    2012-01-01

    Vascular dysfunction and thrombosis have been described in association with anthrax infection in humans and animals but the mechanisms of these dysfunctions, as well as the components involved in thrombi formation are poorly understood. Immunofluorescent microscopy was used to define the composition of thrombi in the liver of mice challenged with the Bacillus anthracis Sterne spores. Lethal infection with the toxigenic Sterne strain, in contrast to the non-lethal, non-toxigenic delta-Sterne strain, demonstrated time-dependent increase in the number of vegetative bacteria inside the liver sinusoids and central vein. Massive appearance of thrombi typically occluding the lumen of the vessels coincided with the sudden death of infected animals. Bacterial chains in the thrombi were stained positive for syndecan-1 (SDC-1), fibronectin, and were surrounded by fibrin polymers, GPIIb-positive platelets, von Willebrand Factor (vWF), CD45-positive leukocytes, and massive amount of shed SDC-1. Experiments with human umbilical vein endothelial cells (HUVECs) demonstrated the active role of the host response to the secreted pathogenic factors of bacteria during the onset of the pro-thrombotic condition. The bacterial culture supernatants, as well as the isolated proteins (the pore-forming toxin anthrolysin O and phospholipase C) induced release of vWF, while anthrolysin O, sphingomyelinase and edema toxin induced release of thrombin from HUVECs and polymerization of fibrin in the presence of human plasma. Our findings suggest that activation of endothelium in response to infection can contribute to the formation of occlusive thrombi consisting of aggregated bacteria, vWF, shed SDC-1, fibrin, activated platelets, fibronectin and leukocytes. Copyright © 2011 Elsevier Ltd. All rights reserved.

  17. Von Willebrand Factor Antigen Predicts Response to Double Dose of Aspirin and Clopidogrel by PFA-100 in Patients Undergoing Primary Angioplasty for St Elevation Myocardial Infarction

    Directory of Open Access Journals (Sweden)

    Jacopo Gianetti

    2013-01-01

    Full Text Available Von Willebrand factor (VWF is an emerging risk factor in acute coronary syndromes. Platelet Function Analyzer (PFA-100 with Collagen/Epinephrine (CEPI is sensitive to functional alterations of VWF and also identifies patients with high on-treatment platelet reactivity (HPR. The objective of this study was to verify the effect of double dose (DD of aspirin and clopidogrel on HPR detected by PFA-100 and its relation to VWF and to its regulatory metalloprotease ADAMTS-13. Between 2009 and 2011 we enrolled 116 consecutive patients with ST elevation myocardial infarction undergoing primary PCI with HPR at day 5 after PCI. Patients recruited were then randomized between a standard dose (SD, n=58 or DD of aspirin and clopidogrel (DD, n=58, maintained for 6 months follow-up. Blood samples for PFA-100, light transmittance aggregometry, and VWF/ADAMTS-13 analysis were collected after 5, 30, and 180 days (Times 0, 1, and 2. At Times 1 and 2 we observed a significantly higher CEPI closure times (CT in DD as compared to SD (P<0.001. Delta of CEPI-CT (T1-T0 was significantly related to VWF (P<0.001 and inversely related to ADAMTS-13 (0.01. Responders had a significantly higher level of VWF at T0. Finally, in a multivariate model analysis, VWF and ADAMTS-13 in resulted significant predictors of CEPI-CT response (P=0.02. HRP detected by PFA-100 in acute myocardial infarction is reversible by DD of aspirin and clopidogrel; the response is predicted by basal levels of VWF and ADAMTS-13. PFA-100 may be a useful tool to risk stratification in acute coronary syndromes given its sensitivity to VWF.

  18. Protein replacement therapy and gene transfer in canine models of hemophilia A, hemophilia B, von willebrand disease, and factor VII deficiency.

    Science.gov (United States)

    Nichols, Timothy C; Dillow, Aaron M; Franck, Helen W G; Merricks, Elizabeth P; Raymer, Robin A; Bellinger, Dwight A; Arruda, Valder R; High, Katherine A

    2009-01-01

    Dogs with hemophilia A, hemophilia B, von Willebrand disease (VWD), and factor VII deficiency faithfully recapitulate the severe bleeding phenotype that occurs in humans with these disorders. The first rational approach to diagnosing these bleeding disorders became possible with the development of reliable assays in the 1940s through research that used these dogs. For the next 60 years, treatment consisted of replacement of the associated missing or dysfunctional protein, first with plasma-derived products and subsequently with recombinant products. Research has consistently shown that replacement products that are safe and efficacious in these dogs prove to be safe and efficacious in humans. But these highly effective products require repeated administration and are limited in supply and expensive; in addition, plasma-derived products have transmitted bloodborne pathogens. Recombinant proteins have all but eliminated inadvertent transmission of bloodborne pathogens, but the other limitations persist. Thus, gene therapy is an attractive alternative strategy in these monogenic disorders and has been actively pursued since the early 1990s. To date, several modalities of gene transfer in canine hemophilia have proven to be safe, produced easily detectable levels of transgene products in plasma that have persisted for years in association with reduced bleeding, and correctly predicted the vector dose required in a human hemophilia B liver-based trial. Very recently, however, researchers have identified an immune response to adeno-associated viral gene transfer vector capsid proteins in a human liver-based trial that was not present in preclinical testing in rodents, dogs, or nonhuman primates. This article provides a review of the strengths and limitations of canine hemophilia, VWD, and factor VII deficiency models and of their historical and current role in the development of improved therapy for humans with these inherited bleeding disorders.

  19. Living with von Willebrand Disease

    Science.gov (United States)

    ... the condition. For example, the school nurse, teacher, daycare provider, coach, or any leader of afterschool activities ... MedlinePlus) Von Willebrand Disease (MedlinePlus) Building 31 31 Center Drive Bethesda, MD 20892 Learn more about getting ...

  20. Myomectomy in a case of von Willebrand's disease in a low ...

    African Journals Online (AJOL)

    Von Willebrand's disease (vWD) is an inherited bleeding disorder with an estimated prevalence of 1% in the general population. It is caused by deficiency or dysfunction of von Willebrand's factor. Surgical procedure on patients with vWD is usually associated with increased haemorrhage. Keywords: Clotting Factors ...

  1. The important role of von Willebrand factor in platelet-derived FVIII gene therapy for murine hemophilia A in the presence of inhibitory antibodies.

    Science.gov (United States)

    Shi, Q; Schroeder, J A; Kuether, E L; Montgomery, R R

    2015-07-01

    Our previous studies have demonstrated that targeting FVIII expression to platelets results in FVIII storage together with von Willebrand factor (VWF) in platelet α-granules and that platelet-derived FVIII (2bF8) corrects the murine hemophilia A phenotype even in the presence of high-titer anti-FVIII inhibitory antibodies (inhibitors). To explore how VWF has an impact on platelet gene therapy for hemophilia A with inhibitors. 2bF8 transgenic mice in the FVIII(-/-) background (2bF8(tg+/-) F8(-/-) ) with varying VWF phenotypes were used in this study. Animals were analyzed by VWF ELISA, FVIII activity assay, Bethesda assay and tail clip survival test. Only 18% of 2bF8(tg+/-) F8(-/-) VWF(-/-) animals, in which VWF was deficient, survived the tail clip challenge with inhibitor titers of 3-8000 BU mL(-1) . In contrast, 82% of 2bF8(tg+/-) F8(-/-) VWF(+/+) mice, which had normal VWF levels, survived tail clipping with inhibitor titers of 10-50,000 BU mL(-1) . All 2bF8(tg+/-) F8(-/-) VWF(-/-) mice without inhibitors survived tail clipping and no VWF(-/-) F8(-/-) mice survived this challenge. Because VWF is synthesized by endothelial cells and megakaryocytes and is distributed in both plasma and platelets in peripheral blood, we further investigated the effect of each compartment of VWF on platelet-FVIII gene therapy for hemophilia A with inhibitors. In the presence of inhibitors, 42% of animals survived tail clipping in the group with plasma-VWF and 50% survived in the platelet-VWF group. VWF is essential for platelet gene therapy for hemophilia A with inhibitors. Both platelet-VWF and plasma-VWF are required for optimal platelet-derived FVIII gene therapy for hemophilia A in the presence of inhibitors. © 2015 International Society on Thrombosis and Haemostasis.

  2. Nordic Haemophilia Council's practical guidelines on diagnosis and management of von Willebrand disease

    DEFF Research Database (Denmark)

    Lassila, Riitta; Holme, Pål André; Landorph, Andrea

    2011-01-01

    Von Willebrand disease (VWD) is the most common inherited bleeding disorder characterized by spontaneous or tissue injury-related, mostly mucocutaneous, bleeding events. VWD affects both males and females and is caused by quantitative or qualitative deficiency of Von Willebrand factor. The diagno...

  3. Current and Emerging Options for the Management of Inherited von Willebrand Disease

    NARCIS (Netherlands)

    Heijdra, J.M. (Jessica M.); M.H. Cnossen (Marjon); F.W.G. Leebeek (Frank)

    2017-01-01

    textabstractVon Willebrand disease (VWD) is the most common inherited bleeding disorder with an estimated prevalence of ~1% and clinically relevant bleeding symptoms in approximately 1:10,000 individuals. VWD is caused by a deficiency and/or defect of von Willebrand factor (VWF). The most common

  4. Von Willebrand Disease in the Netherlands : from genetic variation to phenotypic variability

    NARCIS (Netherlands)

    Y.V. Sanders (Yvonne)

    2015-01-01

    markdownabstractAbstract Von Willebrand Disease (VWD) is the most common inherited bleeding disorder resulting in mucocutaneous bleeding, like epistaxis, oral cavity bleeding and menorrhagia. VWD is caused by reduced or dysfunctional von Willebrand Factor (VWF). VWF levels are highly variable

  5. The metal-ion-dependent adhesion site in the Von Willebrand factor-A domain of α2δ subunits is key to trafficking voltage-gated Ca2+ channels

    Science.gov (United States)

    Cantí, C.; Nieto-Rostro, M.; Foucault, I.; Heblich, F.; Wratten, J.; Richards, M. W.; Hendrich, J.; Douglas, L.; Page, K. M.; Davies, A.; Dolphin, A. C.

    2005-01-01

    All auxiliary α2δ subunits of voltage-gated Ca2+ (CaV) channels contain an extracellular Von Willebrand factor-A (VWA) domain that, in α2δ-1 and -2, has a perfect metal-ion-dependent adhesion site (MIDAS). Modeling of the α2δ-2 VWA domain shows it to be highly likely to bind a divalent cation. Mutating the three key MIDAS residues responsible for divalent cation binding resulted in a MIDAS mutant α2δ-2 subunit that was still processed and trafficked normally when it was expressed alone. However, unlike WT α2δ-2, the MIDAS mutant α2δ-2 subunit did not enhance and, in some cases, further diminished CaV1.2, -2.1, and -2.2 currents coexpressed with β1b by using either Ba2+ or Na+ as a permeant ion. Furthermore, expression of the MIDAS mutant α2δ-2 reduced surface expression and strongly increased the perinuclear retention of CaVα1 subunits at the earliest time at which expression was observed in both Cos-7 and NG108–15 cells. Despite the presence of endogenous α2δ subunits, heterologous expression of α2δ-2 in differentiated NG108–15 cells further enhanced the endogenous high-threshold Ca2+ currents, whereas this enhancement was prevented by the MIDAS mutations. Our results indicate that α2δ subunits normally interact with the CaVα1 subunit early in their maturation, before the appearance of functional plasma membrane channels, and an intact MIDAS motif in the α2δ subunit is required to promote trafficking of the α1 subunit to the plasma membrane by an integrin-like switch. This finding provides evidence for a primary role of a VWA domain in intracellular trafficking of a multimeric complex, in contrast to the more usual roles in binding extracellular ligands in other exofacial VWA domains. PMID:16061813

  6. Inhibition of ADAMTS-13 by Doxycycline Reduces von Willebrand Factor Degradation During Supraphysiological Shear Stress: Therapeutic Implications for Left Ventricular Assist Device-Associated Bleeding.

    Science.gov (United States)

    Bartoli, Carlo R; Kang, Jooeun; Restle, David J; Zhang, David M; Shabahang, Cameron; Acker, Michael A; Atluri, Pavan

    2015-11-01

    The aim of this study was to investigate a potential therapy for left ventricular assist device (LVAD)-associated bleeding. Nonsurgical bleeding is the most frequent complication of LVAD support. Recent evidence has demonstrated that supraphysiological shear stress from continuous-flow LVADs accelerates von Willebrand factor (vWF) metabolism by the action of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13) (the vWF protease). An acquired vWF deficiency causes bleeding. This suggests that ADAMTS-13 is a clinical target to reduce vWF degradation. We tested the hypothesis that inhibition of ADAMTS-13 with doxycycline, an inexpensive, clinically approved drug, reduces vWF degradation during shear stress. Whole blood was collected from human donors (n = 15), and purified, recombinant ADAMTS-13 protein was obtained. An enzyme-linked immunosorbent assay (ELISA) was used to quantify the dose relationship between doxycycline and ADAMTS-13 activity prior to shear stress (n = 10). To determine the effect of shear stress, plasma and recombinant ADAMTS-13 were exposed to LVAD-like supraphysiological shear stress (approximately 175 dyne/cm(2)). vWF multimers and degradation fragments were characterized with electrophoresis and immunoblotting (n = 10). Förster resonance energy transfer was used to quantify plasma ADAMTS-13 activity (n = 10). An ELISA was used to quantify vWF:collagen binding activity. Platelet aggregometry was performed with adenosine 5'-diphosphate, collagen, and ristocetin (vWF-platelet pathway) agonism (n = 10). Doxycycline significantly decreased plasma ADAMTS-13 activity (p = 0.01) and the activity of recombinant human ADAMTS-13 protein by 21%. After plasma was exposed to shear stress, the same pattern of vWF degradation was observed as previously reported for LVAD patients, and vWF:collagen binding activity decreased significantly (p = 0.002). Doxycycline significantly decreased ADAMTS-13 activity (p = 0.04) and

  7. Acquired von Willebrand syndrome: A rare disorder of heterogeneous etiology

    Directory of Open Access Journals (Sweden)

    P Kasatkar

    2013-01-01

    Full Text Available Context: Acquired von Willebrand syndrome (AVWS is a rare bleeding disorder that mimics the inherited form of von Willebrand disease (VWD in terms of laboratory findings and clinical presentation. Aims: To study the etiology of acquired VWD. Settings and Design: The patients referred from various hospitals in and out of Mumbai were included in the study. Materials and Methods: Six patients with AVWS diagnosed at this center over the last 10 years were analyzed against 171 patients with inherited VWD. The differential diagnosis of AVWS was made based on reduced levels of von Willebrand antigen and von Willebrand ristocetin cofactor, decrease in ristocetin induced platelet aggregation, absence of correction in mixing studies with no prior history of bleeding problems and a negative family history for bleeding disorders. Results: In three patients, the disease was associated with systematic lupus erythematosus, out of which one was also associated with Kikuchi lymphadenitis and second with autoimmune hemolytic anemia. Fourth case was associated with hypothyroidism and fifth was a case of dermatitis and vitiligo. The last patient was a case of hemophilia A with Burkitts lymphoma, who developed autoantibodies to von Willebrand factor. Except two patients, all other patients responded to immune suppressive therapy with corticosteroids, while the patient with hypothyroidism responded to oral thyroxine. Conclusion: AVWS is a rare condition and may often be missed or diagnosed as inherited disease associated with heterogeneous disease conditions.

  8. Diagnosing von Willebrand disease: a short history of laboratory milestones and innovations, plus current status, challenges, and solutions.

    Science.gov (United States)

    Favaloro, Emmanuel J

    2014-07-01

    von Willebrand disease (VWD) is a disorder characterized by deficiency of, or defects in, von Willebrand factor (VWF). VWD was originally identified by Erik Adolf von Willebrand, who in early 1924 investigated a large family suffering from a bleeding disorder that seemed to differ from hemophilia. Erik von Willebrand undertook some initial laboratory investigations to conclude the involvement of a plasma factor, the lack of which prolonged the bleeding time, but failed to impair coagulation times and clot retraction. By the end of the 1960s, VWD was accepted as a combined deficiency of factor VIII (FVIII) and another plasma factor responsible for normal platelet adhesion. Just how these two functions were related to each other was less clear and the diagnostic tests available at the time were poorly reproducible, cumbersome, and unreliable; thus, VWD was poorly delineated from other coagulation and platelet disorders. The early 1970s saw a revolution in diagnostics when ristocetin was identified to induce platelet aggregation, and this formed the basis of the first consistent and reliable VWF "activity" test, permitting quantification of the platelet adhesive function missing in VWD. Concurrently, immunoprecipitating techniques specific for VWF were defined, and the application of such technologies permitted a clearer understanding of both VWF and VWD heterogeneity. Continued exploration of the structure and function of VWF contributed greatly to the understanding of platelet physiology, ligand receptor interaction and pathways of cellular interaction and activation. Recently, additional assays evaluating other functions of VWF, including collagen binding, platelet glycoprotein Ib binding, and FVIII binding, have improved the diagnosis of VWD. The purpose of this narrative review is to explore the history of phenotypic VWD diagnostics, with a focus on laboratory milestones from the past as well highlighting recent and ongoing innovations, and ongoing challenges and

  9. Clinical and laboratory diagnosis of von Willebrand disease : A synopsis of the 2008 NHLBI/NIH guidelines

    NARCIS (Netherlands)

    Nichols, William L.; Rick, Margaret E.; Ortel, Thomas L.; Montgomery, Robert R.; Sadler, J. Evan; Yawn, Barbara P.; James, Andra H.; Hultin, Mae B.; Manco-Johnson, Marilyn J.; Weinstein, Mark

    Von Willebrand factor (VWF) mediates blood platelet adhesion and accumulation at sites of blood vessel injury, and also carries coagulation factor VIII (FVIII) that is important for generating procoagulant activity. Von Willebrand disease (VWD), the most common inherited bleeding disorder, affects

  10. Translational medicine advances in von Willebrand disease.

    Science.gov (United States)

    Lillicrap, D

    2013-06-01

    Following the recognition of von Willebrand disease (VWD) in 1926 and the cloning of the gene for von Willebrand factor (VWF) in 1985, significant advances have been made in our fundamental knowledge of both the disease and the protein. Some of this new knowledge has also begun to impact the clinical management of VWD. First, the progressive increase in our understanding of the molecular genetic basis of VWD has resulted in rational applications of molecular testing to complement the current range of phenotypic tests for VWD. These molecular genetic strategies are most effectively directed at the prenatal diagnosis of type 3 VWD and confirmatory testing for types 2B and 2N disease. In contrast, the use of molecular testing to clarify the diagnosis of type 1 VWD is of marginal benefit, at best. In terms of VWD therapies, a new recombinant VWF concentrate has recently completed successful clinical trials and is now awaiting more widespread application. There have even been some preclinical successes with VWF gene transfer although the clinical rationale for this therapeutic strategy needs careful consideration. Much more remains to be learnt about the biology of VWF and further translational advances for the enhancement of VWD care will inevitably be realized. © 2013 International Society on Thrombosis and Haemostasis.

  11. DEEP VEIN THROMBOSIS IN PATIENT WITH VON WILLEBRAND DISEASE

    Directory of Open Access Journals (Sweden)

    V. A. Elykomov

    2016-01-01

    Full Text Available Objective: to identify the possible factors of thrombogenic risk and ways of its prevention in patients with von Willebrand disease.Case description. Patient X., 42 years old, who suffers from von Willebrand disease type 3 with 5-years of age. Asked on reception to the traumatologist in the polyclinic of the Regional Hospital with pain in the left hip joint. Recommended planned operative treatment in the Altai Regional Clinical Hospital. Preoperative preparation included the infusion of concentrate of von Willebrand factor and coagulation factor VIII. Operation – cement total arthroplasty of the left hip joint. In the postoperative period analgesic treatment, elastic compression of the lower extremities, iron supplements, also conducted infusion of concentrate of von Willebrand factor and coagulation factor VIII for 20 days and thromboprophylactic with dabigatran. On the 3rd day after the operation the patient revealed deep vein thrombosis of the femoral segment (floating clot.Results. The patient was operated for emergency indications in the Department of endovascular surgery – installation of venous cava filter “Volan”. Dabigatran is cancelled, appointed clexane for 3 months. In our clinical example the patient lacked risk factors of pulmonary embolism as obesity, age, smoking, prolonged immobilization, estrogen therapy. Overdose of factor VIII were not observed – the level of factor did not exceed 135 % on transfusions. At the same time, the patient was found polymorphisms in the genes ITGA2, FGB, MTHFR, MTR – heterozygote, MTRR – mutant homozygote, which may indicate the genetic factors of thrombogenic risk. Also a significant risk factor was massive surgical intervention (total hip replacement. Despite preventive measures (elastic compression, thromboprophylactic dabigatran, early activation we cannot to avoid thrombotic complications.Conclusion. This article presents a case demonstrating a thrombotic complication in patients

  12. Consumption of nattokinase is associated with reduced blood pressure and von Willebrand factor, a cardiovascular risk marker: results from a randomized, double-blind, placebo-controlled, multicenter North American clinical trial

    Directory of Open Access Journals (Sweden)

    Jensen GS

    2016-10-01

    Full Text Available Gitte S Jensen,1 Miki Lenninger,1 Michael P Ero,2 Kathleen F Benson,1 1NIS Labs, Klamath Falls, OR, 2Machaon Diagnostics, Inc., Oakland, CA, USA Objective: The objective of this study is to evaluate the effects of consumption of nattokinase on hypertension in a North American hypertensive population with associated genetic, dietary, and lifestyle factors. This is in extension of, and contrast to, previous studies on Asian populations.Materials and methods: A randomized, double-blind, placebo-controlled, parallel-arm clinical study was performed to evaluate nattokinase (NSK-SD, a fermented soy extract nattō from which vitamin K2 has been removed. Based on the results from previous studies on Asian populations, 79 subjects were enrolled upon screening for elevated blood pressure (BP; systolic BP ≥130 or diastolic BP ≥90 mmHg who consumed placebo or 100 mg nattokinase/d for the 8-week study duration. Blood collections were performed at baseline and 8 weeks for testing plasma renin activity, von Willebrand factor (vWF, and platelet factor-4. Seventy-four people completed the study with good compliance.Results: Consumption of nattokinase was associated with a reduction in both systolic and diastolic BP. The reduction in systolic BP was seen for both sexes but was more robust in males consuming nattokinase. The average reduction in diastolic BP in the nattokinase group from 87 mmHg to 84 mmHg was statistically significant when compared to that in the group consuming placebo, where the average diastolic BP remained constant at 87 mmHg (P<0.05, and reached a high level of significance for males consuming nattokinase, where the average diastolic BP dropped from 86 mmHg to 81 mmHg (P<0.006. A decrease in vWF was seen in the female population consuming nattokinase (P<0.1. In the subpopulation with low plasma renin activity levels at baseline (<0.29 ng/mL/h, an increase was seen for 66% of the people after 8-week consumption of nattokinase (P

  13. Screening of Von Willebrand Disease in Iranian Women With Menorrhagia

    Science.gov (United States)

    Rahbar, Nahid; Faranoush, Mohammad; Ghorbani, Raheb; Sadr Alsadat, Bahare

    2015-01-01

    Background: Menorrhagia is a common health problem in women, particularly those with bleeding disorders. Little is known about the course of menorrhagia or other bleeding symptoms in women with the most common congenital bleeding disorder, von Willebrand disease (vWD). Objectives: The aim of this study was to estimate the prevalence of vWD in women with diagnosed menorrhagia. Materials and Methods: In this cross-sectional study, a total of 460 consecutive patients, presenting menorrhagia, were analyzed. The initial screening and confirmation tests for the diagnosis of vWD included determination of prothrombin time (PT), partial thromboplastin time (PTT), bleeding time (BT), fibrinogen, factor VIII, vWF antigen, and vWF activity. A questionnaire was filled for every patient. The data were then analyzed using the SPSS software. Results: Mean age of our patients was 32.5 ± 10.6 years. The level of von Willebrand factor in 22.5% and von Willebrand activity in 19.6% of patients was abnormal. The prevalence of vWD among patients with menorrhagia was 24%. Conclusions: The high prevalence of vWD among our patients was the same as other previous reports, suggesting low awareness about this disease and under diagnosis of mild cases. PMID:25763275

  14. How Is von Willebrand Disease Treated?

    Science.gov (United States)

    ... the condition. For example, the school nurse, teacher, daycare provider, coach, or any leader of afterschool activities ... MedlinePlus) Von Willebrand Disease (MedlinePlus) Building 31 31 Center Drive Bethesda, MD 20892 Learn more about getting ...

  15. How Is von Willebrand Disease Diagnosed?

    Science.gov (United States)

    ... the condition. For example, the school nurse, teacher, daycare provider, coach, or any leader of afterschool activities ... MedlinePlus) Von Willebrand Disease (MedlinePlus) Building 31 31 Center Drive Bethesda, MD 20892 Learn more about getting ...

  16. Genetics Home Reference: von Willebrand disease

    Science.gov (United States)

    ... Jun;5(6):1165-9. Citation on PubMed Kessler CM. Diagnosis and treatment of von Willebrand disease: ... consult with a qualified healthcare professional . About Selection Criteria for Links Data Files & API Site Map Customer ...

  17. High-Affinity DNA Aptamer Generation Targeting von Willebrand Factor A1-Domain by Genetic Alphabet Expansion for Systematic Evolution of Ligands by Exponential Enrichment Using Two Types of Libraries Composed of Five Different Bases.

    Science.gov (United States)

    Matsunaga, Ken-Ichiro; Kimoto, Michiko; Hirao, Ichiro

    2017-01-11

    The novel evolutionary engineering method ExSELEX (genetic alphabet expansion for systematic evolution of ligands by exponential enrichment) provides high-affinity DNA aptamers that specifically bind to target molecules, by introducing an artificial hydrophobic base analogue as a fifth component into DNA aptamers. Here, we present a newer version of ExSELEX, using a library with completely randomized sequences consisting of five components: four natural bases and one unnatural hydrophobic base, 7-(2-thienyl)imidazo[4,5-b]pyridine (Ds). In contrast to the limited number of Ds-containing sequence combinations in our previous library, the increased complexity of the new randomized library could improve the success rates of high-affinity aptamer generation. To this end, we developed a sequencing method for each clone in the enriched library after several rounds of selection. Using the improved library, we generated a Ds-containing DNA aptamer targeting von Willebrand factor A1-domain (vWF) with significantly higher affinity (KD = 75 pM), relative to those generated by the initial version of ExSELEX, as well as that of the known DNA aptamer consisting of only the natural bases. In addition, the Ds-containing DNA aptamer was stabilized by introducing a mini-hairpin DNA resistant to nucleases, without any loss of affinity (KD = 61 pM). This new version is expected to consistently produce high-affinity DNA aptamers.

  18. Consumption of nattokinase is associated with reduced blood pressure and von Willebrand factor, a cardiovascular risk marker: results from a randomized, double-blind, placebo-controlled, multicenter North American clinical trial

    Science.gov (United States)

    Jensen, Gitte S; Lenninger, Miki; Ero, Michael P; Benson, Kathleen F

    2016-01-01

    Objective The objective of this study is to evaluate the effects of consumption of nattokinase on hypertension in a North American hypertensive population with associated genetic, dietary, and lifestyle factors. This is in extension of, and contrast to, previous studies on Asian populations. Materials and methods A randomized, double-blind, placebo-controlled, parallel-arm clinical study was performed to evaluate nattokinase (NSK-SD), a fermented soy extract nattō from which vitamin K2 has been removed. Based on the results from previous studies on Asian populations, 79 subjects were enrolled upon screening for elevated blood pressure (BP; systolic BP ≥130 or diastolic BP ≥90 mmHg) who consumed placebo or 100 mg nattokinase/d for the 8-week study duration. Blood collections were performed at baseline and 8 weeks for testing plasma renin activity, von Willebrand factor (vWF), and platelet factor-4. Seventy-four people completed the study with good compliance. Results Consumption of nattokinase was associated with a reduction in both systolic and diastolic BP. The reduction in systolic BP was seen for both sexes but was more robust in males consuming nattokinase. The average reduction in diastolic BP in the nattokinase group from 87 mmHg to 84 mmHg was statistically significant when compared to that in the group consuming placebo, where the average diastolic BP remained constant at 87 mmHg (Pnattokinase, where the average diastolic BP dropped from 86 mmHg to 81 mmHg (Pnattokinase (Pnattokinase (Pnattokinase consumption in a North American population is associated with beneficial changes to BP in a hypertensive population, indicating sex-specific mechanisms of action of nattokinase’s effect on vWF and hypertension. PMID:27785095

  19. Consumption of nattokinase is associated with reduced blood pressure and von Willebrand factor, a cardiovascular risk marker: results from a randomized, double-blind, placebo-controlled, multicenter North American clinical trial.

    Science.gov (United States)

    Jensen, Gitte S; Lenninger, Miki; Ero, Michael P; Benson, Kathleen F

    2016-01-01

    The objective of this study is to evaluate the effects of consumption of nattokinase on hypertension in a North American hypertensive population with associated genetic, dietary, and lifestyle factors. This is in extension of, and contrast to, previous studies on Asian populations. A randomized, double-blind, placebo-controlled, parallel-arm clinical study was performed to evaluate nattokinase (NSK-SD), a fermented soy extract nattō from which vitamin K2 has been removed. Based on the results from previous studies on Asian populations, 79 subjects were enrolled upon screening for elevated blood pressure (BP; systolic BP ≥130 or diastolic BP ≥90 mmHg) who consumed placebo or 100 mg nattokinase/d for the 8-week study duration. Blood collections were performed at baseline and 8 weeks for testing plasma renin activity, von Willebrand factor (vWF), and platelet factor-4. Seventy-four people completed the study with good compliance. Consumption of nattokinase was associated with a reduction in both systolic and diastolic BP. The reduction in systolic BP was seen for both sexes but was more robust in males consuming nattokinase. The average reduction in diastolic BP in the nattokinase group from 87 mmHg to 84 mmHg was statistically significant when compared to that in the group consuming placebo, where the average diastolic BP remained constant at 87 mmHg (Pnattokinase, where the average diastolic BP dropped from 86 mmHg to 81 mmHg (Pnattokinase (Pnattokinase (Pnattokinase consumption in a North American population is associated with beneficial changes to BP in a hypertensive population, indicating sex-specific mechanisms of action of nattokinase's effect on vWF and hypertension.

  20. Changes in bleeding patterns in von Willebrand disease after institution of long-term replacement therapy : results from the von Willebrand Disease Prophylaxis Network

    NARCIS (Netherlands)

    Holm, Elena; Abshire, Thomas C; Bowen, Joel; Álvarez, M Teresa; Bolton-Maggs, Paula; Carcao, Manuel; Federici, Augusto B; Gill, Joan Cox; Halimeh, Susan; Kempton, Christine; Key, Nigel S; Kouides, Peter; Lail, Alice; Landorph, Andrea; Leebeek, Frank; Makris, Michael; Mannucci, Pier; Mauser-Bunschoten, Eveline P; Nugent, Diane; Valentino, Leonard A; Winikoff, Rochelle; Berntorp, Erik

    Clinically, the leading symptom in von Willebrand disease (VWD) is bleeding, chiefly of mucosal type, for example, epistaxis, gingival, or gastrointestinal bleeding, and menorrhagia. In severe forms of VWD with secondary deficiency of factor VIII, spontaneous joint bleeding, resembling that observed

  1. Van Willebrand's disease in the Western Cape

    African Journals Online (AJOL)

    Von Willebrand's disease (VWD) is a mild-ta-moderately severe bleeding disorder characterised by mucosal bleeding such as epistaxis, gingival bleeding, gastro-intestinal bleeding and menorrhagia Haemarthroses, deep subcutaneous and intramuscular haematomas, typically seen in the severe haemophilias. are ...

  2. Joint bleeding in von Willebrand disease

    NARCIS (Netherlands)

    Galen, K.P.M. van

    2017-01-01

    Von Willebrand disease (VWD) is the most common inherited bleeding disorder occurring in approximately 1/100 people. Until now, joint bleeds did not get much attention in clinical research on VWD, since mucocutaneous bleeding is predominant. However, recurrent joint bleeds lead to arthropathy, the

  3. Inheritance of von Willebrand's disease in a colony of Doberman Pinschers.

    Science.gov (United States)

    Riehl, J; Okura, M; Mignot, E; Nishino, S

    2000-02-01

    To determine the mode of inheritance of von Willebrand's disease (vWD) and perform linkage analysis between vWD and coat color or narcolepsy in a colony of Doberman Pinschers. 159 Doberman Pinschers. von Willebrand factor antigen (vWF:Ag) concentration was measured by use of ELISA, and results were used to classify dogs as having low ( 65%) vWF:Ag concentration, compared with results of analysis of standard pooled plasma. Buccal bleeding time was measured, and mode of inheritance of vWD was assessed by pedigree analysis. von Willebrand's disease was transmitted as a single autosomal gene defect. Results suggested that 27.04% of dogs were homozygous for vWD, 62.26% were heterozygous, and 10.69% did not have the defect. Most homozygous and some heterozygous dogs had prolonged bleeding times. Dogs with diluted coat colors (blue and fawn) were significantly overrepresented in the homozygous group, compared with black and red dogs, but a significant link between vWD and coat color was not detected. von Willebrand's disease is transmitted as an autosomal dominant trait with variable penetrance; most dogs in this colony (89.3%) were carriers of vWD. Homozygosity for vWD is not likely to be lethal. Some heterozygous dogs have prolonged bleeding times. An association between diluted coat colors and vWD may exist.

  4. Pseudo (Platelet-type von Willebrand disease in pregnancy: a case report

    Directory of Open Access Journals (Sweden)

    Grover Neetu

    2013-01-01

    Full Text Available Abstract Background Pseudo (platelet-type-von Willebrand disease is a rare autosomal dominant bleeding disorder caused by an abnormal function of the glycoprotein lb protein; the receptor for von Willebrand factor. This leads to an increased removal of VWF multimers from the circulation as well as platelets and this results in a bleeding diathesis. Worldwide, less than 50 patients are reported with platelet type von Willebrand disease (PT-VWD. Case presentation We describe the management of platelet type von Willebrand disease in pregnancy of a 26 year old Caucasian primigravida. The initial diagnosis was made earlier following a significant haemorrhage post tonsillectomy several years prior to pregnancy. The patient was managed under a multidisciplinary team which included obstetricians, haematologists, anaesthetists and neonatologists. Care plans were made for the ante- natal, intra-partum and post-partum periods in partnership with the patient. The patient’s platelet count levels dropped significantly during the antenatal period. This necessitated the active exclusion of other causes of thrombocytopenia in pregnancy. A vaginal delivery was desired and plans were made for induction of labour at 38 weeks of gestation with platelet cover in view of the progressive fall of the platelet count. The patient however went into spontaneous labour on the day of induction. She was transfused two units of platelets before delivery. She had an unassisted vaginal delivery of a healthy baby. The successful antenatal counselling has encouraged the diagnosis of the same condition in her mother and sister. We found this to be a particularly interesting case as well as challenging to manage due to its rarity. Psuedo von Willebrand disease in pregnancy can be confused with a number of other differential diagnoses, such as gestational thrombocutopenia, idiopathatic thrombocytopenia, thrombotic thrombocytopenic purpura and pre-eclampsia; all need consideration

  5. Pseudo (platelet-type) von Willebrand disease in pregnancy: a case report.

    Science.gov (United States)

    Grover, Neetu; Boama, Vincent; Chou, Munazzah Rifat

    2013-01-17

    Pseudo (platelet-type)-von Willebrand disease is a rare autosomal dominant bleeding disorder caused by an abnormal function of the glycoprotein lb protein; the receptor for von Willebrand factor. This leads to an increased removal of VWF multimers from the circulation as well as platelets and this results in a bleeding diathesis. Worldwide, less than 50 patients are reported with platelet type von Willebrand disease (PT-VWD). We describe the management of platelet type von Willebrand disease in pregnancy of a 26 year old Caucasian primigravida. The initial diagnosis was made earlier following a significant haemorrhage post tonsillectomy several years prior to pregnancy. The patient was managed under a multidisciplinary team which included obstetricians, haematologists, anaesthetists and neonatologists. Care plans were made for the ante- natal, intra-partum and post-partum periods in partnership with the patient. The patient's platelet count levels dropped significantly during the antenatal period. This necessitated the active exclusion of other causes of thrombocytopenia in pregnancy. A vaginal delivery was desired and plans were made for induction of labour at 38 weeks of gestation with platelet cover in view of the progressive fall of the platelet count. The patient however went into spontaneous labour on the day of induction. She was transfused two units of platelets before delivery. She had an unassisted vaginal delivery of a healthy baby. The successful antenatal counselling has encouraged the diagnosis of the same condition in her mother and sister. We found this to be a particularly interesting case as well as challenging to manage due to its rarity. Psuedo von Willebrand disease in pregnancy can be confused with a number of other differential diagnoses, such as gestational thrombocutopenia, idiopathatic thrombocytopenia, thrombotic thrombocytopenic purpura and pre-eclampsia; all need consideration during investigations even in a case such as this where the

  6. Levonorgestrel intrauterine system as a treatment option for severe menorrhagia in adolescent with type III von Willebrand disease.

    Science.gov (United States)

    Silva, Carla Donato; Geraldes, Fernanda; Silva, Isabel Santos

    2013-04-30

    The authors describe a case of an adolescent with type III von Willebrand disease and severe menorrhagia since menarche. Antifibrinolytic, hormonal (estroprogestative pill in high doses, etonogestrel implant and gonadotropin-releasing hormone agonist goserelin) and Von Willebrand Factor/Factor VIII replacement therapies were prescribed to the patient, but symptomatic control was only obtained with high doses of VWF/FVIII twice a week. In March 2012, a levonorgestrel intrauterine system was inserted in a 14-year-old. At present, the patient is asymptomatic without regular prophylaxis (VWF/FVIII replacement therapy) and has had a remarkable improvement in her quality of life.

  7. Management of type 2b von Willebrand disease in the neonatal period.

    Science.gov (United States)

    Proud, Lindsay; Ritchey, A Kim

    2017-01-01

    Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting one in 1,000 people. Type 2b VWD is a less common subtype caused by a gain-of-function mutation in von Willebrand factor (VWF) that leads to the formation of large, ineffective VWF-platelet multimers in circulation. This unique pathophysiology creates diagnostic and treatment dilemmas. There is limited information on the management of type 2b VWD in the neonatal period. This report describes the management of a neonate with type 2b VWD with an emphasis on the added benefit of concomitant platelet transfusion and factor replacement therapy over factor replacement therapy alone. © 2016 Wiley Periodicals, Inc.

  8. Prophylaxis escalation in severe von Willebrand disease: A prospective study from the von Willebrand Disease Prophylaxis Network

    NARCIS (Netherlands)

    T.C. Abshire (Thomas Calvin); J. Cox-Gill; C.L. Kempton; F.W.G. Leebeek (Frank); M. Carcao (M.); P. Kouides (P.); S. Donfield (S.); E. Berntorp

    2015-01-01

    textabstractBackground: Treatment of mucosal bleeding (epistaxis, gastrointestinal bleeding, and menorrhagia) and joint bleeding remains problematic in clinically severe von Willebrand disease (VWD). Patients are often unresponsive to treatment (e.g. desmopressin or antifibrinolytic therapy) and may

  9. Pulmonary hypertension secondary to hyperviscosity in a patient with rheumatoid arthritis and acquired von Willebrand disease: a case report.

    Science.gov (United States)

    Hernández-Gilsoul, Thierry; Atisha-Fregoso, Yemil; Vargas-Ruíz, Angel G; Rivero-Sigarroa, Eduardo; Dominguez-Cherit, Guillermo; Namendys-Silva, Silvio A

    2013-10-02

    Acquired von Willebrand disease is initiated by autoantibodies and hyperviscosity syndrome caused by a massive polyclonal hypergammaglobulinemia. Acquired von Willebrand disease associated with autoimmune disease in addition to pulmonary hypertension during emergency room presentation is a rare condition. To the best of our knowledge, this is the second case reported in the literature treated with success; the first one was reported in 1987. A 28-year-old mestizo man with a 3-year history of inflammatory arthritis was admitted to our hospital. An overlap of rheumatoid arthritis with systemic lupus erythematosus was suspected; therefore methotrexate was initiated, and later changed to leflunomide because of liver toxicity. Prothrombin time, international normalized ratio and activated partial thromboplastin times were normal (11/10.4 seconds; 1.2; 31.1/26.9 seconds, respectively), von Willebrand factor activity was observed with low ristocetin cofactor at 33.6UI/dL, high von Willebrand factor antigen >200UI/dL, and a low von Willebrand factor: ristocetin cofactor to von Willebrand factor antigen ratio. He was admitted to the emergency room with a 24-hour evolution of progressive dyspnea, cough, thoracic pain, and palpitations, 104 beats/min, 60/40 mmHg, temperature of 38°C, pulse oximetric saturation 88% and 30 breaths/minute. Cold, pale and mottled skin was also observed. He was then transferred to the intensive care unit. The placement of a pulmonary artery catheter was made. The initial patterns showed a precapillary pulmonary hypertension; acute pulmonary embolism was the first choice for diagnosis. Pulmonary angiography was conducted, and when no clot was discovered, pulmonary artery hypertension associated with connective tissue disease was considered. Serum protein electrophoresis confirmed the presence of a massive polyclonal hypergammaglobulinemia, and no paraproteinemia or monoclonal cell population was found from the electrophoretic pattern of the

  10. Cross-Family Transcription Factor Interactions

    NARCIS (Netherlands)

    Bemer, Marian; Dijk, van Aalt-Jan; Immink, Richard G.H.; Angenent, Gerco C.

    2017-01-01

    Specific and dynamic gene expression strongly depends on transcription factor (TF) activity and most plant TFs function in a combinatorial fashion. They can bind to DNA and control the expression of the corresponding gene in an additive fashion or cooperate by physical interactions, forming larger

  11. Factors in social interaction in cohousing communities

    NARCIS (Netherlands)

    Liek Voorbij; Jantine Bouma

    2008-01-01

    Cohousing communities can be considered alternatives for living independently in old age. However, currently the factors that influence the success of these communities are unclear. Based on literature and case studies gathered by students a new interaction- model was created that shows the

  12. Global quantitative modeling of chromatin factor interactions.

    Directory of Open Access Journals (Sweden)

    Jian Zhou

    2014-03-01

    Full Text Available Chromatin is the driver of gene regulation, yet understanding the molecular interactions underlying chromatin factor combinatorial patterns (or the "chromatin codes" remains a fundamental challenge in chromatin biology. Here we developed a global modeling framework that leverages chromatin profiling data to produce a systems-level view of the macromolecular complex of chromatin. Our model ultilizes maximum entropy modeling with regularization-based structure learning to statistically dissect dependencies between chromatin factors and produce an accurate probability distribution of chromatin code. Our unsupervised quantitative model, trained on genome-wide chromatin profiles of 73 histone marks and chromatin proteins from modENCODE, enabled making various data-driven inferences about chromatin profiles and interactions. We provided a highly accurate predictor of chromatin factor pairwise interactions validated by known experimental evidence, and for the first time enabled higher-order interaction prediction. Our predictions can thus help guide future experimental studies. The model can also serve as an inference engine for predicting unknown chromatin profiles--we demonstrated that with this approach we can leverage data from well-characterized cell types to help understand less-studied cell type or conditions.

  13. Global Quantitative Modeling of Chromatin Factor Interactions

    Science.gov (United States)

    Zhou, Jian; Troyanskaya, Olga G.

    2014-01-01

    Chromatin is the driver of gene regulation, yet understanding the molecular interactions underlying chromatin factor combinatorial patterns (or the “chromatin codes”) remains a fundamental challenge in chromatin biology. Here we developed a global modeling framework that leverages chromatin profiling data to produce a systems-level view of the macromolecular complex of chromatin. Our model ultilizes maximum entropy modeling with regularization-based structure learning to statistically dissect dependencies between chromatin factors and produce an accurate probability distribution of chromatin code. Our unsupervised quantitative model, trained on genome-wide chromatin profiles of 73 histone marks and chromatin proteins from modENCODE, enabled making various data-driven inferences about chromatin profiles and interactions. We provided a highly accurate predictor of chromatin factor pairwise interactions validated by known experimental evidence, and for the first time enabled higher-order interaction prediction. Our predictions can thus help guide future experimental studies. The model can also serve as an inference engine for predicting unknown chromatin profiles — we demonstrated that with this approach we can leverage data from well-characterized cell types to help understand less-studied cell type or conditions. PMID:24675896

  14. Diagnosis and Treatment of von Willebrand Disease and Rare Bleeding Disorders

    Directory of Open Access Journals (Sweden)

    Giancarlo Castaman

    2017-04-01

    Full Text Available Along with haemophilia A and B, von Willebrand disease (VWD and rare bleeding disorders (RBDs cover all inherited bleeding disorders of coagulation. Bleeding tendency, which can range from extremely severe to mild, is the common symptom. VWD, due to a deficiency and/or abnormality of von Willebrand factor (VWF, represents the most frequent bleeding disorder, mostly inherited as an autosomal dominant trait. The diagnosis may be difficult, based on a bleeding history and different diagnostic assays, which evaluate the pleiotropic functions of VWF. Different treatment options are available for optimal management of bleeding and their prevention, and long-term outcomes are generally good. RBDs are autosomal recessive disorders caused by a deficiency of any other clotting factor, apart from factor XII, and cover roughly 5% of all bleeding disorders. The prevalence of the severe forms can range from 1 case in 500,000 up to 1 in 2–3 million, according to the defect. Diagnosis is based on bleeding history, coagulation screening tests and specific factor assays. A crucial problem in RBDs diagnosis is represented by the non-linear relationship between clinical bleeding severity and residual clotting levels; genetic diagnosis may help in understanding the phenotype. Replacement therapies are differently available for patients with RBDs, allowing the successful treatment of the vast majority of bleeding symptoms.

  15. Long-term impact of joint bleeds in von Willebrand disease: a nested case-control study.

    Science.gov (United States)

    van Galen, Karin P M; de Kleijn, Piet; Foppen, Wouter; Eikenboom, Jeroen; Meijer, Karina; Schutgens, Roger E G; Fischer, Kathelijn; Cnossen, Marjon H; de Meris, Joke; Fijnvandraat, Karin; van der Bom, Johanna G; Laros-van Gorkom, Britta A P; Leebeek, Frank W G; Mauser-Bunschoten, Eveline P

    2017-09-01

    Patients with severe von Willebrand disease (VWD) may develop arthropathy after joint bleeds. Information on its prevalence and severity is limited. We aimed to assess the occurrence and severity of arthropathy in VWD and its impact on daily life. VWD patients with and without verified joint bleeds were matched for age, sex and Factor VIII level or von Willebrand Factor activity in a nested case-control study within the Willebrand in the Netherlands study. Assessments included the Hemophilia Joint Health Score (0-124), Pettersson score (0-13 per joint X-ray), Hemophilia Activity List score (0-100), joint pain (Visual Analog Scale 0-10), and the Impact on Participation and Autonomy questionnaire (0-20). Arthropathy was defined as a Hemophilia Joint Health Score of 10 or higher, or a Pettersson score over 3 of at least one joint. We included 48 patients with verified joint bleeds (cases) and 48 controls: 60% males, mean age 46 years (range 18-80), median von Willebrand Factor activity 5 versus 8 IU/dL and Factor VIII 24 versus 36 IU/dL. Arthropathy occurred in 40% of the cases versus 10% of the controls (PList score: 88 vs. 100, P3: 13 of 19 vs. 3 of 28, P<0.01, and median score on the participation questionnaire 6.1 vs. 0.9, P<0.01). In conclusion, arthropathy occurs in 40% of VWD patients after joint bleeds and is associated with pain, radiological abnormalities, functional limitations, and less social participation (Dutch trial register: NTR4548). Copyright© 2017 Ferrata Storti Foundation.

  16. Prevalence of von Willebrand disease in women with iron deficiency anaemia and menorrhagia in Taiwan.

    Science.gov (United States)

    Chen, Y-C; Chao, T-Y; Cheng, S-N; Hu, S-H; Liu, J-Y

    2008-07-01

    Iron deficiency anaemia (IDA) is a frequently encountered disease, which can be attributed to menorrhagia. Most female patients with von Willebrand disease (VWD) have menorrhagia. The aim of this study was to investigate the prevalence of VWD in women with both IDA and menorrhagia in Taiwan. From January to December 2005 and November 2006 to January 2007, 56 consecutive patients with both IDA and menorrhagia were enrolled in this study. Their median age was 41 years (range 18-53). IDA was diagnosed by anaemia plus either low ferritin or transferrin saturation. Menorrhagia was evaluated by patient's menses history. Both von Willebrand factor antigen (VWF:Ag) and ristocetin cofactor activity (VWF:RCo) were measured for each patient. Bleeding time (BT) and platelet function analyser (PFA)-100 assay were determined as ancillary tests. The VWD diagnosis was established if: (i) both VWF:Ag (menorrhagia might develop IDA at younger age (34.3 vs. 39.7, P = 0.09) and had more IDA recurrence (75% vs. 16%, P = 0.03) than those patients without VWD. Of the eight VWD patients with VWF multimer analyses, all were revealed to have type I VWD. Our study demonstrates that VWD was not uncommon in women with both IDA and menorrhagia in Taiwan.

  17. Idiopathic pulmonary hypertension causing acquired von Willebrand disease and menorrhagia.

    Science.gov (United States)

    Sokkary, Nancy A; Dietrich, Jennifer E; Venkateswaran, Lakshmi

    2011-10-01

    Von Willebrand disease (VWD) maybe inherited or acquired; both etiologies can be associated with heavy menstrual bleeding. Pulmonary arterial hypertension may result in acquired VWD due to the destruction of high molecular weight von Willebrand multimers. We report a case of menorrhagia due to acquired VWD in a patient with idiopathic pulmonary hypertension. An adolescent female with known idiopathic pulmonary hypertension developed acquired VWD. Her primary disease necessitates the use of platelet inhibitors and intermittent anticoagulation. At menarche she also developed menorrhagia due to acquired VWD. She is currently controlled with stimate and progesterone-only therapy. VWD in a patient with idiopathic pulmonary hypertension causing menorrhagia. Although VWD and menorrhagia are commonly linked, the treatment and disease process in a patient with idiopathic pulmonary arterial hypertension is incredibly complex. Published by Elsevier Inc.

  18. Consumption of nattokinase is associated with reduced blood pressure and von Willebrand factor, a cardiovascular risk marker: results from a randomized, double-blind, placebo-controlled, multicenter North American clinical trial

    OpenAIRE

    Jensen GS; Lenninger M; Ero MP; Benson KF

    2016-01-01

    Gitte S Jensen,1 Miki Lenninger,1 Michael P Ero,2 Kathleen F Benson,1 1NIS Labs, Klamath Falls, OR, 2Machaon Diagnostics, Inc., Oakland, CA, USA Objective: The objective of this study is to evaluate the effects of consumption of nattokinase on hypertension in a North American hypertensive population with associated genetic, dietary, and lifestyle factors. This is in extension of, and contrast to, previous studies on Asian populations.Materials and methods: A randomized, double-blind, placebo-...

  19. Latent Factors in Student-Teacher Interaction Factor Analysis

    Science.gov (United States)

    Le, Thu; Bolt, Daniel; Camburn, Eric; Goff, Peter; Rohe, Karl

    2017-01-01

    Classroom interactions between students and teachers form a two-way or dyadic network. Measurements such as days absent, test scores, student ratings, or student grades can indicate the "quality" of the interaction. Together with the underlying bipartite graph, these values create a valued student-teacher dyadic interaction network. To…

  20. Interactions of anthropogenic stress factors on phytoplankton

    Directory of Open Access Journals (Sweden)

    Donat P. Häder

    2015-03-01

    Full Text Available Phytoplankton are the main primary producers in aquatic ecosystems. Their biomass production and CO2 sequestration equals that of all terrestrial plants taken together. Phytoplankton productivity is controlled by a number of environmental factors, many of which currently undergo substantial changes due to anthropogenic global climate change. Light availability is an absolute requirement for photosynthesis, but excessive visible and UV radiation impair productivity. Increasing temperatures enhance stratification, decrease the depth of the upper mixing layer exposing the cells to higher solar radiation, and reduce nutrient upward transport from deeper layers. At the same time, stratospheric ozone depletion exposes phytoplankton to higher solar UV-B radiation especially in polar and mid latitudes. Terrestrial runoff carrying sediments and dissolved organic matter into coastal waters leads to eutrophication while reducing UV penetration. All these environmental forcings are known to affect physiological and ecological processes of primary producers. Ocean acidification due to increased atmospheric CO2 concentrations changes the seawater chemistry; it reduces calcification in phytoplankton, macroalgae and many zoological taxa and enhances UV-induced damage. Ocean warming results in changing species composition and favors blooms of toxic prokaryotic and eukaryotic phytoplankton; it moderates UV-induced damage of the photosynthetic apparatus because of higher repair rates. Increasing pollution from crude oil spills, persistent organic pollutants, heavy metal as well as industrial and household wastewaters affect phytoplankton, which is augmented by solar UV radiation. In view of the fact that extensive analyses of the impacts of multiple stressors are scarce, here we review reported findings on the impacts of anthropogenic stressors on phytoplankton with an emphasis on their interactive effects and a prospect for future studies.

