Factor VII and protein C are phosphatidic acid-binding proteins.

PubMed

Tavoosi, Narjes; Smith, Stephanie A; Davis-Harrison, Rebecca L; Morrissey, James H

2013-08-20

Seven proteins in the human blood clotting cascade bind, via their GLA (γ-carboxyglutamate-rich) domains, to membranes containing exposed phosphatidylserine (PS), although with membrane binding affinities that vary by 3 orders of magnitude. Here we employed nanodiscs of defined phospholipid composition to quantify the phospholipid binding specificities of these seven clotting proteins. All bound preferentially to nanobilayers in which PS headgroups contained l-serine versus d-serine. Surprisingly, however, nanobilayers containing phosphatidic acid (PA) bound substantially more of two of these proteins, factor VIIa and activated protein C, than did equivalent bilayers containing PS. Consistent with this finding, liposomes containing PA supported higher proteolytic activity by factor VIIa and activated protein C toward their natural substrates (factors X and Va, respectively) than did PS-containing liposomes. Moreover, treating activated human platelets with phospholipase D enhanced the rates of factor X activation by factor VIIa in the presence of soluble tissue factor. We hypothesize that factor VII and protein C bind preferentially to the monoester phosphate of PA because of its accessibility and higher negative charge compared with the diester phosphates of most other phospholipids. We further found that phosphatidylinositol 4-phosphate, which contains a monoester phosphate attached to its myo-inositol headgroup, also supported enhanced enzymatic activity of factor VIIa and activated protein C. We conclude that factor VII and protein C bind preferentially to monoester phosphates, which may have implications for the function of these proteases in vivo.

Synthesis and P1' SAR exploration of potent macrocyclic tissue factor-factor VIIa inhibitors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ladziata, Vladimir; Glunz, Peter W.; Zou, Yan

Selective tissue factor-factor VIIa complex (TF-FVIIa) inhibitors are viewed as promising compounds for treating thrombotic disease. In this contribution, we describe multifaceted exploratory SAR studies of S1'-binding moieties within a macrocyclic chemotype aimed at replacing cyclopropyl sulfone P1' group. Over the course of the optimization efforts, the 1-(1H-tetrazol-5-yl)cyclopropane P1' substituent emerged as an improved alternative, offering increased metabolic stability and lower clearance, while maintaining excellent potency and selectivity.

Age-related changes in factor VII proteolysis in vivo.

PubMed

Ofosu, F A; Craven, S; Dewar, L; Anvari, N; Andrew, M; Blajchman, M A

1996-08-01

Previous studies have reported that pre-operative plasmas of patients over the age of 40 years who developed post-operative deep vein thrombosis (DVT) had approximately twice the amount of proteolysed factor VII found in plasmas of patients in whom prophylaxis with heparin or low M(r) heparin was successful. These and other studies also reported higher concentrations of thrombin-antithrombin III in pre- and post-operative plasmas of patients who developed post-operative thrombosis than in plasmas of patients in whom prophylaxis was successful. Whether the extent of factor VII proteolysis seen in the patients who developed post-operative DVT is related to the severity of their disease or age is not known. This report investigated age-related changes in the concentrations of total factor VII protein, factor VII zymogen, factor VIIa, tissue factor pathway inhibitor, thrombin-antithrombin III, and prothrombin fragment 1 + 2 in normal plasmas and the relationships between these parameters. With the exception of thrombin-antithrombin III, statistically significant increases in the concentrations of these parameters with age were found. Additionally, the differences between the concentrations of total factor VII protein and factor VII zymogen, an index factor VII proteolysis in vivo, were statistically significant only for individuals over age 40. Using linear regression analysis, a significant correlation was found to exist between the concentrations of plasma factor VIIa and prothrombin fragment 1 + 2. Since factor VIIa-tissue factor probably initiates coagulation in vivo, we hypothesize that the elevated plasma factor VIIa (reflecting a less tightly regulated tissue factor activity and therefore increased thrombin production in vivo) accounts for the high risk for post-operative thrombosis seen in individuals over the age of 40.

26 CFR 25.2522(c)-3T - Transfers not exclusively for charitable, etc., purposes in the case of gifts made after July 31...

Code of Federal Regulations, 2010 CFR

2010-04-01

...) and (c)(2)(vii)(a) of this section that guaranteed annuity interests or unitrust interests... uses an individual other than one permitted in paragraphs (c)(2)(vi)(a) and (c)(2)(vii)(a) of this... of years is determined by taking the factor for valuing the annuity or unitrust interest for the...

Successful use of recombinant factor VIIa in a preterm infant with life-threatening haematuria.

PubMed

Faust, Kirstin; Tröger, Birthe; Kahl, Fritz; Schumacher, Marius; Göpel, Wolfgang; Härtel, Christoph

2009-10-01

We report the case of a preterm male infant with a gestational age of 28 + 1 weeks and birth weight of 715 g who presented with life-threatening haematuria on day 28 of life. The haematuria was unresponsive to administration of platelet concentrates and fresh frozen plasma, but then successfully treated with recombinant factor VIIa. The resulting obstructive uropathy was managed by continuous bladder irrigation through suprapubic and urethral catheters. No other adverse affects were noted, and the boy was discharged from the hospital on day 108 of life.

Thrombin generation during cardiopulmonary bypass: the possible role of retransfusion of blood aspirated from the surgical field

PubMed Central

Weerwind, Patrick W; Lindhout, Theo; Caberg, Nicole EH; de Jong, Dick S

2003-01-01

Background In spite of using heparin-coated extracorporeal circuits, cardiopulmonary bypass (CPB) is still associated with an extensive thrombin generation, which is only partially suppressed by the use of high dosages of heparin. Recent studies have focused on the origins of this thrombotic stimulus and the possible role of retransfused suctioned blood from the thoracic cavities on the activation of the extrinsic coagulation pathway. The present study was designed to find during CPB an association between retransfusion of suctioned blood from the pericardium and pleural space, containing activated factor VIIa and systemic thrombin generation. Methods Blood samples taken from 12 consenting patients who had elective cardiac surgery were assayed for plasma factor VIIa, prothrombin fragment 1+2 (F1+2), and thrombin-antithrombin (TAT) concentrations. Blood aspirated from the pericardium and pleural space was collected separately, assayed for F1+2, TAT, and factor VIIa and retransfused to the patient after the aorta occlusion. Results After systemic heparinization and during CPB thrombin generation was minimal, as indicated by the lower than base line plasma levels of F1+2, and TAT after correction for hemodilution. In contrast, blood aspirated from the thoracic cavities had significantly higher levels of factor VIIa, F1+2, and TAT compared to the simultaneous samples from the blood circulation (P < 0.05). Furthermore, after retransfusion of the suctioned blood (range, 200–1600 mL) circulating levels of F1+2, and TAT rose significantly from 1.6 to 2.9 nmol/L (P = 0.002) and from 5.1 to 37.5 μg/L (P = 0.01), respectively. The increase in both F1+2, and TAT levels correlated significantly with the amount of retransfused suctioned blood (r = 0.68, P = 0.021 and r = 0.90, P = 0.001, respectively). However, the circulating factor VIIa levels did not correlate with TAT and F1+2 levels. Conclusions These data suggest that blood aspirated from the thoracic cavities during CPB is highly thrombogenic. Retransfusion of this blood may, therefore, promote further systemic thrombin generation during CPB. PMID:12904260

Selective tissue factor/factor VIIa Inhibitor, ER-410660, and its prodrug, E5539, have anti-venous and anti-arterial thrombotic effects with a low risk of bleeding.

PubMed

Nagakura, Tadashi; Tabata, Kimiyo; Kira, Kazunobu; Hirota, Shinsuke; Clark, Richard; Matsuura, Fumiyoshi; Hiyoshi, Hironobu

2013-08-01

Many anticoagulant drugs target factors common to both the intrinsic and extrinsic coagulation pathways, which may lead to bleeding complications. Since the tissue factor (TF)/factor VIIa complex is associated with thrombosis onset and specifically activates the extrinsic coagulation pathway, compounds that inhibit this complex may provide therapeutic and/or prophylactic benefits with a decreased risk of bleeding. The in vitro enzyme profile and anticoagulation selectivity of the TF/VIIa complex inhibitor, ER-410660, and its prodrug E5539 were assessed using enzyme inhibitory and plasma clotting assays. In vivo effects of ER-410660 and E5539 were determined using a TF-induced, thrombin generation rhesus monkey model; a stasis-induced, venous thrombosis rat model; a photochemically induced, arterial thrombosis rat model; and a rat tail-cut bleeding model. ER-410660 selectively prolonged prothrombin time, but had a less potent anticoagulant effect on the intrinsic pathway. It also exhibited a dose-dependent inhibitory effect on thrombin generation caused by TF-injection in the rhesus monkey model. ER-410660 also reduced venous thrombus weights in the TF-administered, stasis-induced, venous thrombosis rat model and prolonged the occlusion time induced by arterial thrombus formation after vascular injury. The compound was capable of doubling the total bleeding time in the rat tail-cut model, albeit with a considerably higher dose compared to the effective dose in the venous and arterial thrombosis models. Moreover, E5539, an orally available ER-410660 prodrug, reduced the thrombin-anti-thrombin complex levels, induced by TF-injection, in a dose-dependent manner. Selective TF/VIIa inhibitors have potential as novel anticoagulants with a lower propensity for enhancing bleeding. Copyright © 2013 Elsevier Ltd. All rights reserved.

Coagulation under flow: the influence of flow-mediated transport on the initiation and inhibition of coagulation.

PubMed

Fogelson, Aaron L; Tania, Nessy

2005-01-01

A mathematical model of intravascular coagulation is presented; it encompasses the biochemistry of the tissue factor pathway, platelet activation and deposition on the subendothelium, and flow- and diffusion-mediated transport of coagulation proteins and platelets. Simulation experiments carried out with the model indicate the predominant role played by the physical processes of platelet deposition and flow-mediated removal of enzymes in inhibiting coagulation in the vicinity of vascular injury. Sufficiently rapid production of factors IXa and Xa by the TF:VIIa complex can overcome this inhibition and lead to formation of significant amounts of the tenase complex on the surface of activated platelets and, as a consequence, to substantial thrombin production. Chemical inhibitors are seen to play almost no (TFPI) or little (AT-III and APC) role in determining whether substantial thrombin production will occur. The role of APC is limited by the necessity for diffusion of thrombin from the site of injury to nearby endothelial cells to form the thrombomodulin-thrombin complex and for diffusion in the reverse direction of the APC made by this complex. TFPI plays an insignificant part in inhibiting the TF:VIIa complex under the conditions studied whether its action involves sequential binding of TFPI to Xa and then TFPI:Xa to TF:VIIa, or direct binding of TFPI to Xa already bound to the TF:VIIa complex. Copyright 2005 S. Karger AG, Basel.

Highly active anticancer curcumin analogues.

PubMed

Mosley, Cara A; Liotta, Dennis C; Snyder, James P

2007-01-01

Curcumin, a compound in the human food supply, represents a near-perfect starting point for drug discovery. Consequently, a number of research groups have taken the natural product as a starting point to prepare and biologically evaluate a wide variety of curcumin analogues. One widely used structural modification truncates the central conjugated beta-diketone in curcumin to the monocarbonyl dienone. A diverse array of the latter compounds exhibit cytotoxicities against an equally diverse set of cancer-related cell lines. Importantly, these compounds still retain toxicity profiles in rodents comparable to the parent natural product, whereas some analogues (e.g., EF-24, 41) exhibit good oral bioavailability and good pharmacokinetics in mice. Thiol conjugates of EF-24 analogues have been prepared that address stability and solubility issues while demonstrating cellular activities similar to the unmodified dienones. In parallel experiments, the factor VIIa-tissue factor complex (fVIIa-TF) has been exploited to develop a targeting strategy for the analogues. In particular, the EF24-FFRck-fVIIa protein conjugate is not only somewhat more effective relative to the drug alone against breast cancer and melanocyte cells. Both simple curcumin analogues and the protein conjugate evidence antiangiogenic activity in cell culture. The implication is that the fVIIa-TF targeting process, like the dienone drugs, permits a double-pronged attack with the potential to destroy a tumor directly by apoptosis.

Arginine mimetic structures in biologically active antagonists and inhibitors.

PubMed

Masic, Lucija Peterlin

2006-01-01

Peptidomimetics have found wide application as bioavailable, biostable, and potent mimetics of naturally occurring biologically active peptides. L-Arginine is a guanidino group-containing basic amino acid, which is positively charged at neutral pH and is involved in many important physiological and pathophysiological processes. Many enzymes display a preference for the arginine residue that is found in many natural substrates and in synthetic inhibitors of many trypsin-like serine proteases, e.g. thrombin, factor Xa, factor VIIa, trypsin, and in integrin receptor antagonists, used to treat many blood-coagulation disorders. Nitric oxide (NO), which is produced by oxidation of L-arginine in an NADPH- and O(2)-dependent process catalyzed by isoforms of nitric oxide synthase (NOS), exhibits diverse roles in both normal and pathological physiologies and has been postulated to be a contributor to the etiology of various diseases. Development of NOS inhibitors as well as analogs and mimetics of the natural substrate L-arginine, is desirable for potential therapeutic use and for a better understanding of their conformation when bound in the arginine binding site. The guanidino residue of arginine in many substrates, inhibitors, and antagonists forms strong ionic interactions with the carboxylate of an aspartic acid moiety, which provides specificity for the basic amino acid residue in the active side. However, a highly basic guanidino moiety incorporated in enzyme inhibitors or receptor antagonists is often associated with low selectivity and poor bioavailability after peroral application. Thus, significant effort is focused on the design and preparation of arginine mimetics that can confer selective inhibition for specific trypsin-like serine proteases and NOS inhibitors as well as integrin receptor antagonists and possess reduced basicity for enhanced oral bioavailability. This review will describe the survey of arginine mimetics designed to mimic the function of the arginine moiety in numerous peptidomimetic compounds (thrombin inhibitors, factor Xa inhibitors, factor VIIa inhibitors, integrin receptor antagonists, nitric oxide synthase inhibitors), with the aim of obtaining better activity, selectivity and oral bioavailability.

Effect of Recombinant Factor VIIa as an Adjunctive Therapy in Damage Control for Wartime Vascular Injuries: A Case Control Study

DTIC Science & Technology

2009-04-01

Axillary 1 1 2 4 Iliac 2 2 4 Profunda femoral 1 3 4 Femoral 3 1 1 1 2 1 8 Popliteal 1 2 3 Total 9 1 2 4 25 6 20 2 3 72 * Followed by SV graft...VIIa [database on the Internet ]: US Department of Defense. Available at: https://jpta.fhp.osd.mil. Accessed 2007. 10. Boffard KD, Riou B, Warren B, et al

Use of Recombinant Factor VIIa in a Pediatric Patient With Initial Presentation of Refractory Acute Immune Thrombocytopenic Purpura and Severe Bleeding

PubMed Central

Gurion, Reut; Siu, Anita; Weiss, Aaron R.; Masterson, Margaret

2012-01-01

Severe bleeding in acute immune thrombocytopenic purpura (ITP) is rare but can cause significant complications to the patient. Here we report the case of a pediatric patient with acute ITP and hematuria refractory to anti-D immune globulin, high dose intravenous immunoglobulin G, and high dose steroids. Her hematuria was successfully treated with recombinant factor VIIa (rFVIIa). While further investigation on the use of rFVIIa in ITP is warranted, this case report contributes to the pediatric literature for its use during the course of an initial presentation of ITP with hemorrhagic complications. PMID:23258971

DOE Office of Scientific and Technical Information (OSTI.GOV)

Parvinen, M.; Soeder, O.M.; Mali, P.

Levels of rat testicular interleukin-1-like factor (tIL-1) have been shown to correlate with DNA synthetic activity during the cycle of the rat seminiferous epithelium, suggesting its role as a spermatogonial or meiotic growth factor. To explore this further, a new in vitro model system was developed. Rat seminiferous tubule segments from stages I, V, VIIa, and VIII-IX of the cycle were isolated by transillumination-assisted microdissection, cultured in chemically defined serum-free medium supplemented with human recombinant IL-1 {alpha}, and labeled with (3H)thymidine. During incubation, spontaneous progression of spermatogenesis was noted. Inactive stage VIIa tubule segments differentiated to stage VIII and initiatedmore » DNA synthesis, and concomitantly started to secrete IL-1-like factor. DNA synthesis of stages VIII-IX ceased through differentiation of spermatocytes to leptotene-zygotene (stages XII-XIII of the cycle). IL-1 {alpha} stimulated DNA synthesis significantly in spermatogonia of stage I. Meiotic DNA synthesis at stage VIIa was stimulated (48 h/34 C) and maintained at stages VIII-IX (48 h/34 C). IL-1 {alpha} seems to act as a regulator of spermatogenic DNA synthesis in both mitotic and meiotic phases. It has mainly stimulating and maintaining effects, but it may also be inhibitory under certain conditions.« less

Myosin VIIa, harmonin and cadherin 23, three Usher I gene products that cooperate to shape the sensory hair cell bundle

PubMed Central

Boëda, Batiste; El-Amraoui, Aziz; Bahloul, Amel; Goodyear, Richard; Daviet, Laurent; Blanchard, Stéphane; Perfettini, Isabelle; Fath, Karl R.; Shorte, Spencer; Reiners, Jan; Houdusse, Anne; Legrain, Pierre; Wolfrum, Uwe; Richardson, Guy; Petit, Christine

2002-01-01

Deaf-blindness in three distinct genetic forms of Usher type I syndrome (USH1) is caused by defects in myosin VIIa, harmonin and cadherin 23. Despite being critical for hearing, the functions of these proteins in the inner ear remain elusive. Here we show that harmonin, a PDZ domain-containing protein, and cadherin 23 are both present in the growing stereocilia and that they bind to each other. Moreover, we demonstrate that harmonin b is an F-actin-bundling protein, which is thus likely to anchor cadherin 23 to the stereocilia microfilaments, thereby identifying a novel anchorage mode of the cadherins to the actin cytoskeleton. Moreover, harmonin b interacts directly with myosin VIIa, and is absent from the disorganized hair bundles of myosin VIIa mutant mice, suggesting that myosin VIIa conveys harmonin b along the actin core of the developing stereocilia. We propose that the shaping of the hair bundle relies on a functional unit composed of myosin VIIa, harmonin b and cadherin 23 that is essential to ensure the cohesion of the stereocilia. PMID:12485990

EXTRINSIC COAGULATION BLOCKADE ATTENUATES LUNG INJURY AND PROINFLAMMATORY CYTOKINE RELEASE AFTER INTRATRACHEAL LIPOPOLYSACCHARIDE

EPA Science Inventory

Initiation of coagulation by tissue factor (TF) is a potentially powerful regulator of local inflammatory responses. We hypothesized that blockade of TF-factor VIIa (FVIIa) complex would decrease lung inflammation and proinflammatory cytokine release after tracheal instillation o...

Impacts of Usher syndrome type IB mutations on human myosin VIIa motor function.

PubMed

Watanabe, Shinya; Umeki, Nobuhisa; Ikebe, Reiko; Ikebe, Mitsuo

2008-09-09

Usher syndrome (USH) is a human hereditary disorder characterized by profound congenital deafness, retinitis pigmentosa, and vestibular dysfunction. Myosin VIIa has been identified as the responsible gene for USH type 1B, and a number of missense mutations have been identified in the affected families. However, the molecular basis of the dysfunction of USH gene, myosin VIIa, in the affected families is unknown to date. Here we clarified the effects of USH1B mutations on human myosin VIIa motor function for the first time. The missense mutations of USH1B significantly inhibited the actin activation of ATPase activity of myosin VIIa. G25R, R212C, A397D, and E450Q mutations abolished the actin-activated ATPase activity completely. P503L mutation increased the basal ATPase activity for 2-3-fold but reduced the actin-activated ATPase activity to 50% of the wild type. While all of the mutations examined, except for R302H, reduced the affinity for actin and the ATP hydrolysis cycling rate, they did not largely decrease the rate of ADP release from actomyosin, suggesting that the mutations reduce the duty ratio of myosin VIIa. Taken together, the results suggest that the mutations responsible for USH1B cause the complete loss of the actin-activated ATPase activity or the reduction of duty ratio of myosin VIIa.

Impacts of Usher Syndrome Type IB Mutations on Human Myosin VIIa Motor Function†

PubMed Central

Watanabe, Shinya; Umeki, Nobuhisa; Ikebe, Reiko; Ikebe, Mitsuo

2010-01-01

Usher syndrome (USH) is a human hereditary disorder characterized by profound congenital deafness, retinitis pigmentosa and vestibular dysfunction. Myosin VIIa has been identified as the responsible gene for USH type 1B, and a number of missense mutations have been identified in the affected families. However, the molecular basis of the dysfunction of USH gene, myosin VIIa, in the affected families is unknown to date. Here we clarified the effects of USH1B mutations on human myosin VIIa motor function for the first time. The missense mutations of USH1B significantly inhibited the actin activation of ATPase activity of myosin VIIa. G25R, R212C, A397D and E450Q mutations abolished the actin-activated ATPase activity completely. P503L mutation increased the basal ATPase activity for 2-3 fold, but reduced the actin-activated ATPase activity to 50% of the wild type. While all the mutations examined, except for R302H, reduced the affinity for actin and the ATP hydrolysis cycling rate, they did not largely decrease the rate of ADP release from acto-myosin, suggesting that the mutations reduce the duty ratio of myosin VIIa. Taken together, the results suggest that the mutations responsible for USH1B cause the complete loss of the actin-activated ATPase activity or the reduction of duty ratio of myosin VIIa. PMID:18700726

Human Usher 1B/mouse shaker-1: the retinal phenotype discrepancy explained by the presence/absence of myosin VIIA in the photoreceptor cells.

PubMed

el-Amraoui, A; Sahly, I; Picaud, S; Sahel, J; Abitbol, M; Petit, C

1996-08-01

Usher syndrome type 1 (USH1) associates severe congenital deafness, vestibular dysfunction and progressive retinitis pigmentosa leading to blindness. The gene encoding myosin VIIA is responsible for USH1B. Mutations in the murine orthologous gene lead to the shaker-1 phenotype, which manifests cochlear and vestibular dysfunction, without any retinal defect. To address this phenotypic discrepancy, the expression of myosin VIIA in retinal cells was analyzed in human and mouse during embryonic development and adult life. In the human embryo, myosin VIIA was present first in the pigment epithelium cells, and later in these cells as well as in the photoreceptor cells. In the adult human retina, myosin VIIA was present in both cell types. In contrast, in mouse, only pigment epithelium cells expressed the protein throughout development and adult life. Myosin VIIA was also found to be absent in the photoreceptor cells of other rodents (rat and guinea-pig), whereas these cells expressed the protein in amphibians, avians and primates. These observations suggest that retinitis pigmentosa of USH1B results from a primary rod and cone defect. The USH1B/shaker-1 paradigm illustrates a species-specific cell pattern of gene expression as a possible cause for the discrepancy between phenotypes involving defective orthologous genes in man and mouse. Interestingly, in the photoreceptor cells, myosin VIIA is mainly localized in the inner and base of outer segments as well as in the synaptic ending region where it is co-localized with the synaptic vesicles. Therefore, we suggest that myosin VIIA might play a role in the trafficking of ribbon-synaptic vesicle complexes and the renewal processes of the outer photoreceptor disks.