  1. Acquired von Willebrand syndrome in children with aortic and pulmonary stenosis.

    Science.gov (United States)

    Binnetoğlu, Fatih Köksal; Babaoğlu, Kadir; Filiz, Şayegan Güven; Zengin, Emine; Altun, Gürkan; Kılıç, Suar Çakı; Sarper, Nazan

    This prospective study was planned to investigate the frequency and relationship of acquired von Willebrand syndrome (AVWS) with aortic and pulmonary stenosis in patients. A total of 84 children, ranging from two to 18 years of age, were enrolled in this study. Of these, 28 had isolated aortic stenosis, 32 had isolated pulmonary stenosis and 24 were healthy. Children with aortic and pulmonary stenosis associated with other congenital heart diseases were excluded. Children with hypothyroidism, renal or liver disease, malignancy or autoimmune disease were also excluded. Wholeblood count, blood group, factor VIII level, prothrombin time (PT), activated partial thromboplastin time (aPTT), von Willebrand factor antigen (VWF:Ag), ristocetin co-factor (VWF:RCo), and bleeding time using a platelet-function analyser (PFA-100) were performed in all patients. All of the children in the study underwent a detailed physical examination and echocardiographic evaluation. A history of bleeding was positive in 18% of the aortic stenosis group, 9% of the pulmonary stenosis group, and 4% of the control group. Seven of 60 (12%) patients had laboratory findings that implied a diagnosis of AVWS, and two of these (28%) had a history of bleeding. The frequency of AVWS was 14% in patients with aortic stenosis and 9% in those with pulmonary stenosis. AVWS is not rare in stenotic obstructive cardiac diseases. A detailed history of bleeding should be taken from patients with valvular disease. Even if the history is negative, whole blood count, PT and aPTT should be performed. If necessary, PFA-100 closure time and further tests should be planned for the diagnosis of AVWS.

  2. Postpartum Hemorrhage in Women with Von Willebrand Disease - A Retrospective Observational Study.

    Directory of Open Access Journals (Sweden)

    Igor Govorov

    Full Text Available von Willebrand disease (VWD is a hereditary bleeding disorder, caused by a deficiency in the levels and/or function of von Willebrand factor (VWF. Women with VWD appear to be at increased risk of experiencing postpartum hemorrhage (PPH, though the levels of VWF increase during pregnancy. There is limited knowledge of how PPH is associated with the subtype of VWD, plasma levels of other coagulations factors than VWF and given hemostatic treatment.The aims were to investigate the incidence of PPH in women with VWD and to analyse the correlation between PPH and: (1 type of VWD, (2 laboratory monitoring of VWF and FVIII and (3 hemostatic drug treatment.This was a retrospective observational study. The study participants (n = 34 were recruited from the Coagulation Unit, Karolinska University hospital. Fifty-nine deliveries, which occurred in 14 different obstetrics units (years 1995-2012 were included in the study.The incidence of primary PPH was 44%, severe primary PPH 20% and secondary PPH 12%. VWD type 3 was associated with a higher risk of experiencing severe primary PPH compared to other subtypes. FVIII:C in pregnancy was inversely correlated to blood loss during delivery. There was a significantly higher incidence of secondary PPH when the VWD diagnosis was unknown at time of delivery.The women with VWD are at higher risk of PPH, especially those with type 3 VWD or when diagnosis is unknown prior to delivery. Identification of pregnant women with undiagnosed VWD may be of importance in order to prevent PPH.

  3. Molecular cloning, expression and assembly of multimeric von Willebrand factor

    NARCIS (Netherlands)

    Pannekoek, H.; Voorberg, J.

    1989-01-01

    Recently, substantial progress has been made in our knowledge of the domains involved in correlating structure and function of vWF, as well as in the biosynthesis and assembly of multimeric vWF. These studies were greatly supported by the development of three new techniques. (1) In vitro culturing

  4. Molecular characterization of exon 28 of von Willebrand's factor ...

    African Journals Online (AJOL)

    2016-05-12

    May 12, 2016 ... two probable cases among 95 patients with hemophilia A and 11 with hemophilia B between 1980 and 1986, but full investigation and family studies were not performed. In. Nigeria, we ... bleeding symptoms are epistaxis, menorrhagia (in women), easy bruising, oral cavity bleeding, bleeding after dental.

  5. Effective Factors in Interactions within Japanese EFL Classrooms

    Science.gov (United States)

    Maftoon, Parviz; Ziafar, Meisam

    2013-01-01

    Classroom interactional patterns depend on some contextual, cultural and local factors in addition to the methodologies employed in the classroom. In order to delineate such factors, the focus of classroom interaction research needs to shift from the observables to the unobservables like teachers' and learners' psychological states and cultural…

  6. Genetic heterogeneity in a large cohort of Indian type 3 von Willebrand disease patients.

    Directory of Open Access Journals (Sweden)

    Priyanka Kasatkar

    Full Text Available Though von Willebrand disease (VWD is a common coagulation disorder, due to the complexity of the molecular analysis of von Willebrand factor gene (VWF, not many reports are available from this country. Large size of the gene, heterogeneous nature of mutations and presence of a highly homologous pseudogene region are the major impediments in the genetic diagnosis of VWD. The study is aimed at unravelling the molecular pathology in a large series of VWD patients from India using an effective strategy.We evaluated 85 unrelated Indian type 3 VWD families to identify the molecular defects using a combination of techniques i.e. PCR-RFLP, direct DNA sequencing and multiple ligation probe amplification (MLPA.Mutations could be characterized in 77 unrelated index cases (ICs. 59 different mutations i.e. nonsense 20 (33.9%, missense 13 (22%, splice site 4 (6.8%, gene conversions 6 (10.2%, insertions 2 (3.4%, duplication 1 (1.7%, small deletions 10 (17% and large deletions 3 (5.1% were identified, of which 34 were novel. Two common mutations i.e. p.R1779* and p.L970del were identified in our population with founder effect. Development of alloantibodies to VWF was seen in two patients, one with nonsense mutation (p.R2434* and the other had a large deletion spanning exons 16-52.The molecular pathology of a large cohort of Indian VWD patients could be identified using a combination of techniques. A wide heterogeneity was observed in the nature of mutations in Indian VWD patients.

  7. Technological advances in diagnostic testing for von Willebrand disease: new approaches and challenges.

    Science.gov (United States)

    Hayward, C P M; Moffat, K A; Graf, L

    2014-06-01

    Diagnostic tests for von Willebrand disease (VWD) are important for the assessment of VWD, which is a commonly encountered bleeding disorder worldwide. Technical innovations have been applied to improve the precision and lower limit of detection of von Willebrand factor (VWF) assays, including the ristocetin cofactor activity assay (VWF:RCo) that uses the antibiotic ristocetin to induce plasma VWF binding to glycoprotein (GP) IbIXV on target platelets. VWF-collagen-binding assays, depending on the type of collagen used, can improve the detection of forms of VWD with high molecular weight VWF multimer loss, although the best method is debatable. A number of innovations have been applied to VWF:RCo (which is commonly performed on an aggregometer), including replacing the target platelets with immobilized GPIbα, and quantification by an enzyme-linked immunosorbent assay (ELISA), immunoturbidimetric, or chemiluminescent end-point. Some common polymorphisms in the VWF gene that do not cause bleeding are associated with falsely low VWF activity by ristocetin-dependent methods. To overcome the need for ristocetin, some new VWF activity assays use gain-of-function GPIbα mutants that bind VWF without the need for ristocetin, with an improved precision and lower limit of detection than measuring VWF:RCo by aggregometry. ELISA of VWF binding to mutated GPIbα shows promise as a method to identify gain-of-function defects from type 2B VWD. The performance characteristics of many new VWF activity assays suggest that the detection of VWD, and monitoring of VWD therapy, by clinical laboratories could be improved through adopting newer generation VWF assays. © 2014 John Wiley & Sons Ltd.

  8. Occupational cancer: interaction with life style factors.

    OpenAIRE

    Roe, F. J.

    1990-01-01

    It is argued that as the major occupational cancer risks become matters of historical interest, research epidemiologists working in the field should broaden their approaches to encompass life style factors. In the investigation of possible low-cancer risks, it no longer makes any sense to confine their data-collecting activities solely to exposure to dusts and chemicals at work and to regard exposure to chemicals at home, in the garden or during leisure activities simply as possible confoundi...

  9. Cesariana em paciente com doença de von Willebrand associada à infecção pelo HIV: relato de caso Cesárea en paciente con enfermedad de von Willebrand asociada a la infección por el HIV: relato de caso Anesthesia for cesarean section in patient with von Willebrand's disease and HIV infection: case report

    Directory of Open Access Journals (Sweden)

    Vanessa Rezende Balle

    2004-12-01

    Willebrand y HIV positiva sometida a cesárea. RELATO DEL CASO: Paciente de 24 años, portadora de anemia microcítica, enfermedad de von Willebrand y HIV, llegó a la emergencia obstétrica en inicio de trabajo de alumbramiento. No realizó prenatal. Fue indicada cesárea a fin de disminuir los riesgos de transmisión vertical en paciente con carga vírica de HIV desconocida. Presentaba hematomas por el cuerpo e historia de hematoma de pared abdominal en cesárea anterior. Los tests de coagulación estaban un poco alterados. Después de infusión de concentrado de factor VIII fue realizada anestesia general. Madre y recién nacido presentaron evolución satisfactoria. CONCLUSIONES: La evaluación de manifestaciones clínicas en pacientes con coagulopatia es fundamental en la decisión del tipo de anestesia que será indicada para cada paciente. La evaluación debe ser individualizada, considerando los riesgos y beneficios de la técnica escogida. En estas pacientes, se debe siempre restringir al máximo la indicación de interrupción de la gestación por vía alta, optándose siempre por los métodos menos invasivos. La terapia con concentrado de factor VIII es actualmente la mejor opción de tratamiento, corrigiendo la deficiencia específica y dismunuyendo los riesgos de transmisión vírica.BACKGROUND AND OBJECTIVES: Von Willebrand's disease is the most common hereditary coagulation disorder in young women. The incidence of HIV infection among women has been progressively increasing, and vertical transmission may account for 25% of cases. This report aimed at describing the case of an HIV-positive patient with von Willebrand's disease scheduled for cesarean section. CASE REPORT: Female HIV-positive patient, 24 years old, with microcytic anemia and von Willebrand's disease, admitted to the emergency room in early labor. She had no pre-natal care. Cesarean section was indicated to lower vertical transmission risks since HIV viral count was unknown. Patient had hematomas

  10. Utility of platelet function analyzer as a screening tool for the diagnosis of von Willebrand disease in adolescents with menorrhagia.

    Science.gov (United States)

    Naik, Swati; Teruya, Jun; Dietrich, Jennifer E; Jariwala, Purvi; Soundar, Esther; Venkateswaran, Lakshmi

    2013-07-01

    Von Willebrand disease (VWD), and in particular, VWD type 1 and low VW factor (defined as Von Willebrand Ristocetin cofactor activity (RCoF) menorrhagia and both groups benefit from similar management. Platelet function analyzer (PFA-100®) is often used as a screening test to detect VWD. We analyzed the utility of PFA-100® as a screening tool in the detection of VWD type 1 and low VW factor (VWF) in an exclusive adolescent population with menorrhagia. The study population consisted of adolescents with menorrhagia who had simultaneously drawn blood samples for VWD and PFA-100®. Abnormal PFA-100® was defined as values >183 seconds for collagen/epinephrine and/or >126 seconds for collagen/ADP. Of a total of 235 patients tested, 23 patients had RCoF menorrhagia. We conclude that in the setting of adolescent menorrhagia, PFA-100® does not have utility as an initial screening test for the diagnosis of VWD and in particular, low VWF and that clinicians need to be aware of this limitation of PFA-100® while evaluating adolescents with menorrhagia. Copyright © 2013 Wiley Periodicals, Inc.

  11. [Desmopressin testing in children with von Willebrand syndrome in haemostaseologic centers of Saxonia, Saxonia-Anhalt and Thuringia].

    Science.gov (United States)

    Huhn, B; Hofmann, A; Hofmann, K; Sirb, H; Aumann, V; Kentouche, K; Sauerbrey, A; Franke, D; Kuhlisch, E; Knöfler, R

    2009-10-01

    The influence of desmopressin on hemostasis is mediated by the release of von Willebrand factor and of coagulation factor VIII from vascular endothelium. The necessity of testing desmopressin effectiveness on hemostasis is a matter of controversy and the performance of the test is not yet standardized. For this reason the desmopressin tests in 114 children with von Willebrand syndrome (type 1, n=98; type 2A, n=12; type 2M, n=2; type 2N, n=2) carried out in 7 paediatric haemostaseologic centers were retrospectively analyzed. The effectiveness of desmopressin was assessed using defined response criteria. As expected, the test performance showed a wide variation among the centers. In 99 children desmopressin was given intravenously as a short infusion at a dosage ranging from 0.25 to 0.41 microg/kg and in 15 intranasally at an absolute dose of 40 to 300 microg. The points of time for blood taking after desmopressin application ranged from 0.5 to 12 h. The absent desmopressin response in 7 patients (6%) and the partial response in 15 indicate the necessity of testing desmopressin effectiveness before the first therapeutic use. The application of desmopressin was well tolerated by the patients.

  12. Syringomyelia following surgery for a spontaneous spinal subdural hematoma in a 13-year-old girl with congenital von Willebrand disease: case report and literature review.

    Science.gov (United States)

    Ben Nsir, A; Boubaker, A; Jemel, H

    2016-04-01

    Spontaneous spinal subdural hematomas are rare. Their occurrence in a child with congenital von Willebrand disease and the complication of their surgery by a large secondary syringomyelia have never been previously reported. A 13-year-old girl with congenital von Willebrand disease presented to our emergency department in January 2011 for sudden onset of severe back pain centered in her thoracic spine rapidly aggravated by signs of acute myelopathy without any precipitating factor. MRI scan revealed a thoracic subdural collection anterior to the spinal cord at the T7-T9 level, hyperintense on T1- and T2-weighted sequences consistent with an acute spinal subdural hemorrhage. Evacuation of the subdural hematoma was realized immediately after hemostasis parameter correction, and post-operative course was uneventful with full functional recovery. One year later, the patient presented once again but with progressive and more severe myelopathy caused by a large syringomyelia extending from the T5 level to the conus medullaris. A syringopleural shunting was performed and the patient was unrolled under an intensive care and rehabilitation program. Her condition remarkably improved and she became able to walk independently within 2 weeks post-operatively. von Willebrand disease should be included as a possible factor of spontaneous spinal subdural hemorrhage. Surgery is advised in emergency and can be associated with remarkable recovery especially in children. Delayed syringomyelia can complicate the post-operative course and can be successfully addressed by syringopleural shunting. Long-term clinical and radiological follow-up is advocated.

  13. What Makes Sports Fans Interactive? Identifying Factors Affecting Chat Interactions in Online Sports Viewing.

    Directory of Open Access Journals (Sweden)

    Minsam Ko

    Full Text Available Sports fans are able to watch games from many locations using TV services while interacting with other fans online. In this paper, we identify the factors that affect sports viewers' online interactions. Using a large-scale dataset of more than 25 million chat messages from a popular social TV site for baseball, we extract various game-related factors, and investigate the relationships between these factors and fans' interactions using a series of multiple regression analyses. As a result, we identify several factors that are significantly related to viewer interactions. In addition, we determine that the influence of these factors varies according to the user group; i.e., active vs. less active users, and loyal vs. non-loyal users.

  14. What Makes Sports Fans Interactive? Identifying Factors Affecting Chat Interactions in Online Sports Viewing

    Science.gov (United States)

    Yeo, Jaeryong; Lee, Juyeong

    2016-01-01

    Sports fans are able to watch games from many locations using TV services while interacting with other fans online. In this paper, we identify the factors that affect sports viewers’ online interactions. Using a large-scale dataset of more than 25 million chat messages from a popular social TV site for baseball, we extract various game-related factors, and investigate the relationships between these factors and fans’ interactions using a series of multiple regression analyses. As a result, we identify several factors that are significantly related to viewer interactions. In addition, we determine that the influence of these factors varies according to the user group; i.e., active vs. less active users, and loyal vs. non-loyal users. PMID:26849568

  15. Rinoplastia em paciente com doença de Von Willebrand: relato de caso Rinoplastia en paciente con enfermedad de Von Willebrand: relato de caso Rhinoplasty in a patient with Von Willebrand disease: case report

    Directory of Open Access Journals (Sweden)

    Roberto Martins Matos Junior

    2007-12-01

    aprovado pelo FDA, tem sido uma prática utilizada somente em circunstâncias emergenciais, devido ao risco relativo de contaminação viral. A 1-desamino, 8-D-arginina vasopressina (DDAVP-desmopressina estimula o aumento da concentração do fator VIII, tendo a vantagem de eliminar a exposição aos patógenos transmitidos pelo sangue, além da possibilidade de administração por vias nasal, subcutânea e venosa.JUSTIFICATIVA Y OBJETIVOS: Los pacientes portadores de la enfermedad de von Willebrand presentan sangramiento anormal después de heridas y procedimientos quirúrgicos, ya que esta afecta la hemostasia primaria y secundaria debido a la alteración del factor VIII. El objetivo de este relato es elucidar el manoseo pre, peri y postoperatorio de pacientes con tal enfermedad. RELATO DEL CASO: Paciente del sexo femenino, 42 años, blanca, 165 cm, 61kg, ASA II, fue sometida a la evaluación preanestésica para la realización de rinoplastia, con diagnóstico previo de enfermedad de von Willebrand del tipo 1, siendo liberada para la intervención quirúrgica después de la evaluación hematológica, con test de DDAVP IN26 responsivo. El día de la operación, y después de la medicación preanestésica y del monitoreo adecuado, se le dio oxígeno por catéter nasal e infundida la solución de desmopresina (0,4 µg.kg-1 en 100 mL de NaCl a 0,9% por vía venosa 30 minutos antes de la operación. Enseguida se inició la inducción anestésica con sufentanil (1 µg.kg-1, propofol (4 mg.kg-1 y rocuronio (0,6 mg.kg-1 por vía venosa. A continuación se realizó la intubación traqueal seguida de ventilación controlada mecánica en sistema con absorción de CO2, mantenida con O2, N2O y sevoflurano. El acto quirúrgico duró noventa minutos. En el intraoperatorio la paciente se mantuvo hemodinámicamente estable, presentando sangramiento sin importancia. Al final de la operación fue extubada y llevada a la sala de recuperación post anestésica, donde permaneció por 120

  16. Acquired von Willebrand's disease and hypothyroidism: report of a case presenting with menorrhagia.

    Science.gov (United States)

    Blesing, N. E.; Hambley, H.; McDonald, G. A.

    1990-01-01

    A 17 year old woman presented with severe anaemia due to menorrhagia. On investigation, she was shown to have abnormalities of her haemostatic mechanism consistent with von Willebrand's disease Type I, although there was no family history of this disorder. In addition, she was shown to have severe primary hypothyroidism. On correction of hypothyroidism with oral thyroxine, her coagulation defects returned to normal and menorrhagia ceased. This is consistent with acquired von Willebrand's disease secondary to hypothyroidism. PMID:2217000

  17. Factors associated with social interaction anxiety among Chinese adolescents.

    Science.gov (United States)

    Peng, Z W; Lam, L T; Jin, J

    2011-12-01

    To investigate potential risk factors for social anxiety, particularly social interaction anxiety among the Chinese adolescents. A cross-sectional health survey was conducted in Guangzhou city of the Guangdong Province where high school students aged 13 to 18 years were recruited. The sample was selected from all high schools in the city using a 2-stage random cluster sampling technique. Social interaction anxiety was assessed using the Social Interaction Anxiety Scale. Information collected in the survey included: demographics, self-perception on school performance, relationship with teachers and peers, satisfaction with self-image, achievements, and parenting style of the mother. The parent-child relationship, specifically the relationship between respondents and their mothers, was assessed using the mother attachment subscale of the Inventory of Parent and Peer Attachment. Self-esteem was assessed using the Rosenberg Self-Esteem Scale. The multiple linear regression technique was applied to investigate associations between selected potential risk factors and social interaction anxiety, with adjustments for cluster sampling. Lower family income, lower self-esteem, and hostility were significantly associated with social interaction anxiety among adolescents. Variables identified as risk factors of anxiety disorder in the literature, such as gender, were not associated with social interaction anxiety in this sample. These results were consistent with those of other studies conducted mainly in the United States and Europe. Regarding non-significant results related to gender, they need viewing in the context of parenting styles of Chinese mothers.

  18. Factor Selection and Structural Identification in the Interaction ANOVA Model

    Science.gov (United States)

    Post, Justin B.; Bondell, Howard D.

    2013-01-01

    Summary When faced with categorical predictors and a continuous response, the objective of analysis often consists of two tasks: finding which factors are important and determining which levels of the factors differ significantly from one another. Often times these tasks are done separately using Analysis of Variance (ANOVA) followed by a post-hoc hypothesis testing procedure such as Tukey’s Honestly Significant Difference test. When interactions between factors are included in the model the collapsing of levels of a factor becomes a more difficult problem. When testing for differences between two levels of a factor, claiming no difference would refer not only to equality of main effects, but also equality of each interaction involving those levels. This structure between the main effects and interactions in a model is similar to the idea of heredity used in regression models. This paper introduces a new method for accomplishing both of the common analysis tasks simultaneously in an interaction model while also adhering to the heredity-type constraint on the model. An appropriate penalization is constructed that encourages levels of factors to collapse and entire factors to be set to zero. It is shown that the procedure has the oracle property implying that asymptotically it performs as well as if the exact structure were known beforehand. We also discuss the application to estimating interactions in the unreplicated case. Simulation studies show the procedure outperforms post hoc hypothesis testing procedures as well as similar methods that do not include a structural constraint. The method is also illustrated using a real data example. PMID:23323643

  19. Signaling factor interactions with polysaccharide aggregates of bacterial biofilms.

    Science.gov (United States)

    DeSalvo, Stephen C; Liu, Yating; Choudhary, Geetika Sanjay; Ren, Dacheng; Nangia, Shikha; Sureshkumar, Radhakrishna

    2015-02-17

    Biofilms are surface-attached colonies of bacteria embedded in an extracellular polymeric substance (EPS). Inside the eukaryotic hosts, bacterial biofilms interact with the host cells through signaling factors (SFs). These signaling processes play important roles in the interaction between bacteria and host cells and the outcome of infections and symbiosis. However, how host immune factors diffuse through biofilms is not well understood. Here, we describe synergistic molecular dynamics and experimental approaches for studying the translocation of signaling factors through polysaccharide chain aggregates present in the extracellular matrix of bacterial biofilms. The effect of polysaccharide chain degradation on the energetics of SF-EPS interactions was examined by simulating an EPS consisting of various polysaccharide chain lengths. It is shown that the SF stabilization energy, defined as the average potential of mean force difference between the environments outside and within the matrix, increases linearly with decreasing chain length. This effect has been explained based on the changes in the polysaccharide configurations around the SF. Specifically, shorter chains are packed tightly around the SF, promoting favorable SF-EPS interactions, while longer chains are packed loosely resulting in screening of interactions with neighboring chains. We further investigated the translocation of SFs through the host cell membrane using molecular dynamics simulations. Further, simulations predict the existence of energy barriers greater than 1000 kJ mol(-1) associated with the translocation of the signaling factors necrosis factor-alpha (TNF-α) and granulocyte macrophage colony stimulating factor (GM-CSF) across the lipid bilayer. The agreement of computational and experimental findings motivates future computational studies using a more detailed description of the EPS aimed at understanding the role of the extracellular matrix on biofilm drug resistance.

  20. Temperature can interact with landscape factors to affect songbird productivity

    Science.gov (United States)

    W. Andrew Cox; Frank R. III Thompson; Jennifer L. Reidy; John. Faaborg

    2013-01-01

    Increased temperatures and more extreme weather patterns associated with global climate change can interact with other factors that regulate animal populations, but many climate change studies do not incorporate other threats to wildlife in their analyses. We used 20 years of nest-monitoring data from study sites across a gradient of habitat fragmentation in Missouri,...

  1. Risk factors for potential drug interactions in general practice

    DEFF Research Database (Denmark)

    Bjerrum, Lars; Gonzalez Lopez-Valcarcel, Beatriz; Petersen, Gert

    2008-01-01

    Objective: To identify patient- and practice-related factors associated with potential drug interactions. Methods: A register analysis study in general practices in the county of Funen, Denmark. Prescription data were retrieved from a population-based prescription database (Odense University...... Pharmacoepidemiologic Database, OPED) covering prescriptions to all inhabitants in the county of Funen, Denmark. All individuals exposed to concurrent use of two or more drugs (polypharmacy) were identified. Combinations of drugs with potential interactions were registered and classified as major, moderate, or minor......, depending on the severity of outcome and the quality of documentation. A two-level random coefficient logistic regression model was used to investigate factors related to potential drug interactions. Results: One-third of the population was exposed to polypharmacy, and 6% were exposed to potential drug...

  2. Menopause, obesity and inflammation: interactive risk factors for Alzheimer's disease.

    Science.gov (United States)

    Christensen, Amy; Pike, Christian J

    2015-01-01

    Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder, the development of which is regulated by several environmental and genetic risk factors. Two factors theorized to contribute to the initiation and/or progression of AD pathogenesis are age-related increases in inflammation and obesity. These factors may be particularly problematic in women. The onset of menopause in mid-life elevates the vulnerability of women to AD, an increased risk that is likely associated with the depletion of estrogens. Menopause is also linked with an abundance of additional changes, including increased central adiposity and inflammation. Here, we review the current literature to explore the interactions between obesity, inflammation, menopause and AD.

  3. Characterization of a novel mutation in the von Willebrand factor propeptide in a distinct subtype of recessive von Willebrand disease

    DEFF Research Database (Denmark)

    Lanke, Elsa; Kristoffersson, Ann-Charlotte; Philips, Malou

    2008-01-01

    mutation in the VWFpp abolishes multimerization of VWF. The mutation probably disrupts the normal configuration of the VWFpp, which is essential for correct orientation of the protomers and ultimately multimerization. The mutant amino acid is located in a region that is highly conserved across several...

  4. Characterization of conformation-sensitive antibodies to ADAMTS13, the von Willebrand cleavage protease.

    Directory of Open Access Journals (Sweden)

    Zuben E Sauna

    2009-08-01

    Full Text Available The zinc metalloprotease ADAMTS13 is a multidomain protein that cleaves von Willebrand Factor (VWF and is implicated in Thrombotic Thrombocytopenic Purpura (TTP pathogenesis. Understanding the mechanism of this protein is an important goal. Conformation sensitive antibodies have been used to monitor protein conformation and to decipher the molecular mechanism of proteins as well as to distinguish functional and non-functional mutants.We have characterized several antibodies against ADAMTS13, both monoclonal and polyclonal. We have used flow cytometry to estimate the binding of these antibodies to ADAMTS13 and demonstrate that antibodies raised against the TSP and disintegrin domains detect conformation changes in the ADAMTS13. Thus for example, increased binding of these antibodies was detected in the presence of the substrate (VWF, mainly at 37 degrees C and not at 4 degrees C. These antibodies could also detect differences between wild-type ADAMTS13 and the catalytically deficient mutant (P475S. The flow cytometry approach also allows us to estimate the reactivity of the antibody as well as its apparent affinity.Our results suggest that these antibodies may serve as useful reagents to distinguish functional and non-functional ADAMTS13 and analyze conformational transitions to understand the catalytic mechanism.

  5. Variable bleeding phenotype in an Amish pedigree with von Willebrand disease.

    Science.gov (United States)

    Gupta, Sweta; Heiman, Meadow; Duncan, Natalie; Hinckley, Jesse; Di Paola, Jorge; Shapiro, Amy D

    2016-10-01

    Through a cross-sectional study design, the bleeding phenotype in the Amish in Indiana (IN) and Wisconsin (WI) was described using two different bleeding scores. von Willebrand factor (VWF) testing was performed and bleeding questionnaires from Centers for Disease Control and Prevention (CDC) and European MCMDM-1 (Tosetto bleeding score (BS)) were administered to the IN and WI cohort respectively. Seven hundred and seventy nine subjects were recruited, 17% were diagnosed with VWD based on Ristocetin cofactor, VWF:RCo  T. The WI AF were much younger at a mean age 15 years vs 26 years in IN AF cohort. The AF subjects had a median VWF:RCo of 13IU/dl with a statistically significant higher median BS 1 versus 0 in the WI AF vs WI Unaffected (UA), 2 vs 1 in the IN AF vs IN UA, P Amish with VWD, despite a unifying mutation. Am. J. Hematol. 91:E431-E435, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  6. Autism risk factors: genes, environment, and gene-environment interactions.

    Science.gov (United States)

    Chaste, Pauline; Leboyer, Marion

    2012-09-01

    The aim of this review is to summarize the key findings from genetic and epidemiological research, which show that autism is a complex disorder resulting from the combination of genetic and environmental factors. Remarkable advances in the knowledge of genetic causes of autism have resulted from the great efforts made in the field of genetics. The identification of specific alleles contributing to the autism spectrum has supplied important pieces for the autism puzzle. However, many questions remain unanswered, and new questions are raised by recent results. Moreover, given the amount of evidence supporting a significant contribution of environmental factors to autism risk, it is now clear that the search for environmental factors should be reinforced. One aspect of this search that has been neglected so far is the study of interactions between genes and environmental factors.

  7. Preliminary disposal limits, plume interaction factors, and final disposal limits

    Energy Technology Data Exchange (ETDEWEB)

    Flach, G. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL)

    2018-01-11

    In the 2008 E-Area Performance Assessment (PA), each final disposal limit was constructed as the product of a preliminary disposal limit and a plume interaction factor. The following mathematical development demonstrates that performance objectives are generally expected to be satisfied with high confidence under practical PA scenarios using this method. However, radionuclides that experience significant decay between a disposal unit and the 100-meter boundary, such as H-3 and Sr-90, can challenge performance objectives, depending on the disposed-of waste composition, facility geometry, and the significance of the plume interaction factor. Pros and cons of analyzing single disposal units or multiple disposal units as a group in the preliminary disposal limits analysis are also identified.

  8. Vocalizing Dance Movement for Interactive Sonification of Laban Effort Factors

    OpenAIRE

    Françoise, Jules; Fdili Alaoui, Sarah; Schiphorst, Thecla; Bevilacqua, Frédéric

    2014-01-01

    International audience; We investigate the use of interactive sound feedback for dance pedagogy based on the practice of vocalizing while moving. Our goal is to allow dancers to access a greater range of expressive movement qualities through vocalization. We propose a methodology for the sonification of Effort Factors, as defined in Laban Movement Analysis, based on vocalizations performed by movement experts. Based on the experiential outcomes of an exploratory workshop, we propose a set of ...

  9. Atomic form factor for twisted vortex photons interacting with atoms

    Science.gov (United States)

    Guthrey, Pierson; Kaplan, Lev; McGuire, J. H.

    2014-04-01

    The relatively new atomic form factor for twisted (vortex) beams, which carry orbital angular momentum (OAM), is considered and compared to the conventional atomic form factor for plane-wave beams that carry only spin angular momentum. Since the vortex symmetry of a twisted photon is more complex that that of a plane wave, evaluation of the atomic form factor is also more complex for twisted photons. On the other hand, the twisted photon has additional parameters, including the OAM quantum number, ℓ, the nodal radial number, p, and the Rayleigh range, zR, which determine the cone angle of the vortex. This Rayleigh range may be used as a variable parameter to control the interaction of twisted photons with matter. Here we address (i) normalization of the vortex atomic form factor, (ii) displacement of target atoms away from the center of the beam vortex, and (iii) formulation of transition probabilities for a variety of photon-atom processes. We attend to features related to experiments that can test the range of validity and accuracy of calculations of these variations of the atomic form factor. Using the absolute square of the form factor for vortex beams, we introduce a vortex factor that can be directly measured.

  10. Factors affecting quality of social interaction park in Jakarta

    Science.gov (United States)

    Mangunsong, N. I.

    2018-01-01

    The existence of social interactions park in Jakarta is an oasis in the middle of a concrete jungle. Parks is a response to the need for open space as a place of recreation and community interaction. Often the social interaction parks built by the government does not function as expected, but other functions such as a place to sell, trash, unsafe so be rarely visited by visitors. The purpose of this study was to analyze the factors that affect the quality of social interaction parks in Jakarta by conducting descriptive analysis and correlation analysis of the variables assessment. The results of the analysis can give an idea of social interactions park based on community needs and propose the development of social interactioncity park. The object of study are 25 social interaction parks in 5 municipalities of Jakarta. The method used is descriptive analysis method, correlation analysis using SPSS 19 and using crosstab, chi-square tests. The variables are 5 aspects of Design, Plants composition: Selection type of plant (D); the beauty and harmony (Ind); Maintenance and fertility (P); Cleanliness and Environmental Health (BS); Specificity (Drainage, Multi Function garden, Means, Concern/Mutual cooperation, in dense settlements) (K). The results of analysis show that beauty is the most significant correlation with the value of the park followed by specificity, cleanliness and maintenance. Design was not the most significant variable affecting the quality of the park. The results of this study can be used by the Department of Parks and Cemeteries as input in managing park existing or to be developed and to improve the quality of social interaction park in Jakarta.

  11. Differential interactions between Notch and ID factors control neurogenesis by modulating Hes factor autoregulation.

    Science.gov (United States)

    Boareto, Marcelo; Iber, Dagmar; Taylor, Verdon

    2017-10-01

    During embryonic and adult neurogenesis, neural stem cells (NSCs) generate the correct number and types of neurons in a temporospatial fashion. Control of NSC activity and fate is crucial for brain formation and homeostasis. Neurogenesis in the embryonic and adult brain differ considerably, but Notch signaling and inhibitor of DNA-binding (ID) factors are pivotal in both. Notch and ID factors regulate NSC maintenance; however, it has been difficult to evaluate how these pathways potentially interact. Here, we combined mathematical modeling with analysis of single-cell transcriptomic data to elucidate unforeseen interactions between the Notch and ID factor pathways. During brain development, Notch signaling dominates and directly regulates Id4 expression, preventing other ID factors from inducing NSC quiescence. Conversely, during adult neurogenesis, Notch signaling and Id2/3 regulate neurogenesis in a complementary manner and ID factors can induce NSC maintenance and quiescence in the absence of Notch. Our analyses unveil key molecular interactions underlying NSC maintenance and mechanistic differences between embryonic and adult neurogenesis. Similar Notch and ID factor interactions may be crucial in other stem cell systems. © 2017. Published by The Company of Biologists Ltd.

  12. Spin g -factor due to electronic interactions in graphene

    Science.gov (United States)

    Menezes, Natália; Alves, Van Sérgio; Marino, E. C.; Nascimento, Leonardo; Nascimento, Leandro O.; Morais Smith, C.

    2017-06-01

    The gyromagnetic factor is an important physical quantity relating the magnetic-dipole moment of a particle to its spin. The electron spin g -factor in vacuo is one of the best model-based theoretical predictions ever made, showing agreement with the measured value up to ten parts per trillion [J. Schwinger, Phys. Rev. 73, 416 (1948), 10.1103/PhysRev.73.416; R. S. Van Dyck, Jr. et al., Phys. Rev. Lett. 59, 26 (1987), 10.1103/PhysRevLett.59.26; D. Hanneke et al., Phys. Rev. Lett. 100, 120801 (2008), 10.1103/PhysRevLett.100.120801; T. Aoyama et al., Phys. Rev. Lett. 109, 111807 (2012), 10.1103/PhysRevLett.109.111807]. However, for electrons in a material the g -factor is modified with respect to its value in vacuo because of environment interactions. Here, we show how interaction effects lead to the spin g -factor correction in graphene by considering the full electromagnetic interaction in the framework of pseudo-QED [A. Kovner et al., Phys. Rev. B 42, 4748 (1990), 10.1103/PhysRevB.42.4748; N. Dorey et al., Nucl. Phys. B 386, 614 (1992), 10.1016/0550-3213(92)90632-L; S. Teber, Phys. Rev. D 86, 025005 (2012), 10.1103/PhysRevD.86.025005; S. Teber, Phys. Rev. D 89, 067702 (2014), 10.1103/PhysRevD.89.067702; E. C. Marino, Nucl. Phys. B 408, 551 (1993), 10.1016/0550-3213(93)90379-4]. We compare our theoretical prediction with experiments performed on graphene deposited on SiO2 and SiC, and we find a very good agreement between them.

  13. Assessing the clinical severity of type 1 von Willebrand disease patients with a microchip flow-chamber system.

    Science.gov (United States)

    Nogami, K; Ogiwara, K; Yada, K; Shida, Y; Takeyama, M; Yaoi, H; Minami, H; Furukawa, S; Hosokawa, K; Shima, M

    2016-04-01

    The clinical phenotype of von Willebrand disease (VWD) is heterogeneous, and von Willebrand factor ristocetin cofactor activity (VWF:RCo) does not always reflect clinical severity, especially in VWD type 1. We have reported the potential of a microchip flow-chamber system (Total-Thrombus Formation Analysis System [T-TAS®]) for assessing physiologic hemostasis in VWD. Aim To evaluate the relationship between T-TAS, bleeding score (BS) and laboratory test results in type 1 VWD patients. Microchips coated with collagen (platelet chip [PL-chip]) or collagen/thromboplastin (AR-chip) were used to assess platelet thrombus formation (PTF) at high shear rates or fibrin-rich PTF at low shear rates, respectively, in whole blood from 50 patients. The times needed for the flow pressure to increase by 10 kPa and 30 kPa (T10 and T30 ) from baseline were calculated from flow pressure curves. BS was determined by the use of a standardized questionnaire. PL-T10 values correlated with BS (R(2) ~ 0.45) better than VWF:RCo (R(2) ~ 0.36), irrespective of the flow rate, whereas AR-T10 showed only a weak correlation with BS (R(2) ~ 0.18). Patients with PL-T10 > 10 min or AR-T10 > 30 min had lower VWF levels and higher BS than those with PL-T10 ≤ 10 min or AR-T10 ≤ 30 min, and the greatest differences were observed with PL-T10. Clinical severity appeared to correlate best with PL-T10 > 8 min. BS was significantly higher in patients with VWF:RCo of 8 min than in those with PL-T10 ≤ 8 min. T-TAS could be a useful technique for discriminating and predicting BS in VWD type 1 patients. © 2016 International Society on Thrombosis and Haemostasis.

  14. A 12.3-kb Duplication Within the VWF Gene in Pigs Affected by Von Willebrand Disease Type 3

    Directory of Open Access Journals (Sweden)

    Stefanie Lehner

    2018-02-01

    Full Text Available Von Willebrand Disease (VWD type 3 is a serious and sometimes fatal hereditary bleeding disorder. In pigs, the disease has been known for decades, and affected animals are used as models for the human disease. Due to the recessive mode of inheritance of VWD type 3, severe bleeding is typically seen in homozygous individuals. We sequenced the complete porcine VWF (Von Willebrand Factor complementary DNA (cDNA and detected a tandem duplication of exons 17 and 18, causing a frameshift and a premature termination codon (p.Val814LeufsTer3 in the affected pig. Subsequent next generation sequencing on genomic DNA proved the existence of a 12.3-kb tandem duplication associated with VWD. This duplication putatively originates from porcine Short Interspersed Nuclear Elements (SINEs located within VWF introns 16 and 18 with high identity. The premature termination truncates the VWF open reading frame by a large part, resulting in an almost entire loss of the mature peptide. It is therefore supposed to account for the severe VWD type 3. Our results further indicate the presence of strong, nonsense-mediated decay in VWF messenger RNA (mRNA containing the duplication, which was supported by the almost complete absence of the complete VWF protein in immunohistochemistry analysis of the VWD-affected pig. In the past, differentiation of wild-type and heterozygous pigs in this VWD colony had to rely on clinical examinations and additional laboratory methods. The present study provides the basis to distinguish both genotypes by performing a rapid and simple genetic analysis.

  15. A rapid, automated VWF ristocetin cofactor activity assay improves reliability in the diagnosis of Von Willebrand disease.

    Science.gov (United States)

    Bowyer, Annette E; Shepherd, Fiona; Kitchen, Stephen; Makris, Michael

    2011-04-01

    The effective diagnosis and monitoring of Von Willebrand Disease (VWD) requires an accurate assessment of ristocetin co-factor activity (VWF:RCo). Current methodologies include automated platelet aggregometry and manual visual agglutination both of which are laborious to perform and notoriously subject to a high degree of inter and intra assay variation. We have evaluated an automated VWF:RCo assay (BC Von Willebrand Reagent, Siemens, Marberg, Germany) for use on the Sysmex CS2100i analyser (Milton Keynes, UK) and retrospectively compared the results with an in-house manual visual agglutination assay and VWF antigen (Siemens) in normal subjects and in 53 patients with various types of VWD and 23 patients following VWF therapeutic treatment. The intra and interassay CV was improved with the automated assay (2.3% and 3.8% respectively) compared to 7% with the manual VWF:RCo assay. Good correlation was found between the two assays (r=0.91) in 53 patients with VWD. The mean manual VWF:RCo was 0.25IU/ml and mean automated VWF:RCo was 0.27IU/ml. A comparable increase in VWF:RCo following treatment, mostly with Desmopressin, was found in 13 patients with type 1 VWD (mean 3.9 fold increase with manual VWF:RCo and 3.1 fold with the automated VWF:RCo). In 13 patients with type 2 or 3 VWD following treatment mostly with concentrate , a higher increase was found with the automated VWF:RCo assay than the manual assay (mean 11.9 fold manually and mean 20.3 automated). The automated VWF:RCo assay shows enhanced precision and analysis time in this difficult and time consuming laboratory test and its introduction should greatly improve the reliability of VWF testing. Copyright © 2010. Published by Elsevier Ltd.

  16. Distinguishing Direct versus Indirect Transcription Factor-DNA Interactions

    Science.gov (United States)

    Gordân, Raluca; Hartemink, Alexander J.; Bulyk, Martha L.

    Transcriptional regulation is largely enacted by transcription factors (TFs) binding DNA. Large numbers of TF binding motifs have been revealed by ChIP-chip experiments followed by computational DNA motif discovery. However, the success of motif discovery algorithms has been limited when applied to sequences bound in vivo (such as those identified by ChIP-chip) because the observed TF-DNA interactions are not necessarily direct: some TFs predominantly associate with DNA indirectly through protein partners, while others exhibit both direct and indirect binding.

  17. A systematic review of the effects of hemophilia and von Willebrand disease on arterial trombosis

    NARCIS (Netherlands)

    Biere-Rafi, Sara; Zwiers, M.; Peters, Marjolein; Van Der Meer, Jan; Rosendaal, Frits R; Buller, Harry R; Kamphuisen, Pieter W

    Background: Patients with hemophilia and von Willebrand disease (VWD) may be protected against arterial thrombosis, through a hy-pocoagulable state or atherosclerosis. We performed a systematic review to assess the association between these clotting disorders, arterial thrombosis and the prevalence

  18. Health-related quality of life among adult patients with moderate and severe von Willebrand disease.

    NARCIS (Netherlands)

    Wee, E.M. de; Mauser-Bunschoten, E.P.; Bom, J.G. Van Der; Degenaar-Dujardin, M.E.; Eikenboom, H.C.; Fijnvandraat, K.; Goede-Bolder, A. de; Laros, B.A.P.; Meijer, K.; Raat, H.; Leebeek, F.W.

    2010-01-01

    SUMMARY BACKGROUND: von Willebrand Disease (VWD) is the most frequent inherited bleeding disorder. It is unknown how this disorder affects quality of life. OBJECTIVES: This nationwide multicenter cross-sectional study determined health-related quality of life (HR-QoL) in adult patients with moderate

  19. The effect of haemophilia and von Willebrand disease on arterial thrombosis : A systematic review

    NARCIS (Netherlands)

    Biere-Rafi, S.; Zwiers, M.; Peters, M.; van der Meer, J.; Rosendaal, F. R.; Buller, H. R.; Kamphuisen, P. W.

    Background: Patients with haemophilia and von Willebrand disease (VWD) may have a reduced cardiovascular mortality, due to a hypocoagulable state or decreased atherogenesis. We performed a systematic review to assess the association between haemophilia and VWD, and fatal and nonfatal arterial

  20. Gynaecological and obstetric bleeding in moderate and severe von Willebrand disease

    NARCIS (Netherlands)

    de Wee, Eva M.; Knol, H. Marieke; Mauser-Bunschoten, Eveline P.; van der Bom, Johanna G.; Eikenboom, Jeroen C. J.; Fijnvandraat, Karin; de Goede-Bolder, Arja; Laros-van Gorkom, Britta; Ypma, Paula F.; Zweegman, Sonja; Meijer, Karina; Leebeek, Frank W. G.

    2011-01-01

    A nation-wide cross-sectional study was initiated to assess gynaecological and obstetrical symptoms in an unselected cohort of women with moderate and severe von Willebrand disease (VWD) in the Netherlands. A total of 423 women aged >= 16 years were included. Bleeding severity was measured using the

  1. Gynaecological and obstetric bleeding in moderate and severe von Willebrand disease.

    NARCIS (Netherlands)

    Wee, E.M. de; Knol, H.M.; Mauser-Bunschoten, E.P.; Bom, J.G. Van Der; Eikenboom, J.C.; Fijnvandraat, K.; Goede-Bolder, A. de; Laros-van Gorkom, B.A.P.; Ypma, P.F.; Zweegman, S.; Meijer, K.; Leebeek, F.W.

    2011-01-01

    A nation-wide cross-sectional study was initiated to assess gynaecological and obstetrical symptoms in an unselected cohort of women with moderate and severe von Willebrand disease (VWD) in the Netherlands. A total of 423 women aged >/=16 years were included. Bleeding severity was measured using the

  2. Temperature can interact with landscape factors to affect songbird productivity.

    Science.gov (United States)

    Cox, W Andrew; Thompson, Frank R; Reidy, Jennifer L; Faaborg, John

    2013-04-01

    Increased temperatures and more extreme weather patterns associated with global climate change can interact with other factors that regulate animal populations, but many climate change studies do not incorporate other threats to wildlife in their analyses. We used 20 years of nest-monitoring data from study sites across a gradient of habitat fragmentation in Missouri, USA, to investigate the relative influence of weather variables (temperature and precipitation) and landscape factors (forest cover and edge density) on the number of young produced per nest attempt (i.e., productivity) for three species of songbirds. We detected a strong forest cover × temperature interaction for the Acadian Flycatcher (Empidonax virescens) on productivity. Greater forest cover resulted in greater productivity because of reduced brood parasitism and increased nest survival, whereas greater temperatures reduced productivity in highly forested landscapes because of increased nest predation but had no effect in less forested landscapes. The Indigo Bunting (Passerina cyanea) exhibited a similar pattern, albeit with a marginal forest cover × temperature interaction. By contrast, productivity of the Northern Cardinal (Cardinalis cardinalis) was not influenced by landscape effects or temperature. Our results highlight a potential difficulty of managing wildlife in response to global change such as habitat fragmentation and climate warming, as the habitat associated with the greatest productivity for flycatchers was also that most negatively influenced by high temperatures. The influence of high temperatures on nest predation (and therefore, nest predators) underscores the need to acknowledge the potential complexity of species' responses to climate change by incorporating a more thorough consideration of community ecology in the development of models of climate impacts on wildlife. © 2012 Blackwell Publishing Ltd.

  3. Transcription factor interactions mediate EGF-dependent COX-2 expression.

    Science.gov (United States)

    Xu, Kaiming; Shu, Hui-Kuo G

    2013-08-01

    Cyclooxygenase-2 (COX-2) is linked to poor prognosis in patients with malignant gliomas. Amplification/overexpression of epidermal growth factor receptor (EGFR) is commonly seen in these tumors. EGFR signaling, through activation of the p38-MAPK/PKC-δ/Sp1 cascade, plays an essential role in the regulation of COX-2 expression in glioma cells. Here, we report that Src kinase contributes upstream to this signaling cascade. In addition, more detailed analysis revealed the involvement of FOXM1, a member of the forkhead box family of transcriptional activators, in EGF-dependent COX-2 induction. FOXM1 protein increased after stimulation with EGF, although its role in modulating COX-2 expression does not depend on this increase. While a conventional FOXM1 responsive element resides in a distal region (-2872/-2539 relative to the transcriptional start site) of the COX-2 promoter, this is not required for EGF-dependent induction of COX-2. Instead, FOXM1 forms a cooperative interaction with Sp1 at the Sp1-binding site (-245/-240 relative to the start site) of the COX-2 promoter to mediate EGF-induced COX-2 expression. Definition of this novel interaction provides a clearer understanding of the mechanistic basis for EGF induction of COX-2. These data provide a guide for the evaluation of potential newer therapeutic targets that have relevance in this disease. ©2013 AACR.

  4. Interaction between hepatitis C virus and metabolic factors.

    Science.gov (United States)

    Kawaguchi, Yasunori; Mizuta, Toshihiko

    2014-03-21

    Hepatitis C virus (HCV) infection disrupts the normal metabolism processes, but is also influenced by several of the host's metabolic factors. An obvious and significantly detrimental pathophysiological feature of HCV infection is insulin resistance in hepatic and peripheral tissues. Substantial research efforts have been put forth recently to elucidate the molecular mechanism of HCV-induced insulin resistance, and several cytokines, such as tumor necrosis factor-α, have been identified as important contributors to the development of insulin resistance in the distant peripheral tissues of HCV-infected patients and animal models. The demonstrated etiologies of HCV-induced whole-body insulin resistance include oxidative stress, lipid metabolism abnormalities, hepatic steatosis and iron overload. In addition, myriad effects of this condition have been characterized, including glucose intolerance, resistance to antiviral therapy, progression of hepatic fibrosis, development of hepatocellular carcinoma, and general decrease in quality of life. Metabolic-related conditions and disorders, such as visceral obesity and diabetes mellitus, have been shown to synergistically enhance HCV-induced metabolic disturbance, and are associated with worse prognosis. Yet, the molecular interactions between HCV-induced metabolic disturbance and host-associated metabolic factors remain largely unknown. The diet and lifestyle recommendations for chronic hepatitis C are basically the same as those for obesity, diabetes, and metabolic syndrome. Specifically, patients are suggested to restrict their dietary iron intake, abstain from alcohol and tobacco, and increase their intake of green tea and coffee (to attain the beneficial effects of caffeine and polyphenols). While successful clinical management of HCV-infected patients with metabolic disorders has also been achieved with some anti-diabetic (i.e., metformin) and anti-lipid (i.e., statins) medications, it is recommended that

  5. Personal and Pedagogical Interaction Factors as Determinants of Academic Achievement

    OpenAIRE

    Cardoso, Ana Paula; Ferreira, Manuela; Abrantes, José Luís; Seabra, Cláudia; Costa, Cesário

    2011-01-01

    This study intends to relate self-esteem, teacher-student interaction, student-student interaction and learning performance, and its direct and indirect relationships with academic achievement. Using a sample of about 2000 Portuguese high school students, a structural model reveals that low social self-esteem directly and negatively influences teacher-student interaction and studentstudent interaction and also learning performance. Teacher-student interaction directly and positively influence...

  6. Haemostasis prophylaxis using single dose desmopressin acetate and extended use epsilon aminocaproic acid for adenotonsillectomy in patients with type 1 von Willebrand disease.

    Science.gov (United States)

    Santoro, C; Hsu, F; Dimichele, D M

    2012-03-01

    In patients with confirmed or suspected type 1 von Willebrand disease (VWD), adenotonsillectomy has been reported to be associated with a rate of peri-operative hemorrhage between 8 and 23%. Desmopressin acetate (DDAVP, 1-deamino 8-D arginine- vasopressin) is the treatment of choice for type 1 patients with baseline von Willebrand factor levels of 10 IU/dL or greater. DDAVP is generally well tolerated; however, severe hyponatremia and seizures have been reported in young children less than 2 years of age, limiting its use in this age group. Antifibrinolytic therapy plays an important adjunctive role in the effective treatment of mucocutaneous bleeding, particularly in the oropharynx where the salivary concentration of fibrinolytic enzymes is high. During the past 10 years, we treated 6 pediatric patients with mild/moderate type 1 VWD undergoing an adenotonsillar procedure at our institution with the same hemostatic regimen consisting of one single dose of DDAVP and an extended use of EACA. In this small case series, the above mentioned prophylactic treatment regimen was both well tolerated and efficacious in controlling hemorrhage. Furthermore, DDAVP-related complications were avoided in a pediatric population with a higher risk of developing them. © 2011 Blackwell Publishing Ltd.

  7. The Carmat Bioprosthetic Total Artificial Heart Is Associated With Early Hemostatic Recovery and no Acquired von Willebrand Syndrome in Calves.

    Science.gov (United States)

    Smadja, David M; Susen, Sophie; Rauch, Antoine; Cholley, Bernard; Latrémouille, Christian; Duveau, Daniel; Zilberstein, Luca; Méléard, Denis; Boughenou, Marie-Fazia; Belle, Eric Van; Gaussem, Pascale; Capel, Antoine; Jansen, Piet; Carpentier, Alain

    2017-10-01

    To determine hemostasis perturbations, including von Willebrand factor (VWF) multimers, after implantation of a new bioprosthetic and pulsatile total artificial heart (TAH). Preclinical study SETTING: Single-center biosurgical research laboratory. Female Charolais calves, 2-to-6 months old, weighing 102-to-122 kg. Surgical implantation of TAH through a mid-sternotomy approach. Four of 12 calves had a support duration of several days (4, 4, 8, and 10 days), allowing for the exploration of early steps of hemostasis parameters, including prothrombin time; coagulation factor levels (II, V, VII+X, and fibrinogen); and platelet count. Multimeric analysis of VWF was performed to detect a potential loss of high-molecular weight (HMW) multimers, as previously described for continuous flow rotary blood pumps. Despite the absence of anticoagulant treatment administered in the postoperative phase, no signs of coagulation activation were detected. Indeed, after an immediate postsurgery decrease of prothrombin time, platelet count, and coagulation factor levels, most parameters returned to baseline values. HMW multimers of VWF remained stable either after initiation or during days of support. Coagulation parameters and platelet count recovery in the postoperative phase of the Carmat TAH (Camat SA, Velizy Villacoublay Cedex, France) implantation in calves, in the absence of anticoagulant treatment and associated with the absence of decrease in HMW multimers of VWF, is in line with early hemocompatibility that is currently being validated in human clinical studies. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Interaction factors for two elliptical embedded cracks with a wide range of aspect ratios

    Directory of Open Access Journals (Sweden)

    Kisaburo Azuma

    2017-02-01

    Full Text Available The value of stress intensity factor may be increased through the interaction of multiple cracks that are in close proximity to one another. We investigated the interaction factors of two equal elliptical cracks with a wide range of aspect ratios. Finite element analysis for a linear elastic solid was used to obtain the interaction factor for embedded cracks in an infinite model subjected to remote tension loading. Relationships between interaction factors and dimensionless distances between the cracks were discussed. The results demonstrated that the interaction factors depend on the crack aspect ratio, whose effect is related to the dimensionless distance. Thus, it is suggested that interaction factors can be reasonably characterized using different dimensionless distances depending on the aspect ratio. Finally, we provide a simple empirical formula for obtaining the interaction factors for embedded cracks.

  9. GENÉTICA MOLECULAR DE LA HEMOFILIA A EN UNA FAMILIA COLOMBIANA CON DIAGNÓSTICO DE ENFERMEDAD DE VON WILLEBRAND Y DE HEMOFILIA A

    Directory of Open Access Journals (Sweden)

    Diana Carolina Polanía Villanueva

    2014-12-01

    Full Text Available El Factor von Willebrand circula en el plasma formando un complejo con el Factor VIII de coagulación por enlaces no covalentes. Esta interacción evita la degradación enzimática del Factor VIII y asegura su transporte al lugar de formación del coágulo de fibrina. Debido a su estrecha relación, la disminución de la actividad de un factor puede afectar la actividad del otro, lo que genera un diagnóstico clínico equivocado en cuanto a qué enfermedad se padece, si Hemofilia A o Enfermedad de von Willebrand. Este estudio reporta el caso de una familia colombiana que según diagnóstico clínico de su fenotipo, padecía las dos enfermedades. Sin embargo, dicha familia carecía de un estudio genético que permitiera verificar y contrastar el diagnóstico que hacen las entidades de salud. Por tal razón, se realizó un diagnóstico genético por pruebas moleculares que detectan mutaciones, como las inversiones en los intrones 1 y 22 por PCR de fragmentos largos y la secuenciación del gen del Factor VIII, esta última no aplicada y publicada en Colombia hasta el momento. Se encontraron dos mutaciones sinónimas en los exones 14 y 26 que no alteran la secuencia de aminoácidos en la proteína; por tanto, se descarta la presencia de Hemofilia A en la familia. Se plantea la posibilidad de un caso de Enfermedad de von Willebrand únicamente. El estudio demuestra la necesidad que hay en el país de ampliar las pruebas clínicas y de incluir el diagnóstico genético en casos de ambigüedad en el diagnóstico de estas coagulopatías.

  10. The Factors Influencing Young Children's Social Interaction in Technology Integration

    Science.gov (United States)

    Lim, Eun Mee

    2015-01-01

    When technology integration is accomplished successfully in early childhood education settings, children tend to interact more with one another and exchange information related to computer tasks as well as the overall classroom on-going curriculum themes. Therefore, to explore how young children are interacting in computer areas when using…

  11. Gene-environment interaction study for BMI reveals interactions between genetic factors and physical activity, alcohol consumption and socioeconomic status

    Science.gov (United States)

    Karlsson, Torgny; Ek, Weronica E.

    2017-01-01

    Previous genome-wide association studies (GWAS) have identified hundreds of genetic loci to be associated with body mass index (BMI) and risk of obesity. Genetic effects can differ between individuals depending on lifestyle or environmental factors due to gene-environment interactions. In this study, we examine gene-environment interactions in 362,496 unrelated participants with Caucasian ancestry from the UK Biobank resource. A total of 94 BMI-associated SNPs, selected from a previous GWAS on BMI, were used to construct weighted genetic scores for BMI (GSBMI). Linear regression modeling was used to estimate the effect of gene-environment interactions on BMI for 131 lifestyle factors related to: dietary habits, smoking and alcohol consumption, physical activity, socioeconomic status, mental health, sleeping patterns, as well as female-specific factors such as menopause and childbirth. In total, 15 lifestyle factors were observed to interact with GSBMI, of which alcohol intake frequency, usual walking pace, and Townsend deprivation index, a measure of socioeconomic status, were all highly significant (p = 1.45*10−29, p = 3.83*10−26, p = 4.66*10−11, respectively). Interestingly, the frequency of alcohol consumption, rather than the total weekly amount resulted in a significant interaction. The FTO locus was the strongest single locus interacting with any of the lifestyle factors. However, 13 significant interactions were also observed after omitting the FTO locus from the genetic score. Our analyses indicate that many lifestyle factors modify the genetic effects on BMI with some groups of individuals having more than double the effect of the genetic score. However, the underlying causal mechanisms of gene-environmental interactions are difficult to deduce from cross-sectional data alone and controlled experiments are required to fully characterise the causal factors. PMID:28873402

  12. An examination of social interaction profiles based on the factors measured by the screen for social interaction.

    Science.gov (United States)

    Mahoney, Emery B; Breitborde, Nicholas J K; Leone, Sarah L; Ghuman, Jaswinder Kaur

    2014-10-01

    Deficits in the capacity to engage in social interactions are a core deficit associated with Autistic Disorder (AD) and Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS). These deficits emerge at a young age, making screening for social interaction deficits and interventions targeted at improving capacity in this area important for early identification and intervention. Screening and early intervention efforts are particularly important given the poor short and long term outcomes for children with Autism Spectrum Disorders (ASDs) who experience social interaction deficits. The Screen for Social Interaction (SSI) is a well-validated screening measure that examines a child's capacity for social interaction using a developmental approach. The present study identified four underlying factors measured by the SSI, namely, Connection with Caregiver, Interaction/Imagination, Social Approach/Interest, and Agreeable Nature. The resulting factors were utilized to compare social interaction profiles across groups of children with AD, PDD-NOS, children with non-ASD developmental and/or psychiatric conditions and typically developing children. The results indicate that children with AD and those with PDD-NOS had similar social interaction profiles, but were able to be distinguished from typically developing children on every factor and were able to be distinguished from children with non-ASD psychiatric conditions on every factor except the Connection with Caregiver factor. In addition, children with non-ASD developmental and/or psychiatric conditions could be distinguished from typically developing children on the Connection with Caregiver factor and the Social Approach/Interest factor. These findings have implications for screening and intervention for children with ASDs and non-ASD psychiatric conditions. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. The interaction of the performance factors in ACHIEVE model: A study in Iran

    Directory of Open Access Journals (Sweden)

    Nasim Yousef Saber

    2015-06-01

    Full Text Available According to the ACHIEVE model, seven factors including ability, clarity of roles, organizational support and help, incentive or motivation, evaluation and feedback, validity, and environmental factors affect employee performance. The purpose of this study was to evaluate the interaction among these performance factors. The population for the study consisted of 44 employees in a Web-based software manufacturing company in Iran. Data was collected through a questionnaire relevant to the factors of ACHIEVE. Data analysis was performed using correlation analysis in SPSS. The results of correlation analysis showed that some of these factors had a multiplicative interaction and some others had no interaction. There was also no evidence of reducing interaction. For example, the ability was not associated with other factors. In contrast, incentive and organizational support had some interactions. The article offers management recommendations for decision-making to improve the performance factors. Following this, identifying the effects helps managers to improve their performances.

  14. Interaction of a spinach protein factor with bacteriochlorophyll

    NARCIS (Netherlands)

    Terpstra, Willemke

    1968-01-01

    1. The absorption spectrum of colloidal bacteriochlorophyll gradually changes from one with two absorption maxima in the near infrared part of the spectrum into one with a single maximum in this region. This conversion is accelerated by a spinach protein factor. Spinach protein factor also causes a

  15. Rural children active trachoma risk factors and their interactions ...

    African Journals Online (AJOL)

    The household wealth will have a more protective effect if the child attends school. Washing face with soap and water once a day has equivalent protective effect as washing face three-or-more times a day with water only. Conclusion: The 2-way and 3-way significant interactions effects unfolded some of the controversies ...

  16. Plant integrity: an important factor in plant-pathogen interactions

    DEFF Research Database (Denmark)

    Orlowska, Elzbieta Zofia; Llorente, Briardo; Cvitanich, Cristina

    2013-01-01

    the hemibiotrophic oomycete pathogen Phytophthora infestans. Furthermore, in the Sarpo Mira–P. infestans interactions, the plant’s meristems, the stalks or both, seem to be associated with the development of the hypersensitive response and both the plant’s roots and shoots contain antimicrobial compounds when...

  17. Interpersonal Interaction in Online Learning: Experienced Online Instructors' Perceptions of Influencing Factors

    Science.gov (United States)

    York, Cindy S.; Richardson, Jennifer C.

    2012-01-01

    A multitude of factors influence interpersonal interaction between students and instructors in an online course. This study examines perceptions of six experienced online instructors to determine factors they believe increase interaction among their students and between the students and instructor of online courses. The end result is an inventory…

  18. Antifibrinolytic therapy for preventing oral bleeding in patients with haemophilia or Von Willebrand disease undergoing minor oral surgery or dental extractions.

    Science.gov (United States)

    van Galen, Karin P M; Engelen, Eveline T; Mauser-Bunschoten, Evelien P; van Es, Robert J J; Schutgens, Roger E G

    2015-12-24

    Minor oral surgery or dental extractions (oral or dental procedures) are widely performed and can be complicated by hazardous oral bleeding, especially in people with an inherited bleeding disorder such as haemophilia or Von Willebrand disease. The amount and severity of singular bleedings depend on disease-related factors, such as the severity of the haemophilia, both local and systemic patient factors (such as periodontal inflammation, vasculopathy or platelet dysfunction) and intervention-related factors (such as the type and number of teeth extracted or the dimension of the wound surface). Similar to local haemostatic measures and suturing, antifibrinolytic therapy is a cheap, safe and potentially effective treatment to prevent bleeding complications in individuals with bleeding disorders undergoing oral or dental procedures. However, a systematic review of trials reporting outcomes after oral surgery or a dental procedure in people with an inherited bleeding disorder, with or without, the use of antifibrinolytic agents has not been performed to date. The primary objective was to assess the efficacy of local or systemic use of antifibrinolytic agents to prevent bleeding complications in people with haemophilia or Von Willebrand disease undergoing oral or dental procedures. Secondary objectives were to assess if antifibrinolytic agents can replace or reduce the need for clotting factor concentrate therapy in people with haemophilia or Von Willebrand disease and to further establish the effects of these agents on bleeding in oral or dental procedures for each of these populations. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches of the Cochrane Central Register of Controlled Trials (CENTRAL), of MEDLINE and from handsearching of journals and conference abstract books. We additionally searched the reference lists of relevant articles and reviews. We searched Pub

  19. Interaction between hepatitis C virus and metabolic factors

    OpenAIRE

    Kawaguchi, Yasunori; Mizuta, Toshihiko

    2014-01-01

    Hepatitis C virus (HCV) infection disrupts the normal metabolism processes, but is also influenced by several of the host’s metabolic factors. An obvious and significantly detrimental pathophysiological feature of HCV infection is insulin resistance in hepatic and peripheral tissues. Substantial research efforts have been put forth recently to elucidate the molecular mechanism of HCV-induced insulin resistance, and several cytokines, such as tumor necrosis factor-α, have been identified as im...

  20. Scatter factor and the c-met receptor: a paradigm for mesenchymal/epithelial interaction

    OpenAIRE

    1994-01-01

    Epithelia and mesenchyme interact during various physiologic and pathologic processes. Scatter factor is a mesenchyme-derived cytokine that stimulates motility, proliferation, and morphogenesis of epithelia. Recent studies suggest that scatter factor and its receptor (c-met) mediate mesenchyme/epithelia signalling and even interconversion. In this mini-review, we will discuss how scatter factor and c-met may mediate interactions between mesenchyme and epithelia during embryogenesis, organ rep...

  1. Interaction of Coagulation Defects and Cardiovascular Risk Factors

    NARCIS (Netherlands)

    Doggen, Catharina Jacoba Maria; Manger Cats, Volkert; Bertina, Rogier M.; Rosendaal, Frits R.

    1998-01-01

    Background—A genetic variation located in the 3'-untranslated region of the prothrombin gene (prothrombin 20210 G→A) was recently described as a risk factor for venous thrombosis. We examined how the presence of this mutation affected the risk of myocardial infarction in a population-based

  2. Psychopathy and Violence: The Importance of Factor Level Interactions

    Science.gov (United States)

    Walsh, Zach; Kosson, David S.

    2008-01-01

    The power of scales based on the Psychopathy Checklist (PCL; R. D. Hare, 1980) for prediction of violent behavior is well established. Although evidence suggests that this relationship is chiefly due to the impulsive and antisocial lifestyle component (Factor 2), the predictive power of psychopathy for violence may also reflect the multiplicative…

  3. Situational and Personality Factors: Interactive Effects on Attitude - Active Consistency

    Science.gov (United States)

    Albrecht, Stan L.; Warner, Lyle G.

    1975-01-01

    An examination of the combined effect of a situational factor, disclosure, and two personality variables, "need for approval" and "inner-other directedness" on attitude - action relationships with respect to marijuana related attitudes and behavior of college students. Subjects with different personality characteristics were found to respond…

  4. Severe Plasmodium falciparum malaria is associated with circulating ultra-large von Willebrand multimers and ADAMTS13 inhibition.

    LENUS (Irish Health Repository)

    Larkin, Deirdre

    2009-03-01

    Plasmodium falciparum infection results in adhesion of infected erythrocytes to blood vessel endothelium, and acute endothelial cell activation, together with sequestration of platelets and leucocytes. We have previously shown that patients with severe infection or fulminant cerebral malaria have significantly increased circulatory levels of the adhesive glycoprotein von Willebrand factor (VWF) and its propeptide, both of which are indices of endothelial cell activation. In this prospective study of patients from Ghana with severe (n = 20) and cerebral (n = 13) P. falciparum malaria, we demonstrate that increased plasma VWF antigen (VWF:Ag) level is associated with disproportionately increased VWF function. VWF collagen binding (VWF:CB) was significantly increased in patients with cerebral malaria and severe malaria (medians 7.6 and 7.0 IU\\/ml versus 1.9 IU\\/ml; p<0.005). This increased VWF:CB correlated with the presence of abnormal ultra-large VWF multimers in patient rather than control plasmas. Concomitant with the increase in VWF:Ag and VWF:CB was a significant persistent reduction in the activity of the VWF-specific cleaving protease ADAMTS13 (approximately 55% of normal; p<0.005). Mixing studies were performed using P. falciparum patient plasma and normal pooled plasma, in the presence or absence of exogenous recombinant ADAMTS13. These studies demonstrated that in malarial plasma, ADAMTS13 function was persistently inhibited in a time-dependent manner. Furthermore, this inhibitory effect was not associated with the presence of known inhibitors of ADAMTS13 enzymatic function (interleukin-6, free haemoglobin, factor VIII or thrombospondin-1). These novel findings suggest that severe P. falciparum infection is associated with acute endothelial cell activation, abnormal circulating ULVWF multimers, and a significant reduction in plasma ADAMTS13 function which is mediated at least in part by an unidentified inhibitor.

  5. Autism risk factors: genes, environment, and gene-environment interactions

    OpenAIRE

    Chaste, Pauline; Leboyer, Marion

    2012-01-01

    The aim of this review is to summarize the key findings from genetic and epidemiological research, which show that autism is a complex disorder resulting from the combination of genetic and environmental factors. Remarkable advances in the knowledge of genetic causes of autism have resulted from the great efforts made in the field of genetics. The identification of specific alleles contributing to the autism spectrum has supplied important pieces for the autism puzzle. However, many questions...

  6. Crowds, not Drones: Modeling Human Factors in Interactive Crowdsourcing

    OpenAIRE

    Basu Roy, Senjuti; Lykourentzou, Ioanna; Thirumuruganathan, Saravanan; Amer-Yahia, Sihem; Das, Gautam

    2013-01-01

    International audience; In this vision paper, we propose SmartCrowd, an intelligent and adaptive crowdsourcing framework. Contrary to existing crowdsourcing systems, where the process of hiring workers (crowd), learning their skills, and evaluating the accuracy of tasks they perform are fragmented, siloed, and often ad-hoc, SmartCrowd foresees a paradigm shift in that process, considering unpredictability of human nature, namely human factors. SmartCrowd offers opportunities in making crowdso...

  7. Learning with Interactive Whiteboards: Determining the Factors on Promoting Interactive Whiteboards to Students by Technology Acceptance Model

    Science.gov (United States)

    Kilic, Eylem; Güler, Çetin; Çelik, H. Eray; Tatli, Cemal

    2015-01-01

    Purpose: The purpose of this study is to investigate the factors which might affect the intention to use interactive whiteboards (IWBs) by university students, using Technology Acceptance Model by the structural equation modeling approach. The following hypothesis guided the current study: H1. There is a positive relationship between IWB…

  8. Interacting factors affecting illegitimacy in preindustrial northern England.

    Science.gov (United States)

    Scott, S; Duncan, C J

    1997-04-01

    Illegitimacy in a historic, single community at Penrith, Cumbria (1557-1812), has been studied using aggregative analysis, family reconstitution and time series analysis. This population was living under extreme conditions of hardship. Long, medium and short wavelength cycles in the rate of illegitimacy have been identified by time series analysis; each represents a different response to social and economic pressures. In a complex interaction of events, the peaks of the cycles in wheat prices were associated with rises in adult mortality which promoted an influx of migrants and a concomitant rise in illegitimacy. The association between immigration and illegitimacy was particularly noticeable after the mortality crises of the late sixteenth and early seventeenth centuries. Children of immigrant families also tended to produce illegitimate offspring. Native and immigrant families responded differently to extrinsic fluctuations, and variations in their reproductive behaviour were probably related to access to resources.

  9. Factors Mediating the Interactions between Adviser and Advisee during the Master's Thesis Project: A Quantitative Approach

    Science.gov (United States)

    Rodrigues Jr., Jose Florencio; Lehmann, Angela Valeria Levay; Fleith, Denise De Souza

    2005-01-01

    Building on previous studies centred on the interaction between adviser and advisee in masters thesis projects, in which a qualitative approach was used, the present study uses factor analysis to identify the factors that determine either a successful or unsuccessful outcome for the masters thesis project. There were five factors relating to the…

  10. Long-term impact of joint bleeds in von Willebrand disease: a nested case-control study

    NARCIS (Netherlands)

    Galen, K.P. van; Kleijn, P. de; Foppen, W.; Eikenboom, J.; Meijer, K.; Schutgens, R.E.; Fischer, K.; Cnossen, M.H.; Meris, J. de; Fijnvandraat, K.; Bom, J.G. Van Der; Laros-van Gorkom, B.A.P.; Leebeek, F.W.; Mauser-Bunschoten, E.P.

    2017-01-01

    Patients with severe von Willebrand disease (VWD) may develop arthropathy after joint bleeds. Information on its prevalence and severity is limited. We aimed to assess the occurrence and severity of arthropathy in VWD and its impact on daily life. VWD patients with and without verified joint bleeds

  11. Long-term impact of joint bleeds in von Willebrand disease : A nested case-control study

    NARCIS (Netherlands)

    van Galen, Karin P.M.; de Kleijn, Piet; Foppen, Wouter; Eikenboom, Jeroen H C; Meijer, Karina; Schutgens, Roger E.G.; Fischer, Kathelijn; Cnossen, Marjon H; de Meris, Joke; Fijnvandraat, Karin; van der Bom, Johanna G; Laros-van Gorkom, Britta A P; Leebeek, Frank W G; Mauser-Bunschoten, Eveline P.

    2017-01-01

    Patients with severe von Willebrand disease (VWD) may develop arthropathy after joint bleeds. Information on its prevalence and severity is limited. We aimed to assess the occurrence and severity of arthropathy in VWD and its impact on daily life. VWD patients with and without verified joint bleeds

  12. Long-term impact of joint bleeds in von Willebrand disease : A nested case-control study

    NARCIS (Netherlands)

    van Galen, Karin P. M.; de Kleijn, Piet; Foppen, Wouter; Eikenboom, Jeroen; Meijer, Karina; Schutgens, Roger E. G.; Fischer, Kathelijn; Cnossen, Marjon H.; de Meris, Joke; Fijnvandraat, Karin; van der Bom, Johanna G.; Laros-van Gorkom, Britta A. P.; Leebeek, Frank W. G.; Mauser-Bunschoten, Eveline P.

    Patients with severe von Willebrand disease (VWD) may develop arthropathy after joint bleeds. Information on its prevalence and severity is limited. We aimed to assess the occurrence and severity of arthropathy in VWD and its impact on daily life. VWD patients with and without verified joint bleeds

  13. Long-term impact of joint bleeds in von Willebrand disease: A nested case-control study

    NARCIS (Netherlands)

    K.P.M. van Galen; P. de Kleijn; W. Foppen (Wouter); J.C.J. Eikenboom (Jeroen); K. Meijer; R. Schutgens (Roger); K. Fischer (Kathelijn); M.H. Cnossen (Marjon); J. de Meris (J.); K. Fijnvandraat; J.G. van der Bom (Anske); B.A.P. Laros-Van Gorkom (Britta); F.W.G. Leebeek (Frank); E.P. Mauser-Bunschoten (Eveline)

    2017-01-01

    textabstractPatients with severe von Willebrand disease (VWD) may develop arthropathy after joint bleeds. Information on its prevalence and severity is limited. We aimed to assess the occurrence and severity of arthropathy in VWD and its impact on daily life. VWD patients with and without verified

  14. Interactivity and content as factors of enjoyment in interactive fictions / Interactividad y contenido como factores de disfrute

    Directory of Open Access Journals (Sweden)

    Xavier Ribes Guàrdia

    2009-01-01

    Full Text Available A report is made of the conclusions of an experimental research whose objectives are: 1.- to explore the relationship between interactivity, content and enjoyment; 2.- to observe the relationship between enjoyment and the concepts of entertainment, pleasure and gratification, and 3.- to find out whether there is a relationship between enjoyment and the manifest intention of posterior consumption, the desire to pay per view and the success forecast of such fiction on television. 310 participants were assigned to one four experimental situations derived from the combination between the variables: modality of fiction (interactive or non-interactive and content (happy or tragic ending. The results show that: a.- the content exerts a greater influence on the enjoyment of the narrative than does interactivity; b.- the concepts of enjoyment, entertainment and gratification, although related, describe different aspects of the consumption experience and that 3. enjoyment is linked to the desire for ensuing consumption. Se reportan las conclusiones obtenidas de una investigación experimental que tiene por objetivos: 1.- explorar la relación entre interactividad, contenido y disfrute en la recepción de ficciones interactivas; 2.- observar el vínculo del disfrute con los conceptos de entretenimiento, agrado y gratificación, y 3.- indagar sobre la relación entre disfrute e intención manifiesta de consumo posterior, voluntad de pago por visión o predicción de éxito de las ficciones interactivas en televisión. 310 participantes fueron sometidos a cuatro situaciones experimentales derivadas de la combinación entre las variables modalidad de la ficción (interactiva o no interactiva y contenido (final feliz o trágico. Los resultados señalan que: a.- el contenido ejerce superior impacto en el disfrute de la narrativa que la interactividad; b.- los conceptos de disfrute, entretenimiento y gratificación, aunque relacionados, describen distintos

  15. Tumor interactions with soluble factors and the nervous system

    Directory of Open Access Journals (Sweden)

    Voss Melanie J

    2010-09-01

    Full Text Available Abstract In the genomic era of cancer research, the development of metastases has been attributed to mutations in the tumor that enable the cells to migrate. However, gene analyses revealed that primary tumors and metastases were in some cases genetically identical and the question was raised whether metastasis formation might be an inherent feature of certain tumor cells. In contradiction to this view, the last decade of cancer research has brought to light, that tumor cell migration, similar to leukocyte and fibroblast migration, is a highly regulated process. The nervous system plays an important role in this regulation, at least in two respects: firstly, neurotransmitters are known to regulate the migratory activity of tumor cells, and secondly, nerve fibers are used as routes for perineural invasion. We also summarize here the current knowledge on the innervation of tumors. Such a process might establish a neuro-neoplastic synapse, with the close interaction of tumor cells and nerve cells supporting metastasis formation.

  16. Temporal factors affecting somatosensory-auditory interactions in speech processing

    Directory of Open Access Journals (Sweden)

    Takayuki eIto

    2014-11-01

    Full Text Available Speech perception is known to rely on both auditory and visual information. However, sound specific somatosensory input has been shown also to influence speech perceptual processing (Ito et al., 2009. In the present study we addressed further the relationship between somatosensory information and speech perceptual processing by addressing the hypothesis that the temporal relationship between orofacial movement and sound processing contributes to somatosensory-auditory interaction in speech perception. We examined the changes in event-related potentials in response to multisensory synchronous (simultaneous and asynchronous (90 ms lag and lead somatosensory and auditory stimulation compared to individual unisensory auditory and somatosensory stimulation alone. We used a robotic device to apply facial skin somatosensory deformations that were similar in timing and duration to those experienced in speech production. Following synchronous multisensory stimulation the amplitude of the event-related potential was reliably different from the two unisensory potentials. More importantly, the magnitude of the event-related potential difference varied as a function of the relative timing of the somatosensory-auditory stimulation. Event-related activity change due to stimulus timing was seen between 160-220 ms following somatosensory onset, mostly around the parietal area. The results demonstrate a dynamic modulation of somatosensory-auditory convergence and suggest the contribution of somatosensory information for speech processing process is dependent on the specific temporal order of sensory inputs in speech production.

  17. [Factors influencing juvenile alcohol consumption: the role of gene-environment interactions].

    Science.gov (United States)

    Hinckers, Anne S; Frank, Josef; Heinz, Andreas; Schumann, Gunter; Schmidt, Martin H; Laucht, Manfred

    2006-09-01

    Excessive alcohol consumption in youth increases the risk of subsequent alcohol use disorders. Despite the recognition of genetic and environmental factors, an appropriate aetiological model is needed to take adequate preventative steps. This is in part due to the complex interactions between genotype and environment. In this article we review research on factors determining alcohol use by adolescents and on the development of an unifying model. The data bank Medline Advanced was searched for topical articles that were then checked for relevance and sorted according to genetic factors, environmental factors, and their interactions. Many factors, alone and in combination with others, influence juvenile alcohol consumption. Each single variable, however, can explain only a small part of the variation in consumption behaviour. The manifold possibilities of interactions between these factors become clear. There is a strong need for comprehensive models of juvenile alcohol use and the integration of current results into these models.

  18. Protein-protein interactions in the regulation of WRKY transcription factors.

    Science.gov (United States)

    Chi, Yingjun; Yang, Yan; Zhou, Yuan; Zhou, Jie; Fan, Baofang; Yu, Jing-Quan; Chen, Zhixiang

    2013-03-01

    It has been almost 20 years since the first report of a WRKY transcription factor, SPF1, from sweet potato. Great progress has been made since then in establishing the diverse biological roles of WRKY transcription factors in plant growth, development, and responses to biotic and abiotic stress. Despite the functional diversity, almost all analyzed WRKY proteins recognize the TTGACC/T W-box sequences and, therefore, mechanisms other than mere recognition of the core W-box promoter elements are necessary to achieve the regulatory specificity of WRKY transcription factors. Research over the past several years has revealed that WRKY transcription factors physically interact with a wide range of proteins with roles in signaling, transcription, and chromatin remodeling. Studies of WRKY-interacting proteins have provided important insights into the regulation and mode of action of members of the important family of transcription factors. It has also emerged that the slightly varied WRKY domains and other protein motifs conserved within each of the seven WRKY subfamilies participate in protein-protein interactions and mediate complex functional interactions between WRKY proteins and between WRKY and other regulatory proteins in the modulation of important biological processes. In this review, we summarize studies of protein-protein interactions for WRKY transcription factors and discuss how the interacting partners contribute, at different levels, to the establishment of the complex regulatory and functional network of WRKY transcription factors.

  19. Subject Line Preferences and Other Factors Contributing to Coherence and Interaction in Student Discussion Forums

    Science.gov (United States)

    Skogs, Julie

    2013-01-01

    A number of factors may affect student interaction in an asynchronous online discussion forum used in learning. This study deals with student preferences for the subject line of messages and in what ways the choice of subject line contributes to coherence and interaction reflected in the textual and interpersonal functions of the linguistic items…

  20. Stromal interaction essential for vascular endothelial growth factor A-induced tumour growth via transforming growth factor-beta signalling

    NARCIS (Netherlands)

    Weidenaar, A. C.; ter Elst, A.; Kampen, K. R.; Meeuwsen-de Boer, Geertdina; de Jonge, H. J. M.; Scherpen, F. J. G.; den Dunnen, W. F. A.; Kamps, W. A.; de Bont, E. S. J. M.

    2011-01-01

    BACKGROUND: High vascular endothelial growth factor (VEGFA) levels at the time of diagnosis confer a worse prognosis to multiple malignancies. Our aim was to investigate the role of VEGFA in promoting tumour growth through interaction with its environment. METHODS: HL-60 cells were transduced with

  1. TcoF-DB: dragon database for human transcription co-factors and transcription factor interacting proteins.

    Science.gov (United States)

    Schaefer, Ulf; Schmeier, Sebastian; Bajic, Vladimir B

    2011-01-01

    The initiation and regulation of transcription in eukaryotes is complex and involves a large number of transcription factors (TFs), which are known to bind to the regulatory regions of eukaryotic DNA. Apart from TF-DNA binding, protein-protein interaction involving TFs is an essential component of the machinery facilitating transcriptional regulation. Proteins that interact with TFs in the context of transcription regulation but do not bind to the DNA themselves, we consider transcription co-factors (TcoFs). The influence of TcoFs on transcriptional regulation and initiation, although indirect, has been shown to be significant with the functionality of TFs strongly influenced by the presence of TcoFs. While the role of TFs and their interaction with regulatory DNA regions has been well-studied, the association between TFs and TcoFs has so far been given less attention. Here, we present a resource that is comprised of a collection of human TFs and the TcoFs with which they interact. Other proteins that have a proven interaction with a TF, but are not considered TcoFs are also included. Our database contains 157 high-confidence TcoFs and additionally 379 hypothetical TcoFs. These have been identified and classified according to the type of available evidence for their involvement in transcriptional regulation and their presence in the cell nucleus. We have divided TcoFs into four groups, one of which contains high-confidence TcoFs and three others contain TcoFs which are hypothetical to different extents. We have developed the Dragon Database for Human Transcription Co-Factors and Transcription Factor Interacting Proteins (TcoF-DB). A web-based interface for this resource can be freely accessed at http://cbrc.kaust.edu.sa/tcof/ and http://apps.sanbi.ac.za/tcof/.

  2. TcoF-DB: dragon database for human transcription co-factors and transcription factor interacting proteins

    KAUST Repository

    Schaefer, Ulf

    2010-10-21

    The initiation and regulation of transcription in eukaryotes is complex and involves a large number of transcription factors (TFs), which are known to bind to the regulatory regions of eukaryotic DNA. Apart from TF-DNA binding, protein-protein interaction involving TFs is an essential component of the machinery facilitating transcriptional regulation. Proteins that interact with TFs in the context of transcription regulation but do not bind to the DNA themselves, we consider transcription co-factors (TcoFs). The influence of TcoFs on transcriptional regulation and initiation, although indirect, has been shown to be significant with the functionality of TFs strongly influenced by the presence of TcoFs. While the role of TFs and their interaction with regulatory DNA regions has been well-studied, the association between TFs and TcoFs has so far been given less attention. Here, we present a resource that is comprised of a collection of human TFs and the TcoFs with which they interact. Other proteins that have a proven interaction with a TF, but are not considered TcoFs are also included. Our database contains 157 high-confidence TcoFs and additionally 379 hypothetical TcoFs. These have been identified and classified according to the type of available evidence for their involvement in transcriptional regulation and their presence in the cell nucleus. We have divided TcoFs into four groups, one of which contains high-confidence TcoFs and three others contain TcoFs which are hypothetical to different extents. We have developed the Dragon Database for Human Transcription Co-Factors and Transcription Factor Interacting Proteins (TcoF-DB). A web-based interface for this resource can be freely accessed at http://cbrc.kaust.edu.sa/tcof/ and http://apps.sanbi.ac.za/tcof/. © The Author(s) 2010.

  3. Rsd family proteins make simultaneous interactions with regions 2 and 4 of the primary sigma factor.

    Science.gov (United States)

    Yuan, Andy H; Gregory, Brian D; Sharp, Josh S; McCleary, Katherine D; Dove, Simon L; Hochschild, Ann

    2008-12-01

    Bacterial anti-sigma factors typically regulate sigma factor function by restricting the access of their cognate sigma factors to the RNA polymerase (RNAP) core enzyme. The Escherichia coli Rsd protein forms a complex with the primary sigma factor, sigma(70), inhibits sigma(70)-dependent transcription in vitro, and has been proposed to function as a sigma(70)-specific anti-sigma factor, thereby facilitating the utilization of alternative sigma factors. In prior work, Rsd has been shown to interact with conserved region 4 of sigma(70), but it is not known whether this interaction suffices to account for the regulatory functions of Rsd. Here we show that Rsd and the Rsd orthologue AlgQ, a global regulator of gene expression in Pseudomonas aeruginosa, interact with conserved region 2 of sigma(70). We show further that Rsd and AlgQ can interact simultaneously with regions 2 and 4 of sigma(70). Our findings establish that the abilities of Rsd and AlgQ to interact with sigma(70) region 2 are important determinants of their in vitro and in vivo activities.

  4. The Impact of Interactive Factors on Romanian Students’ Understanding of Place Value

    Directory of Open Access Journals (Sweden)

    Madalina Tanase

    2013-08-01

    Full Text Available Students’ mathematics learning is influenced by school factors (i.e., teachers’ knowledge of content, pedagogy, students, and curriculum and nonschool factors (parental involvement, expectations, and teaching techniques. This study looks holistically at the way these factors impact the learning of mathematics of first-grade Romanian students, examining the interactions between teachers, students, and their parents, as well as the interactions between parents and their children. Findings reveal that successful mathematics learning occurs when teachers and parents meet frequently to discuss the mathematics teaching and learning that takes place at school and at home.

  5. Comparisons of treatment means when factors do not interact in two-factorial studies

    KAUST Repository

    Wei, Jiawei

    2011-05-06

    Scientists in the fields of nutrition and other biological sciences often design factorial studies to test the hypotheses of interest and importance. In the case of two-factorial studies, it is widely recognized that the analysis of factor effects is generally based on treatment means when the interaction of the factors is statistically significant, and involves multiple comparisons of treatment means. However, when the two factors do not interact, a common understanding among biologists is that comparisons among treatment means cannot or should not be made. Here, we bring this misconception into the attention of researchers. Additionally, we indicate what kind of comparisons among the treatment means can be performed when there is a nonsignificant interaction among two factors. Such information should be useful in analyzing the experimental data and drawing meaningful conclusions.

  6. c-Jun interacts with the corepressor TG-interacting factor (TGIF) to suppress Smad2 transcriptional activity

    Science.gov (United States)

    Pessah, Marcia; Prunier, Céline; Marais, Jacqueline; Ferrand, Nathalie; Mazars, Anne; Lallemand, François; Gauthier, Jean-Michel; Atfi, Azeddine

    2001-01-01

    The Sma and Mad related (Smad) family proteins are critical mediators of the transforming growth factor-β (TGF-β) superfamily signaling. After TGF-β-mediated phosphorylation and association with Smad4, Smad2 moves to the nucleus and activates expression of specific genes through cooperative interactions with DNA-binding proteins, including members of the winged-helix family of transcription factors, forkhead activin signal transducer (FAST)-1 and FAST2. TGF-β has also been described to activate other signaling pathways, such as the c-Jun N-terminal Kinase (JNK) pathway. Here, we show that activation of JNK cascade blocked the ability of Smad2 to mediate TGF-β-dependent activation of the FAST proteins. This inhibitory activity is mediated through the transcriptional factor c-Jun, which enhances the association of Smad2 with the nuclear transcriptional corepressor TG-interacting factor (TGIF), thereby interfering with the assembly of Smad2 and the coactivator p300 in response to TGF-β signaling. Interestingly, c-Jun directly binds to the nuclear transcriptional corepressor TGIF and is required for TGIF-mediated repression of Smad2 transcriptional activity. These studies thus reveal a mechanism for suppression of Smad2 signaling pathway by JNK cascade through transcriptional repression. PMID:11371641

  7. Plasma level of von Willebrand factor: An indicator of severity in ...

    African Journals Online (AJOL)

    Background: Sickle cell anaemia is a congenital hemolytic disorder caused by mutation in the â-globin gene at position 6 with replacement of glutamic acid by valine. Patients who arehomozygous for this mutation suffer from hemolytic anaemia and other serious complications. The underlying pathology of much of these ...

  8. Structural studies on B2-glycoprotein I and von Willebrand factor A3 domain

    NARCIS (Netherlands)

    Bouma, B.

    2000-01-01

    The integrity of blood circulation is a prerequisite for life; its malfunctioning is a leading cause of morbidity and mortality in developed countries. For that reason the haemostatic system is a critical component of homeostasis. In Chapter I an overview is given of the biophysical and biochemical

  9. Transient von Willebrand factor-mediated platelet influx stimulates liver regeneration after partial hepatectomy in mice

    NARCIS (Netherlands)

    Kirschbaum, Marc; Jenne, Craig N; Veldhuis, Zwanida J; Sjollema, Klaas A; Lenting, Peter J; Giepmans, Ben N G; Porte, Robert J; Kubes, Paul; Denis, Cécile V; Lisman, Ton

    2017-01-01

    Background & AimsIn addition to their function in thrombosis and haemostasis, platelets play an important role in the stimulation of liver regeneration. It has been suggested that platelets deliver mitogenic cargo to the regenerating liver, and accumulation of platelets in the regenerating liver has

  10. Nitric oxide level and von Willebrand factor (vWF) secretion are not ...

    African Journals Online (AJOL)

    Jane

    2011-08-15

    Aug 15, 2011 ... ACKNOWLEDEGMENTS. We are highly indebted to Dr. Haghjoo for help in NO and. vWF measurement, and Massah A. for his help in. Behjati et al. 8875 luminescence measurement. This study was funded by grant no. 287097 from Deputy of Research, Isfahan. University of Medical Sciences, Isfahan, Iran ...

  11. Leukocyte telomere length is inversely correlated with plasma Von Willebrand factor

    DEFF Research Database (Denmark)

    Hjelmborg, Jacob V B; Nzietchueng, Rosine; Kimura, Masayuki

    2010-01-01

    attrition, ultimately resulting in shortened LTL. METHODS: We studied 3 cohorts: the ADELAHYDE study (age 60-87years), the ERA study (age 41-88years) and the Longitudinal Study of Aging Danish Twins (LSADT) (age 73-94years). RESULTS: Multiple regression analysis with LTL as the dependent variable, and age...... resistance, cigarette smoking and low socio-economic status. We examined the association between LTL and VWF plasma levels to test the hypothesis that high levels of VWF promote an increase in the turnover of blood cells, including leukocytes. Such a process would heighten the rate of age-dependent LTL...

  12. Acute rejection before cytomegalovirus infection enhances von Willebrand factor and soluble VCAM-1 in blood

    NARCIS (Netherlands)

    Kas-Deelen, AM; Harmsen, MC; de Maar, EF; Oost-Kort, WW; Tervaert, JWC; van der Meer, J; van Son, WJ; The, TH

    2000-01-01

    Background. Human cytomegalovirus (HCMV) infections in transplantation patients are associated with vascular endothelial damage. This is reflected by the appearance of cytomegalic endothelial cells (CECs) and noninfected endothelial cells (ECs) in blood. To get more insight in the extent of vascular

  13. Platelet-independent adhesion of calcium-loaded erythrocytes to von Willebrand factor

    NARCIS (Netherlands)

    Smeets, M.W.J. (Michel W.J.); R. Bierings (Ruben); Meems, H. (Henriet); F.P.J. Mul (F. P J); D. Geerts (Dirk); A.P.J. Vlaar (Alexander); J. Voorberg (Jan); P.L. Hordijk (Peter )

    2017-01-01

    textabstractAdhesion of erythrocytes to endothelial cells lining the vascular wall can cause vaso-occlusive events that impair blood flow which in turn may result in ischemia and tissue damage. Adhesion of erythrocytes to vascular endothelial cells has been described in multiple hemolytic disorders,

  14. Transient von Willebrand factor-mediated platelet influx stimulates liver regeneration after partial hepatectomy in mice

    NARCIS (Netherlands)

    Kirschbaum, Marc; Jenne, Craig N; Veldhuis, Zwanida J; Sjollema, Klaas A; Lenting, Peter J; Giepmans, Ben N G; Porte, Robert J; Kubes, Paul; Denis, Cécile V; Lisman, Ton

    2017-01-01

    BACKGROUND & AIMS: In addition to their function in thrombosis and hemostasis, platelets play an important role in the stimulation of liver regeneration. It has been suggested that platelets deliver mitogenic cargo to the regenerating liver, and accumulation of platelets in the regenerating liver

  15. Cellular fibronectin and von Willebrand factor concentrations in plasma of rats treated with monocrotaline pyrrole

    NARCIS (Netherlands)

    Schultze, A.E.; Emeis, J.J.; Roth, R.A.

    1996-01-01

    The monocrotaline pyrrole (MCTP)-treated rat is a useful model for the study of certain chronic pulmonary vascular diseases. A single, i.v. administration of a low dose of MCTP causes pneumotoxicity, pulmonary vascular remodeling, sustained increases in pulmonary arterial pressure, and right

  16. Transcription Factor Functional Protein-Protein Interactions in Plant Defense Responses

    Directory of Open Access Journals (Sweden)

    Murilo S. Alves

    2014-03-01

    Full Text Available Responses to biotic stress in plants lead to dramatic reprogramming of gene expression, favoring stress responses at the expense of normal cellular functions. Transcription factors are master regulators of gene expression at the transcriptional level, and controlling the activity of these factors alters the transcriptome of the plant, leading to metabolic and phenotypic changes in response to stress. The functional analysis of interactions between transcription factors and other proteins is very important for elucidating the role of these transcriptional regulators in different signaling cascades. In this review, we present an overview of protein-protein interactions for the six major families of transcription factors involved in plant defense: basic leucine zipper containing domain proteins (bZIP, amino-acid sequence WRKYGQK (WRKY, myelocytomatosis related proteins (MYC, myeloblastosis related proteins (MYB, APETALA2/ ETHYLENE-RESPONSIVE ELEMENT BINDING FACTORS (AP2/EREBP and no apical meristem (NAM, Arabidopsis transcription activation factor (ATAF, and cup-shaped cotyledon (CUC (NAC. We describe the interaction partners of these transcription factors as molecular responses during pathogen attack and the key components of signal transduction pathways that take place during plant defense responses. These interactions determine the activation or repression of response pathways and are crucial to understanding the regulatory networks that modulate plant defense responses.

  17. Severe potential drug-drug interactions in older adults with dementia and associated factors

    Directory of Open Access Journals (Sweden)

    Michele Bogetti-Salazar

    2016-01-01

    Full Text Available OBJECTIVE: To identify the main severe potential drug-drug interactions in older adults with dementia and to examine the factors associated with these interactions. METHOD: This was a cross-sectional study. The enrolled patients were selected from six geriatrics clinics of tertiary care hospitals across Mexico City. The patients had received a clinical diagnosis of dementia based on the current standards and were further divided into the following two groups: those with severe drug-drug interactions (contraindicated/severe (n=64 and those with non-severe drug-drug interactions (moderate/minor/absent (n=117. Additional socio-demographic, clinical and caregiver data were included. Potential drug-drug interactions were identified using Micromedex Drug Reax 2.0® database. RESULTS: A total of 181 patients were enrolled, including 57 men (31.5% and 124 women (68.5% with a mean age of 80.11±8.28 years. One hundred and seven (59.1% patients in our population had potential drug-drug interactions, of which 64 (59.81% were severe/contraindicated. The main severe potential drug-drug interactions were caused by the combinations citalopram/anti-platelet (11.6%, clopidogrel/omeprazole (6.1%, and clopidogrel/aspirin (5.5%. Depression, the use of a higher number of medications, dementia severity and caregiver burden were the most significant factors associated with severe potential drug-drug interactions. CONCLUSIONS: Older people with dementia experience many severe potential drug-drug interactions. Anti-depressants, antiplatelets, anti-psychotics and omeprazole were the drugs most commonly involved in these interactions. Despite their frequent use, anti-dementia drugs were not involved in severe potential drug-drug interactions. The number and type of medications taken, dementia severity and depression in patients in addition to caregiver burden should be considered to avoid possible drug interactions in this population.

  18. Sequence motifs in MADS transcription factors responsible for specificity and diversification of protein-protein interaction.

    Directory of Open Access Journals (Sweden)

    Aalt D J van Dijk

    Full Text Available Protein sequences encompass tertiary structures and contain information about specific molecular interactions, which in turn determine biological functions of proteins. Knowledge about how protein sequences define interaction specificity is largely missing, in particular for paralogous protein families with high sequence similarity, such as the plant MADS domain transcription factor family. In comparison to the situation in mammalian species, this important family of transcription regulators has expanded enormously in plant species and contains over 100 members in the model plant species Arabidopsis thaliana. Here, we provide insight into the mechanisms that determine protein-protein interaction specificity for the Arabidopsis MADS domain transcription factor family, using an integrated computational and experimental approach. Plant MADS proteins have highly similar amino acid sequences, but their dimerization patterns vary substantially. Our computational analysis uncovered small sequence regions that explain observed differences in dimerization patterns with reasonable accuracy. Furthermore, we show the usefulness of the method for prediction of MADS domain transcription factor interaction networks in other plant species. Introduction of mutations in the predicted interaction motifs demonstrated that single amino acid mutations can have a large effect and lead to loss or gain of specific interactions. In addition, various performed bioinformatics analyses shed light on the way evolution has shaped MADS domain transcription factor interaction specificity. Identified protein-protein interaction motifs appeared to be strongly conserved among orthologs, indicating their evolutionary importance. We also provide evidence that mutations in these motifs can be a source for sub- or neo-functionalization. The analyses presented here take us a step forward in understanding protein-protein interactions and the interplay between protein sequences and

  19. Applied human factors research at the NASA Johnson Space Center Human-Computer Interaction Laboratory

    Science.gov (United States)

    Rudisill, Marianne; Mckay, Timothy D.

    1990-01-01

    The applied human factors research program performed at the NASA Johnson Space Center's Human-Computer Interaction Laboratory is discussed. Research is conducted to advance knowledge in human interaction with computer systems during space crew tasks. In addition, the Laboratory is directly involved in the specification of the human-computer interface (HCI) for space systems in development (e.g., Space Station Freedom) and is providing guidelines and support for HCI design to current and future space missions.

  20. Simplified method to predict mutual interactions of human transcription factors based on their primary structure

    KAUST Repository

    Schmeier, Sebastian

    2011-07-05

    Background: Physical interactions between transcription factors (TFs) are necessary for forming regulatory protein complexes and thus play a crucial role in gene regulation. Currently, knowledge about the mechanisms of these TF interactions is incomplete and the number of known TF interactions is limited. Computational prediction of such interactions can help identify potential new TF interactions as well as contribute to better understanding the complex machinery involved in gene regulation. Methodology: We propose here such a method for the prediction of TF interactions. The method uses only the primary sequence information of the interacting TFs, resulting in a much greater simplicity of the prediction algorithm. Through an advanced feature selection process, we determined a subset of 97 model features that constitute the optimized model in the subset we considered. The model, based on quadratic discriminant analysis, achieves a prediction accuracy of 85.39% on a blind set of interactions. This result is achieved despite the selection for the negative data set of only those TF from the same type of proteins, i.e. TFs that function in the same cellular compartment (nucleus) and in the same type of molecular process (transcription initiation). Such selection poses significant challenges for developing models with high specificity, but at the same time better reflects real-world problems. Conclusions: The performance of our predictor compares well to those of much more complex approaches for predicting TF and general protein-protein interactions, particularly when taking the reduced complexity of model utilisation into account. © 2011 Schmeier et al.

  1. Cross-Family Transcription Factor Interactions: An Additional Layer of Gene Regulation.

    Science.gov (United States)

    Bemer, Marian; van Dijk, Aalt D J; Immink, Richard G H; Angenent, Gerco C

    2017-01-01

    Specific and dynamic gene expression strongly depends on transcription factor (TF) activity and most plant TFs function in a combinatorial fashion. They can bind to DNA and control the expression of the corresponding gene in an additive fashion or cooperate by physical interactions, forming larger protein complexes. The importance of protein-protein interactions between members of a particular plant TF family has long been recognised; however, a significant number of interfamily TF interactions has recently been reported. The biological implications and the molecular mechanisms involved in cross-family interactions have now started to be elucidated and the examples illustrate potential roles in the bridging of biological processes. Hence, cross-family TF interactions expand the molecular toolbox for plants with additional mechanisms to control and fine-tune robust gene expression patterns and to adapt to their continuously changing environment. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Effects of biotic and abiotic factors on the temporal dynamic of bat-fruit interactions

    Science.gov (United States)

    Laurindo, Rafael de Souza; Gregorin, Renato; Tavares, Davi Castro

    2017-08-01

    Mutualistic interactions between animals and plants vary over time and space based on the abundance of fruits or animals and seasonality. Little is known about this temporal dynamic and the influence of biotic and abiotic factors on the structure of interaction networks. We evaluated changes in the structure of network interactions between bats and fruits in relation to variations in rainfall. Our results suggest that fruit abundance is the main variable responsible for temporal changes in network attributes, such as network size, connectance, and number of interactions. In the same way, temperature positively affected the abundance of fruits and bats. An increase in temperature and alterations in rainfall patterns, due to human induced climate change, can cause changes in phenological patterns and fruit production, with negative consequences to biodiversity maintenance, ecological interactions, and ecosystem functioning.

  3. Neighborhood Regularized Logistic Matrix Factorization for Drug-Target Interaction Prediction.

    Directory of Open Access Journals (Sweden)

    Yong Liu

    2016-02-01

    Full Text Available In pharmaceutical sciences, a crucial step of the drug discovery process is the identification of drug-target interactions. However, only a small portion of the drug-target interactions have been experimentally validated, as the experimental validation is laborious and costly. To improve the drug discovery efficiency, there is a great need for the development of accurate computational approaches that can predict potential drug-target interactions to direct the experimental verification. In this paper, we propose a novel drug-target interaction prediction algorithm, namely neighborhood regularized logistic matrix factorization (NRLMF. Specifically, the proposed NRLMF method focuses on modeling the probability that a drug would interact with a target by logistic matrix factorization, where the properties of drugs and targets are represented by drug-specific and target-specific latent vectors, respectively. Moreover, NRLMF assigns higher importance levels to positive observations (i.e., the observed interacting drug-target pairs than negative observations (i.e., the unknown pairs. Because the positive observations are already experimentally verified, they are usually more trustworthy. Furthermore, the local structure of the drug-target interaction data has also been exploited via neighborhood regularization to achieve better prediction accuracy. We conducted extensive experiments over four benchmark datasets, and NRLMF demonstrated its effectiveness compared with five state-of-the-art approaches.

  4. Analytic model for academic research productivity having factors, interactions and implications

    Science.gov (United States)

    2011-01-01

    Financial support is dear in academia and will tighten further. How can the research mission be accomplished within new restraints? A model is presented for evaluating source components of academic research productivity. It comprises six factors: funding; investigator quality; efficiency of the research institution; the research mix of novelty, incremental advancement, and confirmatory studies; analytic accuracy; and passion. Their interactions produce output and patterned influences between factors. Strategies for optimizing output are enabled. PMID:22130145

  5. Cuidados nos pacientes com hemofilia e doença de von Willebrand na cirurgia eletiva otorrinolaringológica Otolaryngology surgery: management of elective surgery in patients with haemophilia and von Willebrand disease

    Directory of Open Access Journals (Sweden)

    Marise P. C. Marques

    2003-01-01

    Full Text Available FORMA DE ESTUDO Clínico prospectivo. MATERIAL E MÉTODO: Foi realizado um estudo prospectivo de 10 anos de 20 pacientes com hemofilias ou doença de von Willebrand (DvW com indicação de cirurgia otorrinolaringológica. Os pacientes foram submetidos a um total de 25 cirurgias otorrinolaringológicas eletivas. A idade média foi de 23,75 anos (2 a 62 anos. O grupo de estudo consistiu em 14 hemofílicos, 11 com hemofilia A grave (1 do sexo feminino, uma portadora com 30% de atividade de fator VIII (FVIII, um hemofílico B leve e uma com deficiência grave de fator X; 6 com DvW, 4 tinham o tipo 1 (3 mulheres, um o tipo 2A e um o tipo 3. Treze hemofílicos tinham síndrome de imunodeficiência adquirida. A duração média do procedimento foi de 1 hora e 37 minutos (15 minutos a 12 horas. O defeito da coagulação foi corrigido com desmopressina (DDAVP, com concentrado de FVIII de pureza intermediária 8Y, com criopreciptado ou com complexo protrombínico não ativado (PPSB, de acordo com os níveis plasmáticos do fator e da severidade da cirurgia. O ácido épsilon aminocapróico também foi usado em associação. Em 1 hemofílico A grave houve sangramento pós-operatório que se resolveu com a elevação do nível mínimo de FVIII para 80% e em 1 paciente com DvW do Tipo 3 houve sangramento pós-operatório pela dificuldade de identificação do melhor concentrado a ser reposto. Após o uso do concentrado de pureza intermediária 8Y, houve controle do sangramento. RESULTADO: Todos os outros pacientes apresentaram a hemostasia considerada normal ou excelente. CONCLUSÃO: Concluiu-se que pacientes com hemofilias ou DvW não apresentam um risco cirúrgico aumentado se for realizada uma terapia adequada.STUD DESIGN: Clinical prospective. MATERIAL AND METHOD: A 10-year prospective research was conducted in 20 patients with hemophilia or von Willebrand disease (vWD. They were submitted to a total of 25 elective otolaryngological surgical events. The

  6. A Psychological Perspective on Preterm Children: The Influence of Contextual Factors on Quality of Family Interactions.