Postpartum hemorrhage in a Jehovah's Witness patient controlled with Tisseel, tranexamic acid, and recombinant factor VIIa.

PubMed

Arab, Tarek Samir; Al-Wazzan, Ahmad Bakr; Maslow, Ken

2010-10-01

The management of a patient refusing blood transfusion who subsequently experiences a severe postpartum hemorrhage is a particular clinical challenge. A 30-year-old nulliparous patient (who was a Jehovah's Witness) had labour induced for post-dates at 41+4 weeks' gestational age after an uncomplicated pregnancy. She delivered by Caesarean section for dystocia and suspected chorioamnionitis, and subsequently developed postpartum hemorrhage that required management with oxytocin, ergometrine, carboprost, uterine artery ligation, and Hayman compression sutures. The patient ultimately required two additional visits to the operating room, culminating in hysterectomy. Use of tranexamic acid, recombinant factor VIIa, and Tisseel was instrumental in halting the ongoing hemorrhage. Optimal management of a patient refusing administration of blood products requires a multidisciplinary approach as well as a combination of traditional and novel therapies.

26 CFR 20.2055-2T - Transfers not exclusively for charitable purposes (temporary).

Code of Federal Regulations, 2010 CFR

2010-04-01

...)(iii) The rule in paragraphs (e)(2)(vi)(a) and (e)(2)(vii)(a) of this section that guaranteed annuity... application of this rule in paragraphs (e)(2)(vi)(a) and (e)(2)(vii)(a) of this section are provided in the...) and (vii)(a) of this section, and the interest does not qualify for this transitional relief, the...

Myosin VIIa as a common component of cilia and microvilli.

PubMed

Wolfrum, U; Liu, X; Schmitt, A; Udovichenko, I P; Williams, D S

1998-01-01

The distribution of myosin VIIa, which is defective or absent in Usher syndrome 1B, was studied in a variety of tissues by immunomicroscopy. The primary aim was to determine whether this putative actin-based mechanoenzyme is a common component of cilia. Previously, it has been proposed that defective ciliary function might be the basis of some forms of Usher syndrome. Myosin VIIa was detected in cilia from cochlear hair cells, olfactory neurons, kidney distal tubules, and lung bronchi. It was also found to cofractionate with the axonemal fraction of retinal photoreceptor cells. Immunolabeling appeared most concentrated in the periphery of the transition zone of the cilia. This general presence of a myosin in cilia is surprising, given that cilia are dominated by microtubules, and not actin filaments. In addition to cilia, myosin VIIa was also found in actin-rich microvilli of different types of cell. We conclude that myosin VIIa is a common component of cilia and microvilli.

Platelet Glycoprotein lb-1X and Malignancy

DTIC Science & Technology

2011-09-01

Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets. Proc Natl Acad Sci...JM, Hakim J, de Prost D. Vascular endothelial growth factor production by fibroblasts in response to factor VIIa binding to tissue factor involves...interactions in vitro. (14) The extrinsic pathway of coagulation triggered by factor VII ( FVII ) and tissue factor can be activated in cancer patients. (15

Human myosin VIIa is a very slow processive motor protein on various cellular actin structures.

PubMed

Sato, Osamu; Komatsu, Satoshi; Sakai, Tsuyoshi; Tsukasaki, Yoshikazu; Tanaka, Ryosuke; Mizutani, Takeomi; Watanabe, Tomonobu M; Ikebe, Reiko; Ikebe, Mitsuo

2017-06-30

Human myosin VIIa (MYO7A) is an actin-linked motor protein associated with human Usher syndrome (USH) type 1B, which causes human congenital hearing and visual loss. Although it has been thought that the role of human myosin VIIa is critical for USH1 protein tethering with actin and transportation along actin bundles in inner-ear hair cells, myosin VIIa's motor function remains unclear. Here, we studied the motor function of the tail-truncated human myosin VIIa dimer (HM7AΔTail/LZ) at the single-molecule level. We found that the HM7AΔTail/LZ moves processively on single actin filaments with a step size of 35 nm. Dwell-time distribution analysis indicated an average waiting time of 3.4 s, yielding ∼0.3 s -1 for the mechanical turnover rate; hence, the velocity of HM7AΔTail/LZ was extremely slow, at 11 nm·s -1 We also examined HM7AΔTail/LZ movement on various actin structures in demembranated cells. HM7AΔTail/LZ showed unidirectional movement on actin structures at cell edges, such as lamellipodia and filopodia. However, HM7AΔTail/LZ frequently missed steps on actin tracks and exhibited bidirectional movement at stress fibers, which was not observed with tail-truncated myosin Va. These results suggest that the movement of the human myosin VIIa motor protein is more efficient on lamellipodial and filopodial actin tracks than on stress fibers, which are composed of actin filaments with different polarity, and that the actin structures influence the characteristics of cargo transportation by human myosin VIIa. In conclusion, myosin VIIa movement appears to be suitable for translocating USH1 proteins on stereocilia actin bundles in inner-ear hair cells. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Early recombinant factor VIIa therapy in acute intracerebral hemorrhage: promising approach.

PubMed

Kumar, Sudhir; Badrinath, H R

2006-03-01

Intracerebral hemorrhage (ICH) is the most devastating form of stroke with a high morbidity and mortality. ICH constitutes about 20-30% of all strokes, with the prevalence being higher in Asian population. Treatment of ICH is predominantly conservative, which includes control of blood pressure, use of anti-cerebral edema measures such as mannitol and mechanical ventilation. The benefit of early surgery in ICH is debatable. Initial hematoma volume and subsequent growth in its size are important predictors of a poor outcome in ICH. This means that therapies aimed at preventing hematoma enlargement in the earliest possible window period could lead to a better outcome in ICH. Recombinant factor VIIa (rFVIIa) is one such agent, which has been shown to prevent hematoma expansion and improve outcome in acute ICH. The purpose of the current review is to focus on the evidence regarding the usefulness of rFVIIa in acute ICH.

Is prophylaxis required for delivery in women with factor VII deficiency?

PubMed Central

Baumann Kreuziger, Lisa M.; Morton, Colleen T.; Reding, Mark T.

2013-01-01

Introduction Factor VII (fVII) deficiency is a rare congenital bleeding disorder in which fVII activity level and bleeding tendency do not completely correlate. Pregnancy and delivery present a significant hemostatic challenge to women with fVII deficiency. Treatment with recombinant factor VIIa (rfVIIa) carries a thrombotic risk and the literature is unclear whether prophylaxis is necessary prior to delivery. Aim To define management, hemorrhagic and thrombotic complications of pregnant women with fVII deficiency through a systematic review. Methods Medical databases (PubMed, MEDLINE, CINAHL, Academic Search Premier, Cochrane Library, Web of Science and Scopus) were searched using “factor VII deficiency” and “pregnancy” or “surgery.” Overall 34 articles, 4 abstracts, and 3 institutional cases were reviewed. Results Literature from 1953–2011 reported 94 live births from 62 women with fVII deficiency. The median fVII activity was 5.5%. Hemostatic prophylaxis was used in 32% of deliveries. Without prophylaxis, 40 vaginal deliveries and 16 cesarean sections were completed. The odds of receiving prophylaxis were 2.9 times higher in women undergoing cesarean section compared to vaginal delivery. Post-partum hemorrhage occurred in 10% of deliveries with prophylaxis and 13% of deliveries without prophylaxis. The fVII level did not significantly differ between women who did and did not receive prophylaxis. Conclusion We present the only systematic review of the management of pregnancy in fVII deficient women. No difference in post-partum hemorrhage was seen in deliveries with and without prophylaxis. Therefore we recommend that rfVIIa be available in the case of hemorrhage or surgical intervention, but not as mandatory prophylaxis. PMID:23607277

Is prophylaxis required for delivery in women with factor VII deficiency?

PubMed

Baumann Kreuziger, L M; Morton, Colleen T; Reding, Mark T

2013-11-01

Factor VII (fVII) deficiency is a rare congenital bleeding disorder in which fVII activity level and bleeding tendency do not completely correlate. Pregnancy and delivery present a significant haemostatic challenge to women with fVII deficiency. Treatment with recombinant factor VIIa (rfVIIa) carries a thrombotic risk and the literature is not clear whether prophylaxis is necessary prior to delivery. The aim of this study was to define management, haemorrhagic and thrombotic complications of pregnant women with fVII deficiency through a systematic review. Medical databases (PubMed, MEDLINE, CINAHL, Academic Search Premier, Cochrane Library, Web of Science and Scopus) were searched using "factor VII deficiency" and "pregnancy" or "surgery." Overall 34 articles, four abstracts, and three institutional cases were reviewed. Literature from 1953 to 2011 reported 94 live births from 62 women with fVII deficiency. The median fVII activity was 5.5%. Haemostatic prophylaxis was used in 32% of deliveries. Without prophylaxis, 40 vaginal deliveries and 16 caesarean sections were completed. The odds of receiving prophylaxis were 2.9 times higher in women undergoing caesarean section compared to vaginal delivery. Post-partum haemorrhage occurred in 10% of deliveries with prophylaxis and 13% of deliveries without prophylaxis. The fVII level did not significantly differ between women who did and did not receive prophylaxis. We present the only systematic review of the management of pregnancy in fVII deficient women. No difference in post-partum haemorrhage was seen in deliveries with and without prophylaxis. Therefore, we recommend that rfVIIa be available in the case of haemorrhage or surgical intervention, but not as mandatory prophylaxis. © 2013 John Wiley & Sons Ltd.

Identification of a novel mutation in the myosin VIIA motor domain in a family with autosomal dominant hearing loss (DFNA11).

PubMed

Di Leva, Francesca; D'Adamo, Pio; Cubellis, Maria Vittoria; D'Eustacchio, Angela; Errichiello, Monica; Saulino, Claudio; Auletta, Gennaro; Giannini, Pasquale; Donaudy, Francesca; Ciccodicola, Alfredo; Gasparini, Paolo; Franzè, Annamaria; Marciano, Elio

2006-01-01

We ascertained a large Italian family with an autosomal dominant form of non-syndromic sensorineural hearing loss with vestibular involvement. A genome-wide scan found linkage to locus DFNA11. Sequencing of the MYO7A gene in the linked region identified a new missense mutation resulting in an Ala230Val change in the motor domain of the myosin VIIA. Myosin VIIA has already been implicated in several forms of deafness, but this is the third mutation causing a dominant form of deafness, located in the myosin VIIA motor domain in a region never involved in hearing loss until now. A modelled protein structure of myosin VII motor domain provides evidence for a significant functional effect of this missense mutation. Copyright (c) 2006 S. Karger AG, Basel.

Thromboelastography to Direct the Administration of Recombinant Activated Factor VII in a Child with Traumatic Injury Requiring Massive Transfusion

DTIC Science & Technology

2009-01-01

in a child with hemophilia and high titer inhibitors to factor VIII: A case report and brief review. J Extra Cor- por Technol 2006; 38:254–259 16...J Trauma 1969; 9:939–965 20. Sorensen B, Ingerslev J: Thromboelastogra- phy and recombinant factor VIIa- hemophilia and beyond. Semin Hematol 2004; 41

Cost-utility analysis of an adjunctive recombinant activated factor VIIa for on-demand treatment of bleeding episodes in dengue haemorrhagic fever.

PubMed

Naing, Cho; Poovorawan, Yong; Mak, Joon Wah; Aung, Kyan; Kamolratankul, Pirom

2015-06-01

The present study aimed to assess the cost-utility analysis of using an adjunctive recombinant activated factor VIIa (rFVIIa) in children for controlling life-threatening bleeding in dengue haemorrhagic fever (DHF)/dengue shock syndrome (DSS). We constructed a decision-tree model, comparing a standard care and the use of an additional adjuvant rFVIIa for controlling life-threatening bleeding in children with DHF/DSS. Cost and utility benefit were estimated from the societal perspective. The outcome measure was cost per quality-adjusted life years (QALYs). Overall, treatment with adjuvant rFVIIa gained QALYs, but the total cost was higher. The incremental cost-utility ratio for the introduction of adjuvant rFVIIa was $4241.27 per additional QALY. Sensitivity analyses showed the utility value assigned for calculation of QALY was the most sensitive parameter. We concluded that despite high cost, there is a role for rFVIIa in the treatment of life-threatening bleeding in patients with DHF/DSS.

A missense mutation in myosin VIIA prevents aminoglycoside accumulation in early postnatal cochlear hair cells.

PubMed

Richardson, G P; Forge, A; Kros, C J; Marcotti, W; Becker, D; Williams, D S; Thorpe, J; Fleming, J; Brown, S D; Steel, K P

1999-11-28

Myosin VIIA is expressed by sensory hair cells in the inner ear and proximal tubule cells in the kidney, the two primary targets of aminoglycoside antibiotics. Using cochlear cultures prepared from early postnatal Myo7a6J mice with a missense mutation in the head region of the myosin VIIA molecule we show that this myosin is required for aminoglycoside accumulation in cochlear hair cells. Hair cells in homozygous mutant Myo7a6J cochlear cultures have disorganized hair bundles, but are otherwise morphologically normal and transduce. However, and in contrast to hair cells from heterozygous Myo7a6J cultures, the homozygous Myo7a6J hair cells do not accumulate [3H]gentamicin and do not exhibit an ototoxic response on exposure to aminoglycoside. Possible roles for myosin VIIA in the process of aminoglycoside accumulation are discussed.

Use of Recombinant Factor VIIA for Control of Combat-Related Haemorrhage

DTIC Science & Technology

2010-02-25

Pallav Bhatnagar, Henno Schoombee, Brian Burgess Southend University Hospital, NHS Foundation Trust, Westcliff -on-Sea, Essex, UK Correspondence to Dr...transfusion requirements, did not result in better survival.11 1San Diego State University , School of Social Work, San Diego, USA 2Health Solutions

Computational Analysis of the Effects of Reduced Temperature on Thrombin Generation: The Contributions of Hypothermia to Coagulopathy

DTIC Science & Technology

2013-09-01

reactions characterize the interactions of factor VII ( FVII ) and factor VIIa (FVIIa) and their complexes with TF and other clotting factors . These...patients), is one of the major factors contributing to coagulopathy of trauma.1–3 Heavy bleeding may result in a decreased blood volume and...tri- phosphate synthesis.4 Transfusion of blood products and resuscitation fluids, which are stored at low temperatures or even in a frozen state

Enhancement of the efficacy of therapeutic proteins by formulation with PEGylated liposomes; a case of FVIII, FVIIa and G-CSF.

PubMed

Yatuv, Rivka; Robinson, Micah; Dayan, Inbal; Baru, Moshe

2010-02-01

Improving the pharmacodynamics of protein drugs has the potential to improve the care and the quality of life of patients suffering from a variety of diseases. Four approaches to improve protein drugs are described: PEGylation, amino acid substitution, fusion to carrier proteins and encapsulation. A new platform technology based on the binding of proteins/peptides to the outer surface of PEGylated liposomes (PEGLip) is then presented. Binding of proteins to PEGLip is non-covalent, highly specific and dependent on an amino acid consensus sequence within the proteins. Association of proteins with PEGLip results in substantial enhancement of the pharmacodynamic properties of proteins following administration. This has been demonstrated in preclinical studies and clinical trials with coagulation factors VIII and VIIa. It has also been demonstrated in preclinical studies with granulocyte colony-stimulating factor. A mechanism is presented that explains the improvements in hemostatic efficacy of PEGLip-formulated coagulation factors VIII and VIIa. The reader will gain an understanding of the advantages and disadvantages of each of the approaches discussed. PEGLip formulation is an important new approach to improve the pharmacodynamics of protein drugs. This approach may be applied to further therapeutic proteins in the future.

Comparative Biochemical and Functional Studies on a Branded Human Recombinant Factor VIIa and a Biosimilar Equivalent Product.

PubMed

Sadeghi, Nasiredin; Kahn, Daniel; Syed, Daneyal; Iqbal, Omer; Abro, Schuharazad; Eshraghi, Reza; Hoppensteadt, Debra; Fareed, Jawed

2014-09-01

Recombinant factor VIIa (rFVIIa; NovoSeven, Novo Nordisk, Copenhagen, Denmark) is used to control bleeding in patients with hemophilia. A generic version of FVIIa was developed by AryoGen (Tehran, Iran). This study compared the composition and functional activities of AryoSeven and NovoSeven. Each product was compared at equigravimetric (1 mg/mL) stock solution for protein content. The proteomic profile was obtained using surface-enhanced laser desorption ionization mass spectrometry. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis was carried out to determine the protein profile and Western blotting was performed using a polyclonal rabbit antihuman FVIIa antibody. The FVIIa-related antigen was also measured using a commercially available enzyme-linked immunosorbent assay method. Functional assay included the prothrombin time correction in FVII-deficient plasma. The protein content was comparable in 2 products and the mass spectra analysis showed a single peak at 50 kDa in all products. The SDS-PAGE and immunoblotting studies were comparable. Both products exhibited similar coagulant properties in different assays. © The Author(s) 2014.

U.S. Army Medical Department Journal, July-September 2004

DTIC Science & Technology

2004-09-01

on the surface of intestinal, lung, and brain cells. The TF protein then converts FVII into an activated form. Activated factor VII then combines...and FIX, which limits generation of thrombin. Platelets are able to increase production of thrombin when increased FVIIa is present. Normally FVII ...hemorrhage in severe neonatal FVII deficiency. Hemophilia. 2000; 6: 50-54. 12. Gilchrist J. Use of recombinant factor VIIa to treat a severe

The M358R variant of α{sub 1}-proteinase inhibitor inhibits coagulation factor VIIa

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sheffield, William P., E-mail: sheffiel@mcmaster.ca; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario; Bhakta, Varsha

The naturally occurring M358R mutation of the plasma serpin α{sub 1}-proteinase inhibitor (API) changes both its cleavable reactive centre bond to Arg–Ser and the efficacy with which it inhibits different proteases, reducing the rate of inhibition of neutrophil elastase, and enhancing that of thrombin, factor XIa, and kallikrein, by several orders of magnitude. Although another plasma serpin with an Arg–Ser reactive centre, antithrombin (AT), has been shown to inhibit factor VIIa (FVIIa), no published data are available with respect to FVIIa inhibition by API M358R. Recombinant bacterially-expressed API M358R and plasma-derived AT were therefore compared using gel-based and kinetic assaysmore » of FVIIa integrity and activity. Under pseudo-first order conditions of excess serpin over protease, both AT and API M358R formed denaturation-resistant inhibitory complexes with FVIIa in reactions accelerated by TF; AT, but not API M358R, also required heparin for maximal activity. The second order rate constant for heparin-independent API M358R-mediated FVIIa inhibition was determined to be 7.8 ± 0.8 × 10{sup 2} M{sup −1}sec{sup −1}. We conclude that API M358R inhibits FVIIa by forming inhibitory complexes of the serpin type more rapidly than AT in the absence of heparin. The likely 20-fold excess of API M358R over AT in patient plasma during inflammation raises the possibility that it could contribute to the hemorrhagic tendencies manifested by rare individuals expressing this mutant serpin. - Highlights: • The inhibitory specificity of the serpin alpha-1-proteinase inhibitor (API) is sharply altered in the M358R variant. • API M358R forms denaturation-resistant complexes with coagulation factor VIIa at a rate accelerated by tissue factor but unaffected by heparin. • Complex formation was shown by gel-based assays and quantified kinetically by inhibition of FVIIa-dependent amidolysis.« less

Therapeutic Correction of Thrombin Generation in Dilution-Induced Coagulopathy: Computational Analysis Based on a Data Set of Healthy Subjects

DTIC Science & Technology

2012-01-01

Factor VIIa tended to primarily impact clotting time, thrombin peak time, and maximum slope of the thrombin curve, whereas in the case of PCC- FVII ...constituents of existing PCCs are the four coagulation factors (F) II (prothrombin), FVII , FIX, and FX.3 Notably, FVII inhibits thrombin generation by...proposed PCC composition (coagulation factors [F] II, IX, and X and the anticoagulant antithrombin), designated PCC-AT, was compared with that of

Intravenous rFVIIa Administered for Hemorrhage Control in Hypothermic Coagulopathic Swine with Grade V Liver Injuries

DTIC Science & Technology

2001-04-01

Hendriks H, Meijer K, Hagenaars A, et al. Recombinant factor VIIa (rFVIIa, NovoSeven) decreases blood loss and blood product requirements during...and John R. Hess, MD, MPH Background: Intravenous adminis- tration of recombinant activated human clotting factor VII (rFVIIa) has been used...onds, fibrinogen was 91 6 20 mg/dL, and platelets were 221 6 57 3 105/mL, with no differences between groups (p > 0.05). Clotting factor levels

Treatment of Ebola Virus Infection With a Recombinant Inhibitor of Factor Vlla/Tissue Factor: A Study in Rhesus Monkeys

DTIC Science & Technology

2003-12-13

ameliorate the effects of Ebola haemorrhagic fever . Here, we tested the notion that blockade of fVIIa/tissue factor is beneficial after infection with...Ebola virus. Methods We used a rhesus macaque model of Ebola haemorrhagic fever , which produces near 100% mortality. We administered recombinant...severe haemorrhagic fever in primates.1,2 Acute mortality caused by the Zaire species of Ebola virus has been about 80% in outbreaks in human beings1

77 FR 61753 - Granting of Request for Early Termination of the Waiting Period Under the Premerger Notification...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-11

..., Inc.; Astria Semiconductor Holdings, Inc.; FormFactor, Inc. 20121365 G ABRY Partners VII, L.P.; Source.... 20121303 G Wind Point Partners L.P.; Mistral Equity Partners, LP; Wind Point Partners VII-A, L.P. 20121307... Dillard. 20121364 G Apollo Investment Fund VII, L.P.; Jimmy Sanders Incorporated; Apollo Investment Fund...

[Hemoglobins, XXXII. Analysis of the primary structure of the monomeric hemoglobin CTT VIIA (erythrocruorin) or Chironomus thummi thummi, Diptera (author's transl)].

PubMed

Kleinschmidt, T; Braunitzer, G

1980-01-01

The dimeric hemoglobin CTT VIIA (erythrocruorin) was isolated from the hemolymph of the larva from Chironomus thummi thummi and purified by preparative polyacrylamide gel electrophoresis. Peptides obtained by limited tryptical digestion were sequenced by automatic Edman degradation. For the elucidation of the sequence in the C-terminal region of the chain, additional cleavages with proteinase of Staphylococcus aureus and chymotrypsin were necessary. CTT VIIA is compared with human beta-chains and other hemoglobins of Chironomus. The amino acid residues in the pocket are especially discussed. Most of them are invariant in all Chironomus hemoglobins, independent of the size of the heme pocket, which is normal in some components and enlarged in others.