    Science.gov (United States)

    Gatta, Michela; Miscioscia, Marina; Svanellini, Lorenza; Peraro, Chiara; Simonelli, Alessandra

    2017-01-01

    Preterm birth has a critical influence on interactive, communicative, and expressive child behaviour, particularly during the first years of life. Few studies have stressed the assessment of mother-father-child interaction in families with preterm children, generating contradictory results. The present study wished to develop these fields: (i) comparing the quality of family interactions between families with preterm children and families with children born at full term; (ii) observing the development of family interactions after six months in the families with children born preterm; (iii) assessing family and contextual factors, as parental stress and social support, in parents of preterm children in order to observe their influence on the quality of family interactions. 78 families are recruited: 39 families with preterm children (M = 19,8 months, SD = 11,05) and 39 families with full-term children (M = 19,66 months; SD = 13,10). Results show that families with preterm children display a low quality of mother-father-child interactions. After six months, family interactions result is generally stable, except for some LTP-scales reflecting a hard adjustment of parenting style to the evolution of the child. In families with preterm children, the parenting stress seemed to be correlated with the quality of mother-father-child interactions.

  7. A Psychological Perspective on Preterm Children: The Influence of Contextual Factors on Quality of Family Interactions

    Directory of Open Access Journals (Sweden)

    Michela Gatta

    2017-01-01

    Full Text Available Preterm birth has a critical influence on interactive, communicative, and expressive child behaviour, particularly during the first years of life. Few studies have stressed the assessment of mother-father-child interaction in families with preterm children, generating contradictory results. The present study wished to develop these fields: (i comparing the quality of family interactions between families with preterm children and families with children born at full term; (ii observing the development of family interactions after six months in the families with children born preterm; (iii assessing family and contextual factors, as parental stress and social support, in parents of preterm children in order to observe their influence on the quality of family interactions. 78 families are recruited: 39 families with preterm children (M = 19,8 months, SD = 11,05 and 39 families with full-term children (M = 19,66 months; SD = 13,10. Results show that families with preterm children display a low quality of mother-father-child interactions. After six months, family interactions result is generally stable, except for some LTP-scales reflecting a hard adjustment of parenting style to the evolution of the child. In families with preterm children, the parenting stress seemed to be correlated with the quality of mother-father-child interactions.

  8. Prevalence and Risk Factors Among Minors for Online Sexual Solicitations and Interactions With Adults.

    Science.gov (United States)

    de Santisteban, Patricia; Gámez-Guadix, Manuel

    2017-11-02

    The research on online child sexual victimization has mainly focused on the sexual solicitation of minors (i.e., sexual requests by an adult), with scarce information available on sexual interactions (e.g., cybersex or meeting in person) in which a minor is exploited by an adult. In the present study, we analyzed the prevalence and risk factors associated with both sexual solicitations and interactions of minors with adults. The sample included 2,731 minors between 12 and 15 years old (50.6% female). The minors completed several self-report questionnaires about sexual solicitations and interactions with adults, including possible risk factors (e.g., sociodemographic variables, Internet use, and psychological adjustment). Of the participants, 15.6% of girls and 9.3% of boys reported sexual solicitations, and 8.2% of girls and 7.4% of boys reported sexualized interactions with adults. Among the variables studied, several appeared related to both sexual solicitations and interactions: older age, having been involved in sexting, being a victim of cyberbullying, having unknown people in friends list, using chat, time spent online on a weekday, and depression symptoms. Gender (being female), using video chat, and instant messaging by computer were significant variables for sexual solicitation but not for sexual interaction; participation in online games was significant only for sexual interactions. Finally, minors reporting sexual interactions presented a higher risk profile than those reporting only sexual solicitations. These findings highlight the relevance of distinguishing between sexual solicitations and sexual interactions and suggest important avenues for prevention programs.

  9. Effects of interspecific interaction-linked habitat factors on moose resource selection and environmental stress.

    Science.gov (United States)

    Bao, Heng; Fryxell, John M; Liu, Hui; Dou, Hongliang; Ma, Yingjie; Jiang, Guangshun

    2017-01-27

    Resource selection of herbivores is a complex ecological process that operates in relation to biological or non-biological factors, which may affect the feeding and movement, and subsequently their spatial distribution and environmental stress. Here, we estimated moose (Alces alces cameloides) resource selection for habitat variables and the effect of interspecific interactions related to roe deer (Capreolus pygargus bedfordi) on its population distribution and environmental stress in the Khingan Mountain region of northeast China at local and regional scales. Different response patterns of moose resource selection, spatial distribution, and environmental stress to interspecific interaction-linked habitat factors were shown at the two scales. A general ecological chain, response of moose to interspecific interaction-linked habitat factors, was exhibited at the regional scale, and at the local scale, heterogeneous responses, linkages of habitat selection and environmental stress of moose population might be driven by different interspecific interaction patterns. Our study firstly suggested that moose resource selection, food availability, diet quality, population density and environmental stress indicators were impacted by interactions with the distribution of other sympatric herbivore species and showed differences in ecological response chains at various spatial scales. These findings are useful for sympatric herbivore assembly conservation, habitat quality monitoring and management.

  10. Urban form and psychosocial factors : Do they interact for leisure-time walking?

    NARCIS (Netherlands)

    Beenackers, Mariëlle A.; Kamphuis, Carlijn B M; Prins, Richard G.; Mackenbach, Johan P.; Burdorf, Alex; Van Lenthe, Frank J.

    2014-01-01

    INTRODUCTION: This cross-sectional study uses an adaptation of a social-ecological model on the hierarchy of walking needs to explore direct associations and interactions of urban-form characteristics and individual psychosocial factors for leisure-time walking. METHODS: Questionnaire data (n = 736)

  11. Urban form and psychosocial factors: Do they interact for leisure-time walking?

    NARCIS (Netherlands)

    M.A. Beenackers (Marielle); C.B.M. Kamphuis (Carlijn); R. Prins (Remco); J.P. Mackenbach (Johan); A. Burdorf (Alex); F.J. van Lenthe (Frank)

    2014-01-01

    textabstractINTRODUCTION: This cross-sectional study uses an adaptation of a social-ecological model on the hierarchy of walking needs to explore direct associations and interactions of urban-form characteristics and individual psychosocial factors for leisure-time walking. METHODS: Questionnaire

  12. Contextual Predictive Factors of Child Sexual Abuse: The Role of Parent-Child Interaction

    Science.gov (United States)

    Ramirez, Clemencia; Pinzon-Rondon, Angela Maria; Botero, Juan Carlos

    2011-01-01

    Objectives: To determine the prevalence of child sexual abuse in the Colombian coasts, as well as to assess the role of parent-child interactions on its occurrence and to identify factors from different environmental levels that predict it. Methods: This cross-sectional study explores the results of 1,089 household interviews responded by mothers.…

  13. Influence of cardiopulmonary bypass on the interaction of recombinant factor VIIa with activated platelets

    DEFF Research Database (Denmark)

    Kjalke, M.; Runge, M.; Rojkjaer, R.

    2009-01-01

    Recombinant factor VIIa (rFVIIa) interacts preferentially with coated platelets characterized by a high exposure of phosphatidyl serine (PS), FV, FVIII, FIX, and FX binding, and fibrinogen. Cardiopulmonary bypass (CPB) is known to impair platelet function. In this study, the influence of CPB...

  14. Interactions among Ecological Factors That Explain the Psychosocial Quality of Life of Children with Complex Needs

    Directory of Open Access Journals (Sweden)

    Sandy Thurston

    2010-01-01

    Full Text Available Purpose. To explore the associations and interactions among ecological factors and explain the psychosocial quality of life of children with complex needs. Methods. In this cross-sectional survey consenting parents were identified by the Children's Treatment Network. Families were eligible if the child from 0 to 19 years, resided in Simcoe/York, and there were multiple family needs. Regression analysis was used to explore associations and interactions. n=429. Results. Younger children, without conduct disorder, without hostile and punitive parenting and with low adverse family impact demonstrated the highest levels of psychosocial quality of life. Statistically significant interactions between processes of care and parent variables highlight the complexity of real life situations. Conclusions. It is not possible to fully understand the child's psychosocial quality of life in complex needs families by considering only simple associations between ecological factors. A multitude of factors and interactions between these factors are simultaneously present and the care of these families requires a holistic approach.

  15. Factors Associated with Social Interactions between Deaf Children and Their Hearing Peers: A Systematic Literature Review

    Science.gov (United States)

    Batten, Georgina; Oakes, Peter M.; Alexander, Tim

    2014-01-01

    Research indicates that deaf children can have marked social difficulties compared with their hearing peers. Factors that influence these social interactions need to be reviewed to inform interventions. A systematic search of 5 key databases and 3 specialized journals identified 14 papers that met the inclusion criteria. Methodological quality of…

  16. Optimum designs versus orthogonal arrays for main effects and two-factor interactions

    NARCIS (Netherlands)

    Schoen, E.D.

    2010-01-01

    Designs with full estimation capacity permit estimation of all main effects and all two-factor interactions. By allowing correlation among the effects, the run size of such designs can be smaller than required for a resolution of 5. To construct a design, one can either use commercial software for

  17. Heavy menstrual bleeding and health-associated quality of life in women with von Willebrand's disease.

    Science.gov (United States)

    Govorov, Igor; Ekelund, Lena; Chaireti, Roza; Elfvinge, Petra; Holmström, Margareta; Bremme, Katarina; Mints, Miriam

    2016-05-01

    Women with the inherited bleeding disorder von Willebrand's disease (VWD) face gender-specific hemostatic challenges during menstruation. Heavy menstrual bleeding (HMB) can negatively affect their overall life activities and the health-associated quality of life. The purpose of the present study was to investigate whether women with VWD experienced HMB and an impaired health-associated quality of life. The study subjects were recruited from the Coagulation Unit of Karolinska University Hospital. Information was retrieved from various self-administered forms and medical records. Of the 30 women (18-52 years) that were included in the present study, 50% suffered from HMB, although the majority received treatment for HMB. In addition, almost all the included women perceived limitations in the overall life activities due to menstruation. The health-associated quality of life for women with HMB was significantly lower (Pwomen of the general population. In conclusion, women with VWD experienced reduced health-associated quality of life as a result of HMB. Therefore, preventing limitations in overall life activities and improving their health-associated quality of life thorough counseling on menstrual bleeding is important for women with VWD.

  18. Cost-utility analysis of von Willebrand disease screening in adolescents with menorrhagia.

    Science.gov (United States)

    Sidonio, Robert Francis; Smith, Kenneth J; Ragni, Margaret V

    2010-09-01

    To construct a decision analysis model to evaluate the cost utility of von Willebrand disease (VWD) testing in adolescents with menorrhagia. A 20-year Markov decision analytic model was constructed to evaluate the cost utility of two strategies: testing or not testing for VWD. The model includes probabilities of remaining well, suffering an acute menorrhagia bleeding event, surgical complications, oral contraceptive pill complications, or dying. Probabilities, costs, and utilities were estimated from published literature. The prevalence of type 1 VWD in adolescent females with menorrhagia was estimated at 13%. The cost of testing adolescents with menorrhagia for VWD was $1790, versus $1251 for not testing for VWD. The effectiveness of not testing in quality-adjusted life-years (QALYs) gained (14.237 QALYs) was similar to the VWD testing strategy (14.246 QALYs). Compared with not testing for VWD, screening for VWD had an incremental cost-effectiveness ratio of $62,791 per QALY, a value typically considered economically reasonable. In adolescents with menorrhagia, testing for VWD before the initiation of oral contraceptives is cost-effective. Copyright (c) 2010 Mosby, Inc. All rights reserved.

  19. Interactions between inflammation, sex steroids, and Alzheimer’s disease risk factors

    Science.gov (United States)

    Uchoa, Mariana F.; Moser, V. Alexandra; Pike, Christian J.

    2016-01-01

    Alzheimer’s disease (AD) is an age-related neurodegenerative disorder for which there are no effective strategies to prevent or slow its progression. Because AD is multifactorial, recent research has focused on understanding interactions among the numerous risk factors and mechanisms underlying the disease. One mechanism through which several risk factors may be acting is inflammation. AD is characterized by chronic inflammation that is observed before clinical onset of dementia. Several genetic and environmental risk factors for AD increase inflammation, including apolipoprotein E4, obesity, and air pollution. Additionally, sex steroid hormones appear to contribute to AD risk, with age-related losses of estrogens in women and androgens in men associated with increased risk. Importantly, sex steroid hormones have anti-inflammatory actions and can interact with several other AD risk factors. This review examines the individual and interactive roles of inflammation and sex steroid hormones in AD, as well as their relationships with the AD risk factors apolipoprotein E4, obesity, and air pollution. PMID:27651175

  20. Regulation of plant growth and development by the GROWTH-REGULATING FACTOR and GRF-INTERACTING FACTOR duo.

    Science.gov (United States)

    Hoe Kim, Jeong; Tsukaya, Hirokazu

    2015-10-01

    Transcription factors are key regulators of gene expression and play pivotal roles in all aspects of living organisms. Therefore, identification and functional characterization of transcription factors is a prerequisite step toward understanding life. This article reviews molecular and biological functions of the two transcription regulator families, GROWTH-REGULATING FACTOR (GRF) and GRF-INTERACTING FACTOR (GIF), which have only recently been recognized. A myriad of experimental evidence clearly illustrates that GRF and GIF are bona fide partner proteins and form a plant-specific transcriptional complex. One of the most conspicuous outcomes from this research field is that the GRF-GIF duo endows the primordial cells of vegetative and reproductive organs with a meristematic specification state, guaranteeing the supply of cells for organogenesis and successful reproduction. It has recently been shown that GIF1 proteins, also known as ANGUSTIFOLIA3, recruit chromatin remodelling complexes to target genes, and that AtGRF expression is directly activated by the floral identity factors, APETALA1 and SEPALLATA3, providing an important insight into understanding of the action of GRF-GIF. Moreover, GRF genes are extensively subjected to post-transcriptional control by microRNA396, revealing the presence of a complex regulatory circuit in regulation of plant growth and development by the GRF-GIF duo. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  1. Hierarchical Interactions of Homeodomain and Forkhead Transcription Factors in Regulating Odontogenic Gene Expression*

    Science.gov (United States)

    Venugopalan, Shankar R.; Li, Xiao; Amen, Melanie A.; Florez, Sergio; Gutierrez, Diana; Cao, Huojun; Wang, Jianbo; Amendt, Brad A.

    2011-01-01

    FoxJ1 is a forkhead transcription factor expressed in multiple tissues during development and a major regulator of cilia development. FoxJ1−/− mice present with defects in odontogenesis, and we correlate these defects to hierarchical interactions between homeodomain factors Pitx2 and Dlx2 with FoxJ1 in regulating their expression through direct physical interactions. Chromatin immunoprecipitation assays reveal endogenous Pitx2 and Dlx2 binding to the Dlx2 promoter and Dlx2 binding to the FoxJ1 promoter as well as Dlx2 and FoxJ1 binding to the amelogenin promoter. PITX2 activation of the Dlx2 promoter is attenuated by a direct Dlx2 physical interaction with PITX2. Dlx2 autoregulates its promoter, and Dlx2 transcriptionally activates the downstream gene FoxJ1. Dlx2 and FoxJ1 physically interact and synergistically regulate both Dlx2 and FoxJ1 promoters. Dlx2 and FoxJ1 also activate the amelogenin promoter, and amelogenin is required for enamel formation and late stage tooth development. FoxJ1−/− mice maxillary and mandibular incisors are reduced in length and width and have reduced amelogenin expression. FoxJ1−/− mice show a reduced and defective ameloblast layer, revealing a biological effect of these transcription factor hierarchies during tooth morphogenesis. These transcriptional mechanisms may contribute to other developmental processes such as neuronal, pituitary, and heart development. PMID:21504905

  2. Evaluating the spatio-temporal factors that structure network parameters of plant-herbivore interactions.

    Directory of Open Access Journals (Sweden)

    Antonio López-Carretero

    Full Text Available Despite the dynamic nature of ecological interactions, most studies on species networks offer static representations of their structure, constraining our understanding of the ecological mechanisms involved in their spatio-temporal stability. This is the first study to evaluate plant-herbivore interaction networks on a small spatio-temporal scale. Specifically, we simultaneously assessed the effect of host plant availability, habitat complexity and seasonality on the structure of plant-herbivore networks in a coastal tropical ecosystem. Our results revealed that changes in the host plant community resulting from seasonality and habitat structure are reflected not only in the herbivore community, but also in the emergent properties (network parameters of the plant-herbivore interaction network such as connectance, selectiveness and modularity. Habitat conditions and periods that are most stressful favored the presence of less selective and susceptible herbivore species, resulting in increased connectance within networks. In contrast, the high degree of selectivennes (i.e. interaction specialization and modularity of the networks under less stressful conditions was promoted by the diversification in resource use by herbivores. By analyzing networks at a small spatio-temporal scale we identified the ecological factors structuring this network such as habitat complexity and seasonality. Our research offers new evidence on the role of abiotic and biotic factors in the variation of the properties of species interaction networks.

  3. Susceptibility genes, social environmental risk factors and their interactions in internalizing disorders among mainland Chinese undergraduates.

    Science.gov (United States)

    Meng, Xiangfei; Kou, Changgui; Shi, Jieping; Yu, Yaqin; Huang, Yueqin

    2011-07-01

    Analyses of large scale psychiatric epidemiology surveys suggest that common mental disorders can be generalized into two underlying dimensions, internalizing disorders (e.g. depression, and anxiety) and externalizing disorders (e.g. addictions). The present study explores the interactions among the genes (SLC6A4, BDNF, and MAOA) and selected environment factors (G×E), and gene×gene (G×G) interactions for internalizing disorders in the sample of Chinese university students. This is a genetic case control study. 259 undergraduates affected with internalizing disorders and 269 healthy controls were included. Multiple logistic regression was used to explore the potential environmental risk factors. G×E interactions were analyzed using the method developed by Mukherjee et al. (2008). Analyses of G×G interactions were conducted by generalized multifactor dimensionality reduction (GMDR) (Lou et al., 2007). We have previously reported on the polymorphism information for ten single nucleotide polymorphisms (SNPs) on SLC6A4, BDNF, and MAOA genes (Meng et al., 2009; Meng, 2010). We found that an offspring's reported parents' negative mood, subject's unwillingness to express emotion, being an only child, having an unfulfilling relationship with his/her mother, and increased activity and behavior restrictions by his/her father were social environment risk factors for internalizing disorders. No statistically significant interactions were found in the G×E analyses. G×G analyses found that subjects with mutational alleles concurrently on rs10835210 and rs2030324 (BDNF gene) were significantly likely to develop internalizing disorders. Those with one mutated allele on either SNPs were 1.761 times, and those with both mutated alleles were 3.353 times, more likely to develop internalizing disorders. A negative family emotional environment was found to be associated with internalizing disorders. BDNF gene variants were also found to be similarly associated. Using conservative

  4. Social interaction of children with visual impairment: Risk and protective factors

    Directory of Open Access Journals (Sweden)

    Vučinić Vesna

    2013-01-01

    Full Text Available Social interaction affects emotional, cognitive and other aspects of child development. Visual analyzer plays an important role in establishing and maintaining relationships with others. The aim of this paper is to provide an overview of the effects of visual impairment and other risk and protective factors on social interaction and related aspects of psychological life in visually impaired and low vision children. Most of the analyzed studies point out visual impairment as a factor which has a negative influence on social development. Together with other negative environmental factors, visual impairment often has a negative influence on social interaction, which is an important factor of development and functioning in other areas. Thus, motor abilities, physical fitness, self-concept, and emotional development are closely related to a child's activity and participation in play activities, which may be hindered by visual impairment and the quality of communication with peers and important adults. Children with visual impairment less frequently initiate and have difficulties in maintaining social interaction. They have fewer friends, which often leads to emotional and behavioral problems. They are not accepted by peers in inclusive classrooms. Sociometric assessments indicate that they are more often in unpopular groups and have fewer opportunities to socialize with visually impaired peers. Therefore, it is important to timely recognize these children's needs and provide professional support and help for them and important people from their environment. This means providing conditions and activities which enable visually impaired children to fulfill their aims and needs in social interaction, and recognize the needs of others, i.e. develop social skills and at the same time allow their peers to get to know them and accept them better.

  5. Membrane Interaction of the Factor VIIIa Discoidin Domains in Atomistic Detail

    DEFF Research Database (Denmark)

    Madsen, Jesper Jonasson; Ohkubo, Y. Zenmei; Peters, Günther H.J.

    2015-01-01

    A recently developed membrane-mimetic model was applied to study membrane interaction and binding of the two anchoring C2-like discoidin domains of human coagulation factor VIIIa (FVIIIa), the C1 and C2 domains. Both individual domains, FVIII C1 and FVIII C2, were observed to bind the phospholipid....... The results indicate that FVIII C1 may be important in modulating the orientation of the FVIIIa molecule to optimize the interaction with FIXa, which is anchored to the membrane via its γ-carboxyglutamic acid-rich (Gla) domain. Additionally, a structural change was observed in FVIII C1 in the coiled main...

  6. Genetic identification of a network of factors that functionally interact with the nucleosome remodeling ATPase ISWI.

    Directory of Open Access Journals (Sweden)

    Giosalba Burgio

    2008-06-01

    Full Text Available Nucleosome remodeling and covalent modifications of histones play fundamental roles in chromatin structure and function. However, much remains to be learned about how the action of ATP-dependent chromatin remodeling factors and histone-modifying enzymes is coordinated to modulate chromatin organization and transcription. The evolutionarily conserved ATP-dependent chromatin-remodeling factor ISWI plays essential roles in chromosome organization, DNA replication, and transcription regulation. To gain insight into regulation and mechanism of action of ISWI, we conducted an unbiased genetic screen to identify factors with which it interacts in vivo. We found that ISWI interacts with a network of factors that escaped detection in previous biochemical analyses, including the Sin3A gene. The Sin3A protein and the histone deacetylase Rpd3 are part of a conserved histone deacetylase complex involved in transcriptional repression. ISWI and the Sin3A/Rpd3 complex co-localize at specific chromosome domains. Loss of ISWI activity causes a reduction in the binding of the Sin3A/Rpd3 complex to chromatin. Biochemical analysis showed that the ISWI physically interacts with the histone deacetylase activity of the Sin3A/Rpd3 complex. Consistent with these findings, the acetylation of histone H4 is altered when ISWI activity is perturbed in vivo. These findings suggest that ISWI associates with the Sin3A/Rpd3 complex to support its function in vivo.

  7. Interactions between risk and protective factors on problem gambling in Asia.

    Science.gov (United States)

    Oei, Tian P S; Goh, Zhengqin

    2015-06-01

    This study examined the relationships between risk (i.e., gambling cognitions, gambling urges, psychological distress) and protective factors (i.e., life satisfaction, resilience, gambling refusal self-efficacy) and problem gambling among 310 Singaporeans aged between 18 and 73 years. Data on demographics, risk and protective factors, and gambling behavior were collected through electronic and paper surveys. Hierarchical multiple regression was employed to assess the contributions of the risk and protective factors in predicting problem gambling. Three risk factors (i.e., gambling cognitions, gambling urges, psychological distress) and two protective factors (i.e., resilience, gambling refusal self-efficacy) were found to significantly and uniquely predict problem gambling. Furthermore, the risk factors significantly interacted with the protective factors to moderate gambling severity. Gambling refusal self-efficacy shows significant protective effects against problem gambling, while the effects of resilience on gambling vary across settings. Both factors need to be taken into account in the understanding of problem gambling.

  8. TIPT2 and geminin interact with basal transcription factors to synergize in transcriptional regulation

    Directory of Open Access Journals (Sweden)

    Pitulescu Mara E

    2009-06-01

    Full Text Available Abstract Background The re-replication inhibitor Geminin binds to several transcription factors including homeodomain proteins, and to members of the polycomb and the SWI/SNF complexes. Results Here we describe the TATA-binding protein-like factor-interacting protein (TIPT isoform 2, as a strong binding partner of Geminin. TIPT2 is widely expressed in mouse embryonic and adult tissues, residing both in cyto- and nucleoplasma, and enriched in the nucleolus. Like Geminin, also TIPT2 interacts with several polycomb factors, with the general transcription factor TBP (TATA box binding protein, and with the related protein TBPL1 (TRF2. TIPT2 synergizes with geminin and TBP in the activation of TATA box-containing promoters, and with TBPL1 and geminin in the activation of the TATA-less NF1 promoter. Geminin and TIPT2 were detected in the chromatin near TBP/TBPL1 binding sites. Conclusion Together, our study introduces a novel transcriptional regulator and its function in cooperation with chromatin associated factors and the basal transcription machinery.

  9. EFFECTS OF NEUTRINO ELECTROMAGNETIC FORM FACTORS ON NEUTRINO INTERACTION WITH FINITE TEMPERATURE ELECTRON MATTERS

    Directory of Open Access Journals (Sweden)

    Anto Sulaksono

    2011-11-01

    Full Text Available The differential cross-section of neutrino interaction with dense and warm electron gasses has been calculated by takinginto account the neutrino electromagnetic form factors. The significant effect of electromagnetic properties of neutrinocan be found if the neutrino dipole moment, μ ν , is ≥ 5.10-9 μB and neutrino charge radius, Rv, is ≥ 5.10-6 MeV-1. Theimportance of the retarded correction, detailed balance and Pauli blocking factors is shown and analyzed. Many-bodyeffects on the target matter which are included via random phase approximation (RPA correlation as well as photoneffective mass are also investigated.

  10. Examining dynamic interactions among experimental factors influencing hydrologic data assimilation with the ensemble Kalman filter

    Science.gov (United States)

    Wang, S.; Huang, G. H.; Baetz, B. W.; Cai, X. M.; Ancell, B. C.; Fan, Y. R.

    2017-11-01

    The ensemble Kalman filter (EnKF) is recognized as a powerful data assimilation technique that generates an ensemble of model variables through stochastic perturbations of forcing data and observations. However, relatively little guidance exists with regard to the proper specification of the magnitude of the perturbation and the ensemble size, posing a significant challenge in optimally implementing the EnKF. This paper presents a robust data assimilation system (RDAS), in which a multi-factorial design of the EnKF experiments is first proposed for hydrologic ensemble predictions. A multi-way analysis of variance is then used to examine potential interactions among factors affecting the EnKF experiments, achieving optimality of the RDAS with maximized performance of hydrologic predictions. The RDAS is applied to the Xiangxi River watershed which is the most representative watershed in China's Three Gorges Reservoir region to demonstrate its validity and applicability. Results reveal that the pairwise interaction between perturbed precipitation and streamflow observations has the most significant impact on the performance of the EnKF system, and their interactions vary dynamically across different settings of the ensemble size and the evapotranspiration perturbation. In addition, the interactions among experimental factors vary greatly in magnitude and direction depending on different statistical metrics for model evaluation including the Nash-Sutcliffe efficiency and the Box-Cox transformed root-mean-square error. It is thus necessary to test various evaluation metrics in order to enhance the robustness of hydrologic prediction systems.

  11. When environmental factors become stressors: interactive effects of vermetid gastropods and sedimentation on corals.

    Science.gov (United States)

    Zill, Julie A; Gil, Michael A; Osenberg, Craig W

    2017-03-01

    Environmental stressors often interact, but most studies of multiple stressors have focused on combinations of abiotic stressors. Here we examined the potential interaction between a biotic stressor, the vermetid snail Ceraesignum maximum, and an abiotic stressor, high sedimentation, on the growth of reef-building corals. In a field experiment, we subjected juvenile massive Porites corals to four treatments: (i) neither stressor, (ii) sedimentation, (iii) vermetids or (iv) both stressors. Unexpectedly, we found no effect of either stressor in isolation, but a significant decrease in coral growth in the presence of both stressors. Additionally, seven times more sediment remained on corals in the presence (versus absence) of vermetids, likely owing to adhesion of sediments to corals via vermetid mucus. Thus, vermetid snails and high sedimentation can interact to drive deleterious effects on reef-building corals. More generally, our study illustrates that environmental factors can combine to have negative interactive effects even when individual effects are not detectable. Such 'ecological surprises' may be easily overlooked, leading to environmental degradation that cannot be anticipated through the study of isolated factors. © 2017 The Author(s).

  12. Proteomic Interactions in the Mouse Vitreous-Retina Complex

    Science.gov (United States)

    Skeie, Jessica M.; Mahajan, Vinit B.

    2013-01-01

    Purpose Human vitreoretinal diseases are due to presumed abnormal mechanical interactions between the vitreous and retina, and translational models are limited. This study determined whether nonstructural proteins and potential retinal biomarkers were expressed by the normal mouse vitreous and retina. Methods Vitreous and retina samples from mice were collected by evisceration and analyzed by liquid chromatography-tandem mass spectrometry. Identified proteins were further analyzed for differential expression and functional interactions using bioinformatic software. Results We identified 1,680 unique proteins in the retina and 675 unique proteins in the vitreous. Unbiased clustering identified protein pathways that distinguish retina from vitreous including oxidative phosphorylation and neurofilament cytoskeletal remodeling, whereas the vitreous expressed oxidative stress and innate immunology pathways. Some intracellular protein pathways were found in both retina and vitreous, such as glycolysis and gluconeogenesis and neuronal signaling, suggesting proteins might be shuttled between the retina and vitreous. We also identified human disease biomarkers represented in the mouse vitreous and retina, including carbonic anhydrase-2 and 3, crystallins, macrophage inhibitory factor, glutathione peroxidase, peroxiredoxins, S100 precursors, and von Willebrand factor. Conclusions Our analysis suggests the vitreous expresses nonstructural proteins that functionally interact with the retina to manage oxidative stress, immune reactions, and intracellular proteins may be exchanged between the retina and vitreous. This novel proteomic dataset can be used for investigating human vitreoretinopathies in mouse models. Validation of vitreoretinal biomarkers for human ocular diseases will provide a critical tool for diagnostics and an avenue for therapeutics. PMID:24312404

  13. Proteomic interactions in the mouse vitreous-retina complex.

    Directory of Open Access Journals (Sweden)

    Jessica M Skeie

    Full Text Available Human vitreoretinal diseases are due to presumed abnormal mechanical interactions between the vitreous and retina, and translational models are limited. This study determined whether nonstructural proteins and potential retinal biomarkers were expressed by the normal mouse vitreous and retina.Vitreous and retina samples from mice were collected by evisceration and analyzed by liquid chromatography-tandem mass spectrometry. Identified proteins were further analyzed for differential expression and functional interactions using bioinformatic software.We identified 1,680 unique proteins in the retina and 675 unique proteins in the vitreous. Unbiased clustering identified protein pathways that distinguish retina from vitreous including oxidative phosphorylation and neurofilament cytoskeletal remodeling, whereas the vitreous expressed oxidative stress and innate immunology pathways. Some intracellular protein pathways were found in both retina and vitreous, such as glycolysis and gluconeogenesis and neuronal signaling, suggesting proteins might be shuttled between the retina and vitreous. We also identified human disease biomarkers represented in the mouse vitreous and retina, including carbonic anhydrase-2 and 3, crystallins, macrophage inhibitory factor, glutathione peroxidase, peroxiredoxins, S100 precursors, and von Willebrand factor.Our analysis suggests the vitreous expresses nonstructural proteins that functionally interact with the retina to manage oxidative stress, immune reactions, and intracellular proteins may be exchanged between the retina and vitreous. This novel proteomic dataset can be used for investigating human vitreoretinopathies in mouse models. Validation of vitreoretinal biomarkers for human ocular diseases will provide a critical tool for diagnostics and an avenue for therapeutics.

  14. Pitfalls in Interventional Pain Medicine: Hyponatremia after DDAVP for a Patient with Von Willebrand Disease Undergoing an Epidural Steroid Injection

    Directory of Open Access Journals (Sweden)

    Talal W. Khan

    2017-01-01

    Full Text Available Desmopressin (DDAVP, a synthetic analog of vasopressin, has been used in patients with von Willebrand disease (VWD, mild hemophilia A, and platelet dysfunction to reduce the risk of bleeding associated with surgical and interventional procedures. We report the case of a patient with VWD presenting with a bulging disc and radicular pain that underwent transforaminal epidural steroid injections. Her course was complicated with the interval development of headaches and dizziness symptomatic of moderate hyponatremia, likely due to excessive fluid intake. This report highlights a relatively rare side effect of DDAVP when used for prophylaxis in patients with VWD and reinforces the need for vigilance in these patients.

  15. Interacting with the public as a risk factor for employee psychological distress.

    Science.gov (United States)

    Hilton, Michael F; Whiteford, Harvey A

    2010-07-25

    The 1-month prevalence of any mental disorder in employees ranges from 10.5% to 18.5%. Mental disorders are responsible for substantial losses in employee productivity in both absenteeism and presenteeism. Potential work related factors contributing to mental difficulties are of increasing interest to employers. Some data suggests that being sales staff, call centre operator, nurse or teacher increases psychological distress. One aspect of these occupations is that there is an interaction with the public. The aim of this study is to evaluate whether employees who interact with the public are at greater risk of psychological distress. Data was collected from two studies. In study one 11,259 employees (60% female; mean age 40-years +/- SD 10-years) from six employers responded to the Health and Work Performance Questionnaire (HPQ) which contained a measure of psychological distress, the Kessler 6 (K6). Employees were coded as to whether or not they interacted with the public. Binomial logistic regression was performed on this data to determine the odds ratio (OR) for moderate or high psychological distress in employees that interacted with the public. Study two administered the HPQ and K6 to sales employees of a large Australian bank (N = 2,129; 67% female; mean age 39-years SD 10-years). This questionnaire also probed how many contacts individuals had with the public in the past week. Analysis of variance was used to determine if the number of contacts was related to psychological distress. In study one the prevalence of psychological distress in those that interacted and did not interact with the public were 19% and 15% respectively (P or = 25 contacts per week (P = 0.016). The results of the current study are indicative that interaction with the public increases levels of psychological distress. Employees dealing with the public may be an employee subgroup that could be targeted by employers with mental health interventions.

  16. Interacting with the public as a risk factor for employee psychological distress

    Directory of Open Access Journals (Sweden)

    Hilton Michael F

    2010-07-01

    Full Text Available Abstract Background The 1-month prevalence of any mental disorder in employees ranges from 10.5% to 18.5%. Mental disorders are responsible for substantial losses in employee productivity in both absenteeism and presenteeism. Potential work related factors contributing to mental difficulties are of increasing interest to employers. Some data suggests that being sales staff, call centre operator, nurse or teacher increases psychological distress. One aspect of these occupations is that there is an interaction with the public. The aim of this study is to evaluate whether employees who interact with the public are at greater risk of psychological distress. Methods Data was collected from two studies. In study one 11,259 employees (60% female; mean age 40-years ± SD 10-years from six employers responded to the Health and Work Performance Questionnaire (HPQ which contained a measure of psychological distress, the Kessler 6 (K6. Employees were coded as to whether or not they interacted with the public. Binomial logistic regression was performed on this data to determine the odds ratio (OR for moderate or high psychological distress in employees that interacted with the public. Study two administered the HPQ and K6 to sales employees of a large Australian bank (N = 2,129; 67% female; mean age 39-years SD 10-years. This questionnaire also probed how many contacts individuals had with the public in the past week. Analysis of variance was used to determine if the number of contacts was related to psychological distress. Results In study one the prevalence of psychological distress in those that interacted and did not interact with the public were 19% and 15% respectively (P Conclusions The results of the current study are indicative that interaction with the public increases levels of psychological distress. Employees dealing with the public may be an employee subgroup that could be targeted by employers with mental health interventions.

  17. Why Some Walk and Others Don't: Exploring Interactions of Perceived Safety and Social Neighborhood Factors with Psychosocial Cognitions

    Science.gov (United States)

    Beenackers, Marielle A.; Kamphuis, Carlijn B. M.; Mackenbach, Johan P.; Burdorf, Alex; van Lenthe, Frank J.

    2013-01-01

    Although physical activity is often believed to be influenced by both environmental and individual factors, little is known about their interaction. This study explores interactions of perceived safety and social neighborhood factors with psychosocial cognitions for leisure-time walking. Cross-sectional data were obtained from residents (age 25-75…

  18. Identification of the blood coagulation factor interacting sequences in staphylococcal superantigen-like protein 10.

    Science.gov (United States)

    Itoh, Saotomo; Takii, Takemasa; Onozaki, Kikuo; Tsuji, Tsutomu; Hida, Shigeaki

    2017-03-25

    Staphylococcal superantigen-like proteins (SSLs) are a family of exoproteins of Staphylococcus aureus. We have shown that SSL10 binds to vitamin K-dependent coagulation factors and inhibits blood coagulation induced by recalcification of citrated plasma. SSL10 was revealed to bind to coagulation factors via their γ-carboxyglutamic acid (Gla) domain. In this study we attempted to identify the responsible sequence of SSL10 for the interaction with coagulation factors. We prepared a series of domain swap mutants between SSL10 and its paralog SSL7 that does not interact with coagulation factors, and examined their binding activity to immobilized prothrombin using ELISA-like binding assay. The domain swap mutants that contained SSL10β1-β3 (23MEMKN ISALK HGKNN LRFKF RGIKI QVL60) bound to immobilized prothrombin, and mutants that contained SSL10β10-β12 (174SFYNL DLRSK LKFKY MGEVI ESKQI KDIEV NLK207) also retained the binding activity. On the other hand, mutants that lacked these two regions did not bind to prothrombin. These sequences, each alone, bound to prothrombin as 33 amino acid length polypeptides. These results suggest that SSL10 has two responsible sequences for the binding to prothrombin. These prothrombin-binding peptides would contribute to the development of new anticoagulants. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. The YEATS family member GAS41 interacts with the general transcription factor TFIIF

    Directory of Open Access Journals (Sweden)

    Ruggieri Alessia

    2010-07-01

    Full Text Available Abstract Background In eukaryotes the transcription initiation by RNA polymerase II requires numerous general and regulatory factors including general transcription factors. The general transcription factor TFIIF controls the activity of the RNA polymerase II both at the initiation and elongation stages. The glioma amplified sequence 41 (GAS41 has been associated with TFIIF via its YEATS domain. Results Using GST pull-down assays, we demonstrated that GAS41 binds to both, the small subunit (RAP30 and the large subunit (RAP74 of TFIIF in vitro. The in vivo interaction of GAS41 and endogenous RAP30 and RAP74 was confirmed by co-immunoprecipitation. GAS41 binds to two non-overlapping regions of the C-terminus of RAP30. There is also an ionic component to the binding between GAS41 and RAP30. There was no evidence for a direct interaction between GAS41 and TBP or between GAS41 and RNA polymerase II. Conclusions Our results demonstrate binding between endogenous GAS41 and the endogenous TFIIF subunits (RAP30 and RAP74. Since we did not find evidence for a binding of GAS41 to TBP or RNA polymerase II, GAS41 seems to preferentially bind to TFIIF. GAS41 that does not contain a DNA-binding domain appears to be a co-factor of TFIIF.

  20. Assessment of the olfactory function in Italian patients with type 3 von Willebrand disease caused by a homozygous 253 Kb deletion involving VWF and TMEM16B/ANO2.

    Directory of Open Access Journals (Sweden)

    Valentina Cenedese

    Full Text Available Type 3 Von Willebrand disease is an autosomal recessive disease caused by the virtual absence of the von Willebrand factor (VWF. A rare 253 kb gene deletion on chromosome 12, identified only in Italian and German families, involves both the VWF gene and the N-terminus of the neighbouring TMEM16B/ANO2 gene, a member of the family named transmembrane 16 (TMEM16 or anoctamin (ANO. TMEM16B is a calcium-activated chloride channel expressed in the olfactory epithelium. As a patient homozygous for the 253 kb deletion has been reported to have an olfactory impairment possibly related to the partial deletion of TMEM16B, we assessed the olfactory function in other patients using the University of Pennsylvania Smell Identification Test (UPSIT. The average UPSIT score of 4 homozygous patients was significantly lower than that of 5 healthy subjects with similar sex, age and education. However, 4 other members of the same family, 3 heterozygous for the deletion and 1 wild type, had a slightly reduced olfactory function indicating that socio-cultural or other factors were likely to be responsible for the observed difference. These results show that the ability to identify odorants of the homozygous patients for the deletion was not significantly different from that of the other members of the family, showing that the 253 kb deletion does not affect the olfactory performance. As other genes may compensate for the lack of TMEM16B, we identified some predicted functional partners from in silico studies of the protein-protein network of TMEM16B. Calculation of diversity for the corresponding genes for individuals of the 1000 Genomes Project showed that TMEM16B has the highest level of diversity among all genes of the network, indicating that TMEM16B may not be under purifying selection and suggesting that other genes in the network could compensate for its function for olfactory ability.

  1. Contribution of coagulation factor VII R353Q polymorphism to the ...

    African Journals Online (AJOL)

    Hanan Azzam

    2016-12-05

    Dec 5, 2016 ... a b s t r a c t. Background: Elevated factor VII (FVII) level is a risk factor for thromboembolic disorders. It was reported that the FVII R353Q polymorphism is associated with variation in plasma FVII levels, where Q allele car- ..... and von Willebrand factor: the CHARGE (Cohorts for Heart and Aging Research.

  2. Interaction between common breast cancer susceptibility variants, genetic ancestry, and nongenetic risk factors in Hispanic women.

    Science.gov (United States)

    Fejerman, Laura; Stern, Mariana C; John, Esther M; Torres-Mejía, Gabriela; Hines, Lisa M; Wolff, Roger K; Baumgartner, Kathy B; Giuliano, Anna R; Ziv, Elad; Pérez-Stable, Eliseo J; Slattery, Martha L

    2015-11-01

    Most genetic variants associated with breast cancer risk have been discovered in women of European ancestry, and only a few genome-wide association studies (GWAS) have been conducted in minority groups. This research disparity persists in post-GWAS gene-environment interaction analyses. We tested the interaction between hormonal and lifestyle risk factors for breast cancer, and ten GWAS-identified SNPs among 2,107 Hispanic women with breast cancer and 2,587 unaffected controls, to gain insight into a previously reported gene by ancestry interaction in this population. We estimated genetic ancestry with a set of 104 ancestry-informative markers selected to discriminate between Indigenous American and European ancestry. We used logistic regression models to evaluate main effects and interactions. We found that the rs13387042-2q35(G/A) SNP was associated with breast cancer risk only among postmenopausal women who never used hormone therapy [per A allele OR: 0.94 (95% confidence intervals, 0.74-1.20), 1.20 (0.94-1.53), and 1.49 (1.28-1.75) for current, former, and never hormone therapy users, respectively, Pinteraction 0.002] and premenopausal women who breastfed >12 months [OR: 1.01 (0.72-1.42), 1.19 (0.98-1.45), and 1.69 (1.26-2.26) for never, 12 months breastfeeding, respectively, Pinteraction 0.014]. The correlation between genetic ancestry, hormone replacement therapy use, and breastfeeding behavior partially explained a previously reported interaction between a breast cancer risk variant and genetic ancestry in Hispanic women. These results highlight the importance of understanding the interplay between genetic ancestry, genetics, and nongenetic risk factors and their contribution to breast cancer risk. ©2015 American Association for Cancer Research.

  3. Multiple interactions of hazard exposures, role stressors and situational factors, and burnout among nurses.

    Science.gov (United States)

    Lu, Jinky Leilanie

    2007-01-01

    This was a cross-sectional study which looked into the interaction between situational factors, role stressors, hazard exposure and personal factors among 135 nurses in the Philippine General Hospital. More than half (58.5%) of the respondents reported being ill due to work in the past year, and 59.3% missed work because of an illness. Regression showed factors associated with burnout were organizational role stress, hazard exposure, self-efficacy, age, number of working years, illness in the past 12 months, migraine, dizziness, sleep disorder, cough and colds, and diarrhea. After multiple regression analysis, organizational role stress (p = .000), migraine (p = .001), age (p = .018) and illness in the past 12 months (p = .000) were found to be significant predictors of burnout. The contribution of the study is in advancing new concepts in the already existing framework of burnout, and thus, assisting nurses and hospital administration in on controlling this problem.

  4. Menopause, obesity and inflammation: interactive risk factors for Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Amy eChristensen

    2015-07-01

    Full Text Available Alzheimer’s disease (AD is a multifactorial neurodegenerative disorder, the development of which is regulated by several environmental and genetic risk factors. Two factors theorized to contribute to the initiation and/or progression of AD pathogenesis are age-related increases in inflammation and obesity. These factors may be particularly problematic in women. The onset of menopause in mid-life elevates the vulnerability of women to AD, an increased risk that is likely associated with the depletion of estrogens. Menopause is also linked with an abundance of additional changes, including increased central adiposity and inflammation. Here, we review the current literature to explore the interactions between obesity, inflammation, menopause and AD.

  5. Menopause, obesity and inflammation: interactive risk factors for Alzheimer’s disease

    Science.gov (United States)

    Christensen, Amy; Pike, Christian J.

    2015-01-01

    Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder, the development of which is regulated by several environmental and genetic risk factors. Two factors theorized to contribute to the initiation and/or progression of AD pathogenesis are age-related increases in inflammation and obesity. These factors may be particularly problematic in women. The onset of menopause in mid-life elevates the vulnerability of women to AD, an increased risk that is likely associated with the depletion of estrogens. Menopause is also linked with an abundance of additional changes, including increased central adiposity and inflammation. Here, we review the current literature to explore the interactions between obesity, inflammation, menopause and AD. PMID:26217222

  6. Factors shaping interactions among community health workers in rural Ethiopia: rethinking workplace trust and teamwork.

    Science.gov (United States)

    Dynes, Michelle M; Stephenson, Rob; Hadley, Craig; Sibley, Lynn M

    2014-01-01

    Worldwide, a shortage of skilled health workers has prompted a shift toward community-based health workers taking on greater responsibility in the provision of select maternal and newborn health services. Research in mid- and high-income settings suggests that coworker collaboration increases productivity and performance. A major gap in this research, however, is the exploration of factors that influence teamwork among diverse community health worker cadres in rural, low-resource settings. The purpose of this study is to examine how sociodemographic and structural factors shape teamwork among community-based maternal and newborn health workers in Ethiopia. A cross-sectional survey was conducted with health extension workers, community health development agents, and traditional birth attendants in 3 districts of the West Gojam Zone in the Amhara region of Ethiopia. Communities were randomly selected from Maternal and Newborn Health in Ethiopia Partnership (MaNHEP) sites; health worker participants were recruited using a snowball sampling strategy. Fractional logit modeling and average marginal effects analyses were carried out to identify the influential factors for frequency of work interactions with each cadre. One hundred and ninety-four health workers participated in the study. A core set of factors-trust in coworkers, gender, and cadre-were influential for teamwork across groups. Greater geographic distance and perception of self-interested motivations were barriers to interactions with health extension workers, while greater food insecurity (a proxy for wealth) was associated with increased interactions with traditional birth attendants. Interventions that promote trust and gender sensitivity and improve perceptions of health worker motivations may help bridge the gap in health services delivery between low- and high-resource settings. Inter-cadre training may be one mechanism to increase trust and respect among diverse health workers, thereby increasing

  7. AKTIP/Ft1, a New Shelterin-Interacting Factor Required for Telomere Maintenance.

    KAUST Repository

    Burla, Romina

    2015-06-25

    Telomeres are nucleoprotein complexes that protect the ends of linear chromosomes from incomplete replication, degradation and detection as DNA breaks. Mammalian telomeres are protected by shelterin, a multiprotein complex that binds the TTAGGG telomeric repeats and recruits a series of additional factors that are essential for telomere function. Although many shelterin-associated proteins have been so far identified, the inventory of shelterin-interacting factors required for telomere maintenance is still largely incomplete. Here, we characterize AKTIP/Ft1 (human AKTIP and mouse Ft1 are orthologous), a novel mammalian shelterin-bound factor identified on the basis of its homology with the Drosophila telomere protein Pendolino. AKTIP/Ft1 shares homology with the E2 variant ubiquitin-conjugating (UEV) enzymes and has been previously implicated in the control of apoptosis and in vesicle trafficking. RNAi-mediated depletion of AKTIP results in formation of telomere dysfunction foci (TIFs). Consistent with these results, AKTIP interacts with telomeric DNA and binds the shelterin components TRF1 and TRF2 both in vivo and in vitro. Analysis of AKTIP- depleted human primary fibroblasts showed that they are defective in PCNA recruiting and arrest in the S phase due to the activation of the intra S checkpoint. Accordingly, AKTIP physically interacts with PCNA and the RPA70 DNA replication factor. Ft1-depleted p53-/- MEFs did not arrest in the S phase but displayed significant increases in multiple telomeric signals (MTS) and sister telomere associations (STAs), two hallmarks of defective telomere replication. In addition, we found an epistatic relation for MST formation between Ft1 and TRF1, which has been previously shown to be required for replication fork progression through telomeric DNA. Ch-IP experiments further suggested that in AKTIP-depleted cells undergoing the S phase, TRF1 is less tightly bound to telomeric DNA than in controls. Thus, our results collectively

  8. Interaction between monocytes and vascular smooth muscle cells induces expression of hepatocyte growth factor.

    Science.gov (United States)

    Okada, M; Hojo, Y; Ikeda, U; Takahashi, M; Takizawa, T; Morishita, R; Shimada, K

    2000-12-01

    To investigate the expression of hepatocyte growth factor (HGF)--a multifunctional factor implicated in tissue regeneration, wound healing and angiogenesis--that is induced by cell-to-cell interactions between monocytes and vascular smooth muscle cells (VSMCs), using coculture of human VSMCs and cells of the human monocytoid cell line, THP-1. We collected supernatant from the coculture medium and measured HGF concentrations with an enzyme-linked immunosorbent assay. Northern blot analysis of HGF mRNA was performed using a specific cDNA. To explore which types of cells produce HGF, we performed immunohistochemistry. Coculture of VSMCs with THP-1 cells for 24 h caused a fivefold increase in HGF concentrations over that in control VSMC culture. Northern blot analysis showed an induction of HGF mRNA in the coculture with a peak at 3 h. Separated cocultures demonstrated that both direct contact and soluble factors contribute to the production of HGF. Immunohistochemistry demonstrated that both types of cells in the coculture produce HGF. Neutralizing antibodies against tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 inhibited the HGF production in THP-1 cells and VSMCs that was induced by the coculture conditioned medium. The protein kinase C inhibitors H-7, calphostin C and K252b, and the tyrosine kinase inhibitor, genistein, significantly inhibited the production of HGF in the coculture. Cell-to-cell interactions between monocytes and VSMCs induced HGF synthesis in both types of cells, suggesting that local HGF production induced by this cell-to-cell interaction has an important role in the pathogenesis of hypertension, atherosclerosis or vascular remodelling.

  9. Peroxiredoxin 1 interacts with and blocks the redox factor APE1 from activating interleukin-8 expression

    Science.gov (United States)

    Nassour, Hassan; Wang, Zhiqiang; Saad, Amine; Papaluca, Arturo; Brosseau, Nicolas; Affar, El Bachir; Alaoui-Jamali, Moulay A.; Ramotar, Dindial

    2016-01-01

    APE1 is an essential DNA repair protein that also possesses the ability to regulate transcription. It has a unique cysteine residue C65, which maintains the reduce state of several transcriptional activators such as NF-κB. How APE1 is being recruited to execute the various biological functions remains unknown. Herein, we show that APE1 interacts with a novel partner PRDX1, a peroxidase that can also prevent oxidative damage to proteins by serving as a chaperone. PRDX1 knockdown did not interfere with APE1 expression level or its DNA repair activities. However, PRDX1 knockdown greatly facilitates APE1 detection within the nucleus by indirect immunofluorescence analysis, even though APE1 level was unchanged. The loss of APE1 interaction with PRDX1 promotes APE1 redox function to activate binding of the transcription factor NF-κB onto the promoter of a target gene, the proinflammatory chemokine IL-8 involved in cancer invasion and metastasis, resulting in its upregulation. Depletion of APE1 blocked the upregulation of IL-8 in the PRDX1 knockdown cells. Our findings suggest that the interaction of PRDX1 with APE1 represents a novel anti-inflammatory function of PRDX1, whereby the association safeguards APE1 from reducing transcription factors and activating superfluous gene expression, which otherwise could trigger cancer invasion and metastasis. PMID:27388124

  10. Specific Roles of MicroRNAs in Their Interactions with Environmental Factors

    Directory of Open Access Journals (Sweden)

    Juan Wang

    2012-01-01

    Full Text Available MicroRNAs (miRNAs have emerged as critical regulators of gene expression by modulating numerous target mRNAs expression at posttranscriptional level. Extensive studies have shown that miRNAs are critical in various important biological processes, including cell growth, proliferation, differentiation, development, and apoptosis. In terms of their importance, miRNA dysfunction has been associated with a broad range of diseases. Increased number of studies have shown that miRNAs can functionally interact with a wide spectrum of environmental factors (EFs including drugs, industrial materials, virus and bacterial pathogens, cigarette smoking, alcohol, nutrition, sleep, exercise, stress, and radiation. More importantly, the interactions between miRNAs and EFs have been shown to play critical roles in determining abnormal phenotypes and diseases. In this paper, we propose an outline of the current knowledge about specific roles of miRNAs in their interactions with various EFs and analyze the literatures detailing miRNAs-EFs interactions in the context of various of diseases.

  11. Identification and analysis of antinutritional factors in possible interactions between medications and food/nutrients in hospitalized patients.

    Science.gov (United States)

    Campos, Adnny Fernanda Lima; Torres, Savina Pereira; Lopes, Everton Moraes; Carvalho, Rumão Batista Nunes de; Freitas, Rivelilson Mendes de; Nunes, Lívio César Cunha

    2011-09-01

    To identify and analyze the presence of antinutritional factors in possible interactions between medications and foods/ nutrients of the diets prescribed for patients of the Hospital Regional Justino Luz, in the city of Picos (PI) in order to suggest their likely mechanisms. The sample was made up of 120 medical records of hospitalized patients. The charts were analyzed to verify the presence or absence of interactions between medications and foods/nutrients of the diets prescribed to the patients at the Hospital Regional Justino Luz, emphasizing the action of antinutritional factors in these interactions. Of the 189 medications prescribed, 128 (67.7%) had a possible interaction with food, totaling up 98 possible interactions between nutrients/foods and medications. Therefore, 20 (20.4%), 12 (12.2%) and 11 (11.2%) possible interactions were identified with captopril, acetylsalicylic acid and spironolactone, respectively, representing, in this order, the greatest frequencies of possible interactions among drugs and foods. A total of nine antinutritional factors were found in seven vegetable foods prescribed to inpatients, in which five (55.6%) were capable of interacting with the medications. Phytates and tannins had the largest quantity of possible interactions with drugs, each with 4 (26.7%) in a total of 15 interactions. The medications aluminum hydroxide, digoxin, and paracetamol attained greater probability of interaction with antinutrients, with 5 (33.3%), 3 (20%) and 3 (20%) interactions, respectively. Due to the large quantity of antinutritional factors capable of interacting with drugs prescribed for inpatients, the involvement of a multiprofessional team is indispensable so that these possible interactions between foods, antinutritional factors and drugs might be foreseen, detected, and resolved.

  12. Designing allosteric inhibitors of factor XIa. Lessons from the interactions of sulfated pentagalloylglucopyranosides.

    Science.gov (United States)

    Al-Horani, Rami A; Desai, Umesh R

    2014-06-12

    We recently introduced sulfated pentagalloylglucopyranoside (SPGG) as an allosteric inhibitor of factor XIa (FXIa) (Al-Horani et al., J. Med Chem. 2013, 56, 867-878). To better understand the SPGG-FXIa interaction, we utilized eight SPGG variants and a range of biochemical techniques. The results reveal that SPGG's sulfation level moderately affected FXIa inhibition potency and selectivity over thrombin and factor Xa. Variation in the anomeric configuration did not affect potency. Interestingly, zymogen factor XI bound SPGG with high affinity, suggesting its possible use as an antidote. Acrylamide quenching experiments suggested that SPGG induced significant conformational changes in the active site of FXIa. Inhibition studies in the presence of heparin showed marginal competition with highly sulfated SPGG variants but robust competition with less sulfated variants. Resolution of energetic contributions revealed that nonionic forces contribute nearly 87% of binding energy suggesting a strong possibility of specific interaction. Overall, the results indicate that SPGG may recognize more than one anion-binding, allosteric site on FXIa. An SPGG molecule containing approximately 10 sulfate groups on positions 2 through 6 of the pentagalloylglucopyranosyl scaffold may be the optimal FXIa inhibitor for further preclinical studies.

  13. Interactive effects of multiple climate change factors on ammonia oxidizers and denitrifiers in a temperate steppe.

    Science.gov (United States)

    Zhang, Cui-Jing; Shen, Ju-Pei; Sun, Yi-Fei; Wang, Jun-Tao; Zhang, Li-Mei; Yang, Zhong-Ling; Han, Hong-Yan; Wan, Shi-Qiang; He, Ji-Zheng

    2017-04-01

    Global climate change could have profound effects on belowground microbial communities and subsequently affect soil biogeochemical processes. The interactive effects of multiple co-occurring climate change factors on microbially mediated processes are not well understood. A four-factorial field experiment with elevated CO2, watering, nitrogen (N) addition and night warming was conducted in a temperate steppe of northern China. Real-time polymerase chain reaction and terminal-restriction fragment length polymorphism, combined with clone library techniques, were applied to examine the effects of those climate change factors on N-related microbial abundance and community composition. Only the abundance of ammonia-oxidizing bacteria significantly increased by nitrogen addition and decreased by watering. The interactions of watering × warming on the bacterial amoA community and warming × nitrogen addition on the nosZ community were found. Redundancy analysis indicated that the ammonia-oxidizing archaeal community was affected by total N and total carbon, while the community of bacterial amoA and nosZ were significantly affected by soil pH. According to a structural equation modeling analysis, climate change influenced net primary production indirectly by altering microbial abundance and activities. These results indicated that microbial responses to the combination of chronic global change tend to be smaller than expected from single-factor global change manipulations. © FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  14. Medical Residents and Interprofessional Interactions in Discharge: An Ethnographic Exploration of Factors That Affect Negotiation.

    Science.gov (United States)

    Goldman, Joanne; Reeves, Scott; Wu, Robert; Silver, Ivan; MacMillan, Kathleen; Kitto, Simon

    2015-10-01

    Interprofessional collaboration is an important aspect of patient discharge from a general internal medicine (GIM) unit. However, there has been minimal empirical or theoretical research that has examined interactions that occur between medical residents and other healthcare professionals in the discharge process. This study provides insight into the social processes that shape and characterize such interactions. To explore factors that shape interactions between medical residents and other healthcare professionals in relation to patient discharge, and to examine the opportunities for negotiations about discharge between these professional groups. A qualitative ethnographic approach using observations, interviews and documentary analysis. Healthcare professionals working in a GIM unit in Canada. Sixty-five hours of observations were undertaken in a range of settings (e.g. interprofessional rounds, medical and nursing rounds, nursing station) in the unit over a 17-month period. A maximum variation sampling approach was used to identify healthcare professionals working in the unit. Twenty-three interviews were completed, recorded and transcribed verbatim. A directed content approach using theories of medical dominance and negotiated order was used to analyze the data. The organization of clinical work in combination with clinical teaching influenced interprofessional interactions and the quality of discharge in this GIM unit. While organizational activities (orientation and rounds) and individual activities (e.g. role modeling, teaching) supported negotiations between medical residents and other healthcare professionals around discharge, participants had varied perspectives about their effectiveness. This study illuminates social factors and processes that require attention in order to address challenges with interprofessional collaboration and discharge in GIM. These findings have implications for medical education, workplace learning, patient safety and quality

  15. Interacting TCP and NLP transcription factors control plant responses to nitrate availability.

    Science.gov (United States)

    Guan, Peizhu; Ripoll, Juan-José; Wang, Renhou; Vuong, Lam; Bailey-Steinitz, Lindsay J; Ye, Dening; Crawford, Nigel M

    2017-02-28

    Plants have evolved adaptive strategies that involve transcriptional networks to cope with and survive environmental challenges. Key transcriptional regulators that mediate responses to environmental fluctuations in nitrate have been identified; however, little is known about how these regulators interact to orchestrate nitrogen (N) responses and cell-cycle regulation. Here we report that teosinte branched1/cycloidea/proliferating cell factor1-20 (TCP20) and NIN-like protein (NLP) transcription factors NLP6 and NLP7, which act as activators of nitrate assimilatory genes, bind to adjacent sites in the upstream promoter region of the nitrate reductase gene, NIA1 , and physically interact under continuous nitrate and N-starvation conditions. Regions of these proteins necessary for these interactions were found to include the type I/II Phox and Bem1p (PB1) domains of NLP6&7, a protein-interaction module conserved in animals for nutrient signaling, and the histidine- and glutamine-rich domain of TCP20, which is conserved across plant species. Under N starvation, TCP20-NLP6&7 heterodimers accumulate in the nucleus, and this coincides with TCP20 and NLP6&7-dependent up-regulation of nitrate assimilation and signaling genes and down-regulation of the G 2 /M cell-cycle marker gene, CYCB1;1 TCP20 and NLP6&7 also support root meristem growth under N starvation. These findings provide insights into how plants coordinate responses to nitrate availability, linking nitrate assimilation and signaling with cell-cycle progression.

  16. Interactions between the spatial and temporal stimulus factors that influence multisensory integration in human performance.

    Science.gov (United States)

    Stevenson, Ryan A; Fister, Juliane Krueger; Barnett, Zachary P; Nidiffer, Aaron R; Wallace, Mark T

    2012-05-01

    In natural environments, human sensory systems work in a coordinated and integrated manner to perceive and respond to external events. Previous research has shown that the spatial and temporal relationships of sensory signals are paramount in determining how information is integrated across sensory modalities, but in ecologically plausible settings, these factors are not independent. In the current study, we provide a novel exploration of the impact on behavioral performance for systematic manipulations of the spatial location and temporal synchrony of a visual-auditory stimulus pair. Simple auditory and visual stimuli were presented across a range of spatial locations and stimulus onset asynchronies (SOAs), and participants performed both a spatial localization and simultaneity judgment task. Response times in localizing paired visual-auditory stimuli were slower in the periphery and at larger SOAs, but most importantly, an interaction was found between the two factors, in which the effect of SOA was greater in peripheral as opposed to central locations. Simultaneity judgments also revealed a novel interaction between space and time: individuals were more likely to judge stimuli as synchronous when occurring in the periphery at large SOAs. The results of this study provide novel insights into (a) how the speed of spatial localization of an audiovisual stimulus is affected by location and temporal coincidence and the interaction between these two factors and (b) how the location of a multisensory stimulus impacts judgments concerning the temporal relationship of the paired stimuli. These findings provide strong evidence for a complex interdependency between spatial location and temporal structure in determining the ultimate behavioral and perceptual outcome associated with a paired multisensory (i.e., visual-auditory) stimulus.

  17. Interaction between FTO gene variants and lifestyle factors on metabolic traits in an Asian Indian population.

    Science.gov (United States)

    Vimaleswaran, Karani S; Bodhini, Dhanasekaran; Lakshmipriya, N; Ramya, K; Anjana, R Mohan; Sudha, Vasudevan; Lovegrove, Julie A; Kinra, Sanjay; Mohan, Viswanathan; Radha, Venkatesan

    2016-01-01

    Lifestyle factors such as diet and physical activity have been shown to modify the association between fat mass and obesity-associated (FTO) gene variants and metabolic traits in several populations; however, there are no gene-lifestyle interaction studies, to date, among Asian Indians living in India. In this study, we examined whether dietary factors and physical activity modified the association between two FTO single nucleotide polymorphisms (rs8050136 and rs11076023) (SNPs) and obesity traits and type 2 diabetes (T2D). The study included 734 unrelated T2D and 884 normal glucose-tolerant (NGT) participants randomly selected from the urban component of the Chennai Urban Rural Epidemiology Study (CURES). Dietary intakes were assessed using a validated interviewer administered semi-quantitative food frequency questionnaire (FFQ). Physical activity was based upon the self-report. Interaction analyses were performed by including the interaction terms in the linear/logistic regression model. There was a significant interaction between SNP rs8050136 and carbohydrate intake (% energy) (Pinteraction = 0.04), where the 'A' allele carriers had 2.46 times increased risk of obesity than those with 'CC' genotype (P = 3.0 × 10(-5)) among individuals in the highest tertile of carbohydrate intake (% energy, 71 %). A significant interaction was also observed between SNP rs11076023 and dietary fibre intake (Pinteraction = 0.0008), where individuals with AA genotype who are in the 3(rd) tertile of dietary fibre intake had 1.62 cm lower waist circumference than those with 'T' allele carriers (P = 0.02). Furthermore, among those who were physically inactive, the 'A' allele carriers of the SNP rs8050136 had 1.89 times increased risk of obesity than those with 'CC' genotype (P = 4.0 × 10(-5)). This is the first study to provide evidence for a gene-diet and gene-physical activity interaction on obesity and T2D in an Asian Indian population. Our findings suggest

  18. Molecular and Cellular Interactions between Mother and Fetus. Pregnancy as a Rejuvenating Factor.

    Science.gov (United States)

    Popkov, V A; Silachev, D N; Jankauskas, S S; Zorova, L D; Pevzner, I B; Babenko, V A; Plotnikov, E Y; Zorov, D B

    2016-12-01

    Aging is associated with a decline of various body functions, including ability to regenerate. Over recent decades, it has been demonstrated that some of these changes could be reversed in response to factors originating from a young organism, for example, fetal stem cells or "young blood" in models of heterochronic parabiosis. Pregnancy might be considered as parabiotic model of the interaction between two organisms of different age. In this work, we analyzed and summarized data on the effects of pregnancy on the maternal organism that confirm the hypothesis that pregnancy rejuvenates the mother's organism or slows its aging.

  19. Interpersonal confidence as a factor in the prevention of disorganized interaction

    Directory of Open Access Journals (Sweden)

    Dontsov, Aleksander I.

    2014-03-01

    Full Text Available Human communities are based on a certain set of everyday attitudes, on the coordination of the actions of “the self ” in a group, and on the regulation of social practices. The results of this study show that a number of factors act as determinants of trust/ distrust ambivalence: the multidimensionality and the dynamics of interactions among people; the high level of subjectivity in evaluating risks resulting from openness and from confidence in partners involved in an interaction; and a subject’s contradictory attitude toward the personal traits of an interacting partner (power, activity, honesty, trustworthiness. Japanese scholars have proved the necessity of taking into account quality of life (QOL as one of the determinants of the development of interpersonal confidence. The study demonstrates that people try to bring trust into their daily routines as a way of organizing conscientious, emotionally open interactions that take into account the interests of all parties. Mistrust blocks access to the emotional, intellectual, and activity-related resources supporting life and undermines faith in the possibility of virtue and morality. Yet a supplementary study (using instant diagnostics indicates that in practice respondents did not demonstrate a high level of confidence (in two cities it was 0%; in one city, it was 4.6%. In spite of emotionally positive views regarding trust, as well as constructive estimates of its moral/behavioral potential, a considerable number of respondents were not open and oriented to the interests of others. A tendency toward caution, inwardness, and constrained sincerity leads to nonconformity in one’s actions in a group and to changes in the vector of social practices from socio-partner regulation to disorganized interaction.

  20. Identification and analysis of antinutritional factors in possible interactions between medications and food/ nutrients in hospitalized patients

    Directory of Open Access Journals (Sweden)

    Adnny Fernanda Lima Campos

    2011-09-01

    Full Text Available Objective: To identify and analyze the presence of antinutritionalfactors in possible interactions between medications and foods/nutrients of the diets prescribed for patients of the Hospital Regional Justino Luz, in the city of Picos (PI in order to suggest their likely mechanisms. Methods: The sample was made up of 120 medical records of hospitalized patients. The charts were analyzed to verify the presence or absence of interactions between medications andfoods/nutrients of the diets prescribed to the patients at the Hospital Regional Justino Luz, emphasizing the action of antinutritional factors in these interactions. Results: Of the 189 medications prescribed, 128 (67.7% had a possible interaction with food, totaling up 98 possible interactions between nutrients/foods and medications. Therefore, 20 (20.4%, 12 (12.2% and 11 (11.2% possible interactions were identified with captopril, acetylsalicylic acid and spironolactone, respectively, representing, in this order, the greatest frequencies of possible interactions among drugs and foods. A total of nine antinutritional factors were found in seven vegetable foods prescribed to inpatients, in which five (55.6% were capable of interacting with the medications. Phytates and tannins had the largest quantity of possible interactions with drugs, each with 4 (26.7% in a total of 15 interactions. The medications aluminum hydroxide, digoxin, and paracetamol attained greater probability of interaction with antinutrients, with 5 (33.3%, 3 (20% and 3 (20% interactions, respectively. Conclusion: Due to the large quantity of antinutritional factors capable of interacting with drugs prescribed for inpatients, the involvement of a multiprofessional team is indispensable so that these possible interactions between foods, antinutritional factors and drugs might be foreseen, detected, and resolved.

  1. Interactions between genes and environmental factors in asthma and atopy: new developments

    Science.gov (United States)

    Sengler, Claudia; Lau, Susanne; Wahn, Ulrich; Nickel, Renate

    2002-01-01

    Asthma and associated phenotypes are complex traits most probably caused by an interaction of multiple disease susceptibility genes and environmental factors. Major achievements have occurred in identifying chromosomal regions and polymorphisms in candidate genes linked to or associated with asthma, atopic dermatitis, IgE levels and response to asthma therapy. The aims of this review are to explain the methodology of genetic studies of multifactorial diseases, to summarize chromosomal regions and polymorphisms in candidate genes linked to or associated with asthma and associated traits, to list genetic alterations that may alter response to asthma therapy, and to outline genetic factors that may render individuals more susceptible to asthma and atopy due to environmental changes. PMID:11806842

  2. Interaction of environmental factors and genetic polymorphism in the etiology of cancer

    Directory of Open Access Journals (Sweden)

    D. G. Zaridze

    2016-01-01

    Full Text Available Еnvironmental and lifestyle factors play a dominant role in etiology of cancer. In addition, genetic factors significantly influence interindividual variation in cancer incidence. The epidemiological studies in which effects of genetic polymorphism on the risk of cancer have been elucidated are somewhat disappointing. An important problem of these studies is their size. Moreover some of them do not have information on life-style and environmental exposures. The epidemiological method used to investigate the effect of genetic polymorphism on cancer risk is a retrospective case-control study. The chance of discovery of the specific «frequent» allelic variant which is associated with small increase in the risk is higher in studies including large numbers of cases and controls. This paper reviews the epidemiologic studies conducted in Department of epidemiology (Institute of carcinogenesis, Russian N. N. Blokhin Cancer Research Centre in cooperation with countries of Central and Eastern Europe (Hungary, Poland, Romania, Slovakia and coordinated by the International Agency for Research on Cancer (IARC. We will cover the studies, in which an attempt has been made to investigate the interaction between polymorphisms of phase 2 xenobiotic metabolism genes (GST, alcohol and aldehyde-metabolizing genes (ADH, ALDH, folate metabolism genes (MTHFR, TYMS and CHECK2 with environmental and life-style factors in etiology of cancers of the lung, kidney and upper aerodigestive tract. The analyses of these studies suggest that genetic polymorphism modifies the effect of environmental exposures (including occupational carcinogens and life-style factors (including tobacco, alcohol and diet on the risk of cancer. The risk of cancer associated with known carcinogenic exposure may increase or decrease depending on the genotype. Interaction between exposure to carcinogenic factor and genotype is a major and significant determinant of cancer risk

  3. Dynamic Distribution and Interaction of the Arabidopsis SRSF1 Subfamily Splicing Factors.

    Science.gov (United States)

    Stankovic, Nancy; Schloesser, Marie; Joris, Marine; Sauvage, Eric; Hanikenne, Marc; Motte, Patrick

    2016-02-01

    Ser/Arg-rich (SR) proteins are essential nucleus-localized splicing factors. Our prior studies showed that Arabidopsis (Arabidopsis thaliana) RSZ22, a homolog of the human SRSF7 SR factor, exits the nucleus through two pathways, either dependent or independent on the XPO1 receptor. Here, we examined the expression profiles and shuttling dynamics of the Arabidopsis SRSF1 subfamily (SR30, SR34, SR34a, and SR34b) under control of their endogenous promoter in Arabidopsis and in transient expression assay. Due to its rapid nucleocytoplasmic shuttling and high expression level in transient assay, we analyzed the multiple determinants that regulate the localization and shuttling dynamics of SR34. By site-directed mutagenesis of SR34 RNA-binding sequences and Arg/Ser-rich (RS) domain, we further show that functional RRM1 or RRM2 are dispensable for the exclusive protein nuclear localization and speckle-like distribution. However, mutations of both RRMs induced aggregation of the protein whereas mutation in the RS domain decreased the stability of the protein and suppressed its nuclear accumulation. Furthermore, the RNA-binding motif mutants are defective for their export through the XPO1 (CRM1/Exportin-1) receptor pathway, but retain nucleocytoplasmic mobility. We performed a yeast two hybrid screen with SR34 as bait and discovered SR45 as a new interactor. SR45 is an unusual SR splicing factor bearing two RS domains. These interactions were confirmed in planta by FLIM-FRET and BiFC and the roles of SR34 domains in protein-protein interactions were further studied. Altogether, our report extends our understanding of shuttling dynamics of Arabidopsis SR splicing factors. © 2016 American Society of Plant Biologists. All Rights Reserved.

  4. Dynamic Distribution and Interaction of the Arabidopsis SRSF1 Subfamily Splicing Factors1

    Science.gov (United States)

    Stankovic, Nancy; Schloesser, Marie; Joris, Marine; Sauvage, Eric; Hanikenne, Marc; Motte, Patrick

    2016-01-01

    Ser/Arg-rich (SR) proteins are essential nucleus-localized splicing factors. Our prior studies showed that Arabidopsis (Arabidopsis thaliana) RSZ22, a homolog of the human SRSF7 SR factor, exits the nucleus through two pathways, either dependent or independent on the XPO1 receptor. Here, we examined the expression profiles and shuttling dynamics of the Arabidopsis SRSF1 subfamily (SR30, SR34, SR34a, and SR34b) under control of their endogenous promoter in Arabidopsis and in transient expression assay. Due to its rapid nucleocytoplasmic shuttling and high expression level in transient assay, we analyzed the multiple determinants that regulate the localization and shuttling dynamics of SR34. By site-directed mutagenesis of SR34 RNA-binding sequences and Arg/Ser-rich (RS) domain, we further show that functional RRM1 or RRM2 are dispensable for the exclusive protein nuclear localization and speckle-like distribution. However, mutations of both RRMs induced aggregation of the protein whereas mutation in the RS domain decreased the stability of the protein and suppressed its nuclear accumulation. Furthermore, the RNA-binding motif mutants are defective for their export through the XPO1 (CRM1/Exportin-1) receptor pathway, but retain nucleocytoplasmic mobility. We performed a yeast two hybrid screen with SR34 as bait and discovered SR45 as a new interactor. SR45 is an unusual SR splicing factor bearing two RS domains. These interactions were confirmed in planta by FLIM-FRET and BiFC and the roles of SR34 domains in protein-protein interactions were further studied. Altogether, our report extends our understanding of shuttling dynamics of Arabidopsis SR splicing factors. PMID:26697894

  5. Comparative transcriptomic analysis of virulence factors in Leptosphaeria maculans during compatible and incompatible interactions with canola

    Directory of Open Access Journals (Sweden)

    Humira Sonah

    2016-12-01

    Full Text Available Leptosphaeria maculans is a hemibiotrophic fungus that causes blackleg of canola (Brassica napus, one of the most devastating diseases of this crop. In the present study, transcriptome profiling of L. maculans was performed in an effort to understand and define the pathogenicity genes that govern both the biotrophic and the necrotrophic phase of the fungus, as well as those that separate a compatible from an incompatible interaction. For this purpose, comparative RNA-seq analyses were performed on L. maculans isolate D5 at four different time points following inoculation on susceptible cultivar Topas-wild or resistant near isogenic line Topas-Rlm2. Analysis of 1.6 billion Illumina reads readily identified differentially expressed genes that were over represented by candidate secretory effector proteins, CAZymes, and other pathogenicity genes. Comparisons between the compatible and incompatible interactions led to the identification of 28 effector proteins whose chronology and level of expression suggested a role in the establishment and maintenance of biotrophy with the plant. These included all known Avr genes of isolate D5 along with eight newly characterized effectors. In addition, another 15 effector proteins were found to be exclusively expressed during the necrotrophic phase of the fungus, which supports the concept that L. maculans has a separate and distinct arsenal contributing to each phase. As for CAZymes, they were often highly expressed at 3 dpi but with no difference in expression between the compatible and incompatible interactions, indicating that other factors were necessary to determine the outcome of the interaction. However, their significantly higher expression at 11 dpi in the compatible interaction confirmed that they contributed to the necrotrophic phase of the fungus. A notable exception was LysM genes whose high expression was singularly observed on the susceptible host at 7 dpi. In the case of TFs, their higher

  6. Platelet interaction with activated endothelium: mechanistic insights from microfluidics.

    Science.gov (United States)

    Coenen, Daniëlle M; Mastenbroek, Tom G; Cosemans, Judith M E M

    2017-10-10

    Traditionally, in vitro flow chamber experiments and in vivo arterial thrombosis studies have been proven to be of vital importance to elucidate the mechanisms of platelet thrombus formation after vessel wall injury. In recent years, it has become clear that platelets also act as modulators of inflammatory processes, such as atherosclerosis. A key element herein is the complex crosstalk between platelets, the coagulation system, leukocytes and the activated endothelium. This review provides insight into the platelet-endothelial interface, based on in vitro flow chamber studies and cross referenced with in vivo thrombosis studies. The main mechanisms of platelet interaction with the activated endothelium encompass i) platelet rolling via interaction of platelet glycoprotein Ib-IX-V with endothelial-released von Willebrand factor with a supporting role for the P-selectin - P-selectin glycoprotein ligand 1 axis, followed by ii) firm platelet adhesion to the endothelium via interaction of platelet αIIbβ3 with endothelial αvβ3 and intercellular adhesion molecule 1, and iii) a stimulatory role for thrombin, the thrombospondin-1 - CD36 axis and cyclooxygenase 1 in subsequent platelet activation and stable thrombus formation. In addition, the molecular mechanisms underlying the stimulatory effect of platelets on leukocyte transendothelial migration, a key mediator of atheroprogression, are discussed. Throughout the review emphasis is placed on recommendations for setting up, reporting, interpreting and comparing endothelial-lined flow chamber studies and on suggestions for future studies. Copyright © 2017 American Society of Hematology.

  7. Thalidomide for treatment of gastrointestinal bleedings due to angiodysplasia : a case report in acquired von Willebrand syndrome and review of the literature

    NARCIS (Netherlands)

    Engelen, E T; van Galen, K P M; Schutgens, R E G

    INTRODUCTION: Acquired von Willebrand syndrome is a rare bleeding disorder and treatment of the associated gastrointestinal (GI) bleeding due to angiodysplasia is challenging. AIM: The aim of this study was to present a new case on the successful use of thalidomide in a patient with acquired von

  8. Antifibrinolytic therapy for preventing oral bleeding in patients with haemophilia or Von Willebrand disease undergoing minor oral surgery or dental extractions

    NARCIS (Netherlands)

    van Galen, Karin Pm|info:eu-repo/dai/nl/325853886; Engelen, Eveline T; Mauser-Bunschoten, Evelien P|info:eu-repo/dai/nl/074719718; van Es, Robert Jj|info:eu-repo/dai/nl/216460646; Schutgens, Roger Eg|info:eu-repo/dai/nl/258752084

    2015-01-01

    BACKGROUND: Minor oral surgery or dental extractions (oral or dental procedures) are widely performed and can be complicated by hazardous oral bleeding, especially in people with an inherited bleeding disorder such as haemophilia or Von Willebrand disease. The amount and severity of singular

  9. The development of a serum-free medium utilizing the interaction between growth factors and biomaterials.

    Science.gov (United States)

    Iwata, Kumiko; Asawa, Yukiyo; Nishizawa, Satoru; Mori, Yoshiyuki; Nagata, Satoru; Takato, Tsuyoshi; Hoshi, Kazuto

    2012-01-01

    To promote clinical application of cartilage tissue engineering, we should establish a serum-free chondrocyte growth medium. The serum-free medium would increase the cell numbers by more than 20-fold within one week, which proliferation ability almost matches that of serum-based one. For that, we examined the combinations of growth factors and the methods to enhance their effects by making use of the interaction with biomaterials. From various growth factors that are contained within the serum, we made the cocktail of FGF-2 (100 ng/mL), insulin (5 μg/mL), EGF (10 pg/mL), PDGF (625 pg/mL) and TGF-β (5 pg/mL), which increased the chondrocyte numbers by approximately 3-fold for 7 days. Moreover, we used the biomaterials including albumin and hyaluronan as the carrier of those factors. By direct mixing of those factors with biomaterials before the administration to the medium, the medium containing those mixture showed the chondrocyte growth of approximately a 25-fold increase by day 10. In this medium, the FGF-2 or insulin concentration hardly decreased, and rather enhanced the activation of ERK. Due to the optimal usage of biomaterials, this serum-free medium will realize a constant harvest of chondrocytes and could contribute to the safety and quality in regenerative medicine. Copyright © 2011 Elsevier Ltd. All rights reserved.

  10. Interacting factors and cellular localization of SR protein-specific kinase Dsk1

    Energy Technology Data Exchange (ETDEWEB)

    Tang, Zhaohua, E-mail: ztang@jsd.claremont.edu [W.M. Keck Science Center, The Claremont Colleges, Claremont, CA 91711 (United States); Luca, Maria; Taggart-Murphy, Laura; Portillio, Jessica; Chang, Cathey; Guven, Ayse [W.M. Keck Science Center, The Claremont Colleges, Claremont, CA 91711 (United States); Lin, Ren-Jang [Department of Molecular and Cellular Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010 (United States); Murray, Johanne; Carr, Antony [Genome Damage and Stability Center, University of Sussex, Falmer, BN1 9RQ (United Kingdom)

    2012-10-01

    Schizosaccharomyces pombe Dsk1 is an SR protein-specific kinase (SRPK), whose homologs have been identified in every eukaryotic organism examined. Although discovered as a mitotic regulator with protein kinase activity toward SR splicing factors, it remains largely unknown about what and how Dsk1 contributes to cell cycle and pre-mRNA splicing. In this study, we investigated the Dsk1 function by determining interacting factors and cellular localization of the kinase. Consistent with its reported functions, we found that pre-mRNA processing and cell cycle factors are prominent among the proteins co-purified with Dsk1. The identification of these factors led us to find Rsd1 as a novel Dsk1 substrate, as well as the involvement of Dsk1 in cellular distribution of poly(A){sup +} RNA. In agreement with its role in nuclear events, we also found that Dsk1 is mainly localized in the nucleus during G{sub 2} phase and at mitosis. Furthermore, we revealed the oscillation of Dsk1 protein in a cell cycle-dependent manner. This paper marks the first comprehensive analysis of in vivo Dsk1-associated proteins in fission yeast. Our results reflect the conserved role of SRPK family in eukaryotic organisms, and provide information about how Dsk1 functions in pre-mRNA processing and cell-division cycle.

  11. Factors influencing interactions in zoos: animal-keeper relationship, animal-public interactions and solitary animals groups

    Directory of Open Access Journals (Sweden)

    Giovanni Quintavalle Pastorino

    2015-07-01

    Full Text Available Interactions that animals experience can have a significant influence on their health and welfare. These interactions can occur between animals themselves, but also between animals and keepers, and animals and the public. Human and non-human animals come into contact with each other in a variety of settings, and wherever there is contact there is the opportunity for interaction to take place. Interaction with companion animals are well known, but human–animal interaction (HAR (Hosey, 2008 also occurs in the context of farms (Hemsworth and Gonyou, 1997; Hemsworth, 2003, laboratories (Chang and Hart, 2002, zoos (Kreger and Mench, 1995 and even the wild (e.g. Cassini, 2001. This project proposes a permanent monitoring scheme to record animal-human interactions and animal-animal interactions in zoos. This will be accompanied by a survey of animal personality for welfare, husbandry, breeding programs and reintroduction purposes. The pilot project is currently based on direct monitoring of animal behaviour, use of time lapse cameras and animal personality questionnaires completed by experienced keepers. The goal of this project is to create a network between zoos to explore the aforementioned interactions to produce husbandry protocols and explore personality and behavioural traits in multiple species. We present provisional data regarding polar bear (Fasano Zoosafari, Italy, Sumatran tigers, Amur tigers and Asiatic lion (ZSL London and Whipsnade zoo interactions with humans and conspecifics. This data is collected across a broad range of environmental conditions and outlines the monitoring protocols developed to collect this data. The first year data show the great adaptability of these species to ex situ environments, low or absent negative impact of visitors’ presence and the relevance of individual personality in these interactions.

  12. MED18 interaction with distinct transcription factors regulates multiple plant functions.

    Science.gov (United States)

    Lai, Zhibing; Schluttenhofer, Craig M; Bhide, Ketaki; Shreve, Jacob; Thimmapuram, Jyothi; Lee, Sang Yeol; Yun, Dae-Jin; Mengiste, Tesfaye

    2014-01-01

    Mediator is an evolutionarily conserved transcriptional regulatory complex. Mechanisms of Mediator function are poorly understood. Here we show that Arabidopsis MED18 is a multifunctional protein regulating plant immunity, flowering time and responses to hormones through interactions with distinct transcription factors. MED18 interacts with YIN YANG1 to suppress disease susceptibility genes glutaredoxins GRX480, GRXS13 and thioredoxin TRX-h5. Consequently, yy1 and med18 mutants exhibit deregulated expression of these genes and enhanced susceptibility to fungal infection. In addition, MED18 interacts with ABA INSENSITIVE 4 and SUPPRESSOR OF FRIGIDA4 to regulate abscisic acid responses and flowering time, respectively. MED18 associates with the promoter, coding and terminator regions of target genes suggesting its function in transcription initiation, elongation and termination. Notably, RNA polymerase II occupancy and histone H3 lysine tri-methylation of target genes are affected in the med18 mutant, reinforcing MED18 function in different mechanisms of transcriptional control. Overall, MED18 conveys distinct cues to engender transcription underpinning plant responses.

  13. Combining a wavelet change point and the Bayes factor for analysing chromosomal interaction data.

    Science.gov (United States)

    Shavit, Yoli; Lio', Pietro

    2014-06-01

    Over the past few decades we have witnessed great efforts to understand the cellular function at the cytoplasm level. Nowadays there is a growing interest in understanding the relationship between function and structure at the nuclear, chromosomal and sub-chromosomal levels. Data on chromosomal interactions that are now becoming available in unprecedented resolution and scale open the way to address this challenge. Consequently, there is a growing need for new methods and tools that will transform these data into knowledge and insights. Here, we have developed all the steps required for the analysis of chromosomal interaction data (Hi-C data). The result is a methodology which combines a wavelet change point with the Bayes factor for useful correction, segmentation and comparison of Hi-C data. We further developed chromoR, an R package that implements the methods presented here. The chromoR package provides researchers with a means to analyse chromosomal interaction data using statistical bioinformatics, offering a new and comprehensive solution to this task.

  14. Multiple neuroendocrine responses to chronic social stress: interaction between individual characteristics and situational factors.

    Science.gov (United States)

    Mormède, P; Lemaire, V; Castanon, N; Dulluc, J; Laval, M; Le Moal, M

    1990-06-01

    After four weeks of individual housing, male Wistar rats (selected for high or low spontaneous aggressiveness by multiple round-robin encounters) were housed three per cage and submitted to four weeks of chronic social stress consisting of changing membership in the social groups by daily rotation of the animals among cages every day according to a random permutation procedure. In addition, half the males in each condition were housed with three females. Each environmental condition triggered different neuroendocrine changes. Cohabitation with females increased the hypothalamo-pituitary-adrenocortical axis activity, including enlargement of adrenals and increased circulating corticosterone levels. On the other hand, daily rotation of the rats between different social groups activated part of the sympathetic nervous system, such as increased phenylethanolamine N-methyl transferase (PNMT) activity in the adrenals. The level of aggressiveness, however, had no direct influence but interacted with environmental factors on such neuroendocrine measures as circulating testosterone or plasma renin activity. These results indicate that during chronic stress, there is no single, unique response by the animal, but a highly complex set of neuroendocrine changes, dependent on the interaction between individual characteristics (the level of aggressiveness is an example) and situational factors.

  15. Interaction of Psychological Factors in Shaping Entrepreneurial Intention among Computer and Electrical Engineering Students

    Directory of Open Access Journals (Sweden)

    Chao-Tung Liang

    2015-01-01

    Full Text Available Numerous technopreneurs start their ventures at college age, but the entrepreneurship of computer and electrical engineering (CEE students remains under-studied. This study analysed both the combined and interactive effects of psychological factors on the entrepreneurial intentions of CEE students. In this study, entrepreneurial intention comprised two dimensions, conviction and preparation. Regarding the direct effects, the results indicated that self-efficacy affected entrepreneurial conviction the most, followed by negative emotion, intrinsic motivation, and metacognition. Negative emotion affected entrepreneurial preparation the most, followed by self-efficacy and positive emotion. The results also revealed several crucial interactive effects resulting from psychological factors. An increase in cognitive load increased the entrepreneurial intention of students exhibiting high intrinsic motivation and reduced the intention of students exhibiting low intrinsic motivation. An increase in metacognition increased the entrepreneurial conviction of students exhibiting either high or low intrinsic motivation. An increase in positive emotion reduced the entrepreneurial intention of students exhibiting high negative emotion and increased the intention of students exhibiting low negative emotion. An increase in self-efficacy increased the entrepreneurial intention of students exhibiting either high or low negative emotion.

  16. The Interaction Effects of Meteorological Factors and Air Pollution on the Development of Acute Coronary Syndrome

    Science.gov (United States)

    Huang, Ching-Hui; Lin, Heng-Cheng; Tsai, Chen-Dao; Huang, Hung-Kai; Lian, Ie-Bin; Chang, Chia-Chu

    2017-03-01

    This study investigated the interaction effects of meteorological factors and air pollutants on the onset of acute coronary syndrome (ACS). Data of ACS patients were obtained from the Taiwan ACS Full Spectrum Registry and comprised 3164 patients with a definite onset date during the period October 2008 and January 2010 at 39 hospitals. Meteorological conditions and air pollutant concentrations at the 39 locations during the 488-day period were obtained. Time-lag Poisson and logistic regression were used to explore their association with ACS incidence. One-day lag atmospheric pressure (AP), humidity, particulate matter (PM2.5, and PM10), and carbon monoxide (CO) all had significant interaction effects with temperature on ACS occurrence. Days on which high temperatures (>26 °C) and low AP (<1009 hPa) occurred the previous day were associated with a greater likelihood of increased incidence of developing ACS. Typhoon Morakot was an example of high temperature with extremely low AP associated with higher ACS incidence than the daily average. Combinations of high concentrations of PM or CO with low temperatures (<21 °C) and high humidity levels with low temperatures were also associated with increased incidence of ACS. Atmospheric pollution and weather factors have synergistic effects on the incidence of ACS.

  17. Novel Burkholderia mallei Virulence Factors Linked to Specific Host-Pathogen Protein Interactions*

    Science.gov (United States)

    Memišević, Vesna; Zavaljevski, Nela; Pieper, Rembert; Rajagopala, Seesandra V.; Kwon, Keehwan; Townsend, Katherine; Yu, Chenggang; Yu, Xueping; DeShazer, David; Reifman, Jaques; Wallqvist, Anders

    2013-01-01

    Burkholderia mallei is an infectious intracellular pathogen whose virulence and resistance to antibiotics makes it a potential bioterrorism agent. Given its genetic origin as a commensal soil organism, it is equipped with an extensive and varied set of adapted mechanisms to cope with and modulate host-cell environments. One essential virulence mechanism constitutes the specialized secretion systems that are designed to penetrate host-cell membranes and insert pathogen proteins directly into the host cell's cytosol. However, the secretion systems' proteins and, in particular, their host targets are largely uncharacterized. Here, we used a combined in silico, in vitro, and in vivo approach to identify B. mallei proteins required for pathogenicity. We used bioinformatics tools, including orthology detection and ab initio predictions of secretion system proteins, as well as published experimental Burkholderia data to initially select a small number of proteins as putative virulence factors. We then used yeast two-hybrid assays against normalized whole human and whole murine proteome libraries to detect and identify interactions among each of these bacterial proteins and host proteins. Analysis of such interactions provided both verification of known virulence factors and identification of three new putative virulence proteins. We successfully created insertion mutants for each of these three proteins using the virulent B. mallei ATCC 23344 strain. We exposed BALB/c mice to mutant strains and the wild-type strain in an aerosol challenge model using lethal B. mallei doses. In each set of experiments, mice exposed to mutant strains survived for the 21-day duration of the experiment, whereas mice exposed to the wild-type strain rapidly died. Given their in vivo role in pathogenicity, and based on the yeast two-hybrid interaction data, these results point to the importance of these pathogen proteins in modulating host ubiquitination pathways, phagosomal escape, and actin

  18. AKTIP/Ft1, a New Shelterin-Interacting Factor Required for Telomere Maintenance.

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    Romina Burla

    2015-06-01

    Full Text Available Telomeres are nucleoprotein complexes that protect the ends of linear chromosomes from incomplete replication, degradation and detection as DNA breaks. Mammalian telomeres are protected by shelterin, a multiprotein complex that binds the TTAGGG telomeric repeats and recruits a series of additional factors that are essential for telomere function. Although many shelterin-associated proteins have been so far identified, the inventory of shelterin-interacting factors required for telomere maintenance is still largely incomplete. Here, we characterize AKTIP/Ft1 (human AKTIP and mouse Ft1 are orthologous, a novel mammalian shelterin-bound factor identified on the basis of its homology with the Drosophila telomere protein Pendolino. AKTIP/Ft1 shares homology with the E2 variant ubiquitin-conjugating (UEV enzymes and has been previously implicated in the control of apoptosis and in vesicle trafficking. RNAi-mediated depletion of AKTIP results in formation of telomere dysfunction foci (TIFs. Consistent with these results, AKTIP interacts with telomeric DNA and binds the shelterin components TRF1 and TRF2 both in vivo and in vitro. Analysis of AKTIP- depleted human primary fibroblasts showed that they are defective in PCNA recruiting and arrest in the S phase due to the activation of the intra S checkpoint. Accordingly, AKTIP physically interacts with PCNA and the RPA70 DNA replication factor. Ft1-depleted p53-/- MEFs did not arrest in the S phase but displayed significant increases in multiple telomeric signals (MTS and sister telomere associations (STAs, two hallmarks of defective telomere replication. In addition, we found an epistatic relation for MST formation between Ft1 and TRF1, which has been previously shown to be required for replication fork progression through telomeric DNA. Ch-IP experiments further suggested that in AKTIP-depleted cells undergoing the S phase, TRF1 is less tightly bound to telomeric DNA than in controls. Thus, our results

  19. Vascular endothelial cell function and cardiovascular risk factors in patients with chronic renal failure

    DEFF Research Database (Denmark)

    Haaber, A B; Eidemak, I; Jensen, T

    1995-01-01

    Cardiovascular risk factors and markers of endothelial cell function were studied in nondiabetic patients with mild to moderate chronic renal failure. The transcapillary escape rate of albumin and the plasma concentrations of von Willebrand factor, fibrinogen, and plasma lipids were measured in 29...

  20. Storage and regulated secretion of factor VIII in blood outgrowth endothelial cells

    NARCIS (Netherlands)

    van den Biggelaar, M.; Bouwens, E.A.M.; Kootstra, N.A.; Hebbel, R.P.; Voorberg, J.; Mertens, K.

    2009-01-01

    Background Gene therapy provides an attractive alternative for protein replacement therapy in hemophilia A patients. Recent studies have shown the potential benefit of directing factor (F)VIII gene delivery to cells that also express its natural carrier protein von Willebrand factor (VWF). In this

  1. Interaction of complement factor h and fibulin3 in age-related macular degeneration.

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    M Keith Wyatt

    Full Text Available Age-related macular degeneration (AMD is a major cause of vision loss. It is associated with development of characteristic plaque-like deposits (soft drusen in Bruch's membrane basal to the retinal pigment epithelium (RPE. A sequence variant (Y402H in short consensus repeat domain 7 (SCR7 of complement factor H (CFH is associated with risk for "dry" AMD. We asked whether the eye-targeting of this disease might be related to specific interactions of CFH SCR7 with proteins expressed in the aging human RPE/choroid that could contribute to protein deposition in drusen. Yeast 2-hybrid (Y2H screens of a retinal pigment epithelium/choroid library derived from aged donors using CFH SCR7 baits detected an interaction with EFEMP1/Fibulin 3 (Fib3, which is the locus for an inherited macular degeneration and also accumulates basal to macular RPE in AMD. The CFH/Fib3 interaction was validated by co-immunoprecipitation of native proteins. Quantitative Y2H and ELISA assays with different recombinant protein constructs both demonstrated higher affinity for Fib3 for the disease-related CFH 402H variant. Immuno-labeling revealed colocalization of CFH and Fib3 in globular deposits within cholesterol-rich domains in soft drusen in two AMD donors homozygous for CFH 402H (H/H. This pattern of labeling was quite distinct from those seen in examples of eyes with Y/Y and H/Y genotypes. The CFH 402H/Fib3 interaction could contribute to the development of pathological aggregates in soft drusen in some patients and as such might provide a target for therapeutic intervention in some forms of AMD.

  2. Nuclear import of transcription factor BR-C is mediated by its interaction with RACK1.

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    Daojun Cheng

    Full Text Available The transcription factor Broad Complex (BR-C is an early ecdysone response gene in insects and contains two types of domains: two zinc finger domains for the activation of gene transcription and a Bric-a-brac/Tramtrack/Broad complex (BTB domain for protein-protein interaction. Although the mechanism of zinc finger-mediated gene transcription is well studied, the partners interacting with the BTB domain of BR-C has not been elucidated until now. Here, we performed a yeast two-hybrid screen using the BTB domain of silkworm BR-C as bait and identified the receptor for activated C-kinase 1 (RACK1, a scaffolding/anchoring protein, as the novel partner capable of interacting with BR-C. The interaction between BR-C and RACK1 was further confirmed by far-western blotting and pull-down assays. Importantly, the disruption of this interaction, via RNAi against the endogenous RACK1 gene or deletion of the BTB domain, abolished the nuclear import of BR-C in BmN4 cells. In addition, RNAi against the endogenous PKC gene as well as phosphorylation-deficient mutation of the predicted PKC phosphorylation sites at either Ser373 or Thr406 in BR-C phenocopied RACK1 RNAi and altered the nuclear localization of BR-C. However, when BTB domain was deleted, phosphorylation mimics of either Ser373 or Thr406 had no effect on the nuclear import of BR-C. Moreover, mutating the PKC phosphorylation sites at Ser373 and Thr406 or deleting the BTB domain significantly decreased the transcriptional activation of a BR-C target gene. Given that RACK1 is necessary for recruiting PKC to close and phosphorylate target proteins, we suggest that the PKC-mediated phosphorylation and nuclear import of BR-C is determined by its interaction with RACK1. This novel finding will be helpful for further deciphering the mechanism underlying the role of BR-C proteins during insect development.

  3. Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): comprehensive genetic analysis by next-generation sequencing of 480 patients.

    Science.gov (United States)

    Borràs, Nina; Batlle, Javier; Pérez-Rodríguez, Almudena; López-Fernández, María Fernanda; Rodríguez-Trillo, Ángela; Lourés, Esther; Cid, Ana Rosa; Bonanad, Santiago; Cabrera, Noelia; Moret, Andrés; Parra, Rafael; Mingot-Castellano, María Eva; Balda, Ignacia; Altisent, Carme; Pérez-Montes, Rocío; Fisac, Rosa María; Iruín, Gemma; Herrero, Sonia; Soto, Inmaculada; de Rueda, Beatriz; Jiménez-Yuste, Víctor; Alonso, Nieves; Vilariño, Dolores; Arija, Olga; Campos, Rosa; Paloma, María José; Bermejo, Nuria; Berrueco, Rubén; Mateo, José; Arribalzaga, Karmele; Marco, Pascual; Palomo, Ángeles; Sarmiento, Lizheidy; Iñigo, Belén; Nieto, María Del Mar; Vidal, Rosa; Martínez, María Paz; Aguinaco, Reyes; César, Jesús María; Ferreiro, María; García-Frade, Javier; Rodríguez-Huerta, Ana María; Cuesta, Jorge; Rodríguez-González, Ramón; García-Candel, Faustino; Cornudella, Rosa; Aguilar, Carlos; Vidal, Francisco; Corrales, Irene

    2017-12-01

    Molecular diagnosis of patients with von Willebrand disease is pending in most populations due to the complexity and high cost of conventional molecular analyses. The need for molecular and clinical characterization of von Willebrand disease in Spain prompted the creation of a multicenter project (PCM-EVW-ES) that resulted in the largest prospective cohort study of patients with all types of von Willebrand disease. Molecular analysis of relevant regions of the VWF, including intronic and promoter regions, was achieved in the 556 individuals recruited via the development of a simple, innovative, relatively low-cost protocol based on microfluidic technology and next-generation sequencing. A total of 704 variants (237 different) were identified along VWF, 155 of which had not been previously recorded in the international mutation database. The potential pathogenic effect of these variants was assessed by in silico analysis. Furthermore, four short tandem repeats were analyzed in order to evaluate the ancestral origin of recurrent mutations. The outcome of genetic analysis allowed for the reclassification of 110 patients, identification of 37 asymptomatic carriers (important for genetic counseling) and re-inclusion of 43 patients previously excluded by phenotyping results. In total, 480 patients were definitively diagnosed. Candidate mutations were identified in all patients except 13 type 1 von Willebrand disease, yielding a high genotype-phenotype correlation. Our data reinforce the capital importance and usefulness of genetics in von Willebrand disease diagnostics. The progressive implementation of molecular study as the first-line test for routine diagnosis of this condition will lead to increasingly more personalized and effective care for this patient population. Copyright© 2017 Ferrata Storti Foundation.

  4. Insights into mRNP biogenesis provided by new genetic interactions among export and transcription factors

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    Estruch Francisco

    2012-09-01

    Full Text Available Abstract Background The various steps of mRNP biogenesis (transcription, processing and export are interconnected. It has been shown that the transcription machinery plays a pivotal role in mRNP assembly, since several mRNA export factors are recruited during transcription and physically interact with components of the transcription machinery. Although the shuttling DEAD-box protein Dbp5p is concentrated on the cytoplasmic fibrils of the NPC, previous studies demonstrated that it interacts physically and genetically with factors involved in transcription initiation. Results We investigated the effect of mutations affecting various components of the transcription initiation apparatus on the phenotypes of mRNA export mutant strains. Our results show that growth and mRNA export defects of dbp5 and mex67 mutant strains can be suppressed by mutation of specific transcription initiation components, but suppression was not observed for mutants acting in the very first steps of the pre-initiation complex (PIC formation. Conclusions Our results indicate that mere reduction in the amount of mRNP produced is not sufficient to suppress the defects caused by a defective mRNA export factor. Suppression occurs only with mutants affecting events within a narrow window of the mRNP biogenesis process. We propose that reducing the speed with which transcription converts from initiation and promoter clearance to elongation may have a positive effect on mRNP formation by permitting more effective recruitment of partially-functional mRNP proteins to the nascent mRNP.

  5. Bovine Lhx8, a Germ Cell-Specific Nuclear Factor, Interacts with Figla.

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    Liyuan Fu

    Full Text Available LIM homeobox 8 (Lhx8 is a germ cell-specific transcription factor essential for the development of oocytes during early oogenesis. In mice, Lhx8 deficiency causes postnatal oocyte loss and affects the expression of many oocyte-specific genes. The aims of this study were to characterize the bovine Lhx8 gene, determine its mRNA expression during oocyte development and early embryogenesis, and evaluate its interactions with other oocyte-specific transcription factors. The bovine Lhx8 gene encodes a protein of 377 amino acids. A splice variant of Lhx8 (Lhx8_v1 was also identified. The predicted bovine Lhx8 protein contains two LIM domains and one homeobox domain. However, one of the LIM domains in Lhx8_v1 is incomplete due to deletion of 83 amino acids near the N terminus. Both Lhx8 and Lhx8_v1 transcripts were only detected in the gonads but none of the somatic tissues examined. The expression of Lhx8 and Lhx8_v1 appears to be restricted to oocytes as none of the transcripts was detectable in granulosa or theca cells. The maternal Lhx8 transcript is abundant in GV and MII stage oocytes as well as in early embryos but disappear by morula stage. A nuclear localization signal that is required for the import of Lhx8 into nucleus was identified, and Lhx8 is predominantly localized in the nucleus when ectopically expressed in mammalian cells. Finally, a novel interaction between Lhx8 and Figla, another transcription factor essential for oogenesis, was detected. The results provide new information for studying the mechanisms of action for Lhx8 in oocyte development and early embryogenesis.

  6. FUNCTIONAL INTERACTION OF LEXICAL AND GRAMMATICAL FACTORS IN THE ENGLISH VERB SYSTEM

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    Nina Sergeevna Kotova

    2017-03-01

    Full Text Available Purpose. The purpose of the research conducted is revealing the peculiarities of lexical paradigmatics influence upon the usage of aspect and temporal verb forms and the opposite impact as well, i.e. the influence of aspect and temporal verb forms upon the lexical meaning of this verb groups under specific conditions of functioning. The lexical paradigmatics is considered as the system of mutually contrasted semantic features of particular verb groups. In this case, we analyze the paradigmatics in the middle language hierarchy for each language level separately. Methodology. The research is conducted synchronically on the material of the contemporary English verb system. Interaction of lexical and grammatical factors in the English verb system is examined in a functional aspect. Such consideration gives a possibility to differentiate the intrasystem phenomena and phenomena of pragmatic character and expose the system-structural mutual relations of lexical and grammatical factors. The research material is the verb as massive word group. From the point of view of interaction of lexical and grammatical factors in the functional and semantic field representing aspectuality, we get interested in the meaning which realizes in the opposition ofatelicity – telicity(telicity correlates the action with the limit, and atelicity demotes the action irrespectively to its limit. The technique applied to the analysis of lexical and grammatical factors in the English verb system is complex combining descriptive and comparative and functional methods. Results. Interrelations and interdependency of lexical and grammatical paradigmatics create particular sustainability in using the lexical unit of this paradigm with aspect and temporal verb forms. In this case, the tendencies of the language sign developing and changing are expressed in the process of the mutual substitution and interpenetration of grammatical forms primarily under the influence of paradigmatic

  7. Essential Assembly Factor Rpf2 Forms Novel Interactions within the 5S RNP in Trypanosoma brucei.

    Science.gov (United States)

    Kamina, Anyango D; Jaremko, Daniel; Christen, Linda; Williams, Noreen

    2017-01-01

    Ribosome biogenesis is a highly complex and conserved cellular process that is responsible for making ribosomes. During this process, there are several assembly steps that function as regulators to ensure proper ribosome formation. One of these steps is the assembly of the 5S ribonucleoprotein particle (5S RNP) in the central protuberance of the 60S ribosomal subunit. In eukaryotes, the 5S RNP is composed of 5S rRNA, ribosomal proteins L5 and L11, and assembly factors Rpf2 and Rrs1. Our laboratory previously showed that in Trypanosoma brucei, the 5S RNP is composed of 5S rRNA, L5, and trypanosome-specific RNA binding proteins P34 and P37. In this study, we characterize an additional component of the 5S RNP, the T. brucei homolog of Rpf2. This is the first study to functionally characterize interactions mediated by Rpf2 in an organism other than fungi. T. brucei Rpf2 (TbRpf2) was identified from tandem affinity purification using extracts prepared from protein A-tobacco etch virus (TEV)-protein C (PTP)-tagged L5, P34, and P37 cell lines, followed by mass spectrometry analysis. We characterized the binding interactions between TbRpf2 and the previously characterized members of the T. brucei 5S RNP. Our studies show that TbRpf2 mediates conserved binding interactions with 5S rRNA and L5 and that TbRpf2 also interacts with trypanosome-specific proteins P34 and P37. We performed RNA interference (RNAi) knockdown of TbRpf2 and showed that this protein is essential for the survival of the parasites and is critical for proper ribosome formation. These studies provide new insights into a critical checkpoint in the ribosome biogenesis pathway in T. brucei. IMPORTANCETrypanosoma brucei is the parasitic protozoan that causes African sleeping sickness. Ribosome assembly is essential for the survival of this parasite through the different host environments it encounters during its life cycle. The assembly of the 5S ribonucleoprotein particle (5S RNP) functions as one of the

  8. Identity-expression interaction in face perception: sex, visual field, and psychophysical factors.

    Science.gov (United States)

    Godard, Ornella; Baudouin, Jean-Yves; Bonnet, Philippe; Fiori, Nicole

    2013-01-01

    We investigated the psychophysical factors underlying the identity-emotion interaction in face perception. Visual field and sex were also taken into account. Participants had to judge whether a probe face, presented in either the left or the right visual field, and a central target face belonging to same person while emotional expression varied (Experiment 1) or to judge whether probe and target faces expressed the same emotion while identity was manipulated (Experiment 2). For accuracy we replicated the mutual facilitation effect between identity and emotion; no sex or hemispheric differences were found. Processing speed measurements, however, showed a lesser degree of interference in women than in men, especially for matching identity when faces expressed different emotions after a left visual presentation probe face. Psychophysical indices can be used to determine whether these effects are perceptual (A') or instead arise at a post-perceptual decision-making stage (B"). The influence of identity on the processing of facial emotion seems to be due to perceptual factors, whereas the influence of emotion changes on identity processing seems to be related to decisional factors. In addition, men seem to be more "conservative" after a LVF/RH probe-face presentation when processing identity. Women seem to benefit from better abilities to extract facial invariant aspects relative to identity.