Targeting the Tissue Factor-Factor VIIa Signaling Pathway to Enhance Activity of mTOR Inhibitors in the Treatment of Breast Cancer

DTIC Science & Technology

2009-09-01

Salzberg M, Ostapenko V, Illiger HJ, Behringer D, Bardy -Bouxin N, Boni J , Kong S, Cincotta M, and Moore L. Phase II study of temsirolimus (CCI-779), a ...factor interaction results in a tissue factor cytoplasmic domain- independent activation of protein synthesis, p70, and p90 S6 kinase phosphorylation. J ...The mTOR Pathway in Breast Cancer. J Mammary Gland Biol Neoplasia 2006; 11: 53-61. 23. Guba M, Yezhelyev, Eichhorn ME, Schmid G, Ischenko, Papyan A

Engineering of a membrane-triggered activity switch in coagulation factor VIIa

PubMed Central

Nielsen, Anders L.; Sorensen, Anders B.; Holmberg, Heidi L.; Gandhi, Prafull S.; Karlsson, Johan; Buchardt, Jens; Lamberth, Kasper; Kjelgaard-Hansen, Mads; Ley, Carsten Dan; Sørensen, Brit B.; Ruf, Wolfram; Olsen, Ole H.; Østergaard, Henrik

2017-01-01

Recombinant factor VIIa (FVIIa) variants with increased activity offer the promise to improve the treatment of bleeding episodes in patients with inhibitor-complicated hemophilia. Here, an approach was adopted to enhance the activity of FVIIa by selectively optimizing substrate turnover at the membrane surface. Under physiological conditions, endogenous FVIIa engages its cell-localized cofactor tissue factor (TF), which stimulates activity through membrane-dependent substrate recognition and allosteric effects. To exploit these properties of TF, a covalent complex between FVIIa and the soluble ectodomain of TF (sTF) was engineered by introduction of a nonperturbing cystine bridge (FVIIa Q64C-sTF G109C) in the interface. Upon coexpression, FVIIa Q64C and sTF G109C spontaneously assembled into a covalent complex with functional properties similar to the noncovalent wild-type complex. Additional introduction of a FVIIa-M306D mutation to uncouple the sTF-mediated allosteric stimulation of FVIIa provided a final complex with FVIIa-like activity in solution, while exhibiting a two to three orders-of-magnitude increase in activity relative to FVIIa upon exposure to a procoagulant membrane. In a mouse model of hemophilia A, the complex normalized hemostasis upon vascular injury at a dose of 0.3 nmol/kg compared with 300 nmol/kg for FVIIa. PMID:29109275

Interaction Between Hippocampus and Cerebellum Crus I in Sequence-Based but not Place-Based Navigation

PubMed Central

Iglói, Kinga; Doeller, Christian F.; Paradis, Anne-Lise; Benchenane, Karim; Berthoz, Alain; Burgess, Neil; Rondi-Reig, Laure

2015-01-01

To examine the cerebellar contribution to human spatial navigation we used functional magnetic resonance imaging and virtual reality. Our findings show that the sensory-motor requirements of navigation induce activity in cerebellar lobules and cortical areas known to be involved in the motor loop and vestibular processing. By contrast, cognitive aspects of navigation mainly induce activity in a different cerebellar lobule (VIIA Crus I). Our results demonstrate a functional link between cerebellum and hippocampus in humans and identify specific functional circuits linking lobule VIIA Crus I of the cerebellum to medial parietal, medial prefrontal, and hippocampal cortices in nonmotor aspects of navigation. They further suggest that Crus I belongs to 2 nonmotor loops, involved in different strategies: place-based navigation is supported by coherent activity between left cerebellar lobule VIIA Crus I and medial parietal cortex along with right hippocampus activity, while sequence-based navigation is supported by coherent activity between right lobule VIIA Crus I, medial prefrontal cortex, and left hippocampus. These results highlight the prominent role of the human cerebellum in both motor and cognitive aspects of navigation, and specify the cortico-cerebellar circuits by which it acts depending on the requirements of the task. PMID:24947462

Identification and functional study of a new missense mutation in the motor head domain of myosin VIIA in a family with autosomal dominant hearing impairment (DFNA11).

PubMed

Sang, Qing; Yan, Xukun; Wang, Huan; Feng, Ruizhi; Fei, Xiang; Ma, Duan; Xing, Qinghe; Li, Qiaoli; Zhao, Xinzhi; Jin, Li; He, Lin; Li, Huawei; Wang, Lei

2013-01-01

The MYO7A encodes a protein classified as an unconventional myosin. Here, we present a family with non-syndromic autosomal dominant hearing impairment that clinically resembles other previously published DFNA11 families. Affected members of the family present with an ascending audiogram affecting low and middle frequencies at young ages and then affecting all frequencies with increasing age. Genome-wide linkage analysis using Illumina Cyto-12 Chip mapped the disease locus to the DFNA11 interval in the family. A c.2003G→A (p.R668H) mutation of the MYO7A, is heterozygous in all affected family members and absent in 100 healthy individuals. Arg668His is located in a region of the myosin VIIA motor domain that is highly conserved among different species. Molecular modeling predicts that the conserved R668 residue plays important structural role in linking different lobes of motor domain together. In the actin-activated ATPase activity assay, the rate of NADH oxidation was higher in the wild-type myosin VIIA, indicating that the ATPase activity in the p.R668H mutant myosin VIIA was significantly destroyed.

Potential Resuscitation Strategies for Treatment of Hemorrhagic Shock

DTIC Science & Technology

2004-09-01

thrombus (the “pop-clot” pressure); 2) an injectable clot stabilizer (“fix-a-leak”) that is a naturally occurring factor in the clotting cascade (human...recombinant Factor VIIa); and 3) the maximum time up to 24 hours for hypotensive resuscitation below the “pop-the-clot” pressure (“how low for how long...To prevent this blood products are given as soon as possible in the emergency department. Only crystalloids and colloids are currently available on

Targeting Tissue Factor-Factor VIIa Signaling Pathway to Enhance Activity of mTOR Inhibitors in the Treatment of Breast Cancer

DTIC Science & Technology

2010-03-01

Salzberg M, Ostapenko V, Illiger HJ, Behringer D, Bardy -Bouxin N, Boni J , Kong S, Cincotta M, and Moore L. Phase II study of temsirolimus (CCI-779), a novel...interaction results in a tissue factor cytoplasmic domain- independent activation of protein synthesis, p70, and p90 S6 kinase phosphorylation. J ...mTOR Pathway in Breast Cancer. J Mammary Gland Biol Neoplasia 2006; 11: 53-61. 23. Guba M, Yezhelyev, Eichhorn ME, Schmid G, Ischenko, Papyan A

Crystal structures of human group-VIIA phospholipase A2 inhibited by organophosphorus nerve agents exhibit non-aged complexes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Samanta, Uttamkumar; Kirby, Stephen D.; Srinivasan, Prabhavathi

The enzyme group-VIIA phospholipase A2 (gVIIA-PLA2) is bound to lipoproteins in human blood and hydrolyzes the ester bond at the sn-2 position of phospholipid substrates with a short sn-2 chain. The enzyme belongs to a serine hydrolase superfamily of enzymes, which react with organophosphorus (OP) nerve agents. OPs ultimately exert their toxicity by inhibiting human acetycholinesterase at nerve synapses, but may additionally have detrimental effects through inhibition of other serine hydrolases. We have solved the crystal structures of gVIIA-PLA2 following inhibition with the OPs diisopropylfluorophosphate, sarin, soman and tabun. The sarin and soman complexes displayed a racemic mix of P{submore » R} and P{sub S} stereoisomers at the P-chiral center. The tabun complex displayed only the P{sub R} stereoisomer in the crystal. In all cases, the crystal structures contained intact OP adducts that had not aged. Aging refers to a secondary process OP complexes can go through, which dealkylates the nerve agent adduct and results in a form that is highly resistant to either spontaneous or oxime-mediated reactivation. Non-aged OP complexes of the enzyme were corroborated by trypsin digest and matrix-assisted laser desorption ionization mass spectrometry of OP-enzyme complexes. The lack of stereoselectivity of sarin reaction was confirmed by gas chromatography/mass spectrometry using a chiral column to separate and quantitate the unbound stereoisomers of sarin following incubation with enzyme. The structural details and characterization of nascent reactivity of several toxic nerve agents is discussed with a long-term goal of developing gVIIA-PLA2 as a catalytic bioscavenger of OP nerve agents.« less

Crystal structures of human group-VIIA phospholipase A2 inhibited by organophosphorus nerve agents exhibit non-aged complexes.

PubMed

Samanta, Uttamkumar; Kirby, Stephen D; Srinivasan, Prabhavathi; Cerasoli, Douglas M; Bahnson, Brian J

2009-08-15

The enzyme group-VIIA phospholipase A2 (gVIIA-PLA2) is bound to lipoproteins in human blood and hydrolyzes the ester bond at the sn-2 position of phospholipid substrates with a short sn-2 chain. The enzyme belongs to a serine hydrolase superfamily of enzymes, which react with organophosphorus (OP) nerve agents. OPs ultimately exert their toxicity by inhibiting human acetycholinesterase at nerve synapses, but may additionally have detrimental effects through inhibition of other serine hydrolases. We have solved the crystal structures of gVIIA-PLA2 following inhibition with the OPs diisopropylfluorophosphate, sarin, soman and tabun. The sarin and soman complexes displayed a racemic mix of P(R) and P(S) stereoisomers at the P-chiral center. The tabun complex displayed only the P(R) stereoisomer in the crystal. In all cases, the crystal structures contained intact OP adducts that had not aged. Aging refers to a secondary process OP complexes can go through, which dealkylates the nerve agent adduct and results in a form that is highly resistant to either spontaneous or oxime-mediated reactivation. Non-aged OP complexes of the enzyme were corroborated by trypsin digest and matrix-assisted laser desorption ionization mass spectrometry of OP-enzyme complexes. The lack of stereoselectivity of sarin reaction was confirmed by gas chromatography/mass spectrometry using a chiral column to separate and quantitate the unbound stereoisomers of sarin following incubation with enzyme. The structural details and characterization of nascent reactivity of several toxic nerve agents is discussed with a long-term goal of developing gVIIA-PLA2 as a catalytic bioscavenger of OP nerve agents.

Identification and Functional Study of a New Missense Mutation in the Motor Head Domain of Myosin VIIA in a Family with Autosomal Dominant Hearing Impairment (DFNA11)

PubMed Central

Feng, Ruizhi; Fei, Xiang; Ma, Duan; Xing, Qinghe; Li, Qiaoli; Zhao, Xinzhi; Jin, Li; He, Lin; Li, Huawei; Wang, Lei

2013-01-01

The MYO7A encodes a protein classified as an unconventional myosin. Here, we present a family with non-syndromic autosomal dominant hearing impairment that clinically resembles other previously published DFNA11 families. Affected members of the family present with an ascending audiogram affecting low and middle frequencies at young ages and then affecting all frequencies with increasing age. Genome-wide linkage analysis using Illumina Cyto-12 Chip mapped the disease locus to the DFNA11 interval in the family. A c.2003G→A (p.R668H) mutation of the MYO7A, is heterozygous in all affected family members and absent in 100 healthy individuals. Arg668His is located in a region of the myosin VIIA motor domain that is highly conserved among different species. Molecular modeling predicts that the conserved R668 residue plays important structural role in linking different lobes of motor domain together. In the actin-activated ATPase activity assay, the rate of NADH oxidation was higher in the wild-type myosin VIIA, indicating that the ATPase activity in the p.R668H mutant myosin VIIA was significantly destroyed. PMID:23383098

Impact of ABO-Identical vs ABO-Compatible Nonidentical Plasma Transfusion in Trauma Patients

DTIC Science & Technology

2010-09-01

and B patients in turn could receive AB donor plasma. Few studies have examined the im- pact of compatible nonidentical plasma transfusion . In platelet ... transfusion ,19 the administration of compatible nonidenti- cal platelets to patients undergoing coro- nary artery bypass grafting or valve re...significantly different (in boldface) and for the volume of packed red blood cells, plasma, platelets , cryoprecipitate, and factor VIIa transfused . cBecause

[Administration of activated recombinant factor VII (novo seven) for the control of massive bleeding in gynecology].

PubMed

Tanchev, S; Pandurski, F; Georgiev, A; Gesheva, Iu; Platikanov, V; Dinov, P

2004-01-01

We report our clinical opinion for recombinant activated factor VII (NovoSeven, Novo Nordisk, Copenhagen, Denmark) administration in gynecology patients with massive haemorrhage. 3 women with gynecology deseases and severe bleeding in recieved NovoSeven in bolus IV. The blood loss and laboratory changes in hematology and haemostasis parameters are monitored. The bleeding was ceased in all cases. Decrease in values of Hb, Er and PTT was noted. The use of recombinant factor VIIA in gynecology patients with severe bleeding is effective and safe enough and could be an alternative to the extreme surgical procedures.

[Our experience with recombinant activated factor VII (NovoSeven) in the high risk cardiosurgical patients with bleeding complication].

PubMed

Miskolczi, Szabolcs; Vaszily, Miklós; Papp, Csaba; Péterffy, Arpád

2008-01-01

Haemorrhagic complications significantly increase mortality and cost of treatment in cardiac surgery. A few years ago recombinant activated factor VII has been introduced to decrease such complications. In our department recombinant activated factor VII has been used in 11 patients between 2004 and 2007. Nine of them underwent a combined (simultaneous CABG and valve replacement) high risk surgery with long aortic cross clamp time and long extracorporeal circulation time. One patient underwent a repeat coronary artery bypass operation and one was operated for aortic dissection. The average dose given was 6.5 mg (2.4-9.6 mg). The average amount of bleeding without NovoSeven given was 5440 ml, however it was only 987 ml when NovoSeven was used. Nine of the patients were completely recovered and discharged from hospital, but two of them died in the postoperative period for delayed use of the recombinant factor VII-a and for severe co-morbidities (bowel ischaemia, cirrhosis of the liver). NovoSeven given in the proper time and dose significantly reduces bleeding following cardiac surgery, even if it cannot be stopped surgically. Using recombinant factor VIIa can save life in case of severe non-surgical diffuse bleeding or in case of suture insufficiency caused by friable soft tissues following high risk combined surgery with extremely long aortic cross clamp time and extracorporeal circulation time. Significant delay in the use of NovoSeven should be avoided because the temporary reduction of bleeding usually does not change fatal outcome.

The roles of USH1 proteins and PDZ domain-containing USH proteins in USH2 complex integrity in cochlear hair cells.

PubMed

Zou, Junhuang; Chen, Qian; Almishaal, Ali; Mathur, Pranav Dinesh; Zheng, Tihua; Tian, Cong; Zheng, Qing Y; Yang, Jun

2017-02-01

Usher syndrome (USH) is the most common cause of inherited deaf-blindness, manifested as USH1, USH2 and USH3 clinical types. The protein products of USH2 causative and modifier genes, USH2A, ADGRV1, WHRN and PDZD7, interact to assemble a multiprotein complex at the ankle link region of the mechanosensitive stereociliary bundle in hair cells. Defects in this complex cause stereociliary bundle disorganization and hearing loss. The four USH2 proteins also interact in vitro with USH1 proteins including myosin VIIa, USH1G (SANS), CIB2 and harmonin. However, it is unclear whether the interactions between USH1 and USH2 proteins occur in vivo and whether USH1 proteins play a role in USH2 complex assembly in hair cells. In this study, we identified a novel interaction between myosin VIIa and PDZD7 by FLAG pull-down assay. We further investigated the role of the above-mentioned four USH1 proteins in the cochlear USH2 complex assembly using USH1 mutant mice. We showed that only myosin VIIa is indispensable for USH2 complex assembly at ankle links, indicating the potential transport and/or anchoring role of myosin VIIa for USH2 proteins in hair cells. However, myosin VIIa is not required for USH2 complex assembly in photoreceptors. We further showed that, while PDZ protein harmonin is not involved, its paralogous USH2 proteins, PDZD7 and whirlin, function synergistically in USH2 complex assembly in cochlear hair cells. In summary, our studies provide novel insight into the functional relationship between USH1 and USH2 proteins in the cochlea and the retina as well as the disease mechanisms underlying USH1 and USH2. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The length of the linker between the epidermal growth factor-like domains in factor VIIa is critical for a productive interaction with tissue factor.

PubMed

Persson, Egon; Madsen, Jesper J; Olsen, Ole H

2014-12-01

Formation of the factor VIIa (FVIIa)-tissue factor (TF) complex triggers the blood coagulation cascade. Using a structure-based rationale, we investigated how the length of the linker region between the two epidermal growth factor (EGF)-like domains in FVIIa influences TF binding and the allosteric activity enhancement, as well as the interplay between the γ-carboxyglutamic acid (Gla)-containing and protease domains. Removal of two residues from the native linker was compatible with normal cofactor binding and accompanying stimulation of the enzymatic activity, as was extension by two (Gly-Ser) residues. In sharp contrast, truncation by three or four residues abolished the TF-mediated stabilization of the active conformation of FVIIa and abrogated TF-induced activity enhancement. In addition, FVIIa variants with short linkers associated 80-fold slower with soluble TF (sTF) as compared with wild-type FVIIa, resulting in a corresponding increase in the equilibrium dissociation constant. Molecular modeling suggested that the shortest FVIIa variants would have to be forced into a tense and energetically unfavorable conformation in order to be able to interact productively with TF, explaining our experimental observations. We also found a correlation between linker length and the residual intrinsic enzymatic activity of Ca(2+)-free FVIIa; stepwise truncation resulting in gradually higher activity with des(83-86)-FVIIa reaching the level of Gla-domainless FVIIa. The linker appears to determine the average distance between the negatively charged Gla domain and a structural element in the protease domain, presumably of opposite charge, and proximity has a negative impact on apo-FVIIa activity. © 2014 The Protein Society.

Tissue Factor-Factor VIIa Complex Triggers Protease Activated Receptor 2-Dependent Growth Factor Release and Migration in Ovarian Cancer

PubMed Central

Chanakira, Alice; Westmark, Pamela R.; Ong, Irene M.; Sheehan, John P.

2017-01-01

Objective Enhanced tissue factor (TF) expression in epithelial ovarian cancer (EOC) is associated with aggressive disease. Our objective was to evaluate the role of the TF-factor VIIa-protease-activated receptor-2 (PAR-2) pathway in human EOC. Methods TCGA RNAseq data from EOC databases were analyzed for PAR expression. Cell and microparticle (MP) associated TF protein expression (Western blot) and MP-associated coagulant activity were determined in human EOC (SKOV-3, OVCAR-3 and CaOV-3) and control cell lines. PAR-1 and PAR-2 protein expression were similarly examined. The PAR dependence of VEGF-A release (ELISA) and chemotactic migration in response to FVIIa and cellular proliferation in response to thrombin was evaluated with small molecule antagonists. Results Relative mRNA expression consistently demonstrated PAR-2>PAR-1≫PAR-3/4 in multiple EOC datasets. Human EOC cell line lysates confirmed expression of TF, PAR-1 and PAR-2 proteins. MPs isolated from EOC cell lines demonstrated markedly enhanced (4–10 fold) TF coagulant activity relative to control cell lines. FVIIa induced a dose-dependent increase in VEGF-A release (2.5-3 fold) from EOC cell lines that was abrogated by the PAR-2 antagonist ENMD-1068. FVIIa treatment of CaOV-3 and OVCAR-3 cells resulted in increased chemotactic migration that was abolished by ENMD-1068. Thrombin induced dose-dependent EOC cell line proliferation was completely reversed by the PAR-1 antagonist vorapaxar. Small molecule antagonists had no effect on these phenotypes without protease present. Conclusions Enhanced activity of the TF-FVIIa-PAR-2 axis may contribute to the EOC progression via PAR-2 dependent signaling that supports an angiogenic and invasive phenotype and local thrombin generation supporting PAR-1 dependent proliferation. PMID:28148395

Mutation profile of all 49 exons of the human myosin VIIA gene, and haplotype analysis, in Usher 1B families from diverse origins.

PubMed

Adato, A; Weil, D; Kalinski, H; Pel-Or, Y; Ayadi, H; Petit, C; Korostishevsky, M; Bonne-Tamir, B

1997-10-01

Usher syndrome types I (USH1A-USH1E) are a group of autosomal recessive diseases characterized by profound congenital hearing loss, vestibular areflexia, and progressive visual loss due to retinitis pigmentosa. The human myosin VIIA gene, located on 11q14, has been shown to be responsible for Usher syndrome type 1B (USH1B). Haplotypes were constructed in 28 USH1 families by use of the following polymorphic markers spanning the USH1B locus: D11S787, D11S527, D11S1789, D11S906, D11S4186, and OMP. Affected individuals and members of their families from 12 different ethnic origins were screened for the presence of mutations in all 49 exons of the myosin VIIA gene. In 15 families myosin VIIA mutations were detected, verifying their classification as USH1B. All these mutations are novel, including three missense mutations, one premature stop codon, two splicing mutations, one frameshift, and one deletion of >2 kb comprising exons 47 and 48, a part of exon 49, and the introns between them. Three mutations were shared by more than one family, consistent with haplotype similarities. Altogether, 16 USH1B haplotypes were observed in the 15 families; most haplotypes were population specific. Several exonic and intronic polymorphisms were also detected. None of the 20 known USH1B mutations reported so far in other world populations were identified in our families.

Human myosin VIIA responsible for the Usher 1B syndrome: a predicted membrane-associated motor protein expressed in developing sensory epithelia.

PubMed

Weil, D; Levy, G; Sahly, I; Levi-Acobas, F; Blanchard, S; El-Amraoui, A; Crozet, F; Philippe, H; Abitbol, M; Petit, C

1996-04-16

The gene encoding human myosin VIIA is responsible for Usher syndrome type III (USH1B), a disease which associates profound congenital sensorineural deafness, vestibular dysfunction, and retinitis pigmentosa. The reconstituted cDNA sequence presented here predicts a 2215 amino acid protein with a typical unconventional myosin structure. This protein is expected to dimerize into a two-headed molecule. The C terminus of its tail shares homology with the membrane-binding domain of the band 4.1 protein superfamily. The gene consists of 48 coding exons. It encodes several alternatively spliced forms. In situ hybridization analysis in human embryos demonstrates that the myosin VIIA gene is expressed in the pigment epithelium and the photoreceptor cells of the retina, thus indicating that both cell types may be involved in the USH1B retinal degenerative process. In addition, the gene is expressed in the human embryonic cochlear and vestibular neuroepithelia. We suggest that deafness and vestibular dysfunction in USH1B patients result from a defect in the morphogenesis of the inner ear sensory cell stereocilia.

Cross-talk between the Tissue Factor/coagulation factor VIIa complex and the tyrosine kinase receptor EphA2 in cancer.

PubMed

Eriksson, Oskar; Thulin, Åsa; Asplund, Anna; Hegde, Geeta; Navani, Sanjay; Siegbahn, Agneta

2016-05-31

Tissue Factor (TF) forms a proteolytically active complex together with coagulation factor VIIa (FVIIa) and functions as the trigger of blood coagulation or alternatively activates cell signaling. We recently described that EphA2 of the Eph tyrosine kinase receptor family is cleaved directly by the TF/FVIIa complex. The aim of the present study was to further characterize the cross-talk between TF/FVIIa and EphA2 using in vitro model systems and human cancer specimens. Cleavage and phosphorylation of EphA2 was studied by Western blot. Subcellular localization of TF and EphA2 was investigated by a proximity ligation assay and confocal microscopy. Phalloidin staining of the actin cytoskeleton was used to study cell rounding and retraction fiber formation. Expression of TF and EphA2 in human colorectal cancer specimens was examined by immunohistochemistry. TF and EphA2 co-localized constitutively in MDA-MB-231 cells, and addition of FVIIa resulted in cleavage of EphA2 by a PAR2-independent mechanism. Overexpression of TF in U251 glioblastoma cells lead to co-localization with EphA2 at the leading edge and FVIIa-dependent cleavage of EphA2. FVIIa potentiated ephrin-A1-induced cell rounding and retraction fiber formation in MDA-MB-231 cells through a RhoA/ROCK-dependent pathway that did not require PAR2-activation. TF and EphA2 were expressed in colorectal cancer specimens, and were significantly correlated. These results suggest that TF/FVIIa-EphA2 cross-talk might potentiate ligand-dependent EphA2 signaling in human cancers, and provide initial evidence that it is possible for this interaction to occur in vivo.

Ala397Asp mutation of myosin VIIA gene segregating in a Spanish family with type-Ib Usher syndrome.

PubMed

Espinós, C; Millán, J M; Sánchez, F; Beneyto, M; Nájera, C

1998-06-01

In the current study, 12 Spanish families affected by type-I Usher syndrome, that was previously linked to chromosome 11q, were screened for the presence of mutations in the N-terminal coding portion of the motor domain of the myosin VIIA gene by single-strand conformation polymorphism analysis of the first 14 exons. A mutation (Ala397Asp) segregating with the disease was identified, and several polymorphisms were also detected. It is presumed that the other USHIB mutations in these families could be located in the unscreened regions of the gene.

Tissue factor-dependent vascular endothelial growth factor production by human fibroblasts in response to activated factor VII.

PubMed

Ollivier, V; Bentolila, S; Chabbat, J; Hakim, J; de Prost, D

1998-04-15

The transmembrane protein tissue factor (TF) is the cell surface receptor for coagulation factor VII (FVII) and activated factor VII (FVIIa). Recently, TF has been identified as a regulator of angiogenesis, tumor growth, and metastasis. This study was designed to link the binding of FVII(a) to its receptor, TF, with the subsequent triggering of angiogenesis through vascular endothelial growth factor (VEGF) production by human lung fibroblasts. We report that incubation of fibroblasts, which express constitutive surface TF, with FVII(a) induces VEGF synthesis. FVII(a)-induced VEGF secretion, assessed by a specific enzyme-linked immunosorbent assay, was time- and concentration-dependent. VEGF secretion was maximal after 24 hours of incubation of the cells with 100 nmol/L FVII(a) and represented a threefold induction of the basal VEGF level. Reverse transcriptase-polymerase chain reaction analysis of VEGF detected three mRNA species of 180, 312, and 384 bp corresponding, respectively, to VEGF121, VEGF165, and VEGF189. A 2.5- to 3.5-fold increase was observed for the 180- and 312-bp transcripts at 12 and 24 hours, respectively. FVII(a)-dependent VEGF production was inhibited by a pool of antibodies against TF, pointing to the involvement of this receptor. On specific active-site inhibition with dansyl-glutamyl-glycinyl-arginyl chloromethyl ketone, FVIIa lost 70% of its capacity to elicit VEGF production. Consistent with this, the native form (zymogen) of FVII only had a 1.8-fold stimulating effect. Protein tyrosine kinase and protein kinase C are involved in signal transduction leading to VEGF production, as shown by the inhibitory effects of genistein and GF 109203X. The results of this study indicate that TF is essential for VIIa-induced VEGF production by human fibroblasts and that its role is mainly linked to the proteolytic activity of the TF-VIIa complex.

Recombinant factor VIIa as an adjunctive therapy for patients requiring large volume transfusion: a pharmacoeconomic evaluation.

PubMed

Loudon, B; Smith, M P

2005-08-01

Acute haemorrhage requiring large volume transfusion presents a costly and unpredictable risk to transfusion services. Recombinant factor VIIa (rFVIIa) (NovoSeven, Novo Nordisk, Bagsvaard, Denmark) may provide an important adjunctive haemostatic strategy for the management of patients requiring large volume blood transfusions. To review blood transfusion over a 12-month period and assess the major costs associated with haemorrhage management. A pharmoeconomic evaluation of rFVIIa intervention for large volume transfusion was conducted to identify the most cost-effective strategy for using this haemostatic product. Audit and analysis of all patients admitted to Christchurch Public Hospital requiring > 5 units of red blood cells (RBC) during a single transfusion episode. Patients were stratified into groups dependent on RBC units received and further stratified with regard to ward category. Cumulative costs were derived to compare standard treatment with an hypothesized rFVIIa intervention for each transfusion group. Sensitivity analyses were performed by varying parameters and comparing to original outcomes. Comparison of costs between the standard and hypothetical model indicated no statistically significant differences between groups (P < 0.05). Univariate and multivariate sensitivity analyses indicate that intervention with rFVIIa after transfusion of 14 RBC units may be cost-effective due to conservation of blood components and reduction in duration of intensive area stay. Intervention with rFVIIa for haemorrhage control is most cost-effective relatively early in the RBC transfusion period. Our hypothetical model indicates the optimal time point is when 14 RBC units have been transfused.

Managing incidentally diagnosed isolated factor VII deficiency perioperatively: a brief expert consensus report.

PubMed

Sheth, Sujit; Soff, Gerald; Mitchell, Beau; Green, David; Kaicker, Shipra; Fireman, Fernando; Tugal, Oya; Guarini, Ludovico; Giardina, Patricia; Aledort, Louis

2012-02-01

While isolated factor VII (FVII) deficiency is being more frequently diagnosed owing to improved preoperative screening procedures, there is no specific guideline for perioperative management of such patients. To complicate the issue, FVII activity levels seem to correlate less well with the risk of hemorrhage than the patient's past and family bleeding history do. We have devised expert consensus recommendations for managing such patients perioperatively, taking into consideration the personal and family bleeding history, the FVII activity level and the inherent bleeding risk of the procedure itself. We hope that clinicians will find this a useful tool in the decision-making process, thereby limiting the use of recombinant factor VIIa to those who need it most, and preventing possible thrombotic complications in those without a strong indication for its use.

Three new triterpenoid saponins from the seeds of Aesculus turbinata.

PubMed

Yang, Xiu-Wei; Zhao, Jing; Hattori, Masao

2008-01-01

Three new triterpenoid saponins, named isoescins VIIa (1), VIa (2), and VIIIa (3), were isolated from the seeds of Aesculus turbinata and identified by spectroscopic analysis and chemical hydrolysis. Their structures were established as 21beta-O-tigloyl-28-O-acetylprotoaescigenin 3beta-O-[beta-d-galactopyranosyl(1 --> 2)][beta-d-glucopyranosyl(1 --> 4)]-beta-d-glucopyranosiduronic acid (Isoescin VIIa, 1), 21beta-O-(2-methylbutyryl)-28-O-acetylprotoaescigenin 3beta-O-[beta-d-glucopyranosyl(1 --> 2)] [beta-d-glucopyranosyl(1 --> 4)]-beta-d-glucopyranosiduronic acid (Isoescin VIa, 2), and 21beta-O-angeloyl-28-O-acetylbarringtogenol C 3beta-O-[beta-d-glucopyranosyl(1 --> 2)] [beta-d-glucopyranosyl(1 --> 4)]-beta-d-glucopyranosiduronic acid (Isoescin VIIIa, 3).

8(th) Symposium on Hemostasis: Translational and Basic Science Discoveries.

PubMed

Margaritis, Paris; Key, Nigel S

2016-05-01

It has been 14 years since the first symposium on hemostasis at UNC Chapel Hill that focused primarily on the tissue factor (TF) and Factor VIIa (FVIIa) biology, biochemistry and translational work for the treatment of bleeding. Concepts, mechanistic data and therapeutic agents have since emerged that permeate not only aspects of the TF and FVIIa functions, but also broader processes in hemostasis and thrombosis. These processes involve circulating proteins, receptors, cells and cellular components that interact within the coagulation system as well as with additional systems that are dysregulated in disorders seemingly unrelated to bleeding/thrombosis. The reviews in this symposium provide the research background to understand such interactions and integrations. Copyright © 2016 Elsevier Ltd. All rights reserved.

In vitro efficacy of pro- and anticoagulant strategies in compensated and acutely ill patients with cirrhosis.

PubMed

Lisman, Ton; Kleiss, Simone; Patel, Vishal C; Fisher, Caleb; Adelmeijer, Jelle; Bos, Sarah; Singanayagam, Arjuna; Stoy, Sidsel Hyldgaard; Shawcross, Debbie L; Bernal, William

2018-05-16

A simultaneous decline in pro- and anticoagulant drivers in patients with liver diseases results in a 'rebalanced' hemostatic system, even in acutely ill patients. Nevertheless, both bleeding and thrombotic events are common. Here, we explored efficacy of pro- and antihemostatic strategies in compensated and acutely ill cirrhotics which may be unpredictable given the profound hemostatic changes. We tested the effects in vitro of the addition of clinically relevant doses of commonly used pro- and antihemostatic strategies in plasma from healthy individuals (n=30) and patients with compensated (n=18) and acutely decompensated cirrhosis (n=18), and acute-on-chronic liver failure (n=10). We used thrombin generation tests and fibrin clot permeability assays to assess potency of various approaches. Fresh frozen plasma and recombinant factor VIIa modestly increased thrombin generation (10-20%). Prothrombin complex concentrate increased thrombin generation 2-fold in controls and 2-4-fold in patients. Clot permeability decreased after addition of fibrinogen concentrate by 51% in controls and by 50-60% in patients. Low molecular weight heparin decreased thrombin generation by 18% in controls and by 23-54% in patients. Similarly, dabigatran decreased thrombin generation by 33% in controls and by 47-100% in patients. In contrast, rivaroxaban decreased thrombin generation by 55% in controls, but only by 11-38% in patients. These in vitro data suggest little prohemostatic effect of fresh frozen plasma and recombinant factor VIIa in acutely ill cirrhotics, whereas prothrombin complex concentrate and fibrinogen concentrate clearly improved hemostasis. Furthermore, our data suggest the requirement for dose-adjustments of commonly used anticoagulants in these patients. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Methodologies for data collection in congenital haemophilia with inhibitors (CHwI): critical assessment of the literature and lessons learned from recombinant factor VIIa.

PubMed

Kessler, C M; Benchikh El Fegoun, S; Worster, A

2018-05-09

To systematically review the effectiveness of on-demand treatment with recombinant coagulation factor VIIa (rFVIIa) in congenital haemophilia with inhibitors and, if feasible, perform a meta-analysis of the data. Publications from Embase ® , MEDLINE ® , MEDLINE ® In-Process and the Cochrane Central Register of Controlled Trials were searched. Selected publications were reviewed for inclusion by two independent expert reviewers. Discrepancies were reconciled by a third independent reviewer. Data from selected studies were extracted using a predefined grid to ensure uniform and comparable results were captured. A systematic search (cut-off date of 2 May 2016) identified 20 studies (13 observational; seven randomized controlled trials). All studies were of sufficient quality to include in this analysis and comprised 1221 participants, with 5981 bleeds in 746 individuals treated with rFVIIa. Haemostatic overall effectiveness of the individual studies identified ranged from 68% to 100% at ≤12 hours, 86% to 96% at 13-24 hours and 76% to 99% at 24-48 hours with rFVIIa <100 μg/kg, with similar rates reported for the ≥250 μg/kg dose. However, heterogeneity between the studies precluded pooling of results. Data from the individual studies confirmed that rFVIIa is an effective therapy for the on-demand treatment of bleeds in congenital haemophilia with inhibitors. However, the high levels of heterogeneity between studies precluded pooling of results for a valid, reliable or precise summary measure. There remains a need to implement standardized clinical definitions and measurements for the effectiveness and safety of haemophilia therapies in future clinical trials. © 2018 John Wiley & Sons Ltd.

Use of the UKHCDO Database for a postmarketing surveillance study of different doses of recombinant factor VIIa in haemophilia.

PubMed

Hay, C R M; Sharpe, T; Dolan, G

2017-05-01

Recombinant factor VIIa (rFVIIa) is recommended in Europe at standard (3 × 90 μg kg -1 ) or high (1 × 270 μg kg -1 ) doses. When granting the license for the high dose, the European Medicines Agency (EMA) requested postmarketing surveillance for thrombosis. This was conducted by the United Kingdom National Haemophilia Database (NHD) on behalf of Novo Nordisk and the EMA. To assess the use and safety of rFVIIa utilizing prospective data collected by the NHD (1 January 2008 to 30 June 2011). Data were obtained from 67 haemophilia A/B patients with inhibitors treated for 1057 bleeds and 31 acquired haemophilia patients treated for 70 bleeds. Initial rFVIIa dose was categorized post hoc as low (<90 μg kg -1 ), intermediate (≥90-<180 μg kg -1 ) or high (≥180-<270 or ≥270 μg kg -1 ). For haemophilia A/B, high and lower initial rFVIIa dose was used for 38.4% and 51.4% of episodes, respectively, while for acquired haemophilia, the values were 11.4% and 77.1% respectively. Median initial doses were higher for haemophilia A/B (146.3 μg kg -1 ) than acquired haemophilia (90.5 μg kg -1 ). A single administration of rFVIIa was the most frequently used regimen for haemophilia A/B, in contrast with standard recommendations and previous reports. For acquired haemophilia, most episodes were treated with multiple doses. No adverse drug reactions or thromboembolic events were reported for any rFVIIa dose. The novel use of a national database for postmarketing surveillance has demonstrated acceptable safety for all recommended doses of rFVIIa. © 2016 John Wiley & Sons Ltd.

Rab GTPases Regulate Endothelial Cell Protein C Receptor-Mediated Endocytosis and Trafficking of Factor VIIa

PubMed Central

Nayak, Ramesh C.; Keshava, Shiva; Esmon, Charles T.; Pendurthi, Usha R.; Rao, L. Vijaya Mohan

2013-01-01

Recent studies have established that factor VIIa (FVIIa) binds to the endothelial cell protein C receptor (EPCR). FVIIa binding to EPCR may promote the endocytosis of this receptor/ligand complex. Rab GTPases are known to play a crucial role in the endocytic and exocytic pathways of receptors or receptor/ligand complexes. The present study was undertaken to investigate the role of Rab GTPases in the intracellular trafficking of EPCR and FVIIa. CHO-EPCR cells and human umbilical vein endothelial cells (HUVEC) were transduced with recombinant adenoviral vectors to express wild-type, constitutively active, or dominant negative mutant of various Rab GTPases. Cells were exposed to FVIIa conjugated with AF488 fluorescent probe (AF488-FVIIa), and intracellular trafficking of FVIIa, EPCR, and Rab proteins was evaluated by immunofluorescence confocal microscopy. In cells expressing wild-type or constitutively active Rab4A, internalized AF488-FVIIa accumulated in early/sorting endosomes and its entry into the recycling endosomal compartment (REC) was inhibited. Expression of constitutively active Rab5A induced large endosomal structures beneath the plasma membrane where EPCR and FVIIa accumulated. Dominant negative Rab5A inhibited the endocytosis of EPCR-FVIIa. Expression of constitutively active Rab11 resulted in retention of accumulated AF488-FVIIa in the REC, whereas expression of a dominant negative form of Rab11 led to accumulation of internalized FVIIa in the cytoplasm and prevented entry of internalized FVIIa into the REC. Expression of dominant negative Rab11 also inhibited the transport of FVIIa across the endothelium. Overall our data show that Rab GTPases regulate the internalization and intracellular trafficking of EPCR-FVIIa. PMID:23555015

Off-label use of recombinant factor VIIa in U.S. hospitals: analysis of hospital records.

PubMed

Logan, Aaron C; Yank, Veronica; Stafford, Randall S

2011-04-19

Recombinant factor VIIa (rFVIIa) is approved for treatment of bleeding in patients who have hemophilia with inhibitors but has been applied to a wide range of off-label indications. To estimate patterns of off-label rFVIIa use in U.S. hospitals. Retrospective database analysis. Data were extracted from the Premier Perspectives database (Premier, Charlotte, North Carolina), which contains discharge records from a sample of academic and nonacademic U.S. hospitals. 12 644 hospitalizations for patients who received rFVIIa during a hospital stay. Hospital diagnoses and patient dispositions from 1 January 2000 to 31 December 2008. Statistical weights for each hospital were used to provide national estimates of rFVIIa use. From 2000 to 2008, off-label use of rFVIIa in hospitals increased more than 140-fold, such that in 2008, 97% (95% CI, 96% to 98%) of 18 311 in-hospital uses were off-label. In contrast, in-hospital use for hemophilia increased less than 4-fold and accounted for 2.7% (CI, 1.9% to 3.5%) of use in 2008. Adult and pediatric cardiovascular surgery (29% [CI, 21% to 33%]), body and brain trauma (29% [CI, 19% to 38%]), and intracranial hemorrhage (11% [CI, 7.7% to 14%]) were the most common indications for rFVIIa use. Across all indications, in-hospital mortality was 27% (CI, 19% to 34%) and 43% (CI, 26% to 59%) of patients were discharged to home. Accuracy and completeness of the discharge diagnoses and patient medication records in the database sample cannot be verified. Off-label use of rFVIIa in the hospital setting far exceeds use for approved indications. These patterns raise concern about the application of rFVIIa to conditions for which strong supporting evidence is lacking.

N-/O-glycosylation analysis of human FVIIa produced in the milk of transgenic rabbits

PubMed Central

Chevreux, Guillaume; Faid, Valegh; Scohyers, Jean-Marc; Bihoreau, Nicolas

2013-01-01

Human coagulation factor VIIa is a glycoprotein that promotes haemostasis through activation of the coagulation cascade extrinsic pathway. Most haemophilia A/B patients with inhibitors are treated by injection of plasma-derived or recombinant FVIIa. The use of recombinant products raises questions about the ability of the host cell to produce efficiently post-translationally modified proteins. Glycosylation is especially critical considering that it can modulate protein safety and efficacy. The present paper reports the N-/O-glycosylation pattern of a new recombinant human factor VIIa expressed in the mammary glands of transgenic rabbits. Glycosylation was investigated by chromatography and advanced mass spectrometry techniques for glycan identification and quantitation. Mass spectrometry (MS)/MS analyses were performed to confirm the glycan structures as well as the position and branching of specific monosaccharides or substituents. The two N-glycosylation sites were found to be fully occupied mostly by mono- and bi-sialylated biantennary complex-type structures, the major form being A2G2S1. Some oligomannose/hybrid structures were retrieved in lower abundance, the major ones being GlcNAcα1,O-phosphorylated at the C6-position of a Man residue (Man-6-(GlcNAcα1,O-)phosphate motif) as commonly observed on lysosomal proteins. No immunogenic glycotopes such as Galili (Galα1,3Gal) and HD antigens (N-glycolylneuraminic acid (NeuGc)) were detected. Concerning O-glycosylation, the product exhibited O-fucose and O-glucose-(xylose)0, 1, 2 motifs as expected. The N-glycosylation consistency was also investigated by varying production parameters such as the period of lactation, the number of consecutive lactations and rabbit generations. Results show that the transgenesis technology is suitable for the long-term production of rhFVIIa with a reproducible glycosylation pattern. PMID:24092837

The use of recombinant factor VIIa (NovoSeven) for treatment of active or impending bleeding in brain injury: broadening the indications.

PubMed

Yusim, Yakov; Perel, Azriel; Berkenstadt, Haim; Attia, Moshe; Knoller, Nachshon; Sidi, Avner

2006-11-01

We report three patients with severe traumatic brain injury, both open and closed, who were treated with recombinant activated factor VII. This treatment was given in a desperate, last-ditch effort to save the life of patient 1, as a preventive or early treatment of a developing hematoma in patient 2, and as treatment of a threatening hematoma in patient 3. One of the three patients survived. During the past few years we have broadened the indications for recombinant activated factor VII and started using it as a preventive measure rather than as a "last line of defense." However, the potential complications of disseminated intravascular coagulation and thrombotic events, as well as the cost-effectiveness in view of the available evidence-based medicine, should be considered.

Synthesis of Phosphatidylserine and Its Stereoisomers: Their Role in Activation of Blood Coagulation.

PubMed

Mallik, Suman; Prasad, Ramesh; Bhattacharya, Anindita; Sen, Prosenjit

2018-05-10

Natural phosphatidylserine (PS), which contains two chiral centers, enhances blood coagulation. However, the process by which PS enhanced blood coagulation is not completely understood. An efficient and flexible synthetic route has been developed to synthesize all of the possible stereoisomers of PS. In this study, we examined the role of PS chiral centers in modulating the activity of the tissue factor (TF)-factor VIIa coagulation initiation complex. Full length TF was relipidated with phosphatidylcholine, and the synthesized PS isomers were individually used to estimate the procoagulant activity of the TF-FVIIa complex via a FXa generation assay. The results revealed that the initiation complex activity was stereoselective and had increased sensitivity to the configuration of the PS glycerol backbone due to optimal protein-lipid interactions.

Identification and biochemical analysis of Slac2-c/MyRIP as a Rab27A-, myosin Va/VIIa-, and actin-binding protein.

PubMed

Kuroda, Taruho S; Fukuda, Mitsunori

2005-01-01

Slac2-c/MyRIP is a specific Rab27A-binding protein that contains an N-terminal synaptotagmin-like protein (Slp) homology domain (SHD, a newly identified GTP-Rab27A-binding motif), but in contrast to the Slp family proteins, it lacks C-terminal tandem C2 domains. In vitro Slac2-c simultaneously directly interacts with both Rab27A and an actin-based motor protein, myosin Va, via its N-terminal SHD and middle region, respectively, consistent with the fact that the overall structure of Slac2-c is similar to that of Slac2-a/melanophilin, a linker protein between Rab27A and myosin Va in the melanosome transport in melanocytes. Unlike Slac2-a, however, the middle region of Slac2-c interacts with two types of myosins, myosin Va and myosin VIIa. In addition, the most C-terminal part of both Slac2-a and Slac2-c functions as an actin-binding domain: it directly interacts with globular and fibrous actin in vitro, and the actin-binding domain of Slac2-a and Slac2-c colocalizes with actin filaments when it is expressed in living cells (i.e., PC12 cells and mouse melanocytes). In this chapter we describe the methods that have been used to analyze the protein-protein interactions of Slac2-c, specifically with Rab27A, myosin Va/VIIa, and actin.