  9. Assessment of Multifactor Gene-Environment Interactions and Ovarian Cancer Risk: Candidate Genes, Obesity, and Hormone-Related Risk Factors.

    Science.gov (United States)

    Usset, Joseph L; Raghavan, Rama; Tyrer, Jonathan P; McGuire, Valerie; Sieh, Weiva; Webb, Penelope; Chang-Claude, Jenny; Rudolph, Anja; Anton-Culver, Hoda; Berchuck, Andrew; Brinton, Louise; Cunningham, Julie M; DeFazio, Anna; Doherty, Jennifer A; Edwards, Robert P; Gayther, Simon A; Gentry-Maharaj, Aleksandra; Goodman, Marc T; Høgdall, Estrid; Jensen, Allan; Johnatty, Sharon E; Kiemeney, Lambertus A; Kjaer, Susanne K; Larson, Melissa C; Lurie, Galina; Massuger, Leon; Menon, Usha; Modugno, Francesmary; Moysich, Kirsten B; Ness, Roberta B; Pike, Malcolm C; Ramus, Susan J; Rossing, Mary Anne; Rothstein, Joseph; Song, Honglin; Thompson, Pamela J; van den Berg, David J; Vierkant, Robert A; Wang-Gohrke, Shan; Wentzensen, Nicolas; Whittemore, Alice S; Wilkens, Lynne R; Wu, Anna H; Yang, Hannah; Pearce, Celeste Leigh; Schildkraut, Joellen M; Pharoah, Paul; Goode, Ellen L; Fridley, Brooke L

    2016-05-01

    Many epithelial ovarian cancer (EOC) risk factors relate to hormone exposure and elevated estrogen levels are associated with obesity in postmenopausal women. Therefore, we hypothesized that gene-environment interactions related to hormone-related risk factors could differ between obese and non-obese women. We considered interactions between 11,441 SNPs within 80 candidate genes related to hormone biosynthesis and metabolism and insulin-like growth factors with six hormone-related factors (oral contraceptive use, parity, endometriosis, tubal ligation, hormone replacement therapy, and estrogen use) and assessed whether these interactions differed between obese and non-obese women. Interactions were assessed using logistic regression models and data from 14 case-control studies (6,247 cases; 10,379 controls). Histotype-specific analyses were also completed. SNPs in the following candidate genes showed notable interaction: IGF1R (rs41497346, estrogen plus progesterone hormone therapy, histology = all, P = 4.9 × 10(-6)) and ESR1 (rs12661437, endometriosis, histology = all, P = 1.5 × 10(-5)). The most notable obesity-gene-hormone risk factor interaction was within INSR (rs113759408, parity, histology = endometrioid, P = 8.8 × 10(-6)). We have demonstrated the feasibility of assessing multifactor interactions in large genetic epidemiology studies. Follow-up studies are necessary to assess the robustness of our findings for ESR1, CYP11A1, IGF1R, CYP11B1, INSR, and IGFBP2 Future work is needed to develop powerful statistical methods able to detect these complex interactions. Assessment of multifactor interaction is feasible, and, here, suggests that the relationship between genetic variants within candidate genes and hormone-related risk factors may vary EOC susceptibility. Cancer Epidemiol Biomarkers Prev; 25(5); 780-90. ©2016 AACR. ©2016 American Association for Cancer Research.

  10. Acquired von Willebrand Syndrome associated to secondary IgM MGUS emerging after Autologous Stem Cell Transplantation for AL Amyloidosis

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    Victor H Jimenez-Zepeda

    2017-05-01

    Full Text Available Acquired von Willebrand syndrome (AVWS is a rare hemorrhagic disorder that occurs in patients with no prior personal or family history of bleeding. Here, we describe a case of AVWS occurring after autologous stem cell transplantation (ASCT. Interestingly, AVWS developed after bortezomib-based induction and conditioning regimens. Recent evidence suggests that the proximity of the bortezomib therapy to the collection of stem cells with consequent depletion of regulatory T cells after the conditioning regimen could explain some of the unusual autoimmune complications reported in patients receiving bortezomib prior to ASCT. In addition, this patient developed a secondary MGUS post-ASCT, which may have also contributed to the AVWS. To the best of our knowledge, this is the first case of post-ASCT AVWS reported. Prospective data is needed to better elucidate the mechanisms by which these unusual complications occur in patients receiving bortezomib prior to ASCT.

  11. Mapping interactions between mRNA export factors in living cells.

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    I-Fang Teng

    Full Text Available The TREX complex couples nuclear mRNA processing events with subsequent export to the cytoplasm. TREX also acts as a binding platform for the mRNA export receptor Nxf1. The sites of mRNA transcription and processing within the nucleus have been studied extensively. However, little is known about where TREX assembly takes place and where Nxf1 is recruited to TREX to form the export competent mRNP. Here we have used sensitized emission Förster resonance energy transfer (FRET and fluorescence lifetime imaging (FLIM-FRET, to produce a spatial map in living cells of the sites for the interaction of two TREX subunits, Alyref and Chtop, with Nxf1. Prominent assembly sites for export factors are found in the vicinity of nuclear speckles in regions known to be involved in transcription, splicing and exon junction complex formation highlighting the close coupling of mRNA export with mRNP biogenesis.

  12. Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection.

    Science.gov (United States)

    Blackburn, Elizabeth H; Epel, Elissa S; Lin, Jue

    2015-12-04

    Telomeres are the protective end-complexes at the termini of eukaryotic chromosomes. Telomere attrition can lead to potentially maladaptive cellular changes, block cell division, and interfere with tissue replenishment. Recent advances in the understanding of human disease processes have clarified the roles of telomere biology, especially in diseases of human aging and in some aging-related processes. Greater overall telomere attrition predicts mortality and aging-related diseases in inherited telomere syndrome patients, and also in general human cohorts. However, genetically caused variations in telomere maintenance either raise or lower risks and progression of cancers, in a highly cancer type-specific fashion. Telomere maintenance is determined by genetic factors and is also cumulatively shaped by nongenetic influences throughout human life; both can interact. These and other recent findings highlight both causal and potentiating roles for telomere attrition in human diseases. Copyright © 2015, American Association for the Advancement of Science.

  13. Functional Characterization of the Maize Phytochrome-Interacting Factors PIF4 and PIF5

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    Qingbiao Shi

    2018-01-01

    Full Text Available Phytochrome-interacting factors (PIFs play important roles in photomorphogenesis, the shade avoidance response, and other aspects of plant growth and development. PIF family proteins have been well-studied in Arabidopsis thaliana, but little is known about their physiological functions and molecular mechanisms in maize (Zea mays. In this study, we investigated the physiological functions of ZmPIF4 and ZmPIF5, two highly conserved members of the PIF gene family. RT-qPCR and western blot analyses revealed that ZmPIF4 and ZmPIF5 expression and ZmPIF4 and ZmPIF5 levels peak at night and remain low during the day. Overexpression of ZmPIF4 and ZmPIF5 in Arabidopsis partially rescued the reduced hypocotyl elongation and defective response to gravity in pif1 pif3 pif4 pif5 quadruple mutants (pifq. In addition, under high red: far-red light conditions, Arabidopsis lines overexpressing ZmPIF4 exhibited a constitutive shade avoidance response, including early flowering, slender leaves and inflorescences, plant lodging and precocious leaf senescence. Furthermore, ZmPIF4 physically interacted with the Arabidopsis DELLA protein REPRESSOR OF GA1-3 (RGA, indicating a potential interaction between ZmPIF4 and gibberellin signaling pathway on plant growth. Taken together, our results revealed that ZmPIF4 and ZmPIF5 are functionally conserved proteins that may play conserved roles in the response to phytochrome signaling in plants.Highlights:In this study, the functions of ZmPIF4 and ZmPIF5 were characterized by expression in Arabidopsis, revealing conserved roles of PIF family proteins in photomorphogenesis and the shade avoidance response in land plants.

  14. Crepuscular flight activity of an invasive insect governed by interacting abiotic factors.

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    Yigen Chen

    Full Text Available Seasonal and diurnal flight patterns of the invasive walnut twig beetle, Pityophthorus juglandis, were assessed between 2011 and 2014 in northern California, USA in the context of the effects of ambient temperature, light intensity, wind speed, and barometric pressure. Pityophthorus juglandis generally initiated flight in late January and continued until late November. This seasonal flight could be divided approximately into three phases (emergence: January-March; primary flight: May-July; and secondary flight: September-October. The seasonal flight response to the male-produced aggregation pheromone was consistently female-biased (mean of 58.9% females. Diurnal flight followed a bimodal pattern with a minor peak in mid-morning and a major peak at dusk (76.4% caught between 1800 and 2200 h. The primarily crepuscular flight activity had a Gaussian relationship with ambient temperature and barometric pressure but a negative exponential relationship with increasing light intensity and wind speed. A model selection procedure indicated that the four abiotic factors collectively and interactively governed P. juglandis diurnal flight. For both sexes, flight peaked under the following second-order interactions among the factors when: 1 temperature between was 25 and 30 °C and light intensity was less than 2000 lux; 2 temperature was between 25 and 35 °C and barometric pressure was between 752 and 762 mba (and declined otherwise; 3 barometric pressure was between 755 and 761 mba and light intensity was less than 2000 lux (and declined otherwise; and 4 temperature was ca. 30 °C and wind speed was ca. 2 km/h. Thus, crepuscular flight activity of this insect can be best explained by the coincidence of moderately high temperature, low light intensity, moderate wind speed, and low to moderate barometric pressure. The new knowledge provides physical and temporal guidelines for the application of semiochemical-based control techniques as part of an IPM

  15. Transition Form Factors: A Unique Opportunity to Connect Non-Perturbative Strong Interactions to QCD

    Energy Technology Data Exchange (ETDEWEB)

    Gothe, Ralf W. [University of South Carolina, Columbia, SC (United States)

    2014-01-01

    Meson-photoproduction measurements and their reaction-amplitude analyses can establish more sensitively, and in some cases in an almost model-independent way, nucleon excitations and non-resonant reaction amplitudes. However, to investigate the strong interaction from explored — where meson-cloud degrees of freedom contribute substantially to the baryon structure — to still unexplored distance scales — where quark degrees of freedom dominate and the transition from dressed to current quarks occurs — we depend on experiments that allow us to measure observables that are probing this evolving non-perturbative QCD regime over its full range. Elastic and transition form factors are uniquely suited to trace this evolution by measuring elastic electron scattering and exclusive single-meson and double-pion electroproduction cross sections off the nucleon. These exclusive measurements will be extended to higher momentum transfers with the energy-upgraded CEBAF beam at JLab to study the quark degrees of freedom, where their strong interaction is responsible for the ground and excited nucleon state formations. After establishing unprecedented high-precision data, the imminent next challenge is a high-quality analysis to extract these relevant electrocoupling parameters for various resonances that then can be compared to state-of-the-art models and QCD-based calculations. Recent results will demonstrate the status of the analysis and of their theoretical descriptions, and an experimental and theoretical outlook will highlight what shall and may be achieved in the new era of the 12-GeV upgraded transition form factor program.

  16. Genetic interactions between Brn3 transcription factors in retinal ganglion cell type specification.

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    Melody Shi

    Full Text Available Visual information is conveyed from the retina to the brain via 15-20 Retinal Ganglion Cell (RGC types. The developmental mechanisms by which RGC types acquire their distinct molecular, morphological, physiological and circuit properties are essentially unknown, but may involve combinatorial transcriptional regulation. Brn3 transcription factors are expressed in RGCs from early developmental stages, and are restricted in adults to distinct, partially overlapping populations of RGC types. Previously, we described cell autonomous effects of Brn3b (Pou4f2 and Brn3a (Pou4f1 on RGC axon and dendrites development.We now have investigated genetic interactions between Brn3 transcription factors with respect to RGC development, by crossing conventional knock-out alleles of each Brn3 gene with conditional knock-in reporter alleles of a second Brn3 gene, and analyzing the effects of single or double Brn3 knockouts on RGC survival and morphology. We find that Brn3b loss results in axon defects and dendritic arbor area and lamination defects in Brn3a positive RGCs, and selectively affects survival and morphology of specific Brn3c (Pou4f3 positive RGC types. Brn3a and Brn3b interact synergistically to control RGC numbers. Melanopsin positive ipRGCs are resistant to combined Brn3 loss but are under the transcriptional control of Isl1, expanding the combinatorial code of RGC specification.Taken together these results complete our knowledge on the mechanisms of transcriptional control of RGC type specification. They demonstrate that Brn3b is required for the correct development of more RGC cell types than suggested by its expression pattern in the adult, but that several cell types, including some Brn3a, Brn3c or Melanopsin positive RGCs are Brn3b independent.

  17. Expression analysis of transcription factors from the interaction between cacao and Moniliophthora perniciosa (Tricholomataceae).

    Science.gov (United States)

    Lopes, M A; Hora, B T; Dias, C V; Santos, G C; Gramacho, K P; Cascardo, J C M; Gesteira, A S; Micheli, F

    2010-07-06

    Cacao (Theobroma cacao) is one of the most important tropical crops; however, production is threatened by numerous pathogens, including the hemibiotrophic fungus Moniliophthora perniciosa, which causes witches' broom disease. To understand the mechanisms that lead to the development of this disease in cacao, we focused our attention on cacao transcription factors (TFs), which act as master regulators of cellular processes and are important for the fine-tuning of plant defense responses. We developed a macroarray with 88 TF cDNA from previously obtained cacao-M. perniciosa interaction libraries. Seventy-two TFs were found differentially expressed between the susceptible (Catongo) and resistant (TSH1188) genotypes and/or during the disease time course--from 24 h to 30 days after infection. Most of the differentially expressed TFs belonged to the bZIP, MYB and WRKY families and presented opposite expression patterns in susceptible and resistant cacao-M. perniciosa interactions (i.e., up-regulated in Catongo and down-regulated in TSH1188). The results of the macroarray were confirmed for bZIP and WRKY TFs by real-time PCR. These differentially expressed TFs are good candidates for subsequent functional analysis as well as for plant engineering. Some of these TFs could also be localized on the cacao reference map related to witches' broom resistance, facilitating the breeding and selection of resistant cacao trees.

  18. UTOPIAN: user-driven topic modeling based on interactive nonnegative matrix factorization.

    Science.gov (United States)

    Choo, Jaegul; Lee, Changhyun; Reddy, Chandan K; Park, Haesun

    2013-12-01

    Topic modeling has been widely used for analyzing text document collections. Recently, there have been significant advancements in various topic modeling techniques, particularly in the form of probabilistic graphical modeling. State-of-the-art techniques such as Latent Dirichlet Allocation (LDA) have been successfully applied in visual text analytics. However, most of the widely-used methods based on probabilistic modeling have drawbacks in terms of consistency from multiple runs and empirical convergence. Furthermore, due to the complicatedness in the formulation and the algorithm, LDA cannot easily incorporate various types of user feedback. To tackle this problem, we propose a reliable and flexible visual analytics system for topic modeling called UTOPIAN (User-driven Topic modeling based on Interactive Nonnegative Matrix Factorization). Centered around its semi-supervised formulation, UTOPIAN enables users to interact with the topic modeling method and steer the result in a user-driven manner. We demonstrate the capability of UTOPIAN via several usage scenarios with real-world document corpuses such as InfoVis/VAST paper data set and product review data sets.

  19. DNA homologous recombination factor SFR1 physically and functionally interacts with estrogen receptor alpha.

    Directory of Open Access Journals (Sweden)

    Yuxin Feng

    Full Text Available Estrogen receptor alpha (ERα, a ligand-dependent transcription factor, mediates the expression of its target genes by interacting with corepressors and coactivators. Since the first cloning of SRC1, more than 280 nuclear receptor cofactors have been identified, which orchestrate target gene transcription. Aberrant activity of ER or its accessory proteins results in a number of diseases including breast cancer. Here we identified SFR1, a protein involved in DNA homologous recombination, as a novel binding partner of ERα. Initially isolated in a yeast two-hybrid screen, the interaction of SFR1 and ERα was confirmed in vivo by immunoprecipitation and mammalian one-hybrid assays. SFR1 co-localized with ERα in the nucleus, potentiated ER's ligand-dependent and ligand-independent transcriptional activity, and occupied the ER binding sites of its target gene promoters. Knockdown of SFR1 diminished ER's transcriptional activity. Manipulating SFR1 expression by knockdown and overexpression revealed a role for SFR1 in ER-dependent and -independent cancer cell proliferation. SFR1 differs from SRC1 by the lack of an intrinsic activation function. Taken together, we propose that SFR1 is a novel transcriptional modulator for ERα and a potential target in breast cancer therapy.

  20. Arabidopsis WRKY38 and WRKY62 transcription factors interact with histone deacetylase 19 in basal defense.

    Science.gov (United States)

    Kim, Kang-Chang; Lai, Zhibing; Fan, Baofang; Chen, Zhixiang

    2008-09-01

    Arabidopsis thaliana WRKY38 and WRKY62, encoding two structurally similar type III WRKY transcription factors, are induced in a Nonexpressor of PR Gene1 (NPR1)-dependent manner by salicylic acid (SA) or by virulent Pseudomonas syringae. Disease resistance and SA-regulated Pathogenesis-Related1 (PR1) gene expression are enhanced in the wrky38 and wrky62 single mutants and, to a greater extent, in the double mutants. Overexpression of WRKY38 or WRKY62 reduces disease resistance and PR1 expression. Thus, WRKY38 and WRKY62 function additively as negative regulators of plant basal defense. WRKY38 and WRKY62 interact with Histone Deacetylase 19 (HDA19). Expression of HDA19 is also induced by P. syringae, and the stability of its induced transcripts depends on SA and NPR1 in infected plants. Disruption of HDA19 leads to compromised resistance, whereas its overexpression results in enhanced resistance to P. syringae. Thus, HDA19 has a role opposite from those of WRKY38 and WRKY62 in basal resistance to the bacterial pathogen. Both WRKY38 and WRKY62 are transcriptional activators in plant cells, but their activation activities are abolished by overexpressed HDA19. Interaction of WRKY38 and WRKY62 with HDA19 may act to fine-tune plant basal defense responses.

  1. Implementation of Biophysical Factors Into the Land Surface and Atmosphere Interaction Model

    Science.gov (United States)

    Hong, S.; Lakshmi, V.; Small, E. E.; Chen, F.

    2006-12-01

    We test the NOAH land surface model implemented into the weather research and forecasting model (WRF) by simulating surface skin temperature, vegetation fraction, and evapotranspiration in order to improve the model simulation. This study has two major questions: 1) Is the model simulation reliable with respect to real- time land surface variation and 2) what improvements from satellite remote sensing can be implemented or parameterized into the model simulations. The relationship between skin temperature and vegetation fraction impacts the variation of evapotranpiration, which is influenced by moisture availability on the surface and vice versa. The skin surface temperature varies with vegetation amount, land cover type, precipitation, topography, soil type and texture. Complex interactions between them determine the relationship between skin temperature and vegetation fraction and hence the evapotranspiration. Of the factors that influence the land surface-atmosphere interactions, water content in vegetation is investigated to examine the possibility of the model improvement. Vegetation water content, which is differently controlled by vegetation types, varies with land cover type as well as with the moisture conditions on the land surface. Oklahoma in the central U.S. is selected as the study area because it shows large variations of vegetation, from bare soil to fully vegetated, and of surface temperature during rainy seasons. The simulated variables are compared to the MODIS satellite data and the Mesonet ground-based observations. The model simulation is calibrated based on the real surface conditions provided by Mesonet observation data.

  2. FLIM-FRET microscopy to visualize transcription factor interactions in the nucleus of the living cell

    Science.gov (United States)

    Day, Richard N.; Demarco, Ignacio A.; Voss, Ty C.; Chen, Ye; Periasamy, Ammasi

    2004-06-01

    Wide-field fluorescence microscopy was used to monitor the co-localization of the homeodomain (HD) transcription factor Pit-1 and the basic-leucine zipper protein CCAAT/enhancer binding protein alpha (C/EBPa), each labeled with fluorescent proteins (FP) in the living cell nucleus. Fluorescence resonance energy transfer (FRET) microscopy was used to resolve the angstrom-scale spatial relationships of these expressed proteins, and the effect of a Pit-1 point mutation on the interaction with C/EBPa was characterized. Two-photon excitation fluorescence lifetime imaging microscopy (2p-FLIM) was then used as an independent method to detect these protein interactions. The excited-state lifetime for the cyan FP (CFP) labeling C/EBPa was determined, and the measurements were repeated in cells co-expressing yellow FP (YFP) labeled-proteins. The CFP lifetime was decreased in the presence of the YFP acceptor, which is consistent with donor quenching by FRET. This was verified by acceptor photobleaching, which caused a shift in the donor lifetime to that similar to the donor alone. However, a significant limitation of this technique was demonstrated by the observation that high-energy 2p-excitation resulted in CFP photobleaching and a parallel decrease in its excited-state lifetime. The key question is whether the sensitivity of this imaging approach will be sufficient to acquire significant data from living cells expressing physiological levels of the labeled proteins.

  3. Assessment of Multifactor Gene-Environment Interactions and Ovarian Cancer Risk: Candidate Genes, Obesity, and Hormone-Related Risk Factors

    NARCIS (Netherlands)

    Usset, J.L.; Raghavan, R.; Tyrer, J.P.; McGuire, V.; Sieh, W.; Webb, P.; Chang-Claude, J.; Rudolph, A.; Anton-Culver, H.; Berchuck, A.; Brinton, L.; Cunningham, J.M.; Defazio, A.; Doherty, J.A.; Edwards, R.P.; Gayther, S.A.; Gentry-Maharaj, A.; Goodman, M.T.; Hogdall, E.; Jensen, A.; Johnatty, S.E.; Kiemeney, L.A.L.M.; Kjaer, S.K.; Larson, M.C.; Lurie, G.; Massuger, L.F.; Menon, U.; Modugno, F.; Moysich, K.B.; Ness, R.B.; Pike, M.C.; Ramus, S.J.; Rossing, M.A.; Rothstein, J.; Song, H.; Thompson, P.J.; Berg, D.J. Van Den; Vierkant, R.A.; Wang-Gohrke, S.; Wentzensen, N.; Whittemore, A.S.; Wilkens, L.R.; Wu, A.H.; Yang, H.; Pearce, C.L.; Schildkraut, J.M.; Pharoah, P.; Goode, E.L.; Fridley, B.L.

    2016-01-01

    BACKGROUND: Many epithelial ovarian cancer (EOC) risk factors relate to hormone exposure and elevated estrogen levels are associated with obesity in postmenopausal women. Therefore, we hypothesized that gene-environment interactions related to hormone-related risk factors could differ between obese

  4. Lunar-Mars Life Support Test Project. Phase 2; Human Factors and Crew Interactions

    Science.gov (United States)

    Ming, D. W.; Hurlbert, K. M.; Kirby, G.; Lewis, J. F.; ORear, P.

    1997-01-01

    Phase 2 of the Lunar-Mars Life Support Test Project was conducted in June and July of 1996 at the NASA Johnson Space Center. The primary objective of Phase 2 was to demonstrate and evaluate an integrated physicochemical air revitalization and regenerative water recovery system capable of sustaining a human crew of four for 30 days inside a closed chamber. The crew (3 males and 1 female) was continuously present inside a chamber throughout the 30-day test. The objective of this paper was to describe crew interactions and human factors for the test. Crew preparations for the test included training and familiarization of chamber systems and accommodations, and medical and psychological evaluations. During the test, crew members provided metabolic loads for the life support systems, performed maintenance on chamber systems, and evaluated human factors inside the chamber. Overall, the four crew members found the chamber to be comfortable for the 30-day test. The crew performed well together and this was attributed in part to team dynamics, skill mix (one commander, two system experts, and one logistics lead), and a complementary mix of personalities. Communication with and support by family, friends, and colleagues were identified as important contributors to the high morale of the crew during the test. Lessons learned and recommendations for future testing are presented by the crew in this paper.

  5. Factors affecting virus dynamics and microbial host-virus interactions in marine environments.

    Science.gov (United States)

    Mojica, Kristina D A; Brussaard, Corina P D

    2014-09-01

    Marine microorganisms constitute the largest percentage of living biomass and serve as the major driving force behind nutrient and energy cycles. While viruses only comprise a small percentage of this biomass (i.e., 5%), they dominate in numerical abundance and genetic diversity. Through host infection and mortality, viruses affect microbial population dynamics, community composition, genetic evolution, and biogeochemical cycling. However, the field of marine viral ecology is currently limited by a lack of data regarding how different environmental factors regulate virus dynamics and host-virus interactions. The goal of the present minireview was to contribute to the evolution of marine viral ecology, through the assimilation of available data regarding the manner and degree to which environmental factors affect viral decay and infectivity as well as influence latent period and production. Considering the ecological importance of viruses in the marine ecosystem and the increasing pressure from anthropogenic activity and global climate change on marine systems, a synthesis of existing information provides a timely framework for future research initiatives in viral ecology. © 2014 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.

  6. Regional factors interact with educational and income tax levels to influence food intake in France.

    Science.gov (United States)

    Wyndels, K; Dallongeville, J; Simon, C; Bongard, V; Wagner, A; Ruidavets, J-B; Arveiler, D; Ferrières, J; Amouyel, P; Dauchet, L

    2011-09-01

    The goal of the present study was to assess whether geographic factors affect the relationship between socioeconomic indicators and adherence to the French National Nutritional Health Programme (Programme National Nutrition Santé (PNNS)) guidelines. The MONA LISA-NUT study (2005-2007) is a cross-sectional survey of a representative sample from northern, northeastern and southwestern France. Educational level and household income tax were recorded by trained interviewers. Food intake was assessed with a 3-day food diary in 3188 subjects aged from 35-64 years. Adherence to the PNNS guidelines was assessed with a validated score (the French score of indicators of the PNNS objective (FSIPO)). Multivariate analyses were adjusted for gender, age, marital status, body mass index, energy intake and medically prescribed diets. The FSIPO score was higher in southwestern France than in the two other regions (Peducational level in northern and northeastern France (Peducation interaction: Peducational level and adherence to the national nutritional health guidelines differs from one region of France to another, suggesting that nutrition education programmes should perhaps be adapted on a regional basis. In contrast, guideline adherence is correlated with income tax level independently of geographical factors, suggesting that financial constraints on food choices are uniform across France.

  7. Imitative and Direct Learning as Interacting Factors in Life History Evolution.

    Science.gov (United States)

    Bullinaria, John A

    2017-01-01

    The idea that lifetime learning can have a significant effect on life history evolution has recently been explored using a series of artificial life simulations. These involved populations of competing individuals evolving by natural selection to learn to perform well on simplified abstract tasks, with the learning consisting of identifying regularities in their environment. In reality, there is more to learning than that type of direct individual experience, because it often includes a substantial degree of social learning that involves various forms of imitation of what other individuals have learned before them. This article rectifies that omission by incorporating memes and imitative learning into revised versions of the previous approach. To do this reliably requires formulating and testing a general framework for meme-based simulations that will enable more complete investigations of learning as a factor in any life history evolution scenarios. It does that by simulating imitative information transfer in terms of memes being passed between individuals, and developing a process for merging that information with the (possibly inconsistent) information acquired by direct experience, leading to a consistent overall body of learning. The proposed framework is tested on a range of learning variations and a representative set of life history factors to confirm the robustness of the approach. The simulations presented illustrate the types of interactions and tradeoffs that can emerge, and indicate the kinds of species-specific models that could be developed with this approach in the future.

  8. Factors influencing streambed hydraulic conductivity and their implications on stream-aquifer interaction: a conceptual review.

    Science.gov (United States)

    Naganna, Sujay Raghavendra; Deka, Paresh Chandra; Ch, Sudheer; Hansen, William F

    2017-11-01

    The estimation and modeling of streambed hydraulic conductivity (K) is an emerging interest due to its connection to water quality, aquatic habitat, and groundwater recharge. Existing research has found ways to sample and measure K at specific sites and with laboratory tests. The challenge undertaken was to review progress, relevance, complexity in understanding and modeling via statistical and geostatistical approaches, literature gaps, and suggestions toward future needs. This article provides an overview of factors and processes influencing streambed hydraulic conductivity (K) and its role in the stream-aquifer interaction. During our synthesis, we discuss the influence of geological, hydrological, biological, and anthropogenic factors that lead to variability of streambed substrates. Literature examples document findings to specific sites that help to portray the role of streambed K and other interrelated factors in the modeling of hyporheic and groundwater flow systems. However, studies utilizing an integrated, comprehensive database are limited, restricting the ability of broader application and understanding. Examples of in situ and laboratory methods of estimating hydraulic conductivity suggest challenges in acquiring representative samples and comparing results, considering the anisotropy and heterogeneity of fluvial bed materials and geohydrological conditions. Arriving at realistic statistical and spatial inference based on field and lab data collected is challenging, considering the possible sediment sources, processes, and complexity. Recognizing that the K for a given particle size group includes several to many orders of magnitude, modeling of streambed K and groundwater interaction remain conceptual and experimental. Advanced geostatistical techniques offer a wide range of univariate or multi-variate interpolation procedures such as kriging and variogram analysis that can be applied to these complex systems. Research available from various studies

  9. Interaction between Corneal and Internal Ocular Aberrations Induced by Orthokeratology and Its Influential Factors

    Science.gov (United States)

    Chen, Qingzhong; Me, Rao; Yu, Yunjie; Shi, Guangsen

    2017-01-01

    Purpose To investigate the interaction between corneal, internal, and total wavefront aberrations (WAs) and their influential factors during orthokeratology (OK) treatment in Chinese adolescents. Methods Thirty teenagers (n = 30 eyes) were enrolled in the study; spherical equivalent refraction (SE), corneal curvature radius (CCR), central corneal thickness (CCT), WAs, and the difference in limbal transverse diameter and OK lens diameter (ΔLLD) were detected before and after one-month OK treatment. Every component of WAs was measured simultaneously by iTrace aberrometer. The influential factors of OK-induced WAs were analyzed. Results SE and CCT decreased while CCR increased significantly (P < 0.01). Higher-order aberrations (HOAs), Spherical aberrations (SAs), and coma increased significantly (P < 0.01). Corneal horizontal coma (Z31-C) and corneal spherical aberrations (Z40-C) increased (P < 0.01). The HOAs, coma, SAs, Z31-C, Z31-T, Z40-C, and Z40-T were positively correlated with SE and CCR (P < 0.01). Z3−1-C showed negative correlations with (ΔLLD) and positive correlations with SE (P < 0.05). Conclusions The increase in OK-induced HOAs is mainly attributed to Z31 and Z40 of cornea. Z3−1 in the internal component showed a compensative effect on the corneal vertical coma. The degree of myopic correction and increase in CCR may be the essential influential factors of the increase in Z31 and Z40. The appropriate size of the OK lens may be helpful to decrease OK-induced vertical coma. PMID:28845432

  10. Regulation of vascular endothelial growth factor expression by homeodomain-interacting protein kinase-2

    Directory of Open Access Journals (Sweden)

    D'Orazi Gabriella

    2008-07-01

    Full Text Available Abstract Background Homeodomain-interacting protein kinase-2 (HIPK2 plays an essential role in restraining tumor progression as it may regulate, by itself or within multiprotein complexes, many proteins (mainly transcription factors involved in cell growth and apoptosis. This study takes advantage of the recent finding that HIPK2 may repress the β-catenin transcription activity. Thus, we investigated whether HIPK2 overexpression may down-regulate vascular endothelial growth factor (VEGF levels (a β-catenin target gene and the role of β-catenin in this regulation, in order to consider HIPK2 as a tool for novel anti-tumoral therapeutical approaches. Methods The regulation of VEGF expression by HIPK2 was evaluated by using luciferase assay with VEGF reporter construct, after overexpression of the β-catenin transcription factor. Relative quantification of VEGF and β-catenin mRNAs were assessed by reverse-transcriptase-PCR (RT-PCR analyses, following HIPK2 overexpression, while β-catenin protein levels were evaluated by western immunoblotting. Results HIPK2 overexpression in tumor cells downregulated VEGF mRNA levels and VEGF promoter activity. The VEGF downregulation was partly depending on HIPK2-mediated β-catenin regulation. Thus, HIPK2 could induce β-catenin protein degradation that was prevented by cell treatment with proteasome inhibitor MG132. The β-catenin degradation was dependent on HIPK2 catalytic activity and independent of p53 and glycogen synthase kinase 3β (GSK-3β activities. Conclusion These results suggest that VEGF might be a target of HIPK2, at least in part, through regulation of β-catenin activity. These findings support the function of HIPK2 as tumor suppressor and hypothesise a role for HIPK2 as antiangiogenic tool in tumor therapy approaches.

  11. Bed sharing among black infants and sudden infant death syndrome: interactions with other known risk factors.

    Science.gov (United States)

    Fu, Linda Y; Moon, Rachel Y; Hauck, Fern R

    2010-01-01

    Bed sharing has been associated with sudden infant death syndrome (SIDS) and may contribute to the racial disparity seen in infant mortality. It is unclear how bed sharing interacts with other factors to impact SIDS risk. We aimed to measure the effects of bed sharing on risk of SIDS in blacks and to determine whether the risk is modified by other characteristics of the sleep environment. Characteristics of 195 black infants who died of SIDS were compared with matched controls. The moderating influence of known SIDS risk factors on the effect of bed sharing on risk of SIDS was examined using logistic regression. Almost half (47.4%) of the study population bed shared during the last/reference sleep (58% cases and 37% controls). Bed sharing was associated with 2 times greater risk of SIDS compared with not bed sharing. The deleterious effect of bed sharing was more pronounced with a soft sleep surface, pillow use, maternal smoking, and younger infant age. However, bed sharing was still associated with an increased risk of SIDS, even when the infant was not using a pillow or sleeping on a firm surface. The strongest predictors of SIDS among bed-sharing infants were soft sleep surface, nonuse of a pacifier, and maternal smoking during pregnancy. Bed sharing is a common practice among black infants. It is associated with a clear and strong increased risk of SIDS, which is even greater when combined with other known risk factors for SIDS. This practice likely contributes to the excess incidence of SIDS among blacks, and culturally competent education methods must be developed to target this high-risk group. Copyright © 2010 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.

  12. INTERACT

    DEFF Research Database (Denmark)

    Jochum, Elizabeth; Borggreen, Gunhild; Murphey, TD

    interaction between a human operator and an artificial actor or agent. We can apply insights from puppetry to develop culturally-aware robots. Here we describe the development of a robotic marionette theatre wherein robotic controllers assume the role of human puppeteers. The system has been built, tested...... including puppetry and dance. However, the aesthetics of these traditions vary across cultures and carry different associative and interpretive meanings. Puppetry offers a useful frame for understanding the relationship between abstract and imitative gestures and behavior, and instantiates the complex...

  13. Decrease of hemostatic cardiovascular risk factors by aggressive vs. conventional atorvastatin treatment in patients with Type 2 diabetes mellitus.

    NARCIS (Netherlands)

    Ree, M.A. van de; Maat, M.P. de; Kluft, C.; Meinders, A.E.; Princen, H.M.; Huisman, M.V.

    2003-01-01

    BACKGROUND: Patients with Type 2 diabetes mellitus have increased levels of hemostatic risk variables for cardiovascular disease, such as fibrinogen, von Willebrand factor (VWF), factor (F)VIIa, d-dimer and plasminogen activator inhibitor-1 (PAI-1). OBJECTIVES: To evaluate the effect of aggressive

  14. Vascular endothelial growth factor receptor-3 directly interacts with phosphatidylinositol 3-kinase to regulate lymphangiogenesis.

    Science.gov (United States)

    Coso, Sanja; Zeng, Yiping; Opeskin, Kenneth; Williams, Elizabeth D

    2012-01-01

    Dysfunctional lymphatic vessel formation has been implicated in a number of pathological conditions including cancer metastasis, lymphedema, and impaired wound healing. The vascular endothelial growth factor (VEGF) family is a major regulator of lymphatic endothelial cell (LEC) function and lymphangiogenesis. Indeed, dissemination of malignant cells into the regional lymph nodes, a common occurrence in many cancers, is stimulated by VEGF family members. This effect is generally considered to be mediated via VEGFR-2 and VEGFR-3. However, the role of specific receptors and their downstream signaling pathways is not well understood. Here we delineate the VEGF-C/VEGF receptor (VEGFR)-3 signaling pathway in LECs and show that VEGF-C induces activation of PI3K/Akt and MEK/Erk. Furthermore, activation of PI3K/Akt by VEGF-C/VEGFR-3 resulted in phosphorylation of P70S6K, eNOS, PLCγ1, and Erk1/2. Importantly, a direct interaction between PI3K and VEGFR-3 in LECs was demonstrated both in vitro and in clinical cancer specimens. This interaction was strongly associated with the presence of lymph node metastases in primary small cell carcinoma of the lung in clinical specimens. Blocking PI3K activity abolished VEGF-C-stimulated LEC tube formation and migration. Our findings demonstrate that specific VEGFR-3 signaling pathways are activated in LECs by VEGF-C. The importance of PI3K in VEGF-C/VEGFR-3-mediated lymphangiogenesis provides a potential therapeutic target for the inhibition of lymphatic metastasis.

  15. Vascular endothelial growth factor receptor-3 directly interacts with phosphatidylinositol 3-kinase to regulate lymphangiogenesis.

    Directory of Open Access Journals (Sweden)

    Sanja Coso

    Full Text Available BACKGROUND: Dysfunctional lymphatic vessel formation has been implicated in a number of pathological conditions including cancer metastasis, lymphedema, and impaired wound healing. The vascular endothelial growth factor (VEGF family is a major regulator of lymphatic endothelial cell (LEC function and lymphangiogenesis. Indeed, dissemination of malignant cells into the regional lymph nodes, a common occurrence in many cancers, is stimulated by VEGF family members. This effect is generally considered to be mediated via VEGFR-2 and VEGFR-3. However, the role of specific receptors and their downstream signaling pathways is not well understood. METHODS AND RESULTS: Here we delineate the VEGF-C/VEGF receptor (VEGFR-3 signaling pathway in LECs and show that VEGF-C induces activation of PI3K/Akt and MEK/Erk. Furthermore, activation of PI3K/Akt by VEGF-C/VEGFR-3 resulted in phosphorylation of P70S6K, eNOS, PLCγ1, and Erk1/2. Importantly, a direct interaction between PI3K and VEGFR-3 in LECs was demonstrated both in vitro and in clinical cancer specimens. This interaction was strongly associated with the presence of lymph node metastases in primary small cell carcinoma of the lung in clinical specimens. Blocking PI3K activity abolished VEGF-C-stimulated LEC tube formation and migration. CONCLUSIONS: Our findings demonstrate that specific VEGFR-3 signaling pathways are activated in LECs by VEGF-C. The importance of PI3K in VEGF-C/VEGFR-3-mediated lymphangiogenesis provides a potential therapeutic target for the inhibition of lymphatic metastasis.

  16. Contextual and individual predictors of physical activity: Interactions between environmental factors and health cognitions.

    Science.gov (United States)

    Schüz, Benjamin; Wurm, Susanne; Ziegelmann, Jochen P; Wolff, Julia K; Warner, Lisa M; Schwarzer, Ralf; Tesch-Römer, Clemens

    2012-11-01

    Although health behavior theories assume a role of the context in health behavior self-regulation, this role is often weakly specified and rarely examined. The two studies in this article test whether properties of the environment (districts) affect if and how health-related cognitions are translated into physical activity. Multilevel modeling was used to examine the assumed cross-level interactions. Study 1 is a large-scale survey representative of the German adult population (N = 6,201). Gross domestic product (GDP) on the level of administrative districts was used to indicate environmental opportunities and barriers. Study 2 examined cross-level interactions of proximal predictors of physical activity (intentions, action planning, and coping planning) in older adults with multiple illnesses (N = 309), a high-risk group for health deteriorations. Study 1 showed that on the individual level, health attitudes (B = .11) and education (B = .71) were significantly associated with physical activity. GDP moderated the attitudes-behavior relation (B = .01), with higher attitude-behavior relations in districts with higher GDP. Study 2 finds that intention (B = .16), action planning (B = .17), and coping planning (B = .13) significantly predict activity. In addition, district-level GDP significantly moderated the relations between action planning and coping planning, but not intention, on physical activity. Results suggest that the effects of health attitudes and planning on physical activity are moderated by environmental factors. Districts with higher GDP provide better contextual opportunities for the enactment of concrete if-then plans for physical activity. This has implications for both theory and health promotion.

  17. Factor solutions of the Social Phobia Scale (SPS) and the Social Interaction Anxiety Scale (SIAS) in a Swedish population.

    Science.gov (United States)

    Mörtberg, Ewa; Reuterskiöld, Lena; Tillfors, Maria; Furmark, Tomas; Öst, Lars-Göran

    2017-06-01

    Culturally validated rating scales for social anxiety disorder (SAD) are of significant importance when screening for the disorder, as well as for evaluating treatment efficacy. This study examined construct validity and additional psychometric properties of two commonly used scales, the Social Phobia Scale and the Social Interaction Anxiety Scale, in a clinical SAD population (n = 180) and in a normal population (n = 614) in Sweden. Confirmatory factor analyses of previously reported factor solutions were tested but did not reveal acceptable fit. Exploratory factor analyses (EFA) of the joint structure of the scales in the total population yielded a two-factor model (performance anxiety and social interaction anxiety), whereas EFA in the clinical sample revealed a three-factor solution, a social interaction anxiety factor and two performance anxiety factors. The SPS and SIAS showed good to excellent internal consistency, and discriminated well between patients with SAD and a normal population sample. Both scales showed good convergent validity with an established measure of SAD, whereas the discriminant validity of symptoms of social anxiety and depression could not be confirmed. The optimal cut-off score for SPS and SIAS were 18 and 22 points, respectively. It is concluded that the factor structure and the additional psychometric properties of SPS and SIAS support the use of the scales for assessment in a Swedish population.

  18. Extracellular superoxide dismutase inhibits hepatocyte growth factor-mediated breast cancer-fibroblast interactions.

    Science.gov (United States)

    Golden, Briana Ormsbee; Griess, Brandon; Mir, Shakeel; Fitzgerald, Matthew; Kuperwasser, Charlotte; Domann, Frederick; Teoh-Fitzgerald, Melissa

    2017-12-08

    We have previously shown tumor suppressive effects of extracellular superoxide dismutase, EcSOD in breast cancer cells. In this study, an RTK signaling array revealed an inhibitory effect of EcSOD on c-Met phosphorylation and its downstream kinase c-Abl in MDA-MB231 cells. Moreover, an extracellular protein array showed that thrombospondin 1 (TSP-1), a scavenger of the c-Met ligand, hepatocyte growth factor (HGF) is significantly up-regulated in EcSOD overexpressing cells (Ec.20). We further determined the effects of EcSOD on HGF/c-Met-mediated cancer-fibroblast interactions by co-culturing normal fibroblasts (RMF) or RMF which overexpresses HGF (RMF-HGF) with MDA-MB231 cells. We observed that while RMF-HGF significantly promoted Matrigel growth of MDA-MB231, overexpression of EcSOD inhibited the HGF-stimulated growth. Similarly, a SOD mimetic, MnTE-2-PyP, inhibited HGF-induced growth and invasion of MDA-MB231. In addition, a long-term heterotypic co-culture study not only showed that Ec.20 cells are resistant to RMF-HGF-induced invasive stimulation but RMF-HGF that were co-cultured with Ec.20 cells showed an attenuated phenotype, suggesting an oxidative-mediated reciprocal interaction between the two cell types. In addition, we demonstrated that RMF-HGF showed an up-regulation of an ROS-generating enzyme, NADPH oxidase 4 (Nox4). Targeting this pro-oxidant significantly suppressed the activated phenotype of RMF-HGF in a collagen contraction assay, suggesting that RMF-HGF contributes to the oxidative tumor microenvironment. We have further shown that scavenging ROS with EcSOD significantly inhibited RMF-HGF-stimulated orthotopic tumor growth of MDA-MB231. This study suggests the loss of EcSOD in breast cancer plays a pivotal role in promoting the HGF/c-Met-mediated cancer-fibroblast interactions.

  19. Cannabis exposure as an interactive cardiovascular risk factor and accelerant of organismal ageing: a longitudinal study.

    Science.gov (United States)

    Reece, Albert Stuart; Norman, Amanda; Hulse, Gary Kenneth

    2016-11-07

    Many reports exist of the cardiovascular toxicity of smoked cannabis but none of arterial stiffness measures or vascular age (VA). In view of its diverse toxicology, the possibility that cannabis-exposed patients may be ageing more quickly requires investigation. Cross-sectional and longitudinal, observational. Prospective. Single primary care addiction clinic in Brisbane, Australia. 11 cannabis-only smokers, 504 tobacco-only smokers, 114 tobacco and cannabis smokers and 534 non-smokers. known cardiovascular disease or therapy or acute exposure to alcohol, amphetamine, heroin or methadone. Radial arterial pulse wave tonometry (AtCor, SphygmoCor, Sydney) performed opportunistically and sequentially on patients between 2006 and 2011. Algorithmically calculated VA. other central haemodynamic variables. Differences between group chronological ages (CA, 30.47±0.48 to 40.36±2.44, mean±SEM) were controlled with linear regression. Between-group sex differences were controlled by single-sex analysis. Mean cannabis exposure among patients was 37.67±7.16 g-years. In regression models controlling for CA, Body Mass Index (BMI), time and inhalant group, the effect of cannabis use on VA was significant in males (p=0.0156) and females (p=0.0084). The effect size in males was 11.84%. A dose-response relationship was demonstrated with lifetime exposure (pcannabis was robust to adjustment and was unrelated to its acute effects. Significant power interactions between cannabis exposure and the square and cube of CA were demonstrated (from pCannabis is an interactive cardiovascular risk factor (additional to tobacco and opioids), shows a prominent dose-response effect and is robust to adjustment. Cannabis use is associated with an acceleration of the cardiovascular age, which is a powerful surrogate for the organismal-biological age. This likely underlies and bi-directionally interacts with its diverse toxicological profile and is of considerable public health and regulatory

  20. Physical cell interactions with their surrounding materials: Mechanics and geometrical factors using microfluidic platforms

    Science.gov (United States)

    Lopez Garcia, Maria Del Carmen

    Microfluidics platforms are employed in: "sperm motion in a microfluidic device" and "mechanical interactions of mammary gland cells with their surrounding three dimensional extra-cellular matrix". Microfluidics has shown promise as a new platform for assisted reproduction. Sperm and fluid motion in microchannels was studied to understand the flow characteristics in the device, how sperm interacted with this flow, and how sperm-oocyte attachment occurs in the device. A threshold fluid velocity was found where sperm transition from traveling with the fluid to a regime in which they can move independently. A population of sperm remained in the inlet well area. There was also the tendency of sperm to travel along surface contours. These observations provide an improved understanding of sperm motion in microchannels and a basis for improved device designs. The effort to understand the development of breast cancer motivates the study of mammary gland cells and their interactions with the extra-cellular matrix. Mammographic density is a risk factor for breast cancer which correlates with collagen density affects cell behavior. Collagen gels with concentrations of 1.3, 2, and 3 mg/mL, were tensile tested to obtain the Young's modulus, E, at low displacement rates of 0.01, 0.1, and 1 mm/min. Local strain measurement in the gage section were used for both strain and strain rate determination. Local strain rates were on the order of cellular generated strain rate. A power law fitting described the relationship between Young's modulus and local strain rate. Mammary gland cells were seeded with collagen and fluorescent beads into microchannels and observed via four-dimensional imaging. The displacements of the beads were used to calculate strains. The Young's modulus due to the rate at which the cell was straining the collagen was obtained from the aforementioned fittings. Three-dimensional elastic theory for an isotropic material was employed to calculate the stress. The

  1. STXBP1 promotes Weibel-Palade body exocytosis through its interaction with the Rab27A effector Slp4-a

    NARCIS (Netherlands)

    van Breevoort, Dorothee; Snijders, Ambrosius P.; Hellen, Nicola; Weckhuysen, Sarah; van Hooren, Kathinka W. E. M.; Eikenboom, Jeroen; Valentijn, Karine; Fernandez-Borja, Mar; Ceulemans, Berten; de Jonghe, Peter; Voorberg, Jan; Hannah, Matthew; Carter, Tom; Bierings, Ruben

    2014-01-01

    Vascular endothelial cells contain unique rod-shaped secretory organelles, called Weibel-Palade bodies (WPBs), which contain the hemostatic protein von Willebrand factor (VWF) and a cocktail of angiogenic and inflammatory mediators. We have shown that the Rab27A effector synaptotagmin-like protein

  2. Bacillus anthracis Prolyl 4-Hydroxylase Interacts with and Modifies Elongation Factor Tu

    Energy Technology Data Exchange (ETDEWEB)

    Schnicker, Nicholas J. [Department; Razzaghi, Mortezaali [Department; Guha Thakurta, Sanjukta [Department; Chakravarthy, Srinivas [Biophysics; Dey, Mishtu [Department

    2017-10-17

    Prolyl hydroxylation is a very common post-translational modification and plays many roles in eukaryotes such as collagen stabilization, hypoxia sensing, and controlling protein transcription and translation. There is a growing body of evidence that suggests that prokaryotes contain prolyl 4-hydroxylases (P4Hs) homologous to the hypoxia-inducible factor (HIF) prolyl hydroxylase domain (PHD) enzymes that act on elongation factor Tu (EFTu) and are likely involved in the regulation of bacterial translation. Recent biochemical and structural studies with a PHD from Pseudomonas putida (PPHD) determined that it forms a complex with EFTu and hydroxylates a prolyl residue of EFTu. Moreover, while animal, plant, and viral P4Hs act on peptidyl proline, most prokaryotic P4Hs have been known to target free l-proline; the exceptions include PPHD and a P4H from Bacillus anthracis (BaP4H) that modifies collagen-like proline-rich peptides. Here we use biophysical and mass spectrometric methods to demonstrate that BaP4H recognizes full-length BaEFTu and a BaEFTu 9-mer peptide for site-specific proline hydroxylation. Using size-exclusion chromatography coupled small-angle X-ray scattering (SEC–SAXS) and binding studies, we determined that BaP4H forms a 1:1 heterodimeric complex with BaEFTu. The SEC–SAXS studies reveal dissociation of BaP4H dimeric subunits upon interaction with BaEFTu. While BaP4H is unusual within bacteria in that it is structurally and functionally similar to the animal PHDs and collagen P4Hs, respectively, this work provides further evidence of its promiscuous substrate recognition. It is possible that the enzyme might have evolved to hydroxylate a universally conserved protein in prokaryotes, similar to the PHDs, and implies a functional role in B. anthracis.

  3. Non-muscle myosin II regulates neuronal actin dynamics by interacting with guanine nucleotide exchange factors.

    Directory of Open Access Journals (Sweden)

    Eun-Young Shin

    Full Text Available BACKGROUND: Non-muscle myosin II (NM II regulates a wide range of cellular functions, including neuronal differentiation, which requires precise spatio-temporal activation of Rho GTPases. The molecular mechanism underlying the NM II-mediated activation of Rho GTPases is poorly understood. The present study explored the possibility that NM II regulates neuronal differentiation, particularly morphological changes in growth cones and the distal axon, through guanine nucleotide exchange factors (GEFs of the Dbl family. PRINCIPAL FINDINGS: NM II colocalized with GEFs, such as βPIX, kalirin and intersectin, in growth cones. Inactivation of NM II by blebbistatin (BBS led to the increased formation of short and thick filopodial actin structures at the periphery of growth cones. In line with these observations, FRET analysis revealed enhanced Cdc42 activity in BBS-treated growth cones. BBS treatment also induced aberrant targeting of various GEFs to the distal axon where GEFs were seldom observed under physiological conditions. As a result, numerous protrusions and branches were generated on the shaft of the distal axon. The disruption of the NM II-GEF interactions by overexpression of the DH domains of βPIX or Tiam1, or by βPIX depletion with specific siRNAs inhibited growth cone formation and induced slender axons concomitant with multiple branches in cultured hippocampal neurons. Finally, stimulation with nerve growth factor induced transient dissociation of the NM II-GEF complex, which was closely correlated with the kinetics of Cdc42 and Rac1 activation. CONCLUSION: Our results suggest that NM II maintains proper morphology of neuronal growth cones and the distal axon by regulating actin dynamics through the GEF-Rho GTPase signaling pathway.