Management of Labour and Delivery in a Patient With Acquired Factor VII Deficiency With Inhibitor: A Case Report.

PubMed

Matei, Anca; Dolan, Sean; Andrews, James; Rivard, Georges-Étienne

2016-02-01

Acquired factor VII (FVII) deficiency with inhibitor increases the risk of hemorrhage during pregnancy. However, there are no published reports guiding its management in the peripartum period. A 24-year-old woman with inhibitory antibodies to FVII delivered at 34 weeks of gestation. The patient was administered recombinant factor VIIa (rFVIIa) and tranexamic acid. There were no bleeding-related complications; however, the FVII level was supratherapeutic. The patient returned during a second pregnancy. A reduced dose of rFVIIa was administered. The delivery was complicated by postpartum hemorrhage, which resolved with the addition of uterotonic agents. Recombinant FVIIa and tranexamic acid offer an effective peripartum treatment in women with inhibitory antibody to FVII. Further research should delineate the optimal time of administration. Copyright © 2016 Society of Obstetricians and Gynaecologists of Canada. Published by Elsevier Inc. All rights reserved.

Inhibitor development after liver transplantation in congenital factor VII deficiency.

PubMed

See, W-S Q; Chang, K-O; Cheuk, D K-L; Leung, Y-Y R; Chan, G C-F; Chan, S-C; Ha, S-Y

2016-09-01

Congenital factor VII (FVII) deficiency is the commonest type of the rare bleeding disorders. Very few cases of congenital FVII deficiency developed inhibitor and liver transplant is considered as definitive treatment. In the literature, twelve patients with congenital FVII deficiency developed inhibitors. Two had spontaneous resolution of inhibitors and one did not respond to high dose recombinant factor VIIa (rFVIIa) and died. Regarding liver transplant in congenital FVII patients, seven patients underwent liver transplant with good prognosis. We report a 5-year-old girl with confirmed severe congenital FVII deficiency since neonatal period. She suffered from recurrent intracranial bleeding despite rFVIIa replacement. After auxiliary liver transplant at the age of 4, she continued to show persistent deranged clotting profile and was found to have inhibitor towards FVII. Interestingly, she was still responsive to rFVIIa replacement. © 2016 John Wiley & Sons Ltd.

Factor VII Tokushima: the first case of factor VII Cys22Gly with the development of myocardial infarction in the proband receiving recombinant factor VIIa replacement therapy.

PubMed

Shigekiyo, Toshio; Sekimoto, Etsuko; Shibata, Hironobu; Ozaki, Shuji; Okumura, Takanobu; Fujinaga, Hiroyuki; Shibata, Hiroshi; Aihara, Ken-ichi; Akaike, Masashi

2015-12-01

An 81-year-old man was referred to our department because of suspected factor VII (FVII) deficiency. His FVII activity was under 1%, whereas the FVII activity levels of his son and granddaughter were 65 and 109%, respectively. The nucleotide at position 3886 of his FVII gene was homozygous for G. A single T to G substitution results in the replacement of wild-type Cys at residue 22 by Gly. His son was heterozygous for G and T at position 3886, whereas his granddaughter was homozygous for wild-type T. These results suggest that he was homozygous for FVII Cys22Gly. He underwent radiofrequency ablation (RFA) for hepatocellular carcinoma, receiving 20 μg/kg of recombinant FVIIa prior to RFA and 10 μg/kg of recombinant FVIIa twice after RFA. He showed no bleeding tendency; however, a myocardial infarction was diagnosed and percutaneous coronary intervention was performed.

Multiple roles of the coagulation protease cascade during virus infection.

PubMed

Antoniak, Silvio; Mackman, Nigel

2014-04-24

The coagulation cascade is activated during viral infections. This response may be part of the host defense system to limit spread of the pathogen. However, excessive activation of the coagulation cascade can be deleterious. In fact, inhibition of the tissue factor/factor VIIa complex reduced mortality in a monkey model of Ebola hemorrhagic fever. Other studies showed that incorporation of tissue factor into the envelope of herpes simplex virus increases infection of endothelial cells and mice. Furthermore, binding of factor X to adenovirus serotype 5 enhances infection of hepatocytes but also increases the activation of the innate immune response to the virus. Coagulation proteases activate protease-activated receptors (PARs). Interestingly, we and others found that PAR1 and PAR2 modulate the immune response to viral infection. For instance, PAR1 positively regulates TLR3-dependent expression of the antiviral protein interferon β, whereas PAR2 negatively regulates expression during coxsackievirus group B infection. These studies indicate that the coagulation cascade plays multiple roles during viral infections.

Differential Expression of Unconventional Myosins in Apoptotic and Regenerating Chick Hair Cells Confirms Two Regeneration Mechanisms

PubMed Central

DUNCAN, LUKE J.; MANGIARDI, DOMINIC A.; MATSUI, JONATHAN I.; ANDERSON, JULIA K.; McLAUGHLIN-WILLIAMSON, KATE; COTANCHE, DOUGLAS A.

2008-01-01

Hair cells of the inner ear are damaged by intense noise, aging, and aminoglycoside antibiotics. Gentamicin causes oxidative damage to hair cells, inducing apoptosis. In mammals, hair cell loss results in a permanent deficit in hearing and balance. In contrast, avians can regenerate lost hair cells to restore auditory and vestibular function. This study examined the changes of myosin VI and myosin VIIa, two unconventional myosins that are critical for normal hair cell formation and function, during hair cell death and regeneration. During the late stages of apoptosis, damaged hair cells are ejected from the sensory epithelium. There was a 4–5-fold increase in the labeling intensity of both myosins and a redistribution of myosin VI into the stereocilia bundle, concurrent with ejection. Two separate mechanisms were observed during hair cell regeneration. Proliferating supporting cells began DNA synthesis 60 hours after gentamicin treatment and peaked at 72 hours postgentamicin treatment. Some of these mitotically produced cells began to differentiate into hair cells at 108 hours after gentamicin (36 hours after bromodeoxyuridine (BrdU) administration), as demonstrated by the colabeling of myosin VI and BrdU. Myosin VIIa was not expressed in the new hair cells until 120 hours after gentamicin. Moreover, a population of supporting cells expressed myosin VI at 78 hours after gentamicin treatment and myosin VIIa at 90 hours. These cells did not label for BrdU and differentiated far too early to be of mitotic origin, suggesting they arose by direct transdifferentiation of supporting cells into hair cells. PMID:17048225

In vitro evidence of a tissue factor-independent mode of action of recombinant factor VIIa in hemophilia.

PubMed

Augustsson, Cecilia; Persson, Egon

2014-11-13

Successful competition of activated factor VII (FVIIa) with zymogen factor VII (FVII) for tissue factor (TF) and loading of the platelet surface with FVIIa are plausible driving forces behind the pharmacological effect of recombinant FVIIa (rFVIIa) in hemophilia patients. Thrombin generation measurements in platelet-rich hemophilia A plasma revealed competition for TF, which potentially could reduce the effective (r)FVIIa:TF complex concentration and thereby attenuate factor Xa production. However, (auto)activation of FVII apparently counteracted the negative effect of zymogen binding; a small impact was observed at endogenous concentrations of FVII and FVIIa but was virtually absent at pharmacological amounts of rFVIIa. Moreover, corrections of the propagation phase in hemophilia A required rFVIIa concentrations above the range where a physiological level of FVII was capable to downregulate thrombin generation. These data strongly suggest that rFVIIa acts independently of TF in hemophilia therapy and that FVII displacement by rFVIIa is a negligible mechanistic component. © 2014 by The American Society of Hematology.

Phase I, randomized, double-blind, placebo-controlled, single-dose escalation study of the recombinant factor VIIa variant BAY 86-6150 in hemophilia.

PubMed

Mahlangu, J N; Coetzee, M J; Laffan, M; Windyga, J; Yee, T T; Schroeder, J; Haaning, J; Siegel, J E; Lemm, G

2012-05-01

BAY 86-6150 is a new human recombinant factor VIIa variant developed for high procoagulant activity and longer action in people with hemophilia with inhibitors. To investigate the safety, tolerability, pharmacodynamics, pharmacokinetics and immunogenicity of BAY 86-6150 in non-bleeding hemophilia subjects. The study included non-bleeding men (18-65 years of age) with moderate or severe hemophilia A or B with or without inhibitors. Sixteen subjects were randomized 3 : 1 to four cohorts of escalating doses of BAY 86-6150 (6.5, 20, 50 or 90 μg kg(-1) [n = 3 per cohort]) or placebo (n = 1 per cohort); an independent data-monitoring committee reviewed previous cohort data before the next dose escalation. Blood sampling was performed predose and postdose; subjects were monitored for 50 days postdose. At the tested doses, BAY 86-6150 was not associated with clinically significant adverse events or dose-limiting toxicities. BAY 86-6150 pharmacokinetics exhibited a linear dose response, with a half-life of 5-7 h. Subjects demonstrated consistent, dose-dependent thrombin generation ex vivo in platelet-poor plasma (PPP) (mean peak effect, 26-237 nm thrombin from 6.5 to 90 μg kg(-1)). Peak thrombin levels over time paralleled BAY 86-6150, with thrombin kinetics appearing to be slightly shorter; thus, circulating BAY 86-6150 retained activity. There were corresponding decreases in activated partial thromboplastin and prothrombin times. No subject developed de novo anti-BAY 86-6150 neutralizing antibodies during the 50-day follow-up. In this first-in-human, multicenter, randomized, double-blind, placebo-controlled, single-dose escalation study, BAY 86-6150 was tolerated at the highest dose (90 μg kg(-1)), with no safety concerns. Safety and efficacy will be further evaluated in phase II/III studies. © 2012 International Society on Thrombosis and Haemostasis.

The E3 ligase Ubr3 regulates Usher syndrome and MYH9 disorder proteins in the auditory organs of Drosophila and mammals.

PubMed

Li, Tongchao; Giagtzoglou, Nikolaos; Eberl, Daniel F; Jaiswal, Sonal Nagarkar; Cai, Tiantian; Godt, Dorothea; Groves, Andrew K; Bellen, Hugo J

2016-06-22

Myosins play essential roles in the development and function of auditory organs and multiple myosin genes are associated with hereditary forms of deafness. Using a forward genetic screen in Drosophila, we identified an E3 ligase, Ubr3, as an essential gene for auditory organ development. Ubr3 negatively regulates the mono-ubiquitination of non-muscle Myosin II, a protein associated with hearing loss in humans. The mono-ubiquitination of Myosin II promotes its physical interaction with Myosin VIIa, a protein responsible for Usher syndrome type IB. We show that ubr3 mutants phenocopy pathogenic variants of Myosin II and that Ubr3 interacts genetically and physically with three Usher syndrome proteins. The interactions between Myosin VIIa and Myosin IIa are conserved in the mammalian cochlea and in human retinal pigment epithelium cells. Our work reveals a novel mechanism that regulates protein complexes affected in two forms of syndromic deafness and suggests a molecular function for Myosin IIa in auditory organs.

Structure of MyTH4-FERM domains in myosin VIIa tail bound to cargo.

PubMed

Wu, Lin; Pan, Lifeng; Wei, Zhiyi; Zhang, Mingjie

2011-02-11

The unconventional myosin VIIa (MYO7A) is one of the five proteins that form a network of complexes involved in formation of stereocilia. Defects in these proteins cause syndromic deaf-blindness in humans [Usher syndrome I (USH1)]. Many disease-causing mutations occur in myosin tail homology 4-protein 4.1, ezrin, radixin, moesin (MyTH4-FERM) domains in the myosin tail that binds to another USH1 protein, Sans. We report the crystal structure of MYO7A MyTH4-FERM domains in complex with the central domain (CEN) of Sans at 2.8 angstrom resolution. The MyTH4 and FERM domains form an integral structural and functional supramodule binding to two highly conserved segments (CEN1 and 2) of Sans. The MyTH4-FERM/CEN complex structure provides mechanistic explanations for known deafness-causing mutations in MYO7A MyTH4-FERM. The structure will also facilitate mechanistic and functional studies of MyTH4-FERM domains in other myosins.

29 CFR 1926.62 - Lead.

Code of Federal Regulations, 2013 CFR

2013-07-01

... annually to reflect the current status of the program. (3) Mechanical ventilation. When ventilation is used... potentially harmful effects of exposure to lead. (vii)(A) The employer shall ensure that the containers of... remove lead from any surface unless the compressed air is used in conjunction with a ventilation system...

29 CFR 1926.62 - Lead.

Code of Federal Regulations, 2012 CFR

2012-07-01

... annually to reflect the current status of the program. (3) Mechanical ventilation. When ventilation is used... potentially harmful effects of exposure to lead. (vii)(A) The employer shall ensure that the containers of... remove lead from any surface unless the compressed air is used in conjunction with a ventilation system...

29 CFR 1926.62 - Lead.

Code of Federal Regulations, 2014 CFR

2014-07-01

... annually to reflect the current status of the program. (3) Mechanical ventilation. When ventilation is used... potentially harmful effects of exposure to lead. (vii)(A) The employer shall ensure that the containers of... remove lead from any surface unless the compressed air is used in conjunction with a ventilation system...

Blood coagulation reactions on nanoscale membrane surfaces

NASA Astrophysics Data System (ADS)

Pureza, Vincent S.

Blood coagulation requires the assembly of several membrane-bound protein complexes composed of regulatory and catalytic subunits. The biomembranes involved in these reactions not only provide a platform for these procoagulant proteins, but can also affect their function. Increased exposure of acidic phospholipids on the outer leaflet of the plasma membrane can dramatically modulate the catalytic efficiencies of such membrane-bound enzymes. Under physiologic conditions, however, these phospholipids spontaneously cluster into a patchwork of membrane microdomains upon which membrane binding proteins may preferentially assemble. As a result, the membrane composition surrounding these proteins is largely unknown. Through the development and use of a nanometer-scale bilayer system that provides rigorous control of the phospholipid membrane environment, I investigated the role of phosphatidylserine, an acidic phospholipid, in the direct vicinity (within nanometers) of two critical membrane-bound procoagulant protein complexes and their respective natural substrates. Here, I present how the assembly and function of the tissue factor˙factor VIIa and factor Va˙factor Xa complexes, the first and final cofactor˙enzyme complexes of the blood clotting cascade, respectively, are mediated by changes in their immediate phospholipid environments.

Tissue Factor Pathway Inhibitor: Multiple Anticoagulant Activities for a Single Protein.

PubMed

Mast, Alan E

2016-01-01

Tissue factor (TF) pathway inhibitor (TFPI) is an anticoagulant protein that inhibits early phases of the procoagulant response. Alternatively spliced isoforms of TFPI are differentially expressed by endothelial cells and human platelets and plasma. The TFPIβ isoform localizes to the endothelium surface where it is a potent inhibitor of TF-factor VIIa complexes that initiate blood coagulation. The TFPIα isoform is present in platelets. TFPIα contains a stretch of 9 amino acids nearly identical to those found in the B-domain of factor V that are well conserved in mammals. These amino acids provide exosite binding to activated factor V, which allows for TFPIα to inhibit prothrombinase during the initiation phase of blood coagulation. Endogenous inhibition at this point in the coagulation cascade was only recently recognized and has provided a biochemical rationale to explain the pathophysiological mechanisms underlying several clinical disorders. These include the east Texas bleeding disorder that is caused by production of an altered form of factor V with high affinity for TFPI and a paradoxical procoagulant effect of heparins. In addition, these findings have led to ideas for pharmacological targeting of TFPI that may reduce bleeding in hemophilia patients. © 2015 American Heart Association, Inc.

[Concepts in anticoagulant therapy - past, present, and future].

PubMed

Graf, L

2012-11-01

The understanding of the clotting system emerged in parallel to the development of anticoagulants. In contrast to vitamin K-antagonists and heparins that where discovered by chance, new anticoagulants have been systematically designed to specifically inhibit single clotting factors. Both clotting factors Xa (FXa) and thrombin play a crucial role within the new cell-based model of hemostasis. Thus it is obvious that FXa and thrombin turned out to be ideal targets for anticoagulation. The proof of the concept of selective inhibition of thrombin and FXa has been provided by hirudin and fondaparinux, respectively. By now, a whole group of new oral anticoagulants has been licensed: the direct FXa-inhibitors rivaroxaban, apixaban, and edoxaban as well as the direct thrombin dabigatran etexilate. Furthermore, a bundle of FXa- and thrombin-inhibitors that differ from the so far licensed products mainly in pharmacokinetics are in an advanced phase of development. A further innovative concept of anticoagulation that entered its clinical phase of development is the inhibition of factor VIII. Other new concepts such as inhibition of initiation of coagulation by blocking factor VIIa, inhibition of contact factor XII, or inhibition of factor IX are in an early phase of development.

[Blunt trauma with bullet-proof vests. Skin lesions are no reliable predictor of injury severity].

PubMed

Doll, D; Illert, B; Bohrer, S; Richter, C; Woelfl, C

2009-04-01

It is well known that so-called bullet-proof vests offer protection against a wide range of penetrating trauma, but their protection against blunt trauma is less well understood. Fast projectiles may result in hematomas and contusions behind the armour. We report a traffic accident involving a young soldier wearing a ballistic protection vest resulting in a right thoracoabdominal blunt trauma leading to a confined liver compression rupture. As nearly no skin marks were detectable, we point out that every emergency department surgeon should be very suspicious if a patient wore a ballistic vest at the time of the accident--there may be no skin marks despite severe intra-abdominal trauma. Our patient recovered following hypotensive ICU treatment, thrombocyte mobilization, and factor VIIa substitution.

Random Forests Are Able to Identify Differences in Clotting Dynamics from Kinetic Models of Thrombin Generation.

PubMed

Arumugam, Jayavel; Bukkapatnam, Satish T S; Narayanan, Krishna R; Srinivasa, Arun R

2016-01-01

Current methods for distinguishing acute coronary syndromes such as heart attack from stable coronary artery disease, based on the kinetics of thrombin formation, have been limited to evaluating sensitivity of well-established chemical species (e.g., thrombin) using simple quantifiers of their concentration profiles (e.g., maximum level of thrombin concentration, area under the thrombin concentration versus time curve). In order to get an improved classifier, we use a 34-protein factor clotting cascade model and convert the simulation data into a high-dimensional representation (about 19000 features) using a piecewise cubic polynomial fit. Then, we systematically find plausible assays to effectively gauge changes in acute coronary syndrome/coronary artery disease populations by introducing a statistical learning technique called Random Forests. We find that differences associated with acute coronary syndromes emerge in combinations of a handful of features. For instance, concentrations of 3 chemical species, namely, active alpha-thrombin, tissue factor-factor VIIa-factor Xa ternary complex, and intrinsic tenase complex with factor X, at specific time windows, could be used to classify acute coronary syndromes to an accuracy of about 87.2%. Such a combination could be used to efficiently assay the coagulation system.

Ni-H2 cell characterization for INTELSAT programs

NASA Technical Reports Server (NTRS)

Dunnet, Andrew F.; Earl, Martin W.

1994-01-01

Various Ni/H2 cell designs manufactured for INTELSAT Programs during the past decade have been characterized electrically as a function of temperature. The resulting data for these INTELSAT V, VI, VII and VIIA cells are assembled in a manner which allows ready comparison of performance. Also included is a detailed description of each design.

Management of Surgical Third Lower Molar Extraction and Postoperative Progress in Patients With Factor VII Deficiency: A Clinical Protocol and Focus on This Rare Pathologic Entity.

PubMed

Passarelli, Pier Carmine; Pasquantonio, Guido; D'Addona, Antonio

2017-10-01

The purpose of the present study was to analyze the management of surgical third molar extraction and postoperative progress in patients with a diagnosis of factor VII deficiency. Close collaboration between the oral-maxillofacial surgeon and hematologist will allow the team to categorize the risk and operate safely, thereby minimizing the incidence and severity of intraoperative and postoperative complications. The present retrospective study included 7 patients with factor VII deficiency who had undergone third lower molar surgery. Their factor VII deficiency ranged from 10.5 to 21.0%. Recombinant activated factor VII (rFVIIa) (coagulation factor VIIa [recombinant]; NovoSeven RT; Novo Nordisk, Bagsvaerd, Denmark) was transfused intravenously in a single dose of 25 μg/kg body weight, 30 minutes before surgical extractions. After the surgery, betamethasone, an analgesic, and an ice pack were administered. Pretreatment with recombinant activated factor VII resulted in excellent hemostasis. No hemorrhagic complications and no postoperative major bleeding were observed. The extraction of the third lower molar appears to be a safe procedure for patients with factor VII deficiency when appropriate prophylaxis with rFVIIa is used. Copyright © 2017 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

The E3 ligase Ubr3 regulates Usher syndrome and MYH9 disorder proteins in the auditory organs of Drosophila and mammals

PubMed Central

Li, Tongchao; Giagtzoglou, Nikolaos; Eberl, Daniel F; Jaiswal, Sonal Nagarkar; Cai, Tiantian; Godt, Dorothea; Groves, Andrew K; Bellen, Hugo J

2016-01-01

Myosins play essential roles in the development and function of auditory organs and multiple myosin genes are associated with hereditary forms of deafness. Using a forward genetic screen in Drosophila, we identified an E3 ligase, Ubr3, as an essential gene for auditory organ development. Ubr3 negatively regulates the mono-ubiquitination of non-muscle Myosin II, a protein associated with hearing loss in humans. The mono-ubiquitination of Myosin II promotes its physical interaction with Myosin VIIa, a protein responsible for Usher syndrome type IB. We show that ubr3 mutants phenocopy pathogenic variants of Myosin II and that Ubr3 interacts genetically and physically with three Usher syndrome proteins. The interactions between Myosin VIIa and Myosin IIa are conserved in the mammalian cochlea and in human retinal pigment epithelium cells. Our work reveals a novel mechanism that regulates protein complexes affected in two forms of syndromic deafness and suggests a molecular function for Myosin IIa in auditory organs. DOI: http://dx.doi.org/10.7554/eLife.15258.001 PMID:27331610

EIAV-based retinal gene therapy in the shaker1 mouse model for usher syndrome type 1B: development of UshStat.