  4. Identification and analysis of antinutritional factors in possible interactions between medications and food/nutrients in hospitalized patients

    OpenAIRE

    Adnny Fernanda Lima Campos; Savina Pereira Torres; Everton Moraes Lopes; Rumão Batista Nunes de Carvalho; Rivelilson Mendes de Freitas; Lívio César Cunha Nunes

    2011-01-01

    ABSTRACT Objective: To identify and analyze the presence of antinutritional factors in possible interactions between medications and foods/ nutrients of the diets prescribed for patients of the Hospital Regional Justino Luz, in the city of Picos (PI) in order to suggest their likely mechanisms. Methods: The sample was made up of 120 medical records of hospitalized patients. The charts were analyzed to verify the presence or absence of interactions between medications and foods/nutrients of ...

  5. Endothelial haemostatic factors are associated with progression of urinary albumin excretion in clinically healthy subjects

    DEFF Research Database (Denmark)

    Clausen, P; Feldt-Rasmussen, B; Jensen, G

    1999-01-01

    A slightly elevated urinary albumin excretion rate (UAER), above 5-10 microgram/min, is a predictor of atherosclerotic cardiovascular disease. Endothelial dysfunction is an important early feature of atherosclerosis. The plasma concentration of von Willebrand factor (vWF), a potential marker of e...

  6. Interactions Between Variation in Candidate Genes and Environmental Factors in the Etiology of Schizophrenia and Bipolar Disorder: a Systematic Review.

    Science.gov (United States)

    Misiak, Błażej; Stramecki, Filip; Gawęda, Łukasz; Prochwicz, Katarzyna; Sąsiadek, Maria M; Moustafa, Ahmed A; Frydecka, Dorota

    2017-08-18

    Schizophrenia and bipolar disorder (BD) are complex and multidimensional disorders with high heritability rates. The contribution of genetic factors to the etiology of these disorders is increasingly being recognized as the action of multiple risk variants with small effect sizes, which might explain only a minor part of susceptibility. On the other site, numerous environmental factors have been found to play an important role in their causality. Therefore, in recent years, several studies focused on gene × environment interactions that are believed to bridge the gap between genetic underpinnings and environmental insults. In this article, we performed a systematic review of studies investigating gene × environment interactions in BD and schizophrenia spectrum phenotypes. In the majority of studies from this field, interacting effects of variation in genes encoding catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF), and FK506-binding protein 5 (FKBP5) have been explored. Almost consistently, these studies revealed that polymorphisms in COMT, BDNF, and FKBP5 genes might interact with early life stress and cannabis abuse or dependence, influencing various outcomes of schizophrenia spectrum disorders and BD. Other interactions still require further replication in larger clinical and non-clinical samples. In addition, future studies should address the direction of causality and potential mechanisms of the relationship between gene × environment interactions and various categories of outcomes in schizophrenia and BD.

  7. [The SNPs analysis of encoding sequence of interacting factor gene in Chinese population].

    Science.gov (United States)

    Li, Jiang; Zhang, Qing-jiong; Xiao, Xue-shan; Li, Jia-zhang; Zhang, Feng-sheng; Li, Shi-qiang; Li, Wei; Li, Tuo; Jia, Xiao-yun; Guo, Li; Guo, Xiang-ming

    2003-10-01

    To screen the variations of TG interacting factor(TGIF) gene in encoding sequence in Chinese high myopia patients and normal controls and to analyze the SNPs of TGIF gene encoding sequence in Chinese population. Genomic DNA was collected from 204 probands with high myopia and 112 unrelated persons without high myopia. The coding sequences of TGIF gene in 316 subjects were analyzed by using exon-by-exon PCR heteroduplex-SSCP analysis and sequencing. There were 3 types of SNP and one single nucleotide mutation in the coding sequence of TGIF gene: IVS-2 nt350 G --> T(36/204), codon140 CCA --> CCG; Pro140Pro codon163 CCG --> CTG;Pro163Leu and codon126 GTG --> GCG; Val126Ala(1/204). The SNPs of codon140 CCA --> CCG and codon163 CCG --> CTG were composed of 3 alleles and 5 genotypes in Chinese population which abide by Hardy-Weinberg law. There was no evidence to prove that mutations in the TGIF gene are responsible for the high myopia in Chinese. Three SNPs of coding sequence TGIF gene in Chinese population abide by Hardy-Weinberg law.

  8. Using Interactive Response Systems in Economics: utility and factors influencing students’ attitudes

    Directory of Open Access Journals (Sweden)

    Lydia Bares López

    2017-04-01

    Full Text Available The European Higher Education Area (EHEA involves changing traditional methods to promote innovative teaching experiences. This paper has two main aims: a to show evidence of the use of Interactive Response Systems (IRS to identify gaps in the understanding of the course contents and b to investigate factors influencing students’ attitudes towards the use of IRS. The experience was developed through a collective tutoring session in the subject of Economics using IRS. Economics is a first-year subject in the Degree of Business Administration and Management offered by the University of Cadiz, which includes contents of Microeconomics and Macroeconomics and uses economic models to explain the function of the economy and the behaviour of economic agents. Results show that IRS technique allows detecting gaps in learning and comprehension. From our econometric estimations, we also identify two strongly significant variables affecting students’ attitudes towards IRS: gender and received explanations regarding the use of IRS. Variables such as first enrolment in the subject and the number of hours devoted to studying have a positive and significant effect on the attitude to IRS, but at a lower level of significance (from 5% to 10%.

  9. Predicting drug-target interactions by dual-network integrated logistic matrix factorization

    Science.gov (United States)

    Hao, Ming; Bryant, Stephen H.; Wang, Yanli

    2017-01-01

    In this work, we propose a dual-network integrated logistic matrix factorization (DNILMF) algorithm to predict potential drug-target interactions (DTI). The prediction procedure consists of four steps: (1) inferring new drug/target profiles and constructing profile kernel matrix; (2) diffusing drug profile kernel matrix with drug structure kernel matrix; (3) diffusing target profile kernel matrix with target sequence kernel matrix; and (4) building DNILMF model and smoothing new drug/target predictions based on their neighbors. We compare our algorithm with the state-of-the-art method based on the benchmark dataset. Results indicate that the DNILMF algorithm outperforms the previously reported approaches in terms of AUPR (area under precision-recall curve) and AUC (area under curve of receiver operating characteristic) based on the 5 trials of 10-fold cross-validation. We conclude that the performance improvement depends on not only the proposed objective function, but also the used nonlinear diffusion technique which is important but under studied in the DTI prediction field. In addition, we also compile a new DTI dataset for increasing the diversity of currently available benchmark datasets. The top prediction results for the new dataset are confirmed by experimental studies or supported by other computational research.

  10. Social Anxiety in Online and Real-Life Interaction and Their Associated Factors

    OpenAIRE

    Yen, Ju-Yu; Yen, Cheng-Fang; Chen, Cheng-Sheng; Wang, Peng-Wei; Chang, Yi-Hsin; Ko, Chih-Hung

    2012-01-01

    Social anxiety was compared between online and real-life interaction in a sample of 2,348 college students. Severity of social anxiety in both real-life and online interaction was tested for associations with depression, Internet addiction, Internet activity type (gaming versus chatting), and scores on Behavioral Inhibition System (BIS)/Behavioral Activation System (BAS) scales. The results showed that social anxiety was lower when interacting online than when interacting offline. Depression,...

  11. Interactions of erythropoietin, granulocyte colony-stimulating factor, stem cell factor, and interleukin-11 on murine hematopoiesis during simultaneous administration

    NARCIS (Netherlands)

    Roeder, [No Value; de Haan, G; Engel, C; Nijhof, W; Dontje, B; Loeffler, M

    1998-01-01

    We investigated how in vivo effects of single hematopoietic cytokines change if given in combination for a prolonged time. Mice were treated with every combination of recombinant human (rh) erythropoietin (EPO), rh granulocyte colony-stimulating factor (G-CSF), recombinant rat (rr) stem cell factor

  12. Response to desmopressin is influenced by the genotype and phenotype in type 1 von Willebrand disease (VWD): results from the European Study MCMDM-1VWD

    DEFF Research Database (Denmark)

    Castaman, G.; Lethagen, S.; Federici, A.B.

    2008-01-01

    We have prospectively evaluated the biologic response to desmopressin in 77 patients with type 1 von Willebrand disease (VWD) enrolled within the Molecular and Clinical Markers for the Diagnosis and Management of type 1 VWD project. Complete response to desmopressin was defined as an increase...... of subtle multimeric abnormalities did not hamper potential clinically useful responses, as in typical type 1 VWD Udgivelsesdato: 2008/4/1...

  13. The transcription elongation factor Bur1-Bur2 interacts with replication protein A and maintains genome stability during replication stress

    DEFF Research Database (Denmark)

    Clausing, Emanuel; Mayer, Andreas; Chanarat, Sittinan

    2010-01-01

    Multiple DNA-associated processes such as DNA repair, replication, and recombination are crucial for the maintenance of genome integrity. Here, we show a novel interaction between the transcription elongation factor Bur1-Bur2 and replication protein A (RPA), the eukaryotic single-stranded DNA...... foci. Interestingly, the DNA damage sensitivity of an rfa1 mutant was suppressed by bur1 mutation, further underscoring a functional link between these two protein complexes. The transcription elongation factor Bur1-Bur2 interacts with RPA and maintains genome integrity during DNA replication stress....

  14. High-resolution profiling of stationary-phase survival reveals yeast longevity factors and their genetic interactions.

    Directory of Open Access Journals (Sweden)

    Erika Garay

    2014-02-01

    Full Text Available Lifespan is influenced by a large number of conserved proteins and gene-regulatory pathways. Here, we introduce a strategy for systematically finding such longevity factors in Saccharomyces cerevisiae and scoring the genetic interactions (epistasis among these factors. Specifically, we developed an automated competition-based assay for chronological lifespan, defined as stationary-phase survival of yeast populations, and used it to phenotype over 5,600 single- or double-gene knockouts at unprecedented quantitative resolution. We found that 14% of the viable yeast mutant strains were affected in their stationary-phase survival; the extent of true-positive chronological lifespan factors was estimated by accounting for the effects of culture aeration and adaptive regrowth. We show that lifespan extension by dietary restriction depends on the Swr1 histone-exchange complex and that a functional link between autophagy and the lipid-homeostasis factor Arv1 has an impact on cellular lifespan. Importantly, we describe the first genetic interaction network based on aging phenotypes, which successfully recapitulated the core-autophagy machinery and confirmed a role of the human tumor suppressor PTEN homologue in yeast lifespan and phosphatidylinositol phosphate metabolism. Our quantitative analysis of longevity factors and their genetic interactions provides insights into the gene-network interactions of aging cells.

  15. Amount of H Antigen Expressed on Circulating von Willebrand Factor Is Modified by ABO Blood Group Genotype and Is a Major Determinant of Plasma von Willebrand Factor Antigen Levels

    National Research Council Canada - National Science Library

    O’Donnell, James; Boulton, Frank E; Manning, Richard A; Laffan, Michael A

    2002-01-01

    .... AvWF was correlated strongly with plasma levels of A transferase activity. Thus, we have clearly demonstrated a direct relationship between ABO genotype, A transferase expression, and the amount of A antigen expressed on circulating vWF...

  16. Interactions between factors related to the decision of sex offenders to confess during police interrogation: a classification-tree approach.

    Science.gov (United States)

    Beauregard, Eric; Deslauriers-Varin, Nadine; St-Yves, Michel

    2010-09-01

    Most studies of confessions have looked at the influence of individual factors, neglecting the potential interactions between these factors and their impact on the decision to confess or not during an interrogation. Classification and regression tree analyses conducted on a sample of 624 convicted sex offenders showed that certain factors related to the offenders (e.g., personality, criminal career), victims (e.g., sex, relationship to offender), and case (e.g., time of day of the crime) were related to the decision to confess or not during the police interrogation. Several interactions were also observed between these factors. Results will be discussed in light of previous findings and interrogation strategies for sex offenders.

  17. Growth factors and chemotactic factors from parasitic helminths: molecular evidence for roles in host-parasite interactions versus parasite development.

    Science.gov (United States)

    Freitas, Tori C; Pearce, Edward J

    2010-06-01

    For decades molecular helminthologists have been interested in identifying proteins expressed by the parasite that have roles in modulating the host immune response. In some cases, the aim was targeting parasite-derived orthologues of mammalian cytokines and growth factors known to have functions in immune modulation. In others, novel proteins without homology to mammalian cytokines were isolated by investigating effects of purified worm extracts on various immunological processes. Often, the role parasite-derived growth factors play in worm development was ignored. Here, we review growth factors and chemotactic factors expressed by parasitic helminths and discuss their recognised and potential roles in immunomodulation and/or parasite development. (c) 2010 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.

  18. The role of abiotic factors modulating the plant-microbe-soil interactions: toward sustainable agriculture. A review

    OpenAIRE

    Gustavo Santoyo; Claudia Hernández-Pacheco; Julie Hernández-Salmerón; Rocio Hernández-León

    2017-01-01

    Microbial soil communities are active players in the biogeochemical cycles, impacting soil fertility and interacting with aboveground organisms. Although soil microbial diversity has been studied in good detail, the factors that modulate its structure are still relatively unclear, especially the environmental factors. Several abiotic elements may play a key role in modulating the diversity of soil microbes, including those inhabiting the rhizosphere (known as the rhizosphere microbiome). This...

  19. Do ethylene response factorS9 and -14 repress PR gene expression in the interaction between Piriformospora indica and Arabidopsis?

    Science.gov (United States)

    Camehl, Iris; Oelmüller, Ralf

    2010-08-01

    The plant hormone ethylene (ET) plays a crucial role in the signalling network when plants have to respond to biotic stresses. We investigate the beneficial interaction between the model plant Arabidopsis thaliana and the endophytic fungus Piriformospora indica. Recently, we showed that ET signalling and ETHYLENE RESPONSE FACTOR (ERF)1 are important to balance beneficial and nonbeneficial traits in this symbiosis. 147 ERF genes in Arabidopsis encode transcriptional regulators with a variety of functions involved in development, physiological processes as well as plant/microbe interactions. In the beneficial symbiosis between Arabidopsis and P. indica, overexpression of ERF1 activates defence responses, strongly reduces root colonization and thus abolishes the benefits for the plants. Here we show that additional transcription factors of the ERF family, the ERF DOMAIN PROTEIN9 (ERF9) and the ETHYLENE-RESPONSIVE ELEMENT BINDING FACTOR14 (ERF14) are involved in the interaction between the two symbionts and are required for growth promotion of the host plant. Expression of these genes is upregulated in colonized wild-type roots. Insertional inactivation of ERF9 and ERF14 diminishes the P. indica-induced growth promotion and activates the expression of the PATHOGENESIS-RELATED (PR)-1 and PR-2 genes. We propose that ERF9 and ERF14 repress PR gene expression in colonized Arabidopsis roots and thus contribute to the establishment of a beneficial interaction.

  20. Interaction between Social/Psychosocial Factors and Genetic Variants on Body Mass Index: A Gene-Environment Interaction Analysis in a Longitudinal Setting.

    Science.gov (United States)

    Zhao, Wei; Ware, Erin B; He, Zihuai; Kardia, Sharon L R; Faul, Jessica D; Smith, Jennifer A

    2017-09-29

    Obesity, which develops over time, is one of the leading causes of chronic diseases such as cardiovascular disease. However, hundreds of BMI (body mass index)-associated genetic loci identified through large-scale genome-wide association studies (GWAS) only explain about 2.7% of BMI variation. Most common human traits are believed to be influenced by both genetic and environmental factors. Past studies suggest a variety of environmental features that are associated with obesity, including socioeconomic status and psychosocial factors. This study combines both gene/regions and environmental factors to explore whether social/psychosocial factors (childhood and adult socioeconomic status, social support, anger, chronic burden, stressful life events, and depressive symptoms) modify the effect of sets of genetic variants on BMI in European American and African American participants in the Health and Retirement Study (HRS). In order to incorporate longitudinal phenotype data collected in the HRS and investigate entire sets of single nucleotide polymorphisms (SNPs) within gene/region simultaneously, we applied a novel set-based test for gene-environment interaction in longitudinal studies (LGEWIS). Childhood socioeconomic status (parental education) was found to modify the genetic effect in the gene/region around SNP rs9540493 on BMI in European Americans in the HRS. The most significant SNP (rs9540488) by childhood socioeconomic status interaction within the rs9540493 gene/region was suggestively replicated in the Multi-Ethnic Study of Atherosclerosis (MESA) (p = 0.07).

  1. Factors Which Facilitate or Impede Interpersonal Interactions and Relationships after Spinal Cord Injury: A Scoping Review with Suggestions for Rehabilitation

    Directory of Open Access Journals (Sweden)

    Delena Amsters

    2016-01-01

    Full Text Available Interpersonal interactions and relationships can influence an individual’s perceptions of health and quality of life in the presence of disability. In the case of people with spinal cord injury (SCI, positive interpersonal interactions and relationships have been shown to contribute to resilience and adaptability. Understanding factors which facilitate or impede the development and maintenance of relationships after SCI may form the basis for proactive relationship support for people with SCI. To gain a broad insight into these factors, a scoping review was undertaken. Databases were searched for English language studies published between 2000 and 2015 that informed the review question. Sixty-two (62 studies were identified. Thematic analysis was conducted on data extracted from the studies and 51 factors which may facilitate relationships and 38 factors which may impede relationships after SCI were noted. The majority of factors could be categorized as environmental or personal according to the domains of the International Classification of Functioning, Disability, and Health (ICF. The facilitating factors included partner and social support, reciprocity in relationships, and presenting oneself positively. Impeding factors included physical environmental barriers, real and perceived social biases, and poor self-image. Factors identified may inform the provision of supportive, holistic rehabilitation for people with SCI.

  2. Interaction of sigma factor sigmaN with Escherichia coli RNA polymerase core enzyme.

    Science.gov (United States)

    Scott, D J; Ferguson, A L; Gallegos, M T; Pitt, M; Buck, M; Hoggett, J G

    2000-12-01

    The equilibrium binding and kinetics of assembly of the DNA-dependent RNA polymerase (RNAP) sigma(N)-holoenzyme has been investigated using biosynthetically labelled 7-azatryptophyl- (7AW)sigma(N). The spectroscopic properties of such 7AW proteins allows their absorbance and fluorescence to be monitored selectively, even in the presence of high concentrations of other tryptophan-containing proteins. The 7AWsigma(N) retained its biological activity in stimulating transcription from sigma(N)-specific promoters, and in in vitro gel electrophoresis assays of binding to core RNAP from Escherichia coli. Furthermore, five Trp-->Ala single mutants of sigma(N) were shown to support growth under conditions of nitrogen limitation, and showed comparable efficiency in activating the sigma(N)-dependent nifH promoter in vivo, indicating that none of the tryptophan residues were essential for activity. The equilibrium binding of 7AWsigma(N) to core RNAP was examined by analytical ultracentrifugation. In sedimentation equilibrium experiments, absorbance data at 315 nm (which reports selectively on the distribution of free and bound 7AWsigma(N)) established that a 1:1 complex was formed, with a dissociation constant lower than 2 microM. The kinetics of the interaction between 7AWsigma(N) and core RNAP was investigated using stopped-flow spectrofluorimetry. A biphasic decrease in fluorescence intensity was observed when samples were excited at 280 nm, whereas only the slower of the two phases was observed at 315 nm. The kinetic data were analysed in terms of a mechanism in which a fast bimolecular association of sigma(N) with core RNAP is followed by a relatively slow isomerization step. The consequences of these findings on the competition between sigma(N) and the major sigma factor, sigma(70), in Escherichia coli are discussed.

  3. Hypothesis: Genetic and epigenetic risk factors interact to modulate vulnerability and resilience to FASD

    Directory of Open Access Journals (Sweden)

    Elif eTunc-Ozcan

    2014-08-01

    Full Text Available Fetal alcohol spectrum disorder (FASD presents a collection of symptoms representing physiological and behavioral phenotypes caused by maternal alcohol consumption. Symptom severity is modified by genetic differences in fetal susceptibility and resistance as well as maternal genetic factors such as maternal alcohol sensitivity. Animal models demonstrate that both maternal and paternal genetics contribute to the variation in the fetus’ vulnerability to alcohol exposure. Maternal and paternal genetics define the variations in these phenotypes even without the effect of alcohol in utero, as most of these traits are polygenic, non-Mendelian, in their inheritance. In addition, the epigenetic alterations that instigate the alcohol induced neurodevelopmental deficits can interact with the polygenic inheritance of respective traits. Here, based on specific examples, we present the hypothesis that the principles of non-Mendelian inheritance, or ‘exceptions’ to Mendelian genetics, can be the driving force behind the severity of the prenatal alcohol-exposed individual’s symptomology. One such exception is when maternal alleles lead to an altered intrauterine hormonal environment and, therefore, produce variations in the long-term consequences on the development of the alcohol-exposed fetus. Another exception is when epigenetic regulation of allele-specific gene expression generates disequilibrium between the maternal versus paternal genetic contributions, and thereby, modifies the effect of prenatal alcohol exposure on the fetus. We propose that these situations in which one parent has an exaggerated influence over the offspring’s vulnerability to prenatal alcohol are major contributing mechanisms responsible for the variations in the symptomology of FASD in the exposed generation and beyond.

  4. Social anxiety in online and real-life interaction and their associated factors.

    Science.gov (United States)

    Yen, Ju-Yu; Yen, Cheng-Fang; Chen, Cheng-Sheng; Wang, Peng-Wei; Chang, Yi-Hsin; Ko, Chih-Hung

    2012-01-01

    Social anxiety was compared between online and real-life interaction in a sample of 2,348 college students. Severity of social anxiety in both real-life and online interaction was tested for associations with depression, Internet addiction, Internet activity type (gaming versus chatting), and scores on Behavioral Inhibition System (BIS)/Behavioral Activation System (BAS) scales. The results showed that social anxiety was lower when interacting online than when interacting offline. Depression, Internet addiction, and high BIS and BAS scores were associated with high social anxiety. The social anxiety decreased more in online interaction among subjects with high social anxiety, depression, BIS, and BAS. This result suggests that the Internet has good potential as an alternative medium for delivering interventions for social anxiety. Further, the effect of BIS on social anxiety is decreased in online interaction. More attention should be paid for BIS when the treatment for social anxiety is delivered online.

  5. Molecular analysis of the interaction between the hematopoietic master transcription factors GATA-1 and PU.1

    DEFF Research Database (Denmark)

    Liew, Chu Wai; Rand, Kasper Dyrberg; Simpson, Raina J Y

    2006-01-01

    also become clear that this functional antagonism involves direct interactions between the two proteins. However, the molecular basis for these interactions is not known, and a number of inconsistencies exist in the literature. We have used a range of biophysical methods to define the molecular details...... of the GATA-1-PU.1 interaction. A combination of NMR titration data and extensive mutagenesis revealed that the PU.1-Ets domain and the GATA-1 C-terminal zinc finger (CF) form a low affinity interaction in which specific regions of each protein are implicated. Surprisingly, the interaction cannot be disrupted...... by single alanine substitution mutations, suggesting that binding is distributed over an extended interface. The C-terminal basic tail region of CF appears to be sufficient to mediate an interaction with PU.1-Ets, and neither acetylation nor phosphorylation of a peptide corresponding to this region disrupts...

  6. Interaction between genetic and environmental risk factors for Alzheimer's disease: A reanalysis of case-control studies

    NARCIS (Netherlands)

    C.M. van Duijn (Cornelia); D.G. Clayton (David); V. Chandra; L. Fratiglioni (Laura); A.B. Graves; A. Heyman; A.F. Jorm; E. Kokmen (Emre); K. Kondo; J.A. Mortimer; W.A. Rocca (Walter); S.L. Shalat; H. Soininen (H.); A. Hofman (Albert)

    1994-01-01

    textabstractTo study the interaction among genetic and environmental risk factors, a reanalysis of case-control studies of Alzheimer's disease (AD) was conducted based on the original data of all studies carried out to January 1, 1990. Seven studies were included in the present analysis, comprising

  7. Interaction between genetic and environmental risk factors for Alzheimer's disease: a re-analysis of case-control studies

    NARCIS (Netherlands)

    C.M. van Duijn (Cornelia); D.G. Clayton (David); V. Chandra; L. Fratiglioni (Laura); A.B. Graves; A. Heyman; A.F. Jorm; E. Kokmen (Emre); K. Kondo; J.A. Mortimer; W.A. Rocca; S.L. Shalat; H. Soininen; A. Hofman (Albert)

    1994-01-01

    textabstractTo study the interaction among genetic and environmental risk factors, a reanalysis of case-control studies of Alzheimer's disease (AD) was conducted based on the original data of all studies carried out to January 1, 1990. Seven studies were included in the present analysis, comprising

  8. The Multigenerational Workforce within Two-Year Public Community Colleges: A Study of Generational Factors Affecting Employee Learning and Interaction

    Science.gov (United States)

    Starks, Florida Elizabeth

    2014-01-01

    The purpose of this quantitative study is to broaden multigenerational workforce research involving factors affecting employee learning and interaction by using a population of Baby Boomer, Generation X, and Millennial faculty and staff age cohorts employed at two-year public community college organizations. Researchers have studied…

  9. An Empirical Study of Factors Affecting Mobile Wireless Technology Adoption for Promoting Interactive Lectures in Higher Education

    Science.gov (United States)

    Gan, Chin Lay; Balakrishnan, Vimala

    2016-01-01

    Use of mobile technology is widespread, particularly among the younger generation. There is a huge potential for utilizing such technology in lecture classes with large numbers of students, serving as an interaction tool between the students and lecturers. The challenge is to identify significant adoption factors to ensure effective adoption of…

  10. Using Social Networking Environments to Support Collaborative Learning in a Chinese University Class: Interaction Pattern and Influencing Factors

    Science.gov (United States)

    Lu, Jie; Churchill, Daniel

    2014-01-01

    This paper reports a study that investigated the social interaction pattern of collaborative learning and the factors affecting the effectiveness of collaborative learning in a social networking environment (SNE). A class of 55 undergraduate students enrolled in an elective course at a Chinese university was recruited for the study. The…

  11. Identification and Characterization of Novel Variations in Platelet G-Protein Coupled Receptor (GPCR Genes in Patients Historically Diagnosed with Type 1 von Willebrand Disease.

    Directory of Open Access Journals (Sweden)

    Jacqueline Stockley

    Full Text Available The clinical expression of type 1 von Willebrand disease may be modified by co-inheritance of other mild bleeding diatheses. We previously showed that mutations in the platelet P2Y12 ADP receptor gene (P2RY12 could contribute to the bleeding phenotype in patients with type 1 von Willebrand disease. Here we investigated whether variations in platelet G protein-coupled receptor genes other than P2RY12 also contributed to the bleeding phenotype. Platelet G protein-coupled receptor genes P2RY1, F2R, F2RL3, TBXA2R and PTGIR were sequenced in 146 index cases with type 1 von Willebrand disease and the potential effects of identified single nucleotide variations were assessed using in silico methods and heterologous expression analysis. Seven heterozygous single nucleotide variations were identified in 8 index cases. Two single nucleotide variations were detected in F2R; a novel c.-67G>C transversion which reduced F2R transcriptional activity and a rare c.1063C>T transition predicting a p.L355F substitution which did not interfere with PAR1 expression or signalling. Two synonymous single nucleotide variations were identified in F2RL3 (c.402C>G, p.A134 =; c.1029 G>C p.V343 =, both of which introduced less commonly used codons and were predicted to be deleterious, though neither of them affected PAR4 receptor expression. A third single nucleotide variation in F2RL3 (c.65 C>A; p.T22N was co-inherited with a synonymous single nucleotide variation in TBXA2R (c.6680 C>T, p.S218 =. Expression and signalling of the p.T22N PAR4 variant was similar to wild-type, while the TBXA2R variation introduced a cryptic splice site that was predicted to cause premature termination of protein translation. The enrichment of single nucleotide variations in G protein-coupled receptor genes among type 1 von Willebrand disease patients supports the view of type 1 von Willebrand disease as a polygenic disorder.

  12. Interactions between Social/ behavioral factors and ADRB2 genotypes may be associated with health at advanced ages in China

    DEFF Research Database (Denmark)

    Zeng, Y.; Cheng, L. G.; Zhao, L.

    2013-01-01

    ages. This study intends to fill in this research gap. Method: We conducted an exploratory analysis, using longitudinal survey phenotype/genotype data from 877 oldest-old aged 90+. To estimate association of GxE interactions with health outcome, adjusted for the potential correlation between genotypes...... and social/behavioral factors and various other potentially confounding factors, we develop and test an innovative three-step procedure which combines logistic regression and structural equation methods. Results: Interaction between regular exercise and carrying rs1042718 minor allele is significantly...... analysis found that, adjusted for the confounding effects of correlation of the ADRB2 SNPs with negative emotion, interaction between negative emotion and carrying rs1042718 or rs1042719 minor allele is significantly and negatively associated with cognitive function. The positive association of regular...

  13. Anestesia para septoplastia e turbinectomia em paciente portador de doença de von Willebrand: relato de caso Anestesia para septoplastia y turbinectomia en paciente portador de enfermedad de von Willebrand: relato de caso Anesthesia for septoplasty and turbinectomy in von Willebrand disease patient: case report

    Directory of Open Access Journals (Sweden)

    Múcio Paranhos de Abreu

    2003-06-01

    Full Text Available JUSTIFICATIVA E OBJETIVOS: Embora a doença de von Willebrand seja o mais comum dos distúrbios hemorrágicos hereditários, as publicações nacionais, relacionando esta doença e a prática anestésica, são escassas. O objetivo deste relato é apresentar um caso de anestesia geral para septoplastia e turbinectomia em paciente portador de doença de von Willebrand - Tipo I, tratado profilaticamente com desmopressina (1-deamino-8-D-arginina vasopressina, DDAVP nos períodos pré e pós-operatório. RELATO DO CASO: Paciente com 19 anos, sexo feminino, 58 kg, portadora de hipotiroidismo, controlado com L-tiroxina (75 mg, e de doença de von Willebrand, que se manifestou há três anos, após extração dentária dos sisos, com sangramento persistente no período pós-operatório. Com o objetivo de se evitar novos episódios hemorrágicos nos períodos per e pós-operatório da cirurgia de septoplastia e turbinectomia a que foi submetida, a paciente foi tratada profilaticamente com desmopressina (0,3 µg.kg-1. A indução anestésica foi realizada com midazolam (2,5 mg, fentanil (150 µg, droperidol (2,5 mg, lidocaína (60 mg, atracúrio (30 mg e metoprolol (4 mg, seguida de intubação traqueal e ventilação sob pressão positiva intermitente. A manutenção da anestesia foi realizada com mistura de oxigênio e óxido nitroso a 50% e sevoflurano a 2%. Esta técnica proporcionou um bom controle da freqüência cardíaca e dos níveis pressóricos durante a cirurgia. A paciente permaneceu com tampão nasal por 24 horas e, quando este foi retirado, não houve sangramento. A paciente recebeu alta hospitalar no dia seguinte ao da cirurgia, sem intercorrências. Não houve episódio hemorrágico no período pós-operatório imediato ou tardio. CONCLUSÕES: O tratamento profilático com DDAVP associado à técnica anestésica utilizada nesse caso, mostrou-se eficaz no controle do sangramento per e pós-operatório.JUSTIFICATIVA Y OBJETIVOS: Aun cuando

  14. Factor VIII C1 domain spikes 2092-2093 and 2158-2159 comprise regions that modulate cofactor function and cellular uptake

    NARCIS (Netherlands)

    Bloem, Esther; van den Biggelaar, Maartje; Wroblewska, Aleksandra; Voorberg, Jan; Faber, Johan H.; Kjalke, Marianne; Stennicke, Henning R.; Mertens, Koen; Meijer, Alexander B.

    2013-01-01

    The C1 domain of factor VIII (FVIII) has been implicated in binding to multiple constituents, including phospholipids, von Willebrand factor, and low-density lipoprotein receptor-related protein (LRP). We have previously described a human monoclonal antibody called KM33 that blocks these

  15. Structural and functional analysis of VQ motif-containing proteins in Arabidopsis as interacting proteins of WRKY transcription factors.

    Science.gov (United States)

    Cheng, Yuan; Zhou, Yuan; Yang, Yan; Chi, Ying-Jun; Zhou, Jie; Chen, Jian-Ye; Wang, Fei; Fan, Baofang; Shi, Kai; Zhou, Yan-Hong; Yu, Jing-Quan; Chen, Zhixiang

    2012-06-01

    WRKY transcription factors are encoded by a large gene superfamily with a broad range of roles in plants. Recently, several groups have reported that proteins containing a short VQ (FxxxVQxLTG) motif interact with WRKY proteins. We have recently discovered that two VQ proteins from Arabidopsis (Arabidopsis thaliana), SIGMA FACTOR-INTERACTING PROTEIN1 and SIGMA FACTOR-INTERACTING PROTEIN2, act as coactivators of WRKY33 in plant defense by specifically recognizing the C-terminal WRKY domain and stimulating the DNA-binding activity of WRKY33. In this study, we have analyzed the entire family of 34 structurally divergent VQ proteins from Arabidopsis. Yeast (Saccharomyces cerevisiae) two-hybrid assays showed that Arabidopsis VQ proteins interacted specifically with the C-terminal WRKY domains of group I and the sole WRKY domains of group IIc WRKY proteins. Using site-directed mutagenesis, we identified structural features of these two closely related groups of WRKY domains that are critical for interaction with VQ proteins. Quantitative reverse transcription polymerase chain reaction revealed that expression of a majority of Arabidopsis VQ genes was responsive to pathogen infection and salicylic acid treatment. Functional analysis using both knockout mutants and overexpression lines revealed strong phenotypes in growth, development, and susceptibility to pathogen infection. Altered phenotypes were substantially enhanced through cooverexpression of genes encoding interacting VQ and WRKY proteins. These findings indicate that VQ proteins play an important role in plant growth, development, and response to environmental conditions, most likely by acting as cofactors of group I and IIc WRKY transcription factors.

  16. The path analysis of online interpersonal interaction on purchase intention based on two-factor structure of trust and distrust

    Directory of Open Access Journals (Sweden)

    Lei Zhang

    2017-03-01

    Full Text Available Compared with technical competence, online interpersonal interaction is a stronger inspiring element, which significantly impacts the purchase intention. Under the influence of the media characteristics of internet, online transactions are riskier with much stronger uncertainty. This makes customer trust more complicated and diversified, which even displays the coexisting situation of trust and distrust, as well as correlation and difference. This research sets out to clarify the measuring dimensions of online interpersonal interaction, explore the two-factor structure of trust and distrust, and further establish the driving approaches from online interpersonal interaction to purchase intention with empirical test. This research conforms to the macroscopical objective of industry structure upgrade of our country as its achieved results can furthermore help enterprises achieve efficient interaction, stimulate loyalty and improve performance.

  17. Exploring cultural factors in human-robot interaction: A matter of personality?

    NARCIS (Netherlands)

    Weiss, Astrid; Evers, Vanessa

    2011-01-01

    This paper proposes an experimental study to investigate task-dependence and cultural-background dependence of the personality trait attribution on humanoid robots. In Human-Robot Interaction, as well as in Human-Agent Interaction research, the attribution of personality traits towards intelligent

  18. Fires following bark beetles: Factors controlling severity and disturbance interactions in ponderosa pine

    Science.gov (United States)

    Carolyn H. Sieg; Rodman R. Linn; Francois Pimont; Chad M. Hoffman; Joel D. McMillin; Judith Winterkamp; L. Scott Baggett

    2017-01-01

    Previous studies have suggested that bark beetles and fires can be interacting disturbances, whereby bark beetle-caused tree mortality can alter the risk and severity of subsequent wildland fires. However, there remains considerable uncertainty around the type and magnitude of the interaction between fires following bark beetle attacks, especially in drier forest types...

  19. Transcription factors do it together : the hows and whys of studying protein-protein interactions

    NARCIS (Netherlands)

    Immink, R.G.H.; Angenent, G.C.

    2002-01-01

    Protein–protein interactions are intrinsic to virtually every cellular process. Recent breakthroughs in techniques to study protein-interaction and the availability of fully sequenced plant genomes have attracted many plant scientists to undertake the first steps in the field of protein

  20. Comparing the epidermal growth factor interaction with four different cell lines: intriguing effects imply strong dependency of cellular context.

    Directory of Open Access Journals (Sweden)

    Hanna Björkelund

    Full Text Available The interaction of the epidermal growth factor (EGF with its receptor (EGFR is known to be complex, and the common over-expression of EGF receptor family members in a multitude of tumors makes it important to decipher this interaction and the following signaling pathways. We have investigated the affinity and kinetics of (125I-EGF binding to EGFR in four human tumor cell lines, each using four culturing conditions, in real time by use of LigandTracer®.Highly repeatable and precise measurements show that the overall apparent affinity of the (125I-EGF - EGFR interaction is greatly dependent on cell line at normal culturing conditions, ranging from K(D ≈ 200 pM on SKBR3 cells to K(D≈8 nM on A431 cells. The (125I-EGF - EGFR binding curves (irrespective of cell line have strong signs of multiple simultaneous interactions. Furthermore, for the cell lines A431 and SKOV3, gefitinib treatment increases the (125I-EGF - EGFR affinity, in particular when the cells are starved. The (125I-EGF - EGFR interaction on cell line U343 is sensitive to starvation while as on SKBR3 it is insensitive to gefitinib and starvation.The intriguing pattern of the binding characteristics proves that the cellular context is important when deciphering how EGF interacts with EGFR. From a general perspective, care is advisable when generalizing ligand-receptor interaction results across multiple cell-lines.

  1. Protective Factors Against Child Victimization in the School and Community: An Exploratory Systematic Review of Longitudinal Predictors and Interacting Variables.

    Science.gov (United States)

    Jackson, Vicki; Chou, Shihning; Browne, Kevin

    2015-10-22

    Protective factors against the victimization of children and young people within the school and community environments (extrafamilial victimization) have received less attention than risk factors. To date, there has been no systematic review on protective factors. This systematic review therefore aimed to synthesize the prospective longitudinal research findings on the protective factors against extrafamilial victimization. A systematic search of multiple sources led to the identification of 19,053 studies. Following application of a predefined inclusion and quality assessment criteria, 13 studies exploring protective factors against peer victimization and exposure to violence were included in this review. Across these studies, 19 protective factors were explored: 9 individual factors and 10 contextual factors. Four studies also explored the impact of mediating and moderating variables on the relationship between predictors and extrafamilial victimization. Findings highlight inconsistencies in the definition and measurement of victimization, along with bias in a number of areas. Nevertheless, a small number of variables (perceptions of social competence, physical strength, and aggression) were identified as potential protective factors against extrafamilial victimization. Additionally, mediating and moderating variables were identified, and the interaction between individual and contextual protective and risk factors were highlighted. These findings are explored under the theoretical framework of the ecological systems theory and their practical and research-based implications are discussed. © The Author(s) 2015.

  2. Interaction between MyRIP and the actin cytoskeleton regulates Weibel-Palade body trafficking and exocytosis.

    Science.gov (United States)

    Conte, Ianina L; Hellen, Nicola; Bierings, Ruben; Mashanov, Gregory I; Manneville, Jean-Baptiste; Kiskin, Nikolai I; Hannah, Matthew J; Molloy, Justin E; Carter, Tom

    2016-02-01

    Weibel-Palade body (WPB)-actin interactions are essential for the trafficking and secretion of von Willebrand factor; however, the molecular basis for this interaction remains poorly defined. Myosin Va (MyoVa or MYO5A) is recruited to WPBs by a Rab27A-MyRIP complex and is thought to be the prime mediator of actin binding, but direct MyRIP-actin interactions can also occur. To evaluate the specific contribution of MyRIP-actin and MyRIP-MyoVa binding in WPB trafficking and Ca(2+)-driven exocytosis, we used EGFP-MyRIP point mutants with disrupted MyoVa and/or actin binding and high-speed live-cell fluorescence microscopy. We now show that the ability of MyRIP to restrict WPB movement depends upon its actin-binding rather than its MyoVa-binding properties. We also show that, although the role of MyRIP in Ca(2+)-driven exocytosis requires both MyoVa- and actin-binding potential, it is the latter that plays a dominant role. In view of these results and together with the analysis of actin disruption or stabilisation experiments, we propose that the role of MyRIP in regulating WPB trafficking and exocytosis is mediated largely through its interaction with actin rather than with MyoVa. © 2016. Published by The Company of Biologists Ltd.

  3. Interaction between MyRIP and the actin cytoskeleton regulates Weibel–Palade body trafficking and exocytosis

    Science.gov (United States)

    Conte, Ianina L.; Hellen, Nicola; Bierings, Ruben; Mashanov, Gregory I.; Manneville, Jean-Baptiste; Kiskin, Nikolai I.; Hannah, Matthew J.; Molloy, Justin E.; Carter, Tom

    2016-01-01

    ABSTRACT Weibel–Palade body (WPB)–actin interactions are essential for the trafficking and secretion of von Willebrand factor; however, the molecular basis for this interaction remains poorly defined. Myosin Va (MyoVa or MYO5A) is recruited to WPBs by a Rab27A–MyRIP complex and is thought to be the prime mediator of actin binding, but direct MyRIP–actin interactions can also occur. To evaluate the specific contribution of MyRIP–actin and MyRIP–MyoVa binding in WPB trafficking and Ca2+-driven exocytosis, we used EGFP–MyRIP point mutants with disrupted MyoVa and/or actin binding and high-speed live-cell fluorescence microscopy. We now show that the ability of MyRIP to restrict WPB movement depends upon its actin-binding rather than its MyoVa-binding properties. We also show that, although the role of MyRIP in Ca2+-driven exocytosis requires both MyoVa- and actin-binding potential, it is the latter that plays a dominant role. In view of these results and together with the analysis of actin disruption or stabilisation experiments, we propose that the role of MyRIP in regulating WPB trafficking and exocytosis is mediated largely through its interaction with actin rather than with MyoVa. PMID:26675235

  4. Investigation of human teeth with respect to the photon interaction, energy absorption and buildup factor

    Energy Technology Data Exchange (ETDEWEB)

    Kurudirek, Murat, E-mail: mkurudirek@gmail.co [Faculty of Science, Department of Physics, Ataturk University, 25240 Erzurum (Turkey); Topcuoglu, Sinan [Faculty of Dentistry, Department of Endodontic, Ataturk University, 25240 Erzurum (Turkey)

    2011-05-15

    The effective atomic numbers and electron densities of human teeth have been calculated for total photon interaction (Z{sub PI{sub e{sub f{sub f}}}},Ne{sub PI{sub e{sub f{sub f}}}}) and photon energy absorption (Z{sub PEA{sub e{sub f{sub f}}}},Z{sub RW{sub e{sub f{sub f}}}}Ne{sub PEA{sub e{sub f{sub f}}}}) in the energy region 1 keV-20 MeV. Besides, the energy absorption (EABF) and exposure (EBF) buildup factors have been calculated for these samples by using the geometric progression fitting approximation in the energy region 0.015-15 MeV up to 40 mfp (mean free path). Wherever possible the results were compared with experiment. Effective atomic numbers (Z{sub PI{sub e{sub f{sub f}}}}) of human teeth were calculated using different methods. Discrepancies were noted in Z{sub PI{sub e{sub f{sub f}}}} between the direct and interpolation methods in the low and high energy regions where absorption processes dominate while good agreement was observed in intermediate energy region where Compton scattering dominates. Significant variations up to 22% were observed between Z{sub PI{sub e{sub f{sub f}}}} and Z{sub PEA{sub e{sub f{sub f}}}} in the energy region 30-150 keV which is the used energy range in dental cone beam computed tomography (CBCT) X-ray machines. The Z{sub eff} values of human teeth were found to relatively vary within 1% if different laser treatments are applied. In this variation, the Er:YAG laser treated samples were found to be less effected than Nd:YAG laser treated ones when compared with control group. Relative differences between EABF and EBF were found to be significantly high in the energy region 60 keV-1 MeV even though they have similar variations with respect to the different parameters viz. photon energy, penetration depth.

  5. ADAM 12, a disintegrin metalloprotease, interacts with insulin-like growth factor-binding protein-3

    DEFF Research Database (Denmark)

    Shi, Z; Xu, Wei; Loechel, F

    2000-01-01

    , as yet the pregnancy-specific protease, or proteases, have not been identified. We utilized a yeast two-hybrid assay and a human placental cDNA library to investigate IGFBP-3-interacting proteins. A disintegrin and metalloprotease-12 (ADAM 12), a member of a family of metalloprotease disintegrins...... that is highly expressed in placental tissue, was identified as interacting with IGFBP-3. This interaction involved the cysteine-rich domain of ADAM 12. Unlike other members of this family of disintegrin metalloproteases that are membrane proteins, ADAM 12 exists as an alternatively spliced soluble secreted...

  6. Dietary Magnesium and Genetic Interactions in Diabetes and Related Risk Factors: A Brief Overview of Current Knowledge

    Science.gov (United States)

    Hruby, Adela; McKeown, Nicola M.; Song, Yiqing; Djoussé, Luc

    2013-01-01

    Nutritional genomics has exploded in the last decade, yielding insights—both nutrigenomic and nutrigenetic—into the physiology of dietary interactions and our genes. Among these are insights into the regulation of magnesium transport and homeostasis and mechanisms underlying magnesium’s role in insulin and glucose handling. Recent observational evidence has attempted to examine some promising research avenues on interaction between genetics and dietary magnesium in relation to diabetes and diabetes risk factors. This brief review summarizes the recent evidence on dietary magnesium’s role in diabetes and related traits in the presence of underlying genetic risk, and discusses future potential research directions. PMID:24322525

  7. Interaction between common breast cancer susceptibility variants, genetic ancestry, and non-genetic risk factors in Hispanic women

    Science.gov (United States)

    Fejerman, Laura; Stern, Mariana C.; John, Esther M.; Torres-Mejía, Gabriela; Hines, Lisa M.; Wolff, Roger K.; Baumgartner, Kathy B.; Giuliano, Anna R.; Ziv, Elad; Pérez-Stable, Eliseo J.; Slattery, Martha L.

    2015-01-01

    Background Most genetic variants associated with breast cancer risk have been discovered in women of European ancestry, and only a few genome-wide association studies (GWAS) have been conducted in minority groups. This research disparity persists in post-GWAS gene-environment interaction analyses. We tested the interaction between hormonal and lifestyle risk factors for breast cancer, and ten GWAS-identified single nucleotide polymorphisms (SNPs) among 2,107 Hispanic women with breast cancer and 2,587 unaffected controls, to gain insight into a previously reported gene by ancestry interaction in this population. Methods We estimated genetic ancestry with a set of 104 ancestry-informative markers selected to discriminate between Indigenous American and European ancestry. We used logistic regression models to evaluate main effects and interactions. Results We found that the rs13387042-2q35(G/A) SNP was associated with breast cancer risk only among postmenopausal women who never used hormone therapy [per A allele odds ratio (OR): 0.94 (95% confidence interval 0.74–1.20), 1.20 (0.94–1.53) and 1.49 (1.28–1.75) for current, former and never hormone therapy users, respectively, P-interaction 0.002] and premenopausal women who breastfed >12 months [OR: 1.01 (0.72–1.42), 1.19 (0.98–1.45) and 1.69 (1.26–2.26) for never, 12 months breastfeeding, respectively, P-interaction 0.014]. Conclusions The correlation between genetic ancestry, hormone replacement therapy use, and breastfeeding behavior partially explained a previously reported interaction between a breast cancer risk variant and genetic ancestry in Hispanic women. Impact These results highlight the importance of understanding the interplay between genetic ancestry, genetics, and non-genetic risk factors and their contribution to breast cancer risk. PMID:26364163

  8. The Interaction among Microbiota, Immunity, and Genetic and Dietary Factors Is the Condicio Sine Qua Non Celiac Disease Can Develop

    Directory of Open Access Journals (Sweden)

    D. Pagliari

    2015-01-01

    Full Text Available Celiac disease (CD is an immune-mediated enteropathy, triggered by dietary wheat gluten and similar proteins of barley and rye in genetically susceptible individuals. This is a complex disorder involving both environmental and immune-genetic factors. The major genetic risk factor for CD is determined by HLA-DQ genes. Dysfunction of the innate and adaptive immune systems can conceivably cause impairment of mucosal barrier function and development of localized or systemic inflammatory and autoimmune processes. Exposure to gluten is the main environmental trigger responsible for the signs and symptoms of the disease, but exposure to gluten does not fully explain the manifestation of CD. Thus, both genetic determination and environmental exposure to gluten are necessary for the full manifestation of CD; neither of them is sufficient alone. Epidemiological and clinical data suggest that other environmental factors, including infections, alterations in the intestinal microbiota composition, and early feeding practices, might also play a role in disease development. Thus, this interaction is the condicio sine qua non celiac disease can develop. The breakdown of the interaction among microbiota, innate immunity, and genetic and dietary factors leads to disruption of homeostasis and inflammation; and tissue damage occurs. Focusing attention on this interaction and its breakdown may allow a better understanding of the CD pathogenesis and lead to novel translational avenues for preventing and treating this widespread disease.

  9. Neural cell adhesion molecule differentially interacts with isoforms of the fibroblast growth factor receptor

    DEFF Research Database (Denmark)

    Christensen, Claus; Berezin, Vladimir; Bock, Elisabeth

    2011-01-01

    -binding immunoglobulin-like modules 2 and 3 of FGFR1b, FGFR1c, FGFR2b, FGFR2c, FGFR3b, FGFR3c, and FGFR4, and found that all FGFR isoforms, except for FGFR4, interacted with NCAM. The binding affinity of NCAM-FGFR interactions was considerably higher for splice variant 'b' than for splice variant 'c'. We suggest...

  10. [Research on potential interaction between mitochondrial DNA copy number and related factors on risk of hypertension in coal miners].

    Science.gov (United States)

    Guo, J Y; Lei, L J; Qiao, N; Fan, G Q; Sun, C M; Huang, J J; Wang, T

    2017-01-10

    Objective: To investigate the effects of mitochondrial DNA (mtDNA) copy number in peripheral blood and related factors on the risk of hypertension in coal miners. Methods: A case-control study was conducted in 378 coal miners with hypertension and 325 healthy coal miners recruited from Datong Coal Mine Group. A standard questionnaire was used to collect their general information, such as demographic characteristics, habits and occupational history. Fluorescence quantitative PCR was performed to detect the copy number of mtDNA. Logistic regression model was applied for identifying the related risk factors of hypertension and analyzing the interaction between mtDNA copy number and risk factors. Results: The prevalence of hypertension of high mtDNA copy number was lower than mtDNA copy numberin 0-5.67 group, but the difference was not statistically significant (P=0.414). Alcohol drinking (OR=1.80, 95% CI: 1.26-2.56), family history of hypertension (OR=1.74, 95% CI: 1.20- 2.50), work shifts (OR=0.69, 95% CI: 0.48-0.99), education level (P=0.012) and family monthly income level (P=0.001) were related to the prevalence of hypertension. There were potential interactions between mtDNA copy number and alcohol drinking, family monthly income level, family history of hypertension, respectively. Alcohol drinking was a risk factor for hypertension [1.77 (1.25-2.50)]. Potential interactions between mtDNA copy number and alcohol drinking reduced the risk of hypertension (OR=1.20, 95% CI: 1.07-1.35). Family history of hypertension was a risk factor for hypertension [1.81(1.26-2.59)]. Potential interactions between mtDNA copy number and family history of hypertension reduced the risk of hypertension (OR=1.24, 95%CI: 1.09-1.41). Family monthly income level was a protect factor for hypertension [0.55(0.46-0.66)]. Potential interactions between mtDNA copy number and family monthly income level increased the protection role of hypertension (OR=0.90, 95% CI: 0.86-0.94). Conclusion: mt

  11. Secretomic Analysis of Host-Pathogen Interactions Reveals That Elongation Factor-Tu Is a Potential Adherence Factor of Helicobacter pylori during Pathogenesis.

    Science.gov (United States)

    Chiu, Kuo-Hsun; Wang, Ling-Hui; Tsai, Tsung-Ting; Lei, Huan-Yao; Liao, Pao-Chi

    2017-01-06

    The secreted proteins of bacteria are usually accompanied by virulence factors, which can cause inflammation and damage host cells. Identifying the secretomes arising from the interactions of bacteria and host cells could therefore increase understanding of the mechanisms during initial pathogenesis. The present study used a host-pathogen coculture system of Helicobacter pylori and monocytes (THP-1 cells) to investigate the secreted proteins associated with initial H. pylori pathogenesis. The secreted proteins from the conditioned media from H. pylori, THP-1 cells, and the coculture were collected and analyzed using SDS-PAGE and LC-MS/MS. Results indicated the presence of 15 overexpressed bands in the coculture. Thirty-one proteins were identified-11 were derived from THP-1 cells and 20 were derived from H. pylori. A potential adherence factor from H. pylori, elongation factor-Tu (EF-Tu), was selected for investigation of its biological function. Results from confocal microscopic and flow cytometric analyses indicated the contribution of EF-Tu to the binding ability of H. pylori in THP-1. The data demonstrated that fluorescence of EF-Tu on THP-1 cells increased after the addition of the H. pylori-conditioned medium. This study reports a novel secretory adherence factor in H. pylori, EF-Tu, and further elucidates mechanisms of H. pylori adaptation for host-pathogen interaction during pathogenesis.