PubMed

Zallocchi, Marisa; Binley, Katie; Lad, Yatish; Ellis, Scott; Widdowson, Peter; Iqball, Sharifah; Scripps, Vicky; Kelleher, Michelle; Loader, Julie; Miskin, James; Peng, You-Wei; Wang, Wei-Min; Cheung, Linda; Delimont, Duane; Mitrophanous, Kyriacos A; Cosgrove, Dominic

2014-01-01

Usher syndrome type 1B is a combined deaf-blindness condition caused by mutations in the MYO7A gene. Loss of functional myosin VIIa in the retinal pigment epithelia (RPE) and/or photoreceptors leads to blindness. We evaluated the impact of subretinally delivered UshStat, a recombinant EIAV-based lentiviral vector expressing human MYO7A, on photoreceptor function in the shaker1 mouse model for Usher type 1B that lacks a functional Myo7A gene. Subretinal injections of EIAV-CMV-GFP, EIAV-RK-GFP (photoreceptor specific), EIAV-CMV-MYO7A (UshStat) or EIAV-CMV-Null (control) vectors were performed in shaker1 mice. GFP and myosin VIIa expression was evaluated histologically. Photoreceptor function in EIAV-CMV-MYO7A treated eyes was determined by evaluating α-transducin translocation in photoreceptors in response to low light intensity levels, and protection from light induced photoreceptor degeneration was measured. The safety and tolerability of subretinally delivered UshStat was evaluated in macaques. Expression of GFP and myosin VIIa was confirmed in the RPE and photoreceptors in shaker1 mice following subretinal delivery of the EIAV-CMV-GFP/MYO7A vectors. The EIAV-CMV-MYO7A vector protected the shaker1 mouse photoreceptors from acute and chronic intensity light damage, indicated by a significant reduction in photoreceptor cell loss, and restoration of the α-transducin translocation threshold in the photoreceptors. Safety studies in the macaques demonstrated that subretinal delivery of UshStat is safe and well-tolerated. Subretinal delivery of EIAV-CMV-MYO7A (UshStat) rescues photoreceptor phenotypes in the shaker1 mouse. In addition, subretinally delivered UshStat is safe and well-tolerated in macaque safety studies These data support the clinical development of UshStat to treat Usher type 1B syndrome.

Hematoma Expansion Following Acute Intracerebral Hemorrhage

PubMed Central

Brouwers, H. Bart; Greenberg, Steven M.

2013-01-01

Intracerebral hemorrhage, the most devastating form of stroke, has no specific therapy proven to improve outcome by randomized controlled trial. Location and baseline hematoma volume are strong predictors of mortality, but are non-modifiable by the time of diagnosis. Expansion of the initial hematoma is a further marker of poor prognosis that may be at least partly preventable. Several risk factors for hematoma expansion have been identified, including baseline ICH volume, early presentation after symptom onset, anticoagulation, and the CT angiography spot sign. Although the biological mechanisms of hematoma expansion remain unclear, accumulating evidence supports a model of ongoing secondary bleeding from ruptured adjacent vessels surrounding the initial bleeding site. Several large clinical trials testing therapies aimed at preventing hematoma expansion are in progress, including aggressive blood pressure reduction, treatment with recombinant factor VIIa guided by CT angiography findings, and surgical intervention for superficial hematomas without intraventricular extension. Hematoma expansion is so far the only marker of outcome that is amenable to treatment and thus a potentially important therapeutic target. PMID:23466430

Recombinant factor VIIa in major abdominal surgery and liver transplantation.

PubMed

da Silva Viana, J

2006-04-01

The author reviewed the literature regarding recombinant activated Factor VII (rFVIIa) in major abdominal surgery and liver transplantation and concluded that, on the basis of evidence-based medicine, there is no evidence to support an extensive use of rFVIIa. Nevertheless, various case reports suggest the usefulness of rFVIIa to treat life-threatening bleeding after failure of conventional therapies. It appears that there is a consensus that rFVIIa can be used with good results as a rescue therapy in extremely severe situations. Economic cost and potential thrombosis risk remain arguments against more widespread use of rFVIIa. Doses from 5 to 120 kg/kg in each administration have been reported without clear evidence to support a specific protocol. Efficacy of 15 to 20 kg/kg in surgical settings has been reported, but higher doses are more frequently used. The majority of the reviewed investigators accepted the use of rFVIIa after or simultaneously with the use of aprotinin; no data refute the safety of this association.

Adapting the Training Site to Training Needs. Self-Paced Instructional Module. Module Number VII-A.

ERIC Educational Resources Information Center

King, Sylvester; Brooks, Kent

One of 33 self-paced instructional modules for training industry services leaders to provide guidance in the performance of manpower services by public agencies to new and expanding private industry, this module contains three sequential learning activities on adapting the training site to training needs. The first learning activity is designed to…

Crystallization and Preliminary X-ray Diffraction Analysis of Hemextin A: A Unique Anticoagulant Protein from Hemachatus haemachatus Venom

DOE Office of Scientific and Technical Information (OSTI.GOV)

Banerjee,Y.; Kumar, S.; Jobichen, C.

2007-01-01

Hemextin A was isolated and purified from African Ringhals cobra (Hemachatus haemachatus). It is a three-finger toxin that specifically inhibits blood coagulation factor VIIa and clot formation and that also interacts with hemextin B to form a unique anticoagulant complex. Hemextin A was crystallized by the hanging-drop vapor-diffusion method by equilibration against 0.2 M ammonium acetate, 0.1 M sodium acetate trihydrate pH 4.6 and 30% PEG 4000 as the precipitating agent. The crystals belong to space group P2{sub 1}2{sub 1}2{sub 1}, with unit-cell parameters a = 49.27, b = 49.51, c = 57.87 {angstrom} and two molecules in the asymmetricmore » unit. They diffracted to 1.5 {angstrom} resolution at beamline X25 at BNL.« less

Recombinant expression of Ixolaris, a Kunitz-type inhibitor from the tick salivary gland, for NMR studies.

PubMed

De Paula, V S; Silva, F H S; Francischetti, I M B; Monteiro, R Q; Valente, A P

2017-11-01

Ixolaris is an anticoagulant protein identified in the tick saliva of Ixodes scapularis. Ixolaris contains 2 Kunitz like domains and binds to Factor Xa or Factor X as a scaffold for inhibition of the Tissue Factor (TF)/Factor VIIa (FVIIa). In contrast to tissue factor pathway inhibitor (TFPI), however, Ixolaris does not bind to the active site cleft of FXa. Instead, complex formation is mediated by the FXa heparin-binding exosite. Due to its potent and long-lasting antithrombotic activity, Ixolaris is a promising agent for anticoagulant therapy. Although numerous functional studies of Ixolaris exist, three-dimensional structure of Ixolaris has not been obtained at atomic resolution. Using the pET32 vector, we successfully expressed a TRX-His 6 -Ixolaris fusion protein. By combining Ni-NTA chromatography, enterokinase protease cleavage, and reverse phase HPLC (RP-HPLC), we purified isotopically labeled Ixolaris for NMR studies. 1D 1 H and 2D 15 N- 1 H NMR analysis yielded high quality 2D 15 N- 1 H HSQC spectra revealing that the recombinant protein is folded. These studies represent the first steps in obtaining high-resolution structural information by NMR for Ixolaris enabling the investigation of the molecular basis for Ixolaris-coagulation factors interactions. Copyright © 2017 Elsevier Inc. All rights reserved.

Fusion proteins comprising annexin V and Kunitz protease inhibitors are highly potent thrombogenic site-directed anticoagulants

PubMed Central

Chen, Hsiu-Hui; Vicente, Cristina P.; He, Li; Tollefsen, Douglas M.; Wun, Tze-Chein

2005-01-01

The anionic phospholipid, phosphatidyl-l-serine (PS), is sequestered in the inner layer of the plasma membrane in normal cells. Upon injury, activation, and apoptosis, PS becomes exposed on the surfaces of cells and sheds microparticles, which are procoagulant. Coagulation is initiated by formation of a tissue factor/factor VIIa complex on PS-exposed membranes and propagated through the assembly of intrinsic tenase (factor VIIIa/factor IXa), prothrombinase (factor Va/factor Xa), and factor XIa complexes on PS-exposed activated platelets. We constructed a novel series of recombinant anticoagulant fusion proteins by linking annexin V (ANV), a PS-binding protein, to the Kunitz-type protease inhibitor (KPI) domain of tick anticoagulant protein, an aprotinin mutant (6L15), amyloid β-protein precursor, or tissue factor pathway inhibitor. The resulting ANV-KPI fusion proteins were 6- to 86-fold more active than recombinant tissue factor pathway inhibitor and tick anticoagulant protein in an in vitro tissue factor–initiated clotting assay. The in vivo antithrombotic activities of the most active constructs were 3- to 10-fold higher than that of ANV in a mouse arterial thrombosis model. ANV-KPI fusion proteins represent a new class of anticoagulants that specifically target the anionic membrane-associated coagulation enzyme complexes present at sites of thrombogenesis and are potentially useful as antithrombotic agents. PMID:15677561

Ca2+-Induced Rigidity Change of the Myosin VIIa IQ Motif-Single α Helix Lever Arm Extension.

PubMed

Li, Jianchao; Chen, Yiyun; Deng, Yisong; Unarta, Ilona Christy; Lu, Qing; Huang, Xuhui; Zhang, Mingjie

2017-04-04

Several unconventional myosins contain a highly charged single α helix (SAH) immediately following the calmodulin (CaM) binding IQ motifs, functioning to extend lever arms of these myosins. How such SAH is connected to the IQ motifs and whether the conformation of the IQ motifs-SAH segments are regulated by Ca 2+ fluctuations are not known. Here, we demonstrate by solving its crystal structure that the predicted SAH of myosin VIIa (Myo7a) forms a stable SAH. The structure of Myo7a IQ5-SAH segment in complex with apo-CaM reveals that the SAH sequence can extend the length of the Myo7a lever arm. Although Ca 2+ -CaM remains bound to IQ5-SAH, the Ca 2+ -induced CaM binding mode change softens the conformation of the IQ5-SAH junction, revealing a Ca 2+ -induced lever arm flexibility change for Myo7a. We further demonstrate that the last IQ motif of several other myosins also binds to both apo- and Ca 2+ -CaM, suggesting a common Ca 2+ -induced conformational regulation mechanism. Copyright © 2017 Elsevier Ltd. All rights reserved.

Two Finnish USH1B patients with three novel mutations in myosin VIIA.

PubMed

Vastinsalo, Hanna; Isosomppi, Juha; Aittakorpi, Anne; Sankila, Eeva-Marja

2006-09-21

Usher syndrome (USH) is an autosomal recessive disorder resulting in retinal degeneration and sensorineural deafness caused by mutations in at least 10 gene loci. USH is divided into three main clinical types: USH1 (33-44%), USH2 (56-67%), and USH3. Worldwide, USH1 and USH2 account for most of the Usher syndrome cases with rare occurrence of USH3. In Finland, however, USH3 is the most common type (40%), explained by genetic and geographical isolation accompanied with a founder mutation, while USH1 is estimated to comprise 34% and USH2 12% of all USH cases. We examined two unrelated Finnish USH1 patients by sequencing. We found three new myosin VIIA (MYO7A) mutations: p.K923AfsX8, p.Q1896X, and p.E1349K. The p.K923AfsX8 mutation was present in both patients as well as in one of 200 Finnish control chromosomes. This is the first molecular genetic study of USH1 in Finland. We have found three new pathological mutations causing either premature termination of translation or replacement of an evolutionary conserved MYO7A amino acid.

Synthetic heparin-binding growth factor analogs

DOEpatents

Pena, Louis A.; Zamora, Paul; Lin, Xinhua; Glass, John D.

2007-01-23

The invention provides synthetic heparin-binding growth factor analogs having at least one peptide chain that binds a heparin-binding growth factor receptor, covalently bound to a hydrophobic linker, which is in turn covalently bound to a non-signaling peptide that includes a heparin-binding domain. The synthetic heparin-binding growth factor analogs are useful as soluble biologics or as surface coatings for medical devices.

Effect of chitosan and coagulation factors on the wound repair phenotype of bioengineered blood clots.

PubMed

Hoemann, Caroline D; Marchand, Catherine; Rivard, Georges-Etienne; El-Gabalawy, Hani; Poubelle, Patrice E

2017-11-01

Controlling the blood clot phenotype in a surgically prepared wound is an evolving concept in scaffold-guided tissue engineering. Here, we investigated the effect of added chitosan (80% or 95% Degree of Deacetylation, DDA) or coagulation factors (recombinant human Factor VIIa, Tissue Factor, thrombin) on inflammatory factors released by blood clots. We tested the hypothesis that 80% DDA chitosan specifically enhances leukotriene B 4 (LTB 4 ) production. Human or rabbit whole blood was combined with isotonic chitosan solutions, coagulation factors, or lipopolysaccharide, cultured in vitro at 37°C, and after 4hours the serum was assayed for LTB 4 or inflammatory factors. Only 80% DDA chitosan clots produced around 15-fold more LTB 4 over other clots including 95% DDA chitosan clots. All serum contained high levels of PDGF-BB and CXCL8. Normal clots produced very low type I cytokines compared to lipopolysaccharide clots, with even lower IL-6 and IL-12 and more CCL3/CCL4 produced by chitosan clots. Coagulation factors had no detectable effect on clot phenotype. Conclusion In blood clots from healthy individuals, 80% DDA chitosan has a unique influence of inducing more LTB 4 , a potent neutrophil chemoattractant, with similar production of PDGF-BB and CXCL8, and lower type I cytokines, compared to whole blood clots. Copyright © 2017 Elsevier B.V. All rights reserved.

Effect of platelet-derived β-thromboglobulins on coagulation.

PubMed

Egan, Karl; van Geffen, Johanna P; Ma, Hui; Kevane, Barry; Lennon, Aine; Allen, Seamus; Neary, Elaine; Parsons, Martin; Maguire, Patricia; Wynne, Kieran; O' Kennedy, Richard; Heemskerk, Johan W M; Áinle, Fionnuala Ní

2017-06-01

β-thromboglobulins are derived from the cleavage of the CXC chemokine platelet basic protein and are released in high concentrations by activated platelets. Platelet-derived β-thromboglobulins (βTG) share 70% homology with platelet factor 4 (PF4), another CXC chemokine released by activated platelets. PF4 modulates coagulation by inhibiting heparin-antithrombin interactions, promoting protein C activation, and attenuating the activity of activated protein C. In contrast, the effect of βTG on coagulation is unknown. Clotting times, thrombin generation, chromogenic clotting factor assays, and surface plasmon resonance (SPR) were used to assess the effect of purified βTG on coagulation. In normal pooled plasma, βTG shortened the lagtime and time to peak thrombin generation of tissue factor (TF)-dependent and TF-independent thrombin generation. In factor VIII and factor IX-deficient plasmas, βTG induced thrombin generation in the absence of a TF stimulus and in the presence of anti-TF and factor VIIa inhibitory antibodies. The procoagulant effect was not observed when thrombin generation was independent of factor X activation (supplementation of factor X-deficient plasma with factor Xa). Cleavage of a factor Xa-specific chromogenic substrate was observed when βTG was incubated with factor X, suggesting a direct interaction between βTG and factor X. Using SPR, βTG were found to bind to immobilised factor X in a dose dependent manner. βTG modulate coagulation in vitro via an interaction with factor X. Copyright © 2017 Elsevier Ltd. All rights reserved.

Probing the coagulation pathway with aptamers identifies combinations that synergistically inhibit blood clot formation

PubMed Central

Bompiani, Kristin M; Lohrmann, Jens L; Pitoc, George A; Frederiksen, James W; Mackensen, George B; Sullenger, Bruce A

2014-01-01

SUMMARY Coordinated enzymatic reactions regulate blood clot generation. To explore the contributions of various coagulation enzymes in this process, we utilized a panel of aptamers against factors VIIa, IXa, Xa, and prothrombin. Each aptamer dose-dependently inhibited clot formation, yet none was able to completely impede this process in highly procoagulant settings. However several combinations of two aptamers synergistically impaired clot formation. One extremely potent aptamer combination was able to maintain human blood fluidity even during extracorporeal circulation, a highly procoagulant setting encountered during cardiopulmonary bypass surgery. Moreover, this aptamer cocktail could be rapidly reversed with antidotes to restore normal hemostasis, indicating that even highly potent aptamer combinations can be rapidly controlled. These studies highlight the potential utility of using sets of aptamers to probe the functions of proteins in molecular pathways for research and therapeutic ends. PMID:25065530

Resuscitation in massive obstetric haemorrhage using an intraosseous needle.

PubMed

Chatterjee, D J; Bukunola, B; Samuels, T L; Induruwage, L; Uncles, D R

2011-04-01

A 38-year-old woman experienced a massive postpartum haemorrhage 30 minutes after emergency caesarean delivery. The patient became severely haemodynamically compromised with an unrecordable blood pressure. Rapid fluid resuscitation was limited by the capacity of the intravenous cannula in place at the time and inability to establish additional vascular access using conventional routes in a timely manner. An intraosseous needle was inserted in the proximal humerus at the first attempt and administration of resuscitation fluid by this route subsequently enabled successful placement of further intravenous lines. Blood and blood products were deployed in conjunction with intra-operative cell salvage and transoesophageal Doppler cardiac output monitoring was used to assess adequacy of volume replacement. Haemorrhage control was finally achieved with the use of recombinant factor VIIa and hysterectomy. © 2011 The Authors. Anaesthesia © 2011 The Association of Anaesthetists of Great Britain and Ireland.

FGF growth factor analogs

DOEpatents

Zamora, Paul O [Gaithersburg, MD; Pena, Louis A [Poquott, NY; Lin, Xinhua [Plainview, NY; Takahashi, Kazuyuki [Germantown, MD

2012-07-24

The present invention provides a fibroblast growth factor heparin-binding analog of the formula: ##STR00001## where R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, X, Y and Z are as defined, pharmaceutical compositions, coating compositions and medical devices including the fibroblast growth factor heparin-binding analog of the foregoing formula, and methods and uses thereof.

Cost-Effectiveness Analysis of Plasma Versus Recombinant Factor VIIa for Placing Intracranial Pressure Monitors in Pretransplant Patients With Acute Liver Failure.

PubMed

Pham, Huy P; Sireci, Anthony N; Kim, Chong H; Schwartz, Joseph

2014-09-01

Both plasma- and recombinant activated factor VII (rFVIIa)-based algorithms can be used to correct coagulopathy in preliver transplant patients with acute liver failure requiring intracranial pressure monitor (ICPM) placement. A decision model was created to compare the cost-effectiveness of these methods. A 70-kg patient could receive either 1 round of plasma followed by coagulation testing or 2 units of plasma and 40 μg/kg rFVIIa. Intracranial pressure monitor is placed without coagulation testing after rFVIIa administration. In the plasma algorithm, the probability of ICPM placement was estimated based on expected international normalized ratio (INR) after plasma administration. Risks of rFVIIa thrombosis and transfusion reactions were also included. The model was run for patients with INRs ranging from 2 to 6 with concomitant adjustments to model parameters. The model supported the initial use of rFVIIa for ICPM placement as a cost-effective treatment when INR ≥2 (with incremental cost-effectiveness ratio of at most US$7088.02). © The Author(s) 2014.

[Factor XIII-guided treatment algorithm reduces blood transfusion in burn surgery].

PubMed

Carneiro, João Miguel Gonçalves Valadares de Morais; Alves, Joana; Conde, Patrícia; Xambre, Fátima; Almeida, Emanuel; Marques, Céline; Luís, Mariana; Godinho, Ana Maria Mano Garção; Fernandez-Llimos, Fernando

Major burn surgery causes large hemorrhage and coagulation dysfunction. Treatment algorithms guided by ROTEM ® and factor VIIa reduce the need for blood products, but there is no evidence regarding factor XIII. Factor XIII deficiency changes clot stability and decreases wound healing. This study evaluates the efficacy and safety of factor XIII correction and its repercussion on transfusion requirements in burn surgery. Randomized retrospective study with 40 patients undergoing surgery at the Burn Unit, allocated into Group A those with factor XIII assessment (n = 20), and Group B, those without assessment (n = 20). Erythrocyte transfusion was guided by a hemoglobin trigger of 10g.dL -1 and the other blood products by routine coagulation and ROTEM ® tests. Analysis of blood product consumption included units of erythrocytes, fresh frozen plasma, platelets, and fibrinogen. The coagulation biomarker analysis compared the pre- and post-operative values. Group A (with factor XIII study) and Group B had identical total body surface area burned. All patients in Group A had a preoperative factor XIII deficiency, whose correction significantly reduced units of erythrocyte concentrate transfusion (1.95 vs. 4.05, p = 0.001). Pre- and post-operative coagulation biomarkers were similar between groups, revealing that routine coagulation tests did not identify factor XIII deficiency. There were no recorded thromboembolic events. Correction of factor XIII deficiency in burn surgery proved to be safe and effective for reducing perioperative transfusion of erythrocyte units. Copyright © 2017 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

Use of recombinant factor VIIa in US military casualties for a five-year period.

PubMed

Wade, Charles E; Eastridge, Brian J; Jones, John A; West, Susan A; Spinella, Philip C; Perkins, Jeremy G; Dubick, Michael A; Blackbourne, Lorne H; Holcomb, John B

2010-08-01

Two prospective randomized trauma trials have shown recombinant factor VIIa (rFVIIa) to be safe and to decrease transfusion requirements. rFVIIa is presently used in 22% of massively transfused civilian trauma patients. The US Military has used rFVIIa in combat trauma patients for five years, and two small studies of massively transfused patients described an association with improved outcomes. This study was undertaken to assess how deployed physicians are using rFVIIa and its impact on casualty outcomes. US combat casualties (n = 2,050) receiving any blood transfusion from 2003 to 2009 were reviewed to compare patients receiving rFVIIa (n = 506) with those who did not (n = 1,544). Propensity-score matching (primary analysis) and multivariable logistic regression were used to compare outcomes. Differences were determined at p < 0.05. Twenty-five percent of patients received rFVIIa. Significant differences were noted between groups in indices of injury severity (Injury Severity Score, Abbreviated Injury Scale score, and Glasgow Coma Scale score), admission physiology (systolic blood pressure, diastolic blood pressure, heart rate, temperature, base deficit, hemoglobin, and international normalization ratio), and use of blood products, indicating that patients treated with rFVIIa were more severely injured, in shock, and coagulopathic. For propensity-score matching, factors associated with death were used: Injury Severity Score, Glasgow Coma Scale score, heart rate, systolic blood pressure, diastolic blood pressure, Hgb, and total packed red blood cell. A total of 266 patients per group were matched; 52% of the rFVIIa group. After pairing, there were no significant differences in any of the demographics, including incidence of massive transfusion (53% vs. 51%). There was no difference in the rate of complications (21% vs. 21%) or mortality (14% vs. 20%) for patients not treated or receiving rFVIIa, respectively. In military casualties, rFVIIa is used in the most severely injured patients based on physician selection rather than on guideline criteria. Use of rFVIIa is not associated with an improvement in survival or an increase in complications. The undetected bias of physician selection of patients for treatment with rFVIIa, likely, has an impact on case matching to achieve equivalence similar to that of randomized control studies. This inability to match populations, thus, prevents definitive interpretation of this study and others studies of similar design. This problem emphasizes the need to develop entry criteria to identify patients who could potentially benefit from use of rFVIIa and the need to subsequently perform efficacy studies.

Hemostatic effect of a monoclonal antibody mAb 2021 blocking the interaction between FXa and TFPI in a rabbit hemophilia model.

PubMed

Hilden, Ida; Lauritzen, Brian; Sørensen, Brit Binow; Clausen, Jes Thorn; Jespersgaard, Christina; Krogh, Berit Olsen; Bowler, Andrew Neil; Breinholt, Jens; Gruhler, Albrecht; Svensson, L Anders; Petersen, Helle Heibroch; Petersen, Lars Christian; Balling, Kristoffer W; Hansen, Lene; Hermit, Mette Brunsgaard; Egebjerg, Thomas; Friederichsen, Birgitte; Ezban, Mirella; Bjørn, Søren Erik

2012-06-14

Hemophilia is treated by IV replacement therapy with Factor VIII (FVIII) or Factor IX (FIX), either on demand to resolve bleeding, or as prophylaxis. Improved treatment may be provided by drugs designed for subcutaneous and less frequent administration with a reduced risk of inhibitor formation. Tissue factor pathway inhibitor (TFPI) down-regulates the initiation of coagulation by inhibition of Factor VIIa (FVIIa)/tissue factor/Factor Xa (FVIIa/TF/FXa). Blockage of TFPI inhibition may facilitate thrombin generation in a hemophilic setting. A high-affinity (K(D) = 25pM) mAb, mAb 2021, against TFPI was investigated. Binding of mAb 2021 to TFPI effectively prevented inhibition of FVIIa/TF/FXa and improved clot formation in hemophilia blood and plasma. The binding epitope on the Kunitz-type protease inhibitor domain 2 of TFPI was mapped by crystallography, and showed an extensive overlap with the FXa contact region highlighting a structural basis for its mechanism of action. In a rabbit hemophilia model, an intravenous or subcutaneous dose significantly reduced cuticle bleeding. mAb 2021 showed an effect comparable with that of rFVIIa. Cuticle bleeding in the model was reduced for at least 7 days by a single intravenous dose of mAb 2021. This study suggests that neutralization of TFPI by mAb 2021 may constitute a novel treatment option in hemophilia.

Tissue factor expression by endothelial cells in sickle cell anemia.

PubMed

Solovey, A; Gui, L; Key, N S; Hebbel, R P

1998-05-01

The role of the vascular endothelium in activation of the coagulation system, a fundamental homeostatic mechanism of mammalian biology, is uncertain because there is little evidence indicating that endothelial cells in vivo express tissue factor (TF), the system's triggering mechanism. As a surrogate for vessel wall endothelium, we examined circulating endothelial cells (CEC) from normals and patients with sickle cell anemia, a disease associated with activation of coagulation. We find that sickle CEC abnormally express TF antigen (expressed as percent CEC that are TF-positive), with 66+/-13% positive in sickle patients in steady-state, 83+/-19% positive in sickle patients presenting with acute vasoocclusive episodes, and only 10+/-13% positive in normal controls. Repeated samplings confirmed this impression that TF expression is greater when sickle patients develop acute vasoocclusive episodes. Sickle CEC are also positive for TF mRNA, with excellent concurrence between antigen and mRNA expression. The TF expressed on the antigen-positive CEC is functional, as demonstrated by a binding assay for Factor VIIa and a chromogenic assay sensitive to generation of Factor Xa. By establishing that endothelial cells in vivo can express TF, these data imply that the vast endothelial surface area does provide an important pathophysiologic trigger for coagulation activation.

Synthetic heparin-binding factor analogs

DOEpatents

Pena, Louis A [Poquott, NY; Zamora, Paul O [Gaithersburg, MD; Lin, Xinhua [Plainview, NY; Glass, John D [Shoreham, NY

2010-04-20

The invention provides synthetic heparin-binding growth factor analogs having at least one peptide chain, and preferably two peptide chains branched from a dipeptide branch moiety composed of two trifunctional amino acid residues, which peptide chain or chains bind a heparin-binding growth factor receptor and are covalently bound to a non-signaling peptide that includes a heparin-binding domain, preferably by a linker, which may be a hydrophobic linker. The synthetic heparin-binding growth factor analogs are useful as pharmaceutical agents, soluble biologics or as surface coatings for medical devices.

Preparation of factor VII concentrate using CNBr-activated Sepharose 4B immunoaffinity chromatography

PubMed Central

Mousavi Hosseini, Kamran; Nasiri, Saleh

2015-01-01

Background: Factor VII concentrates are used in patients with congenital or acquired factor VII deficiency or treatment of hemophilia patients with inhibitors. In this research, immunoaffinity chromatography was used to purify factor VII from prothrombin complex (Prothrombin- Proconvertin-Stuart Factor-Antihemophilic Factor B or PPSB) which contains coagulation factors II, VII, IX and X. The aim of this study was to improve purity, safety and tolerability as a highly purified factor VII concentrate. Methods: PPSB was prepared using DEAE-Sephadex and was used as the starting material for purification of coagulation factor VII. Prothrombin complex was treated by solvent/detergent at 24°C for 6 h with constant stirring. The mixture of PPSB in the PBS buffer was filtered and then chromatographed using CNBr-activated Sepharose 4B coupled with specific antibody. Factors II, IX, VII, X and VIIa were assayed on the fractions. Fractions of 48-50 were pooled and lyophilized as a factor VII concentrate. Agarose gel electrophoresis was performed and Tween 80 was measured in the factor VII concentrate. Results: Specific activity of factor VII concentrate increased from 0.16 to 55.6 with a purificationfold of 347.5 and the amount of activated factor VII (FVIIa) was found higher than PPSB (4.4-fold). Results of electrophoresis on agarose gel indicated higher purity of Factor VII compared to PPSB; these finding revealed that factor VII migrated as alpha-2 proteins. In order to improve viral safety, solvent-detergent treatment was applied prior to further purification and nearly complete elimination of tween 80 (2 μg/ml). Conclusion: It was concluded that immuonoaffinity chromatography using CNBr-activated Sepharose 4B can be a suitable choice for large-scale production of factor VII concentrate with higher purity, safety and activated factor VII. PMID:26034723

Preparation of factor VII concentrate using CNBr-activated Sepharose 4B immunoaffinity chromatography.

PubMed

Mousavi Hosseini, Kamran; Nasiri, Saleh

2015-01-01

Factor VII concentrates are used in patients with congenital or acquired factor VII deficiency or treatment of hemophilia patients with inhibitors. In this research, immunoaffinity chromatography was used to purify factor VII from prothrombin complex (Prothrombin- Proconvertin-Stuart Factor-Antihemophilic Factor B or PPSB) which contains coagulation factors II, VII, IX and X. The aim of this study was to improve purity, safety and tolerability as a highly purified factor VII concentrate. PPSB was prepared using DEAE-Sephadex and was used as the starting material for purification of coagulation factor VII. Prothrombin complex was treated by solvent/detergent at 24°C for 6 h with constant stirring. The mixture of PPSB in the PBS buffer was filtered and then chromatographed using CNBr-activated Sepharose 4B coupled with specific antibody. Factors II, IX, VII, X and VIIa were assayed on the fractions. Fractions of 48-50 were pooled and lyophilized as a factor VII concentrate. Agarose gel electrophoresis was performed and Tween 80 was measured in the factor VII concentrate. Specific activity of factor VII concentrate increased from 0.16 to 55.6 with a purificationfold of 347.5 and the amount of activated factor VII (FVIIa) was found higher than PPSB (4.4-fold). RESULTS of electrophoresis on agarose gel indicated higher purity of Factor VII compared to PPSB; these finding revealed that factor VII migrated as alpha-2 proteins. In order to improve viral safety, solvent-detergent treatment was applied prior to further purification and nearly complete elimination of tween 80 (2 μg/ml). It was concluded that immuonoaffinity chromatography using CNBr-activated Sepharose 4B can be a suitable choice for large-scale production of factor VII concentrate with higher purity, safety and activated factor VII.

In vitro characterization of high purity factor IX concentrates for the treatment of hemophilia B.

PubMed

Limentani, S A; Gowell, K P; Deitcher, S R

1995-04-01

This study employed sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis and immunoblotting to assess the purity of seven high purity factor IX concentrates: Aimafix (Aima), AlphaNine-SD (Alpha Therapeutic), Factor IX VHP (Biotransfusion), Immunine (Immuno), Mononine (Armour Pharmaceutical), Nanotiv (Kabi Pharmacia), and 9MC (Blood Products Laboratory). The mean specific activity of these products ranged from 68 U factor IX/mg (Aimafix) to 246 U factor IX/mg (Mononine). SDS-PAGE analysis showed that the highest purity product, Mononine, had a single contaminating band under non-reducing conditions. Two additional bands were detected when this product was analyzed under reducing conditions. All other products had multiple contaminating bands that were more apparent under reducing than non-reducing conditions. The immunoblot for factor IX showed a dominant factor IX band for all products. In addition, visible light chain of factor IX was detected for AlphaNine-SD, Factor IX VHP, Immunine, Mononine, Nanotiv, and 9MC, suggesting that the factor IX in these products had undergone partial activation to factor IXa. Another contaminating band was visible at 49,500 for all of the products except 9MC. In addition to this band, high molecular weight contaminants were apparent for some products, most notably AlphaNine-SD. The identity of these bands is unknown. Immunoblotting failed to demonstrate factor VII as a contaminant of any of the high purity products, although factor VIIa could be detected in some lots of Immunine, Nanotiv, and 9MC by a clot-based assay. Factor X contaminated Aimafix, AlphaNine-SD, Factor IX VHP, Immunine, Nanotiv, and 9MC, but activation products of factor X were not detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemophilia and von Willebrand's disease: 2. Management. Association of Hemophilia Clinic Directors of Canada.

PubMed Central

1995-01-01

OBJECTIVE: To present current strategies for the treatment of hemophilia and von Willebrand's disease. OPTIONS: Prophylactic and corrective therapy with hemostatic and adjunctive agents: DDAVP (1-desamino-8-D-arginine vasopressin [desmopressin acetate]), recombinant coagulation products (human Factor VIII and human Factor VIIa) or virally inactivated plasma-derived products (high- or ultra-high-purity human Factor VIII or human Factor VIII concentrate containing von Willebrand factor activity, porcine Factor VIII, high-purity human Factor IX, human prothrombin-complex concentrate, human activated prothrombin-complex concentrate), adjunctive antifibrinolytic agents, topical thrombin and fibrin sealant. The induction of immune tolerance in patients in whom inhibitors develop should also be considered. OUTCOMES: Morbidity and quality of life associated with bleeding and treatment. EVIDENCE: Relevant clinical studies and reports published from 1974 to 1994 were examined. A search was conducted of our reprint files, MEDLINE, citations in the articles reviewed and references provided by colleagues. In the MEDLINE search the following terms were used singly or in combination: "hemophilia," "von Willebrand's disease," "Factor VIII," "Factor IX," "von Willebrand factor," "diagnosis," "management," "home care," "comprehensive care," "inhibitor," "AIDS," "hepatitis," "life expectancy," "complications," "practice guidelines," "consensus statement" and "controlled trial." The in-depth review included only articles written in English from North America and Europe that were relevant to human disease and pertinent to a predetermined outline. The availability of treatment products in Canada was also considered. VALUES: Minimizing morbidity and maximizing functional status and quality of life were given a high value. BENEFITS, HARMS AND COSTS: Proper prophylactic or early treatment with appropriate hemostatic agents minimizes morbidity and functional disability and improves quality of life. Economic gains are realized through the reduction of mortality and morbidity and their associated costs. The patient has a better opportunity to contribute to society through gainful employment and the fulfillment of social roles. Potential harms include HIV infection, hepatitis B, hepatitis C and the development of inhibitor antibodies to clotting-factor concentrates. The risk of viral transmission has been minimized through the development of procedures for the viral inactivation of plasma-derived clotting-factor concentrates and through the use of recombinant coagulation-factor concentrates and other non-plasma-derived hemostatic agents. RECOMMENDATIONS: DDAVP is the drug of choice for patients with mild hemophilia or type 1 or 2 (except 2B) von Willebrand's disease whose response to DDAVP in previous testing has been found to be adequate. Therapeutic blood components of choice include recombinant products and virally inactivated plasma-derived products. In Canada the recommended products are recombinant Factor VIII for hemophilia A, high-purity plasma-derived Factor IX for hemophilia B and plasma-derived Factor VIII concentrates containing adequate von Willebrand factor (e.g., Haemate P) for von Willebrand's disease. Dosages vary according to specific indications. Adjunctive antifibrinolytic agents, topical thrombin and fibrin sealant are useful for the treatment of oral or dental bleeds and localized bleeds in accessible sites. In patients with inhibitor antibodies, high-dose human or porcine Factor VIII is usually effective when the inhibitor titre is less than 5 Bethesda units/mL. In nonresponsive patients, or in those whose inhibitor titre is higher, "bypassing" agents (e.g., activated prothrombin-complex concentrate and recombinant Factor VIIa) are useful. Long-term management may include immune-tolerance induction.VALIDATION: These recommendations were reviewed and approved by the Association of Hemophilia Clinic Directors of Canada (AHCDC) and the Medical and Scientific Advisory Committee of the Canadian Hemophilia Society. No similar consensus statements or practice guidelines are available for comparison. SPONSORS: These recommendations were developed at the request of the Canadian Blood Agency, which funds the provision of all coagulation-factor concentrates for people with congenital bleeding disorders, and were developed and endorsed by the AHCDC and the Medical and Scientific Advisory Committee of the Canadian Hemophilia Society. PMID:7600466

Dual chain synthetic heparin-binding growth factor analogs

DOEpatents

Zamora, Paul O [Gaithersburg, MD; Pena, Louis A [Poquott, NY; Lin, Xinhua [Plainview, NY

2012-04-24

The invention provides synthetic heparin-binding growth factor analogs having two peptide chains each branched from a branch moiety, such as trifunctional amino acid residues, the branch moieties separated by a first linker of from 3 to about 20 backbone atoms, which peptide chains bind a heparin-binding growth factor receptor and are covalently bound to a non-signaling peptide that includes a heparin-binding domain, preferably by a second linker, which may be a hydrophobic second linker. The synthetic heparin-binding growth factor analogs are useful as pharmaceutical agents, soluble biologics or as surface coatings for medical devices.

Dual chain synthetic heparin-binding growth factor analogs

DOEpatents

Zamora, Paul O [Gaithersburg, MD; Pena, Louis A [Poquott, NY; Lin, Xinhua [Plainview, NY

2009-10-06

The invention provides synthetic heparin-binding growth factor analogs having two peptide chains each branched from a branch moiety, such as trifunctional amino acid residues, the branch moieties separated by a first linker of from 3 to about 20 backbone atoms, which peptide chains bind a heparin-binding growth factor receptor and are covalently bound to a non-signaling peptide that includes a heparin-binding domain, preferably by a second linker, which may be a hydrophobic second linker. The synthetic heparin-binding growth factor analogs are useful as pharmaceutical agents, soluble biologics or as surface coatings for medical devices.

Advances in hemophilia care: report of two symposia at the Hemophilia 2010 World Congress.

PubMed

Dolan, Gerry; Cruz, Jussara Almeida; Steinhagen-Thiessen, Elisabeth; Kessler, Craig; Haaning, Jesper; Lemm, Georg; Altisent, Carmen; Guerrero, Caesar; Hermans, Cedric; Riske, Brenda; Bolton-Maggs, Paula

2012-04-01

The World Federation of Hemophilia (WFH) 2010 World Congress held in Buenos Aires, Argentina, in July 2010, attracted more than 4,300 participants from 106 countries. This report summarizes two symposia held during the congress. The first, titled "Emerging Co-Morbidities in the Aging Hemophilia Population: Healthcare Challenges and Treatment Opportunities," chaired by Gerry Dolan, MD, and Jussara Almeida Cruz, MD, examined the co-morbidities experienced by the aging hemophilic patient population, such as cardiovascular disease, cancer, arthritis, osteoporosis, hypertension, and obesity. In addition, Bayer's products in preclinical and clinical development were reviewed, including a novel factor VIIa variant and a long-acting factor VIII molecule, i.e., one that has undergone site-specific PEGylation (attachment of polyethylene glycol [PEG] polymer chains to another molecule). The other symposium, titled "Practical Steps to Making Better Care for Hemophilia Patients a Reality," chaired by Carmen Altisent, MD, and Cesar Guerrero, RN, reviewed the steps that hemophilia caregivers can take to improve the care of their patients. Issues such as the treatment of hemarthroses, the role of the research nurse, and the management of pediatric patients transitioning to adulthood were discussed.

BONE MARROW MESENCHYMAL STEM CELLS ARE PROGENITORS IN VITRO FOR INNER EAR HAIR CELLS

PubMed Central

Jeon, Sang-Jun; Oshima, Kazuo; Heller, Stefan; Edge, Albert S.B.

2011-01-01

Stem cells have been demonstrated in the inner ear but they do not spontaneously divide to replace damaged sensory cells. Mesenchymal stem cells (MSC) from bone marrow have been reported to differentiate into multiple lineages including neurons, and we therefore asked whether MSCs could generate sensory cells. Overexpression of the prosensory transcription factor, Math1, in sensory epithelial precursor cells induced expression of myosin VIIa, espin, Brn3c, p27Kip, and jagged2, indicating differentiation to inner ear sensory cells. Some of the cells displayed F-actin positive protrusions in the morphology characteristic of hair cell stereociliary bundles. Hair cell markers were also induced by culture of mouse MSC-derived cells in contact with embryonic chick inner ear cells, and this induction was not due to a cell fusion event, because the chick hair cells could be identified with a chick-specific antibody and chick and mouse antigens were never found in the same cell. PMID:17113786

National Waterways Study. Waterway Science and Technology.

DTIC Science & Technology

1981-08-01

Revetments 278 VII-A Split Hull Type Trailing Suction Hopper Dredge 304 VII-B Drag Heads 306 VII-C Overflow Systems 307 VII-D Trailing Suction Hopper... head reversals are possible. Poor approach conditions currently exist at some locks which could have been mitigated if modern, improved design...of ti,.c that a navigable pass section can be used. Navigation dams must be designed to pass high flows and floods with minor swell head and without in

Variable hearing impairment in a DFNB2 family with a novel MYO7A missense mutation.

PubMed

Hildebrand, M S; Thorne, N P; Bromhead, C J; Kahrizi, K; Webster, J A; Fattahi, Z; Bataejad, M; Kimberling, W J; Stephan, D; Najmabadi, H; Bahlo, M; Smith, R J H

2010-06-01

Myosin VIIA mutations have been associated with non-syndromic hearing loss (DFNB2; DFNA11) and Usher syndrome type 1B (USH1B). We report clinical and genetic analyses of a consanguineous Iranian family segregating autosomal recessive non-syndromic hearing loss (ARNSHL). The hearing impairment was mapped to the DFNB2 locus using Affymetrix 50K GeneChips; direct sequencing of the MYO7A gene was completed. The Iranian family (L-1419) was shown to segregate a novel homozygous missense mutation (c.1184G>A) that results in a p.R395H amino acid substitution in the motor domain of the myosin VIIA protein. As one affected family member had significantly less severe hearing loss, we used a candidate approach to search for a genetic modifier. This novel MYO7A mutation is the first reported to cause DFNB2 in the Iranian population and this DFNB2 family is the first to be associated with a potential modifier. The absence of vestibular and retinal defects, and less severe low frequency hearing loss, is consistent with the phenotype of a recently reported Pakistani DFNB2 family. Thus, we conclude this family has non-syndromic hearing loss (DFNB2) rather than USH1B, providing further evidence that these two diseases represent discrete disorders.

Manifestation of cryptic fibroblast tissue factor occurs at detergent concentrations which dissolve the plasma membrane.

PubMed

Carson, S D

1996-04-01

Cultured fibroblasts treated with increasing concentrations of detergents expressed only encrypted levels of tissue factor activity (measured by fX activation in the presence of fVIIa), characteristic of undamaged cells, until each detergent reached a critical concentration at which the cryptic tissue factor activity was manifested. Beyond the narrow ranges of concentrations over which the detergents stimulated tissue factor activity, the detergents were inhibitory. Studies with Triton X-100 and octyl glucoside revealed that manifestation of tissue factor activity coincided with breakdown of the plasma membrane. The magnitude of the increased tissue factor activity differed among detergents, with octyl glucoside giving the largest response. The tissue factor that was active after Triton X-100 treatment remained mostly associated with the insoluble cell residue, whereas the concentration of octyl glucoside which stimulated activity released tissue factor activity into the supernatant. Radiolabeled antibody against human tissue factor was used to show that a small percentage of the total accessible tissue factor remained in the insoluble fraction after treatment with either non-ionic detergent. Chromatographic analysis of lipids extracted from cells treated with detergents and dansyl chloride showed dansyl-reactivity of phosphatidylserine on intact cells, and solubilization of membrane lipids at sublytic concentrations of detergents. These findings reveal that there is a critical level of detergent-induced membrane damage at which tissue factor activity is maximally expressed, in essentially an all-or-none manner. The results are consistent with a major role for phospholipid asymmetry in regulation of tissue factor specific activity, but require either maintenance of asymmetry during sublytic detergent perturbation of the plasma membrane or additional control mechanisms.

Anti-inflammatory effect of thalidomide dithiocarbamate and dithioate analogs.

PubMed

Talaat, Roba; El-Sayed, Waheba; Agwa, Hussein S; Gamal-Eldeen, Amira M; Moawia, Shaden; Zahran, Magdy A H

2015-08-05

Thalidomide has anti-inflammatory, immunomodulatory, and anti-angiogenic properties. It has been used to treat a variety of cancers and autoimmune diseases. This study aimed to characterize anti-inflammatory activities of novel thalidomide analogs by exploring their effects on splenocytes proliferation and macrophage functions and their antioxidant activity. MTT assay was used to assess the cytotoxic effect of thalidomide analogs against splenocytes. Tumor necrosis factor (TNF-α) and nuclear factor kappa B (NF-κB-P65) were determined by enzyme-linked immunosorbent assay (ELISA). Nitric oxide (NO) was estimated by colorimetric assay. Antioxidant activity was examined by ORAC assay. Our results demonstrated that thalidomide dithioate analog 2 and thalidomide dithiocarbamate analog 4 produced a slight increase in splenocyte proliferation compared with thalidomide. Thalidomide dithiocarbamate analog 1 is a potent inhibitor of TNF-α production, whereas thalidomide dithiocarbamate analog 5 is a potent inhibitor of both TNF-α and NO. Analog 2 has a pronounced inhibitory effect on NF-κB-P65 production level. All thalidomide analogs showed prooxidant activity against hydroxyl (OH) radical. Analog 1 and thalidomide dithioate analog 3 have prooxidant activity against peroxyl (ROO) radical in relation to thalidomide. On the other hand, analog 4 has a potent scavenging capacity against peroxyl (ROO) radical compared with thalidomide. Taken together, the results of this study suggest that thalidomide analogs might have valuable anti-inflammatory activities with more pronounced effect than thalidomide itself. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Alcohol conversion

DOEpatents

Wachs, Israel E.; Cai, Yeping

2002-01-01

Preparing an aldehyde from an alcohol by contacting the alcohol in the presence of oxygen with a catalyst prepared by contacting an intimate mixture containing metal oxide support particles and particles of a catalytically active metal oxide from Groups VA, VIA, or VIIA, with a gaseous stream containing an alcohol to cause metal oxide from the discrete catalytically active metal oxide particles to migrate to the metal oxide support particles and to form a monolayer of catalytically active metal oxide on said metal oxide support particles.