  12. Asymmetrical peer interaction as a factor of formal operations development in more competent students

    Directory of Open Access Journals (Sweden)

    Stepanović-Ilić Ivana

    2015-01-01

    Full Text Available This paper deals with the role of asymmetrical peer interaction in the development of formal operational thinking. The relevance of the research lies in the fact that influence of peers’ interaction is rarely examined in the context of the development of formal operations and in the fact that effects of asymmetrical interaction are more investigated regarding the less competent participants. The results show no influence of the interaction on the development of formal operations in more competent children. This is in accordance with some research findings. However, there are some more competent students who significantly progressed and others who considerably regressed after the interaction. That deserves attention and suggests that next important step is analysis of peers’ dialogues. Such examination could reveal interaction attributes that can influence cognitive development which has theoretical relevance, but also practical implications in the classroom. [Projekat Ministarstva nauke Republike Srbije, br. 179018: Identification, measurement and development of cognitive and emotional competences important for a society oriented toward European integrations

  13. TATA binding protein associated factor 3 (TAF3 interacts with p53 and inhibits its function

    Directory of Open Access Journals (Sweden)

    Tora Laszlo

    2008-06-01

    Full Text Available Abstract Background The tumour suppressor protein p53 is a sequence specific DNA-binding transcription regulator, which exerts its versatile roles in genome protection and apoptosis by affecting the expression of a large number of genes. In an attempt to obtain a better understanding of the mechanisms by which p53 transcription function is regulated, we studied p53 interactions. Results We identified BIP2 (Bric-à-brac interacting protein 2, the fly homolog of TAF3, a histone fold and a plant homeodomain containing subunit of TFIID, as an interacting partner of Drosophila melanogaster p53 (Dmp53. We detected physical interaction between the C terminus of Dmp53 and the central region of TAF3 both in yeast two hybrid assays and in vitro. Interestingly, DmTAF3 can also interact with human p53, and mammalian TAF3 can bind to both Dmp53 and human p53. This evolutionarily conserved interaction is functionally significant, since elevated TAF3 expression severely and selectively inhibits transcription activation by p53 in human cell lines, and it decreases the level of the p53 protein as well. Conclusion We identified TAF3 as an evolutionarily conserved negative regulator of p53 transcription activation function.

  14. Biotic and abiotic factors investigated in two Drosophila species – evidence of both negative and positive effects of interactions on performance

    DEFF Research Database (Denmark)

    Ørsted, Michael; Schou, Mads Fristrup; Kristensen, Torsten Nygaard

    2017-01-01

    Multiple environmental factors acting in concert can interact and strongly influence population fitness and ecosystem composition. Studies investigating interactions usually involve only two environmental factors; most frequently a chemical and another abiotic factor such as a stressful temperature...... the consequences on several performance measures. Results are highly species and trait specific with evidence of two- and three-way interactions in approximately 30% of all cases, suggesting that additive effects of combined environmental factors are most common, and that interactions are not universal. To provide...... more informative descriptions of complex interactions we implemented re-conceptualised definitions of synergism and antagonism. We found approximately equal proportions of synergistic and antagonistic interactions in both species, however the effects of interactions on performance differed between...

  15. Biotic and abiotic factors investigated in two Drosophila species – evidence of both negative and positive fitness effects of interactions on performance

    DEFF Research Database (Denmark)

    Ørsted, Michael; Schou, Mads Fristrup; Kristensen, Torsten Nygård

    2017-01-01

    Multiple environmental factors acting in concert can interact and strongly influence population fitness and ecosystem composition. Studies investigating interactions usually involve only two environmental factors; most frequently a chemical and another abiotic factor such as a stressful temperatu...... the two. Furthermore, we found negative impacts on performance in only 60% of interactions, thus our study also reveals a high proportion of cases with positive effects of interactions........ Here we investigate the effects of three environmental factors: temperature, an insecticide (dimethoate) and interspecific co-occurrence. We expose two naturally co-occurring species of Drosophila (D. hydei and D. melanogaster) to the different environments during development and examine...... the consequences on several performance measures. Results are highly species and trait specific with evidence of two- and three-way interactions in approximately 30% of all cases, suggesting that additive effects of combined environmental factors are most common, and that interactions are not universal. To provide...

  16. Functional mapping of factor VIII C2 domain.

    Science.gov (United States)

    Pellequer, Jean-Luc; Chen, Shu-wen W; Saboulard, Didier; Delcourt, Marc; Négrier, Claude; Plantier, Jean-Luc

    2011-07-01

    The factor VIII (FVIII) is a cofactor of the coagulation cascade. The FVIII C2 domain is a critical domain that participates in the interactions with the von Willebrand factor and the phospholipidic surfaces. To assess the importance of each residue of this domain in the maintenance of the structure and the function of FVIII, a number (n=139) of mutants were generated by substituting the original residues, from Ser2173 to Gly2325, by an alanine. Mutants were built within a complete B domain-deleted FVIII and expressed in COS-1 cells. Mutant antigen levels and procoagulant activities were measured. Two in silico analyses, a sliding average procedure and an analysis of the mutation energy cost were conducted in parallel on the FVIII structure. Both results were in agreement with the functional data, and illustrated the benefit of using such strategies prior to targeting specific residues in the aim of generating active recombinant molecules. The functional assays identify the residues that are important to maintaining the structure of the C2 domain, mainly those forming β-sheet, and those that can afford substitution, establishing a detailed functional relation with the available crystallographic data. This study provided a comprehensive functional mapping of the FVIII C2 domain and discussed the implication of specific residues in respect to the maintenance in the activity and structure stability, the efficiency in secretion, the binding to phospholipids and the formation of epitope.

  17. Interactions Between Anandamide and Corticotropin-Releasing Factor Signaling Modulate Human Amygdala Function and Risk for Anxiety Disorders: An Imaging Genetics Strategy for Modeling Molecular Interactions.

    Science.gov (United States)

    Demers, Catherine H; Drabant Conley, Emily; Bogdan, Ryan; Hariri, Ahmad R

    2016-09-01

    Preclinical models reveal that stress-induced amygdala activity and impairment in fear extinction reflect reductions in anandamide driven by corticotropin-releasing factor receptor type 1 (CRF1) potentiation of the anandamide catabolic enzyme fatty acid amide hydrolase. Here, we provide clinical translation for the importance of these molecular interactions using an imaging genetics strategy to examine whether interactions between genetic polymorphisms associated with differential anandamide (FAAH rs324420) and CRF1 (CRHR1 rs110402) signaling modulate amygdala function and anxiety disorder diagnosis. Analyses revealed that individuals with a genetic background predicting relatively high anandamide and CRF1 signaling exhibited blunted basolateral amygdala habituation, which further mediated increased risk for anxiety disorders among these same individuals. The convergence of preclinical and clinical data suggests that interactions between anandamide and CRF1 represent a fundamental molecular mechanism regulating amygdala function and anxiety. Our results further highlight the potential of imaging genetics to powerfully translate complex preclinical findings to clinically meaningful human phenotypes. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  18. A structure-based Multiple-Instance Learning approach to predicting in vitro transcription factor-DNA interaction.

    Science.gov (United States)

    Gao, Zhen; Ruan, Jianhua

    2015-01-01

    Understanding the mechanism of transcriptional regulation remains an inspiring stage of molecular biology. Recently, in vitro protein-binding microarray experiments have greatly improved the understanding of transcription factor-DNA interaction. We present a method - MIL3D - which predicts in vitro transcription factor binding by multiple-instance learning with structural properties of DNA. Evaluation on in vitro data of twenty mouse transcription factors shows that our method outperforms a method based on simple-instance learning with DNA structural properties, and the widely used k-mer counting method, for nineteen out of twenty of the transcription factors. Our analysis showed that the MIL3D approach can utilize subtle structural similarities when a strong sequence consensus is not available. Combining multiple-instance learning and structural properties of DNA has promising potential for studying biological regulatory networks.

  19. Systematic Analysis Reveals Elongation Factor 2 and α-Enolase as Novel Interaction Partners of AKT2.

    Directory of Open Access Journals (Sweden)

    Katharina Bottermann

    Full Text Available AKT2 is one of the three isoforms of the protein kinase AKT being involved in the modulation of cellular metabolism. Since protein-protein interactions are one possibility to convey specificity in signal transduction, we performed AKT2-protein interaction analysis to elucidate their relevance for AKT2-dependent cellular functions. We identified heat shock protein 90 kDa (HSP90, Cdc37, heat shock protein 70 kDa (HSP70, 78 kDa glucose regulated protein (GRP78, tubulin, GAPDH, α-enolase and elongation factor 2 (EF2 as AKT2-interacting proteins by a combination of tandem affinity purification and mass spectrometry in HEK293T cells. Quantitative MS-analysis using stable isotope labeling by amino acids in cell culture (SILAC revealed that only HSP90 and Cdc37 interact stably with AKT2, whereas the other proteins interact with low affinity with AKT2. The interactions of AKT2 with α-enolase and EF2 were further analyzed in order to uncover the functional relevance of these newly discovered binding partners. Despite the interaction of AKT2 and α-enolase, which was additionally validated by proximity ligation assay (PLA, no significant impact of AKT on α-enolase activity was detected in activity measurements. AKT stimulation via insulin and/or inhibition with the ATP-competitive inhibitor CCT128930 did not alter enzymatic activity of α-enolase. Interestingly, the direct interaction of AKT2 and EF2 was found to be dynamically regulated in embryonic rat cardiomyocytes. Treatment with the PI3-kinase inhibitor LY294002 before stimulation with several hormones stabilized the complex, whereas stimulation alone led to complex dissociation which was analyzed in situ with PLA. Taken together, these findings point to new aspects of AKT2-mediated signal transduction in protein synthesis and glucose metabolism.

  20. Factors affecting the properties of PLA/CaSO4 composites: homogeneity and interactions

    Directory of Open Access Journals (Sweden)

    2009-01-01

    Full Text Available Composites were prepared from poly(lactic acid (PLA and a natural CaSO4 filler to study the developed structure and the interaction of the components. The filler was characterized very thoroughly by several techniques and the results indicated that the filler contains a considerable amount of small particles with size much below the volume average size of 4.4 µm. The presence of these small particles did not result in inhomogeneity, considerable extent of aggregation was not observed in the composites. The filler was coated with stearic acid to modify interactions and optimum coverage corresponded to the amount estimated from the specific surface area of the filler. Mechanical properties changed only slightly with increasing amounts of the uncoated filler, but coating resulted in a drastic change of tensile properties and deformation behavior. Considerable plastic flow was observed around filler particles on the fracture surface of broken specimens. The quantitative estimation of interfacial interactions and their comparison to existing data proved that the interaction of PLA and CaSO4 corresponds to values observed in other mineral filled polymers. On the other hand, the reinforcing effect of the coated filler is extremely poor indicating almost zero interaction. Additional experiments proved that considerable amount of stearic acid dissolves in PLA and plasticizes the polymer. Stearic acid seems to desorb also from the surface of the filler, dissolve in the polymer and modify matrix properties.

  1. Tumor-host interactions in the gallbladder suppress distal angiogenesis and tumor growth: involvement of transforming growth factor beta1.

    Science.gov (United States)

    Gohongi, T; Fukumura, D; Boucher, Y; Yun, C O; Soff, G A; Compton, C; Todoroki, T; Jain, R K

    1999-10-01

    Angiogenesis inhibitors produced by a primary tumor can create a systemic anti-angiogenic environment and maintain metastatic tumor cells in a state of dormancy. We show here that the gallbladder microenvironment modulates the production of transforming growth factor (TGF)-beta1, a multifunctional cytokine that functions as an endogenous anti-angiogenic and anti-tumor factor in a cranial window preparation. We found that a wide variety of human gallbladder tumors express TGF-beta1 irrespective of histologic type. We implanted a gel impregnated with basic fibroblast growth factor or Mz-ChA-2 tumor in the cranial windows of mice without tumors or mice with subcutaneous or gallbladder tumors to study angiogenesis and tumor growth at a secondary site. Angiogenesis, leukocyte-endothelial interaction in vessels and tumor growth in the cranial window were substantially inhibited in mice with gallbladder tumors. The concentration of TGF-beta1 in the plasma of mice with gallbladder tumors was 300% higher than that in the plasma of mice without tumors or with subcutaneous tumors. In contrast, there was no difference in the plasma levels of other anti- and pro-angiogenic factors. Treatment with neutralizing antibody against TGF-beta1 reversed both angiogenesis suppression and inhibition of leukocyte rolling induced by gallbladder tumors. TGF-beta1 also inhibited Mz-ChA-2 tumor cell proliferation. Our results indicate that the production of anti-angiogenesis/proliferation factors is regulated by tumor-host interactions.

  2. Structural equation model of interactions between risk factors and work-related musculoskeletal complaints among Iranian hospital nurses.

    Science.gov (United States)

    Mehralizadeh, Semira; Dehdashti, Alireza; Motalebi Kashani, Masoud

    2017-01-01

    Statistics indicate a high risk of developing work-related musculoskeletal disorders among hospital nurses. The challenge is to understand the associations between musculoskeletal symptoms and various individual and occupational risk factors. This study examined the direct and indirect interactions of various risk factors with musculoskeletal complaints in hospital nurses. In a cross-sectional design, Iranian hospital nurses from Semnan University of Medical Sciences participated in a questionnaire survey reporting their perceived perceptions of various work-related risk factors and musculoskeletal symptoms. We tested our proposed structural equation model to evaluate the relations between latent and observed concepts and the relative importance and strength of exogenous variables in explaining endogenous musculoskeletal complaints. Measurement model fits the data relatively acceptable. Our findings showed direct effects of psychological, role-related and work posture stressors on musculoskeletal complaints. Fatigue mediated the adverse indirect relations of psychological, role-related, work posture and individual factors with musculoskeletal complaints. Structural equation modeling may provide methodological opportunities in occupational health research with a potential to explain the complexity of interactions among risk factors. Prevention of work-related musculoskeletal disorders among nurses must account for physical and psychosocial conditions.

  3. Antigen-specific T contrasuppressor factor in cell-mediated immunity: interactions leading to eradication of the tolerant state.

    Science.gov (United States)

    Ptak, W; Bereta, M; Ptak, M; Gershon, R K; Green, D R

    1984-09-01

    Interactions between a T cell-derived, antigen-specific, contrasuppressor factor (TcsF) and immune T cells that block the action of T suppressor factors and allow the transfer of cellular immunity into tolerant recipients are described. Immune T cells from contact-sensitized donors are capable of transferring specific immunity into normal recipients but not into animals rendered tolerant to the specific antigen. Brief exposure of the immune cells to the TcsF enables the effective transfer of immunity into such tolerant recipients. In addition, treated immune cells become resistant to subsequent exposure to T suppressor factor (capable of inhibiting transfer of immunity to normal recipients). A cyclophosphamide-sensitive, I-J+, Ly-2 T transducer cell is required in the immune donor cell population for contrasuppression to be induced by the TcsF plus specific antigen. These cells release an antigen-non-specific contrasuppressive factor capable of rendering immune targets, depleted of transducer cells, resistant to suppression (either by suppressor factor or in the tolerant recipient). The results indicate that contrasuppression in contact sensitivity is antigen specific and that the balance of suppression and contrasuppression determines tolerance vs responsiveness in this system. The symmetrical resemblance of the contrasuppressive interactions to those of suppression in contact sensitivity are discussed.

  4. Intracellular Localization and Cellular Factors Interaction of HTLV-1 and HTLV-2 Tax Proteins: Similarities and Functional Differences

    Directory of Open Access Journals (Sweden)

    Maria Grazia Romanelli

    2011-05-01

    Full Text Available Human T-lymphotropic viruses type 1 (HTLV-1 and type 2 (HTLV-2 present very similar genomic structures but HTLV-1 is more pathogenic than HTLV-2. Is this difference due to their transactivating Tax proteins, Tax-1 and Tax-2, which are responsible for viral and cellular gene activation? Do Tax-1 and Tax-2 differ in their cellular localization and in their interaction pattern with cellular factors? In this review, we summarize Tax-1 and Tax-2 structural and phenotypic properties, their interaction with factors involved in signal transduction and their localization-related behavior within the cell. Special attention will be given to the distinctions between Tax-1 and Tax-2 that likely play an important role in their transactivation activity.

  5. Structural and functional analysis of the related transcriptional enhancer factor-1 and NF-κB interaction.

    Science.gov (United States)

    Ma, Jieliang; Zhang, Li; Tipton, Aaron R; Wu, Jiaping; Messmer-Blust, Angela F; Philbrick, Melissa J; Qi, Yajuan; Liu, Song-Tao; Liu, Hongsheng; Li, Jian; Guo, Shaodong

    2014-01-15

    The related transcriptional enhancer factor-1 (RTEF-1) increases gene transcription of hypoxia-inducible factor 1α (HIF-1α) and enhances angiogenesis in endothelium. Both hypoxia and inflammatory factor TNF-α regulate gene expression of HIF-1α, but how RTEF-1 and TNF-α coordinately regulate HIF-1α gene transcription is unclear. Here, we found that RTEF-1 interacts with p65 subunit of NF-κB, a primary mediator of TNF-α. RTEF-1 increased HIF-1α promoter activity, whereas expression of p65 subunit inhibited the stimulatory effect. By contrast, knockdown of p65 markedly enhanced RTEF-1 stimulation on the HIF-1α promoter activity (7-fold). A physical interaction between RTEF-1 and p65 was confirmed by coimmunoprecipitation experiments in cells and glutathione S-transferase (GST)-pull-down assays. A computational analysis of RTEF-1 crystal structures revealed that a conserved surface of RTEF-1 potentially interacts with p65 via four amino acid residues located at T347, Y349, R351, and Y352. We performed site-directed mutagenesis and GST-pull-down assays and demonstrated that Tyr352 (Y352) in RTEF-1 is a key site for the formation of RTEF-1 and p65-NF-κB complex. An alanine mutation at Y352 of RTEF-1 disrupted the interaction of RTEF-1 with p65. Moreover, expression of RTEF-1 decreased TNF-α-induced HIF-1α promoter activity, IL-1β, and IL-6 mRNA levels in cells; however, the effect of RTEF-1 was largely lost when Y352 was mutated to alanine. These results indicate that RTEF-1 interacts with p65-NF-κB through Y352 and that they antagonize each other for HIF-1α transcriptional activation, suggesting a novel mechanism by which RTEF-1 regulates gene expression, linking hypoxia to inflammation.

  6. Role of hemostatic factors on the risk of venous thrombosis in people with impaired kidney function.

    Science.gov (United States)

    Ocak, Gürbey; Vossen, Carla Y; Lijfering, Willem M; Verduijn, Marion; Dekker, Friedo W; Rosendaal, Frits R; Cannegieter, Suzanne C

    2014-02-11

    Factors explaining the association between impaired kidney function and venous thrombosis have not been identified so far. The aim of our study was to determine whether the association between impaired kidney function and venous thrombosis can be explained by the concurrent presence of genetic or acquired venous thrombosis risk factors. The glomerular filtration rate was estimated (eGFR) in 2473 venous thrombosis patients and 2936 controls from a population-based case-control study. Kidney function was grouped into 6 categories based on percentiles of the eGFR in the controls (>50th [reference], 10th-50th, 5th-10th, 2.5th-5th, 1st-2.5th, and percentile). Several hemostatic factors showed a procoagulant shift with decreasing kidney function in controls, most notably factor VIII and von Willebrand factor. Compared with eGFR >50th percentile, factor VIII levels (adjusted mean difference, 60 IU/dL for the percentile category) and von Willebrand factor levels (adjusted mean difference, 60 IU/dL for the percentile category) increased with each percentile category. The odds ratios for venous thrombosis similarly increased across the categories from 1.1 (95% confidence interval, 0.9-1.3) for the 10th to 50th percentile to 3.7 (95% confidence interval, 2.4-5.7) for the percentile category. Adjustment for factor VIII or von Willebrand factor attenuated these odds ratios, indicating an effect of eGFR on thrombosis through these factors. Adjustments for other risk factors for venous thrombosis did not affect the odds ratios. Impaired kidney function affects venous thrombosis risk via concurrently raised factor VIII and von Willebrand factor levels.

  7. Positive Affectivity and Fear Trajectories in Infancy: Contributions of Mother-Child Interaction Factors.

    Science.gov (United States)

    Gartstein, Maria A; Hancock, Gregory R; Iverson, Sydney L

    2017-05-24

    Fear and positive emotionality were considered in a growth modeling context. Mothers, primarily Caucasian (91.9%) and of middle socioeconomic status, participated in play interactions with infants at 4 months (N = 148). Infant fear and positive affectivity were evaluated at 6, 8, 10, and 12 months of age. A linear trajectory was superior in explaining growth for parent report and observation-based indicators of positive affectivity and parent report of fearfulness; a piecewise model explained the nonlinear growth of observation-based fear. Responsiveness in mother-infant interactions emerged as a significant predictor of the fear trajectory, with higher sensitivity predicting lower levels of observed fear. Reciprocity, tempo, emotional tone, and intensity of mother-infant interactions also made significant contributions to temperament development; however, analyses addressing these were exploratory. © 2017 The Authors. Child Development © 2017 Society for Research in Child Development, Inc.

  8. True versus false parasite interactions: a robust method to take risk factors into account and its application to feline viruses.

    Directory of Open Access Journals (Sweden)

    Eléonore Hellard

    Full Text Available BACKGROUND: Multiple infections are common in natural host populations and interspecific parasite interactions are therefore likely within a host individual. As they may seriously impact the circulation of certain parasites and the emergence and management of infectious diseases, their study is essential. In the field, detecting parasite interactions is rendered difficult by the fact that a large number of co-infected individuals may also be observed when two parasites share common risk factors. To correct for these "false interactions", methods accounting for parasite risk factors must be used. METHODOLOGY/PRINCIPAL FINDINGS: In the present paper we propose such a method for presence-absence data (i.e., serology. Our method enables the calculation of the expected frequencies of single and double infected individuals under the independence hypothesis, before comparing them to the observed ones using the chi-square statistic. The method is termed "the corrected chi-square." Its robustness was compared to a pre-existing method based on logistic regression and the corrected chi-square proved to be much more robust for small sample sizes. Since the logistic regression approach is easier to implement, we propose as a rule of thumb to use the latter when the ratio between the sample size and the number of parameters is above ten. Applied to serological data for four viruses infecting cats, the approach revealed pairwise interactions between the Feline Herpesvirus, Parvovirus and Calicivirus, whereas the infection by FIV, the feline equivalent of HIV, did not modify the risk of infection by any of these viruses. CONCLUSIONS/SIGNIFICANCE: This work therefore points out possible interactions that can be further investigated in experimental conditions and, by providing a user-friendly R program and a tutorial example, offers new opportunities for animal and human epidemiologists to detect interactions of interest in the field, a crucial step in the

  9. True versus false parasite interactions: a robust method to take risk factors into account and its application to feline viruses.

    Science.gov (United States)

    Hellard, Eléonore; Pontier, Dominique; Sauvage, Frank; Poulet, Hervé; Fouchet, David

    2012-01-01

    Multiple infections are common in natural host populations and interspecific parasite interactions are therefore likely within a host individual. As they may seriously impact the circulation of certain parasites and the emergence and management of infectious diseases, their study is essential. In the field, detecting parasite interactions is rendered difficult by the fact that a large number of co-infected individuals may also be observed when two parasites share common risk factors. To correct for these "false interactions", methods accounting for parasite risk factors must be used. In the present paper we propose such a method for presence-absence data (i.e., serology). Our method enables the calculation of the expected frequencies of single and double infected individuals under the independence hypothesis, before comparing them to the observed ones using the chi-square statistic. The method is termed "the corrected chi-square." Its robustness was compared to a pre-existing method based on logistic regression and the corrected chi-square proved to be much more robust for small sample sizes. Since the logistic regression approach is easier to implement, we propose as a rule of thumb to use the latter when the ratio between the sample size and the number of parameters is above ten. Applied to serological data for four viruses infecting cats, the approach revealed pairwise interactions between the Feline Herpesvirus, Parvovirus and Calicivirus, whereas the infection by FIV, the feline equivalent of HIV, did not modify the risk of infection by any of these viruses. This work therefore points out possible interactions that can be further investigated in experimental conditions and, by providing a user-friendly R program and a tutorial example, offers new opportunities for animal and human epidemiologists to detect interactions of interest in the field, a crucial step in the challenge of multiple infections.

  10. Characterization of an Hsp90-independent interaction between the co-chaperone p23 and the transcription factor p53.

    Science.gov (United States)

    Wu, Huiwen; Hyun, Jashil; Martinez-Yamout, Maria A; Park, Sung Jean; Dyson, Jane

    2018-01-15

    The cancer-suppressing transcription factor p53 is regulated by a wide variety of cellular factors, including many chaperones. The DNA-binding domain (DBD) of p53 is known to interact with the chaperone Hsp90, but the role of other members of the chaperone network, including co-chaperones such as p23 is unknown. Using a combination of NMR titration, isothermal titration calorimetry, fluorescence anisotropy and native agarose gel electrophoresis, we have identified a direct interaction between the p53 DBD and the Hsp90 co-chaperone p23 that occurs in the absence of Hsp90. The affinity is relatively weak, and largely determined by electrostatic interactions between the acidic C-terminal disordered tail of p23 and the two DNA binding regions of p53 DBD. We show by NMR and native agarose gel electrophoresis that a p53-specific double-stranded DNA sequence competes successfully with p23 for binding to the p53 DBD. The Hsp90-independence of the interaction between p23 and p53 DBD, together with the p23-DNA competition for p53, raise the intriguing possibility that p23, like other small charged proteins, may affect the p53 in hitherto-unknown ways.

  11. Combined and Interactive Effects of Environmental and GWAS-Identified Risk Factors in Ovarian Cancer

    NARCIS (Netherlands)

    Pearce, C.L.; Rossing, M.A.; Lee, A.W.; Ness, R.B.; Webb, P.M.; Chenevix-Trench, G.; Jordan, S.M.; Stram, D.A.; Chang-Claude, J.; Hein, R.; Nickels, S.; Lurie, G.; Thompson, P.J.; Carney, M.E.; Goodman, M.T.; Moysich, K.; Hogdall, E.; Jensen, A.; Goode, E.L.; Fridley, B.L.; Cunningham, J.M.; Vierkant, R.A.; Weber, R.P.; Ziogas, A.; Anton-Culver, H.; Gayther, S.A.; Gentry-Maharaj, A.; Menon, U.; Ramus, S.J.; Brinton, L.; Wentzensen, N.; Lissowska, J.; Garcia-Closas, M.; Massuger, L.F.A.G.; Kiemeney, L.A.L.M.; Altena, A.M. van; Aben, K.K.H.; Berchuck, A.; Doherty, J.A.; Iversen, E.; McGuire, V.; Moorman, P.G.; Pharoah, P.; Pike, M.C.; Risch, H.; Sieh, W.; Stram, D.O.; Terry, K.L.; Whittemore, A.; Wu, A.H.; Schildkraut, J.M.; Kjaer, S.K.

    2013-01-01

    BACKGROUND: There are several well-established environmental risk factors for ovarian cancer, and recent genome-wide association studies have also identified six variants that influence disease risk. However, the interplay between such risk factors and susceptibility loci has not been studied.

  12. Combined and interactive effects of environmental and GWAS-identified risk factors in ovarian cancer

    DEFF Research Database (Denmark)

    Pearce, Celeste Leigh; Rossing, Mary Anne; Lee, Alice W

    2013-01-01

    There are several well-established environmental risk factors for ovarian cancer, and recent genome-wide association studies have also identified six variants that influence disease risk. However, the interplay between such risk factors and susceptibility loci has not been studied....

  13. Sorting Nexin 27 Protein Regulates Trafficking of a p21-activated Kinase (PAK) Interacting Exchange Factor (β-Pix)-G Protein-coupled Receptor Kinase Interacting Protein (GIT) Complex via a PDZ Domain Interaction*

    Science.gov (United States)

    Valdes, Julie L.; Tang, Jingrong; McDermott, Mark I.; Kuo, Jean-Cheng; Zimmerman, Seth P.; Wincovitch, Stephen M.; Waterman, Clare M.; Milgram, Sharon L.; Playford, Martin P.

    2011-01-01

    Sorting nexin 27 (SNX27) is a 62-kDa protein localized to early endosomes and known to regulate the intracellular trafficking of ion channels and receptors. In addition to a PX domain, SNX27 is the only sorting family member that contains a PDZ domain. To identify novel SNX27-PDZ binding partners, we performed a proteomic screen in mouse principal kidney cortical collecting duct cells using a GST-SNX27 fusion construct as bait. We found that β-Pix (p21-activated kinase-interactive exchange factor), a guanine nucleotide exchange factor for the Rho family of small GTPases known to regulate cell motility directly interacted with SNX27. The association of β-Pix and SNX27 is specific for β-Pix isoforms terminating in the type-1 PDZ binding motif (ETNL). In the same screen we also identified Git1/2 as a potential SNX27 interacting protein. The interaction between SNX27 and Git1/2 is indirect and mediated by β-Pix. Furthermore, we show recruitment of the β-Pix·Git complex to endosomal sites in a SNX27-dependent manner. Finally, migration assays revealed that depletion of SNX27 from HeLa and mouse principal kidney cortical collecting duct cells significantly decreases cell motility. We propose a model by which SNX27 regulates trafficking of β-Pix to focal adhesions and thereby influences cell motility. PMID:21926430

  14. Epithelial-mesenchymal interactions and lung branching morphogenesis. Role of polyamines and transforming growth factor ß1

    Directory of Open Access Journals (Sweden)

    G Stabellini

    2009-12-01

    Full Text Available Lung branching morphogenesis is a result of epithelial-mesenchymal interactions, which are in turn dependent on extracellular matrix composition and cytokine regulation. Polyamines have recently been demonstrated as able to modify chick embryo skin differentiation. In this work we have examined the effects of putrescine and spermidine during chick embryo lung morphogenesis in organotypic cultures by morphological, histochemical and biochemical examination. To verify the role of polyamines, we used specific inhibitors, such as bis-cyclohexylammonium sulphate and alfa-difluoromethylornithine, and transforming growth factor ß1, an ornithine decarboxylase and polyamine stimulator. Our data show that lung morphogenesis is significantly altered following the induced mesenchymal glycosaminoglycan changes. The increase of mesenchymal glycosaminoglycans is correlated with a stimulation of lung development in the presence of polyamines, and with its inhibition when transforming growth factor ß1 is added to the culture medium. The morphometric data show a uniform increase of both the mesenchyme and epithelial branching with spermidine and putrescine stimulus, whereas the mesenchymal substance alone is significantly increased in apical-median lung sections with transforming growth factor ß1 and transforming growth factor ß1 + spermidine lung cultures. Transforming growth factor ß1 and transforming growth factor ß1 + spermidine confirm the blocking of epithelial branching formations and fibroblast activation, and show that polyamines are unable to prevent the blocking of epithelial cells due to the inhibitory effect of transforming growth factor ß1.

  15. Interaction of Physical Exposures and Occupational Factors on Sickness Absence in Automotive Industry Workers.

    Science.gov (United States)

    Valirad, Fateme; Ghaffari, Mostafa; Abdi, Alireza; Attarchi, Mirsaeed; Mircheraghi, Seyed Farzin; Mohammadi, Saber

    2015-04-23

    Increased sickness absence in recent years has been a trouble making issue in industrial society. Identify the causes of sickness absence and its influencing factors, is an important step to control and reduce its associated complications and costs. The aim of this study was to evaluate main factors associated with the incidence of sickness absence. In 2012, a cross-sectional study on 758 employees of a car accessories producing company was applied and relevant information about the number of days and episodes of sickness absence, Disease resulting in absence from work, personal features, occupational factors and physical exposures were collected. To determine risk factors associated with sickness absence, Logistic regression analysis was used. The most common diseases leading to sickness absence in order of frequency were Respiratory diseases, musculoskeletal disorders, gastrointestinal diseases and injuries at work. Musculoskeletal disorders increased the danger of long term absence by 4/33 times. Blue collar and shift works were the most important occupational factors associated with the incidence of sickness absence. The main physical factors that affect incidence of sickness absence were frequent bending-twisting and heavy lifting. Identifying controllable factors of sickness absence and trying to prevent and modify them such as compliance of ergonomic principals to decrease physical can be effective in reducing sickness absence.

  16. A combined experimental and molecular simulation study of factors influencing interaction of quinoa proteins-carrageenan.

    Science.gov (United States)

    Montellano Duran, Natalia; Spelzini, Darío; Wayllace, Natael; Boeris, Valeria; Barroso da Silva, Fernando L

    2017-09-21

    The interaction between quinoa proteins isolate (QP isolate) and the negatively charged polysaccharide ι-Carragennan (Carr) as a function of pH was studied. Experimental measurements as turbidity, hydrophobic surface, ζ-potential, and hydrodynamic size were carried out. Associative interaction between QP and Carr was found in the pH range between 1 and 2.9. When both molecules are negatively charged (pH>5,5), a pure Coulombic repulsion regime is observed and the self-association of QP due to the Carr exclusion is proposed. In the intermediate pH range, the experimental data suggests that the charge regulation mechanism can overcome the electrostatic repulsion that may take place (and an attraction between QP and Carr can still be observed). Computational simulations by means of free energy derivatives using the Monte Carlo method were carried out to better understand the interaction mechanism between QP and Carr. QP was modeled as a single protein using one of the major proteins, Chenopodin (Ch), and Carr was modeled as a negatively charged polyelectrolyte (NCP) chain, both in the cell model framework. Simulation results showed attractive interactions in agreement with the experimental data. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Interactive Whiteboard Factor in Education: Students' Points of View and Their Problems

    Science.gov (United States)

    Aytac, Tufan

    2013-01-01

    The main purpose of this study is to investigate the students' viewpoints and the problems they face during the use of Interactive Whiteboard (IWB). This research has been applied on 202 students in primary school and high school in Ankara. In this study, the quantitative data were collected through "IWB Survey Questions" (Student…

  18. Interacting with a Computer-Simulated Pet: Factors Influencing Children's Humane Attitudes and Empathy

    Science.gov (United States)

    Tsai, Yueh-Feng; Kaufman, David

    2014-01-01

    Previous research by Tsai and Kaufman (2010a, 2010b) has suggested that computer-simulated virtual pet dogs can be used as a potential medium to enhance children's development of empathy and humane attitudes toward animals. To gain a deeper understanding of how and why interacting with a virtual pet dog might influence children's social and…

  19. Using ANN to predict E. coli accumulation in coves based on interaction amongst various physical, chemical and biological factors

    Science.gov (United States)

    Dwivedi, D.; Mohanty, B. P.; Lesikar, B. J.

    2008-12-01

    The accumulation of Escherichia Coli (E. coli) in canals, coves and streams is the result of a number of interacting processes operating at multiple spatial and temporal scales. Fate and transport of E. coli in surface water systems is governed by different physical, chemical, and biological processes. Various models developed to quantify each of these processes occurring at different scales are not so far pooled into a single predictive model. At present, very little is known about the fate and transport of E. coli in the environment. We hypothesize that E. coli population heterogeneity in canals and coves is affected by physical factors (average stream width and/ depth, secchi depth, flow and flow severity, day since precipitation, aquatic vegetation, solar radiation, dissolved and total suspended solids etc.); chemical factors (basic water quality, nutrients, organic compounds, pH, and toxicity etc.); and biological factors (type of bacterial strain, predation, and antagonism etc.). The specific objectives of this study are to: (1) examine the interactions between E. coli and various coupled physical, chemical and biological factors; (2) examine the interactions between E. coli and toxic organic pollutants and other pathogens (viruses); and (3) evaluate qualitatively the removal efficiency of E. coli. We suggest that artificial neural networks (ANN) may be used to provide a possible solution to this problem. To demonstrate the application of the approach, we develop an ANN representing E. coli accumulation in two polluted sites at Lake Granbury in the upper part of the Brazos River in North Central Texas. The graphical structure of ANN explicitly represents cause- and-effect relationship between system variables. Each of these relationships can then be quantified independently using an approach suitable for the type and scale of information available. Preliminary results revealed that E. coli concentrations in canals show seasonal variations regardless of change

  20. Interaction of human mitochondrial transcription factor A in mitochondria: its involvement in the dynamics of mitochondrial DNA nucleoids.

    Science.gov (United States)

    Kasashima, Katsumi; Endo, Hitoshi

    2015-12-01

    Mitochondrial transcription factor A (TFAM) is a key regulator of mitochondrial DNA (mtDNA). TFAM interacts with itself and forms dimers; however, the precise interaction domain in vivo has not yet been determined. We herein showed that human TFAM formed oligomers in mitochondria by in situ chemical cross-linking. We used the separated fluorescent protein, monomeric Kusabira-Green, as a reporter to monitor their self-association in mitochondria. This reporter successfully detected the TFAM-TFAM interaction in cells as fluorescent signals on mitochondria. We also found that the N-terminal high-mobility group box domain was sufficient for this interaction. The expression of the dimer-defective mutant induced enlarged mtDNA nucleoids, suggesting the importance of dimerization in the distribution of mtDNA. The reporter system also supported the association and mixture between independent nucleoids through TFAM by a cell fusion assay using hemagglutinating virus of Japan. We here, for the first time, visualized the interaction of TFAM molecules in mitochondria and proposed its implications for the dynamics of mtDNA nucleoids. © 2015 The Molecular Biology Society of Japan and Wiley Publishing Asia Pty Ltd.

  1. Hypertensive heart disease and obesity: a complex interaction between hemodynamic and not hemodynamic factors.

    Science.gov (United States)

    Sarzani, Riccardo; Bordicchia, Marica; Spannella, Francesco; Dessì-Fulgheri, Paolo; Fedecostante, Massimiliano

    2014-06-01

    The worldwide prevalence of obesity has nearly doubled, with an increase in obesity-related cardiovascular disease and mortality. Several factors are involved in the genesis of hypertension and hypertensive heart disease (HHD) in overweight/obesity. This review is focused on bridging factors between excessive adiposity and HHD, presenting a unifying hypothesis of vascular-metabolic syndrome, where an "handicap" of the natriuretic peptide system has a central role both in adipocyte dysmetabolism as well as in increased blood pressure and HHD.

  2. Parental and Infant Gender Factors in Parent–Infant Interaction: State-Space Dynamic Analysis

    Directory of Open Access Journals (Sweden)

    M. Angeles Cerezo

    2017-10-01

    Full Text Available This study aimed to investigate the influence of parental gender on their interaction with their infants, considering, as well, the role of the infant’s gender. The State Space Grid (SSG method, a graphical tool based on the non-linear dynamic system (NDS approach was used to analyze the interaction, in Free-Play setting, of 52 infants, aged 6 to 10 months, divided into two groups: half of the infants interacted with their fathers and half with their mothers. There were 50% boys in each group. MANOVA results showed no differential parenting of boys and girls. Additionally, mothers and fathers showed no differences in the Diversity of behavioral dyadic states nor in Predictability. However, differences associated with parent’s gender were found in that the paternal dyads were more “active” than the maternal dyads: they were faster in the rates per second of behavioral events and transitions or change of state. In contrast, maternal dyads were more repetitive because, once they visited a certain dyadic state, they tend to be involved in more events. Results showed a significant discriminant function on the parental groups, fathers and mothers. Specifically, the content analyses carried out for the three NDS variables, that previously showed differences between groups, showed particular dyadic behavioral states associated with the rate of Transitions and the Events per Visit ratio. Thus, the transitions involving ‘in–out’ of ‘Child Social Approach neutral – Sensitive Approach neutral’ state and the repetitions of events in the dyadic state ‘Child Play-Sensitive Approach neutral’ distinguished fathers from mothers. The classification of dyads (with fathers and mothers based on this discriminant function identified 73.10% (19/26 of the father–infant dyads and 88.5% (23/26 of the mother–infant dyads. The study of father-infant interaction using the SSG approach offers interesting possibilities because it characterizes and

  3. On the application of motivation theory to human factors/ergonomics: motivational design principles for human-technology interaction.

    Science.gov (United States)

    Szalma, James L

    2014-12-01

    Motivation is a driving force in human-technology interaction. This paper represents an effort to (a) describe a theoretical model of motivation in human technology interaction, (b) provide design principles and guidelines based on this theory, and (c) describe a sequence of steps for the. evaluation of motivational factors in human-technology interaction. Motivation theory has been relatively neglected in human factors/ergonomics (HF/E). In both research and practice, the (implicit) assumption has been that the operator is already motivated or that motivation is an organizational concern and beyond the purview of HF/E. However, technology can induce task-related boredom (e.g., automation) that can be stressful and also increase system vulnerability to performance failures. A theoretical model of motivation in human-technology interaction is proposed, based on extension of the self-determination theory of motivation to HF/E. This model provides the basis for both future research and for development of practical recommendations for design. General principles and guidelines for motivational design are described as well as a sequence of steps for the design process. Human motivation is an important concern for HF/E research and practice. Procedures in the design of both simple and complex technologies can, and should, include the evaluation of motivational characteristics of the task, interface, or system. In addition, researchers should investigate these factors in specific human-technology domains. The theory, principles, and guidelines described here can be incorporated into existing techniques for task analysis and for interface and system design.

  4. UHM–ULM interactions in the RBM39–U2AF65 splicing-factor complex

    Energy Technology Data Exchange (ETDEWEB)

    Stepanyuk, Galina A.; Serrano, Pedro; Peralta, Eigen; Farr, Carol L.; Axelrod, Herbert L.; Geralt, Michael; Das, Debanu; Chiu, Hsiu-Ju; Jaroszewski, Lukasz; Deacon, Ashley M.; Lesley, Scott A.; Elsliger, Marc-André; Godzik, Adam; Wilson, Ian A.; Wüthrich, Kurt; Salomon, Daniel R.; Williamson, James R.

    2016-03-24

    RNA-binding protein 39 (RBM39) is a splicing factor and a transcriptional co-activator of estrogen receptors and Jun/AP-1, and its function has been associated with malignant progression in a number of cancers. The C-terminal RRM domain of RBM39 belongs to the U2AF homology motif family (UHM), which mediate protein–protein interactions through a short tryptophan-containing peptide known as the UHM-ligand motif (ULM). Here, crystal and solution NMR structures of the RBM39-UHM domain, and the crystal structure of its complex with U2AF65-ULM, are reported. The RBM39–U2AF65 interaction was confirmed by co-immunoprecipitation from human cell extracts, by isothermal titration calorimetry and by NMR chemical shift perturbation experiments with the purified proteins. When compared with related complexes, such as U2AF35–U2AF65 and RBM39–SF3b155, the RBM39-UHM–U2AF65-ULM complex reveals both common and discriminating recognition elements in the UHM–ULM binding interface, providing a rationale for the known specificity of UHM–ULM interactions. This study therefore establishes a structural basis for specific UHM–ULM interactions by splicing factors such as U2AF35, U2AF65, RBM39 and SF3b155, and a platform for continued studies of intermolecular interactions governing disease-related alternative splicing in eukaryotic cells.

  5. Chromatin insulator factors involved in long-range DNA interactions and their role in the folding of the Drosophila genome.

    Science.gov (United States)

    Vogelmann, Jutta; Le Gall, Antoine; Dejardin, Stephanie; Allemand, Frederic; Gamot, Adrien; Labesse, Gilles; Cuvier, Olivier; Nègre, Nicolas; Cohen-Gonsaud, Martin; Margeat, Emmanuel; Nöllmann, Marcelo

    2014-08-01

    Chromatin insulators are genetic elements implicated in the organization of chromatin and the regulation of transcription. In Drosophila, different insulator types were characterized by their locus-specific composition of insulator proteins and co-factors. Insulators mediate specific long-range DNA contacts required for the three dimensional organization of the interphase nucleus and for transcription regulation, but the mechanisms underlying the formation of these contacts is currently unknown. Here, we investigate the molecular associations between different components of insulator complexes (BEAF32, CP190 and Chromator) by biochemical and biophysical means, and develop a novel single-molecule assay to determine what factors are necessary and essential for the formation of long-range DNA interactions. We show that BEAF32 is able to bind DNA specifically and with high affinity, but not to bridge long-range interactions (LRI). In contrast, we show that CP190 and Chromator are able to mediate LRI between specifically-bound BEAF32 nucleoprotein complexes in vitro. This ability of CP190 and Chromator to establish LRI requires specific contacts between BEAF32 and their C-terminal domains, and dimerization through their N-terminal domains. In particular, the BTB/POZ domains of CP190 form a strict homodimer, and its C-terminal domain interacts with several insulator binding proteins. We propose a general model for insulator function in which BEAF32/dCTCF/Su(HW) provide DNA specificity (first layer proteins) whereas CP190/Chromator are responsible for the physical interactions required for long-range contacts (second layer). This network of organized, multi-layer interactions could explain the different activities of insulators as chromatin barriers, enhancer blockers, and transcriptional regulators, and suggest a general mechanism for how insulators may shape the organization of higher-order chromatin during cell division.

  6. Testing for interactive and non-linear effects of risk factors for binge eating and purging eating disorders.

    Science.gov (United States)

    Allen, Karina L; Byrne, Susan M; Crosby, Ross D; Stice, Eric

    2016-12-01

    Almost no research has tested whether risk factors interact in the prediction of future eating disorder onset, which might suggest qualitatively distinct etiologic pathways. Accordingly, this prospective study tested for possible interactions between risk factors in the prediction of binge eating and purging eating disorders in adolescents. It also examined sex differences in pathways to risk. Two analytical approaches were used: (1) classification tree analysis (CTA), which is ideally suited to identifying non-linear interactions and the optimal cut-points for defining risk, with follow-up random forest analyses; and (2) two-way interaction terms in a series of logistic regression models. Data were drawn from the Western Australian Pregnancy Cohort (Raine) Study, a population-based study that followed participants from pre-birth to young adulthood. This study involved 1297 adolescents (49% male), 146 (11%) of whom developed bulimia nervosa, binge eating disorder or purging disorder in late adolescence. In CTA, sex was the first and most potent predictor of eating disorder risk with females showing a 5-fold increase in risk relative to males. For males and females, weight and eating concerns were the next most potent predictor of risk and three risk groups emerged, reflecting non-linear risk. For females with intermediate weight and eating concerns, externalizing problems emerged as an additional predictor. Interaction terms in logistic regression models did not produce significant results after correcting for multiple testing. Findings advance knowledge on risk pathways to eating disorder onset, highlight non-linear risk processes, and provide cut-points for prospectively identifying high-risk youth for prevention programs. Copyright © 2016. Published by Elsevier Ltd.

  7. The Interaction of Language-Specific and Universal Factors During the Acquisition of Morphophonemic Alternations With Exceptions.

    Science.gov (United States)

    Baer-Henney, Dinah; Kügler, Frank; van de Vijver, Ruben

    2015-09-01

    Using the artificial language paradigm, we studied the acquisition of morphophonemic alternations with exceptions by 160 German adult learners. We tested the acquisition of two types of alternations in two regularity conditions while additionally varying length of training. In the first alternation, a vowel harmony, backness of the stem vowel determines backness of the suffix. This process is grounded in substance (phonetic motivation), and this universal phonetic factor bolsters learning a generalization. In the second alternation, tenseness of the stem vowel determines backness of the suffix vowel. This process is not based in substance, but it reflects a phonotactic property of German and our participants benefit from this language-specific factor. We found that learners use both cues, while substantive bias surfaces mainly in the most unstable situation. We show that language-specific and universal factors interact in learning. Copyright © 2014 Cognitive Science Society, Inc.

  8. Strategic environmental assessment performance factors and their interaction: An empirical study in China

    Energy Technology Data Exchange (ETDEWEB)

    Li, Tianwei, E-mail: li.tianwei@mep.gov.cn [Appraisal Center for Environment and Engineering, MEP (China); Wang, Huizhi, E-mail: huizhiwangnk@163.com [Tianjin Academy of Social Sciences (China); Deng, Baole, E-mail: dengbaolekobe@126.com [Tianjin Environmental Monitoring Center (China); Ren, Wei, E-mail: wei.ren1012@gmail.com [School of the Built Environment, Oxford Brookes University (United Kingdom); Xu, He, E-mail: seacenter@nankai.edu.cn [Research center for Strategic Environmental Assessment, Nankai University (China)

    2016-07-15

    Strategic Environmental Assessment (SEA) has been seen as a preventive and participatory environmental management tool designed to integrate environmental protection into the decision-making process. However, the debate about SEA performance and effectiveness has increased in recent decades. Two main challenges exist in relation to this issue. The first is identifying the key influencing factors that affect SEA effectiveness, and the second is analyzing the relationship between SEA and these influencing factors. In this study, influencing factors were investigated through questionnaire surveys in the Chinese context, and then a Structural Equation Model (SEM) was developed and tested to identify potential links and causal relationships among factors. The associations between the independent factors were divided into direct and indirect causal associations. The results indicate that the decision-making process and policy context directly affect SEA implementation, while information and data sharing, public participation, expertise and SEA institutions are indirectly related with SEA. The results also suggest that a lack of cooperation between different sectors is an obstacle to the implementation of SEA. These findings could potentially contribute to the future management and implementation of SEA or enhance existing knowledge of SEA. The results show that the proposed model has a degree of feasibility and applicability. - Highlights: • Influencing factors were identified and investigated through questionnaire surveys. • Structural Equation Model (SEM) was developed and tested to identify potential links and causal relationships among factors. • Decision-making process and policy context directly affect SEA implementation. • Lack of cooperation among different sectors is an obstacle to the implementation of SEA. • The proposed model has a degree of feasibility and applicability.

  9. Molecular studies on IAV nucleoprotein: interaction with host factors and its role in virus life cycle

    OpenAIRE

    Batra, Jyoti

    2017-01-01

    Influenza A viruses (IAV) are obligate intracellular pathogens, causing substantial health and economic impacts worldwide. Like other RNA viruses, IAV greatly rely on the exploitation and subversion of host cellular proteins and pathways to facilitate virus replication. Insight into the molecular biology of these relationships could lead to novel antiviral strategies and has the potential to identify host specific interactions that would act as a barrier to pandemic emergence. IAV genom...

  10. Torsional and Electronic Factors Control the C-H⋅⋅⋅O Interaction.

    Science.gov (United States)

    Driver, Russell W; Claridge, Timothy D W; Scheiner, Steve; Smith, Martin D

    2016-11-07

    The precise role of non-conventional hydrogen bonds such as the C-H⋅⋅⋅O interaction in influencing the conformation of small molecules remains unresolved. Here we survey a series of β-turn mimetics using X-ray crystallography and NMR spectroscopy in conjunction with quantum calculation, and conclude that favourable torsional and electronic effects are important for the population of states with conformationally influential C-H⋅⋅⋅O interactions. Our results also highlight the challenge in attempting to deconvolute a myriad of interdependent noncovalent interactions in order to focus on the contribution of a single one. Within a small molecule that is designed to resemble the complexity of the environment within peptides and proteins, the interplay of different steric burdens, hydrogen-acceptor/-donor properties and rotational profiles illustrate why unambiguous conclusions based solely on NMR chemical shift data are extremely challenging to rationalize. © 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

  11. The Interaction between Genetic Ancestry and Breast Cancer Risk Factors among Hispanic Women: The Breast Cancer Health Disparities Study.

    Science.gov (United States)

    Hines, Lisa M; Sedjo, Rebecca L; Byers, Tim; John, Esther M; Fejerman, Laura; Stern, Mariana C; Baumgartner, Kathy B; Giuliano, Anna R; Torres-Mejia, Gabriela; Wolff, Roger K; Harrall, Kylie K; Slattery, Martha L

    2017-05-01

    Background: Hispanic women have lower breast cancer incidence rates than non-Hispanic white (NHW) women. To what extent genetic versus nongenetic factors account for this difference is unknown. Methods: Using logistic regression, we evaluated the interactive influences of established risk factors and ethnicity (self-identified and identified by ancestral informative markers) on breast cancer risk among 2,326 Hispanic and 1,854 NHW postmenopausal women from the United States and Mexico in the Breast Cancer Health Disparities Study. Results: The inverse association between the percentage of Native American (NA) ancestry and breast cancer risk was only slightly attenuated after adjusting for known risk factors [lowest versus highest quartile: odds ratio (OR) =1.39, 95% confidence interval (CI) = 1.00-1.92 among U.S. Hispanics; OR = 1.92 (95% CI, 1.29-2.86) among Mexican women]. The prevalence of several risk factors, as well as the associations with certain factors and breast cancer risk, differed according to genetic admixture. For example, higher body mass index (BMI) was associated with reduced risk among women with lower NA ancestry only [BMI 30: OR = 0.65 (95% CI, 0.44-0.98) among U.S. Hispanics; OR = 0.53 (95% CI, 0.29-0.97) among Mexicans]. The average number of risk factors among cases was inversely related to the percentage of NA ancestry. Conclusions: The lower NA ancestry groups were more likely to have the established risk factors, with the exception of BMI. Although the majority of factors were associated with risk in the expected directions among all women, BMI had an inverse association among Hispanics with lower NA ancestry. Impact: These data suggest that the established risk factors are less relevant for breast cancer development among women with more NA ancestry. Cancer Epidemiol Biomarkers Prev; 26(5); 692-701. ©2016 AACR . ©2016 American Association for Cancer Research.

  12. Evolution of the interaction between Runx2 and VDR, two transcription factors involved in osteoblastogenesis

    Directory of Open Access Journals (Sweden)

    Barriga Elias H

    2010-03-01

    Full Text Available Abstract Background The mineralized skeleton is a major evolutionary novelty that has contributed to the impressive morphological diversifications of the vertebrates. Essential to bone biology is the solidified extracellular matrix secreted by highly specialized cells, the osteoblasts. We now have a rather complete view of the events underlying osteogenesis, from a cellular, molecular, genetic, and epigenetic perspective. Because this knowledge is still largely restricted to mammals, it is difficult, if not impossible, to deduce the evolutionary history of the regulatory network involved in osteoblasts specification and differentiation. In this study, we focused on the transcriptional regulators Runx2 and VDR (the Vitamin D Receptor that, in mammals, directly interact together and stabilize complexes of co-activators and chromatin remodellers, thereby allowing the transcriptional activation of target genes involved in extracellular matrix mineralization. Using a combination of functional, biochemical, and histological approaches, we have asked if the interaction observed between Runx2 and VDR represents a recent mammalian innovation, or if it results from more ancient changes that have occurred deep in the vertebrate lineage. Results Using immunohistochemistry and in situ hybridization in developing embryos of chick, frog and teleost fishes, we have revealed that the co-expression of Runx2 and VDR in skeletal elements has been particularly strengthened in the lineage leading to amniotes. We show that the teleost Runx2 orthologue as well as the three mammalian Runx1, Runx2 and Runx3 paralogues are able to co-immunoprecipitate with the VDR protein present in nuclear extracts of rat osteoblasts stimulated with 1α,25-dihydroxyvitamin D3. In addition, the teleost Runx2 can activate the transcription of the mammalian osteocalcin promoter in transfection experiments, and this response can be further enhanced by 1α,25-dihydroxyvitamin D3. Finally

  13. Imaging of hypoxia-inducible factor 1α and septin 9 interaction by bi