Isolation of Genes Involved in Rac Induced Invasion and Metastasis of Breast Carcinoma Cells

DTIC Science & Technology

2001-08-01

dystrophy kinase-related Cdc42-binding kinase acts 64 oetGPernCaL.adMcr,1..(20) Myotonic4dystrophyrkinaseoretatedCdc42-bindingekrnasezatson. The cell...kinase homologous to myotonic dystrophy kinase. EMBO J. J. Biol. Chem. 273, 5542-5548. 15, 1885-1893. 97. Fukata, Y., Oshiro, N., Kinoshita, N., Kawano... Becker , D., Williams, D.S., Thorpe, J., Fleming, J., Brown, S.D. and Steel, K.P.: A missense mutation in myosin VIIA prevents aminoglycoside accumulation

Design and characterization of an APC-specific serpin for the treatment of hemophilia

PubMed Central

Polderdijk, Stéphanie G. I.; Adams, Ty E.; Ivanciu, Lacramioara; Camire, Rodney M.; Baglin, Trevor P.

2017-01-01

Hemophilia is a bleeding disorder caused by deficiency in factors VIII or IX, the two components of the intrinsic Xase complex. Treatment with replacement factor can lead to the development of inhibitory antibodies, requiring the use of bypassing agents such as factor VIIa and factor concentrates. An alternative approach to bypass the Xase complex is to inhibit endogenous anticoagulant activities. Activated protein C (APC) breaks down the complex that produces thrombin by proteolytically inactivating factor Va. Defects in this mechanism (eg, factor V Leiden) are associated with thrombosis but result in less severe bleeding when co-inherited with hemophilia. Selective inhibition of APC might therefore be effective for the treatment of hemophilia. The endogenous inhibitors of APC are members of the serpin family: protein C inhibitor (PCI) and α1-antitrypsin (α1AT); however, both exhibit poor reactivity and selectivity for APC. We mutated residues in and around the scissile P1-P1′ bond in PCI and α1AT, resulting in serpins with the desired specificity profile. The lead candidate was shown to promote thrombin generation in vitro and to restore fibrin and platelet deposition in an intravital laser injury model in hemophilia B mice. The power of targeting APC was further demonstrated by the complete normalization of bleeding after a severe tail clip injury in these mice. These results demonstrate that the protein C anticoagulant system can be successfully targeted by engineered serpins and that administration of such agents is effective at restoring hemostasis in vivo. PMID:27789479

Carbohydrates and activity of natural and recombinant tissue factor.

PubMed

Krudysz-Amblo, Jolanta; Jennings, Mark E; Mann, Kenneth G; Butenas, Saulius

2010-01-29

The effect of glycosylation on tissue factor (TF) activity was evaluated, and site-specific glycosylation of full-length recombinant TF (rTF) and that of natural TF from human placenta (pTF) were studied by liquid chromatography-tandem mass spectrometry. The amidolytic activity of the TF.factor VIIa (FVIIa) complex toward a fluorogenic substrate showed that the catalytic efficiency (V(max)) of the complex increased in the order rTF(1-243) (Escherichia coli) < rTF(1-263) (Sf9 insect cells) < pTF for the glycosylated and deglycosylated forms. Substrate hydrolysis was unaltered by deglycosylation. In FXase, the K(m) of FX for rTF(1-263)-FVIIa remained unchanged after deglycosylation, whereas the k(cat) decreased slightly. A pronounced decrease, 4-fold, in k(cat) was observed for pTF.FVIIa upon deglycosylation, whereas the K(m) was minimally altered. The parameters of FX activation by both rTF(1-263D)-FVIIa and pTF(D)-FVIIa were identical and similar to those for rTF(1-243)-FVIIa. In conclusion, carbohydrates significantly influence the activity of TF proteins. Carbohydrate analysis revealed glycosylation on asparagines 11, 124, and 137 in both rTF(1-263) and pTF. The carbohydrates of rTF(1-263) contain high mannose, hybrid, and fucosylated glycans. Natural pTF contains no high mannose glycans but is modified with hybrid, highly fucosylated, and sialylated sugars.

A homozygous MYO7A mutation associated to Usher syndrome and unilateral auditory neuropathy spectrum disorder.

PubMed

Xia, Hong; Hu, Pengzhi; Yuan, Lamei; Xiong, Wei; Xu, Hongbo; Yi, Junhui; Yang, Zhijian; Deng, Xiong; Guo, Yi; Deng, Hao

2017-10-01

Usher syndrome (USH) is an autosomal recessive disorder characterized by sensorineural hearing loss, progressive visual loss and night blindness due to retinitis pigmentosa (RP), with or without vestibular dysfunction. The purpose of this study was to detect the causative gene in a consanguineous Chinese family with USH. A c.3696_3706del (p.R1232Sfs*72) variant in the myosin VIIa gene (MYO7A) was identified in the homozygous state by exome sequencing. The co‑segregation of the MYO7A c.3696_3706del variant with the phenotype of deafness and progressive visual loss in the USH family was confirmed by Sanger sequencing. The variant was absent in 200 healthy controls. Therefore, the c.3696_3706del variant may disrupt the interaction between myosin VIIa and other USH1 proteins, and impair melanosome transport in retinal pigment epithelial cells. Notably, bilateral auditory brainstem responses were absent in two patients of the USH family, while distortion product otoacoustic emissions were elicited in the right ears of the two patients, consistent with clinical diagnosis of unilateral auditory neuropathy spectrum disorder. These data suggested that the homozygous c.3696_3706del variant in the MYO7A gene may be the disease‑causing mutation for the disorder in this family. These findings broaden the phenotype spectrum of the MYO7A gene, and may facilitate understanding of the molecular pathogenesis of the disease, and genetic counseling for the family.

Factor X/Xa elicits protective signaling responses in endothelial cells directly via PAR-2 and indirectly via endothelial protein C receptor-dependent recruitment of PAR-1.

PubMed

Bae, Jong-Sup; Yang, Likui; Rezaie, Alireza R

2010-11-05

We recently demonstrated that the Gla domain-dependent interaction of protein C with endothelial protein C receptor (EPCR) leads to dissociation of the receptor from caveolin-1 and recruitment of PAR-1 to a protective signaling pathway. Thus, the activation of PAR-1 by either thrombin or PAR-1 agonist peptide elicited a barrier-protective response if endothelial cells were preincubated with protein C. In this study, we examined whether other vitamin K-dependent coagulation protease zymogens can modulate PAR-dependent signaling responses in endothelial cells. We discovered that the activation of both PAR-1 and PAR-2 in endothelial cells pretreated with factor FX (FX)-S195A, but not other procoagulant protease zymogens, also results in initiation of protective intracellular responses. Interestingly, similar to protein C, FX interaction with endothelial cells leads to dissociation of EPCR from caveolin-1 and recruitment of PAR-1 to a protective pathway. Further studies revealed that, FX activated by factor VIIa on tissue factor bearing endothelial cells also initiates protective signaling responses through the activation of PAR-2 independent of EPCR mobilization. All results could be recapitulated by the receptor agonist peptides to both PAR-1 and PAR-2. These results suggest that a cross-talk between EPCR and an unknown FX/FXa receptor, which does not require interaction with the Gla domain of FX, recruits PAR-1 to protective signaling pathways in endothelial cells.

Teamwork in high-risk environments analogous to space

NASA Technical Reports Server (NTRS)

Kanki, Barbara G.

1990-01-01

Mountaineering expeditions combine a number of factors which make them potentially good analogs to the planetary exploration facet of long-duration space missions. A study of mountain climbing teams was conducted in order to evaluate the usefulness of the environment as a space analog and to specifically identify the factors and issues surrounding teamwork and 'successful' team performance in two mountaineering environments. This paper focuses on social/organizational factors, including team size and structure, leadership styles and authority structure which were found in the sample of 22 climb teams (122 individuals). The second major issue discussed is the construction of a valid performance measure in this high-risk environment.

Reinforcement of a minor alternative splicing event in MYO7A due to a missense mutation results in a mild form of retinopathy and deafness.

PubMed

Ben Rebeh, Imen; Morinière, Madeleine; Ayadi, Leila; Benzina, Zeineb; Charfedine, Ilhem; Feki, Jamel; Ayadi, Hammadi; Ghorbel, Abdelmonem; Baklouti, Faouzi; Masmoudi, Saber

2010-09-30

Recessive mutations of the myosin VIIA (MYO7A) gene are reported to be responsible for both a deaf-blindness syndrome (Usher type 1B [USH1B] and atypical Usher syndrome) and nonsyndromic hearing loss (HL; Deafness, Neurosensory, Autosomal Recessive 2 [DFNB2]). The existence of DFNB2 is controversial, and often there is no relationship between the type and location of the MYO7A mutations corresponding to the USH1B and DFNB2 phenotype. We investigated the molecular determinant of a mild form of retinopathy in association with a subtle splicing modulation of MYO7A mRNA. Affected members underwent detailed audiologic and ocular characterization. DNA samples from family members were genotyped with polymorphic microsatellite markers. Sequencing of MYO7A was performed. Endogenous lymphoid RNA analysis and a splicing minigene assay were used to study the effect of the c.1935G>A mutation. Funduscopy showed mild retinitis pigmentosa in adults with HL. Microsatellite analysis showed linkage to markers in the region on chromosome 11q13.5. Sequencing of MYO7A revealed a mutation in the last nucleotide of exon 16 (c.1935G>A), which corresponds to a substitution of a methionine to an isoleucine residue at amino acid 645 of the myosin VIIA. However, structural prediction of the molecular model of myosin VIIA shows that this amino acid replacement induces only minor structural changes in the immediate environment of the mutation and thus does not alter the overall native structure. We found that, although predominantly included in mature mRNA, exon 16 is in fact alternatively spliced in control cells and that the mutation at the very last position is associated with a switch toward a predominant exclusion of that exon. This observation was further supported using a splicing minigene transfection assay; the c.1935G>A mutation was found to trigger a partial impairment of the adjacent donor splice site, suggesting that the unique change at the last position of the exon is responsible for the enhanced exon exclusion in this family. This study shows how an exonic mutation that weakens the 5' splice site enhances a minor alternative splicing without abolishing a complete exclusion of the exon and therefore causes a less severe retinitis pigmentosa than the USH1B-associated alleles. It would be interesting to examine a possible correlation between intrafamilial phenotypic variability and the subtle variation in exon 16 inclusion, probably related to genetic background specificities.

Kinetic modeling sheds light on the mode of action of recombinant factor VIIa on thrombin generation.

PubMed

Mitrophanov, Alexander Y; Reifman, Jaques

2011-10-01

The therapeutic potential of a hemostatic agent can be assessed by investigating its effects on the quantitative parameters of thrombin generation. For recombinant activated factor VII (rFVIIa)--a promising hemostasis-inducing biologic--experimental studies addressing its effects on thrombin generation yielded disparate results. To elucidate the inherent ability of rFVIIa to modulate thrombin production, it is necessary to identify rFVIIa-induced effects that are compatible with the available biochemical knowledge about thrombin generation mechanisms. The existing body of knowledge about coagulation biochemistry can be rigorously represented by a computational model that incorporates the known reactions and parameter values constituting the biochemical network. We used a thoroughly validated numerical model to generate activated factor VII (FVIIa) titration curves in the cases of normal blood composition, hemophilia A and B blood, blood lacking factor VII, blood lacking tissue factor pathway inhibitor, and diluted blood. We utilized the generated curves to perform systematic fold-change analyses for five quantitative parameters characterizing thrombin accumulation. The largest fold changes induced by increasing FVIIa concentration were observed for clotting time, thrombin peak time, and maximum slope of the thrombin curve. By contrast, thrombin peak height was much less affected by FVIIa titrations, and the area under the thrombin curve stayed practically unchanged. Comparisons with experimental data demonstrated that the computationally derived patterns can be observed in vitro. rFVIIa modulates thrombin generation primarily by accelerating the process, without significantly affecting the total amount of generated thrombin. Copyright © 2011 Elsevier Ltd. All rights reserved.

Impaired factor XIIa-dependent activation of fibrinolysis in treated antiphospholipid syndrome gestations developing late-pregnancy complications.

PubMed

Carmona, Francisco; Lázaro, Isabel; Reverter, Juan C; Tàssies, Dolors; Font, Josep; Cervera, Ricard; Balasch, Juan

2006-02-01

The objective of the study was to investigate the potential role of impaired factor XII-dependent activation of fibrinolysis in treated antiphospholipid syndrome gestations developing late-pregnancy complications. This was a prospective study in a third-level teaching hospital, including 75 patients: 25 pregnant patients having the antiphospholipid syndrome and carrying their pregnancies until 26 weeks' gestation or later (group 1); 25 pregnant patients having normal term pregnancies and delivery and no previous miscarriage (group 2); and 25 pregnant patients being diagnosed as having severe pre-eclampsia and/or intrauterine growth restriction but testing negative for antiphospholipid antibodies (group 3). Hemostatic evaluation was carried out from patients in groups 1 and 2 between 6 and 10 weeks, between 18 and 22 weeks, and between 28 and 32 weeks' gestation. Patients in group 3 were sampled between 28 and 32 weeks. An additional blood sample was obtained 4 to 6 months after delivery (baseline). The Mann-Whitney U test, the Friedman test, and the chi2 test were used. Patients in group 1 were characterized by increased factor VIIa levels, increased prothrombin fragment 1+2 levels, reduced factor XIIa levels, diminished functional urokinase-type plasminogen activator levels, and decreased levels of plasmin/alpha-2-plasmin inhibitor complexes. These abnormalities were more evident in patients in group 1 developing pre-eclampsia and/or intrauterine growth restriction. Impaired factor XIIa-dependent activation of fibrinolysis seems to be a key mechanism related to late-pregnancy complications in patients with the antiphospholipid syndrome.

Elevated prothrombin time on routine preoperative laboratory results in a healthy infant undergoing craniosynostosis repair: Diagnosis and perioperative management of congenital factor VII deficiency.

PubMed

Jones, Kareen L; Greenberg, Robert S; Ahn, Edward S; Kudchadkar, Sapna R

2016-01-01

Congenital factor VII deficiency is a rare bleeding disorder with high phenotypic variability. It is critical that children with congenital Factor VII deficiency be identified early when high-risk surgery is planned. Cranial vault surgery is common for children with craniosynostosis, and these surgeries are associated with significant morbidity mostly secondary to the risk of massive blood loss. A two-month old infant who presented for elective craniosynostosis repair was noted to have an elevated prothrombin time (PT) with a normal activated partial thromboplastin time (aPTT) on preoperative labs. The infant had no clinical history or reported family history of bleeding disorders, therefore a multidisciplinary decision was made to repeat the labs under general anesthesia and await the results prior to incision. The results confirmed the abnormal PT and the case was canceled. Hematologic workup during admission revealed factor VII deficiency. The patient underwent an uneventful endoscopic strip craniectomy with perioperative administration of recombinant Factor VIIa. Important considerations for perioperative laboratory evaluation and management in children with factor VII deficiency are discussed. Anesthetic and surgical management of the child with factor VII deficiency necessitates meticulous planning to prevent life threatening bleeding during the perioperative period. A thorough history and physical examination with a high clinical suspicion are vital in preventing hemorrhage during surgeries in children with coagulopathies. Abnormal preoperative lab values should always be confirmed and addressed before proceeding with high-risk surgery. A multidisciplinary discussion is essential to optimize the risk-benefit ratio during the perioperative period. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Effect of long-term administration of an analog of growth hormone-releasing factor on the GH response in rats.

PubMed

Karashima, T; Olsen, D; Schally, A V

1987-06-22

The effect of the repeated or continuous administration of an analog of GH releasing factor (GH-RF), D-Tyr-1, D-Ala-2, Nle-27, GH-RF(1-29)-NH2 (DBO-29), on the subsequent response to this peptide was investigated in pentobarbital-anesthetized male rats. A sc administration of this analog induced a greater and more prolonged GH release than doses 10 times larger of GH-RF(1-29). The GH increase after sc injection of 10 micrograms/kg bw of the analog was greater than that induced by iv administration of 2 micrograms/kg bw of GH-RF(1-44). Pretreatment with 10 micrograms/kg bw of the analog did not affect the pituitary response to a strong stimulus (20 micrograms/kg bw) of GH-RF(1-44), 24 h later. Pretreatment with the analog in doses of 10 micrograms/kg bw, sc twice a day, 5 days per week for 4 weeks, significantly diminished the GH release in response to a sc injection of the analog (10 micrograms/kg bw), as compared to vehicle-pretreated controls (P less than 0.01). On the other hand, a continuous sc administration of 0.4 micrograms/h of the analog to intact rats for 7 days did not result in a decrease in GH response to a sc injection of the analog (10 micrograms/kg bw). Since the rats injected repeatedly with the analog for 4 weeks still showed a marked, although somewhat reduced response, analogs of this type may be useful clinically.

Formation of alcohol conversion catalysts

DOEpatents

Wachs, Israel E.; Cai, Yeping

2001-01-01

The method of the present invention involves a composition containing an intimate mixture of (a) metal oxide support particles and (b) a catalytically active metal oxide from Groups VA, VIA, or VIIA, its method of manufacture, and its method of use for converting alcohols to aldehydes. During the conversion process, catalytically active metal oxide from the discrete catalytic metal oxide particles migrates to the oxide support particles and forms a monolayer of catalytically active metal oxide on the oxide support particle to form a catalyst composition having a higher specific activity than the admixed particle composition.

A Computational Account of Children's Analogical Reasoning: Balancing Inhibitory Control in Working Memory and Relational Representation

ERIC Educational Resources Information Center

Morrison, Robert G.; Doumas, Leonidas A. A.; Richland, Lindsey E.

2011-01-01

Theories accounting for the development of analogical reasoning tend to emphasize either the centrality of relational knowledge accretion or changes in information processing capability. Simulations in LISA (Hummel & Holyoak, 1997, 2003), a neurally inspired computer model of analogical reasoning, allow us to explore how these factors may…

Young Children's Analogical Reasoning across Cultures: Similarities and Differences

ERIC Educational Resources Information Center

Richland, Lindsey Engle; Chan, Tsz-Kit; Morrison, Robert G.; Au, Terry Kit-Fong

2010-01-01

A cross-cultural comparison between U.S. and Hong Kong preschoolers examined factors responsible for young children's analogical reasoning errors. On a scene analogy task, both groups had adequate prerequisite knowledge of the key relations, were the same age, and showed similar baseline performance, yet Chinese children outperformed U.S. children…

Learning Plate Tectonics Using a Pre-Analogy Step

NASA Astrophysics Data System (ADS)

Glesener, G. B.; Sandoval, W. A.

2011-12-01

Previous research has shown that children tend to demonstrate lower performance on analogical reasoning tasks at a causal relations level compared to most adults (Gentner & Toupin, 1986). This tendency is an obstacle that geoscience educators must overcome because of the high frequency of analogies used in geoscience pedagogy. In particular, analog models are used to convey complex systems of non-everyday/non-observable events found in nature, such as plate tectonics. Key factors in successful analogical reasoning that have been suggested by researchers include knowledge of the causal relations in the base analog (Brown & Kane, 1988; Gentner, 1988; Gentner & Toupin, 1986), and development of learning strategies and metaconceptual competence(Brown & Kane, 1988). External factors, such as guiding cues and hints have been useful cognitive supports that help students reason through analogical problems (Gick & Holyoak, 1980). Cognitive supports have been seen by researchers to decrease processing demands on retrieval and working memory (Richland, Zur, & Holyoak, 2007). We observed third and fourth graders learning about plate tectonics beginning with a pre-analogy step-a cognitive support activity a student can do before working with an analogy to understand the target. This activity was designed to aid students in developing their understanding of object attributes and relations within an analog model so that more focus can be placed on mapping the corresponding higher-order relations between the base and target. Students learned targeted concepts of plate tectonics, as measured by pre to post gains on items adapted from the Geosciences Concept Inventory. Analyses of classroom interaction showed that students used the object attributes and higher-order relations highlighted in the pre-analogy activity as resources to reason about plate boundaries and plate movement during earthquakes.

What’s special about task in dystonia? A voxel-based morphometry and diffusion weighted imaging study

PubMed Central

Ramdhani, Ritesh A.; Kumar, Veena; Velickovic, Miodrag; Frucht, Steven J.; Tagliati, Michele; Simonyan, Kristina

2014-01-01

Background Numerous brain imaging studies have demonstrated structural changes in the basal ganglia, thalamus, sensorimotor cortex and cerebellum across different forms of primary dystonia. However, our understanding of brain abnormalities contributing to the clinically well-described phenomenon of task-specificity in dystonia remained limited. Methods We used high-resolution MRI with voxel-based morphometry and diffusion tensor imaging with tract-based spatial statistics of fractional anisotropy to examine gray and white matter organization in two task-specific dystonia forms, writer’s cramp and laryngeal dystonia, and two non-task-specific dystonia forms, cervical dystonia and blepharospasm. Results A direct comparison between the both dystonia forms revealed that characteristic gray matter volumetric changes in task-specific dystonia involve the brain regions responsible for sensorimotor control during writing and speaking, such as primary somatosensory cortex, middle frontal gyrus, superior/inferior temporal gyrus, middle/posterior cingulate cortex, occipital cortex as well as the striatum and cerebellum (lobules VI-VIIa). These gray matter changes were accompanied by white matter abnormalities in the premotor cortex, middle/inferior frontal gyrus, genu of the corpus callosum, anterior limb/genu of the internal capsule, and putamen. Conversely, gray matter volumetric changes in non-task-specific group were limited to the left cerebellum (lobule VIIa) only, while white matter alterations were found to underlie the primary sensorimotor cortex, inferior parietal lobule and middle cingulate gyrus. Conclusion Distinct microstructural patterns in task-specific and non-task-specific dystonias may represent neuroimaging markers and provide evidence that these two dystonia subclasses likely follow divergent pathophysiological mechanisms precipitated by different triggers. PMID:24925463

Modified friction factor correlation for CICC's based on a porous media analogy

NASA Astrophysics Data System (ADS)

Lewandowska, Monika; Bagnasco, Maurizio

2011-09-01

A modified correlation for the bundle friction factor in CICC's based on a porous media analogy is presented. The correlation is obtained by the analysis of the collected pressure drop data measured for 23 CICC's. The friction factors predicted by the proposed correlation are compared with those resulting from the pressure drop data for two CICC's measured recently using cryogenic helium in the SULTAN test facility at EPFL-CRPP.

The Computation of Orthogonal Independent Cluster Solutions and Their Oblique Analogs in Factor Analysis.

ERIC Educational Resources Information Center

Hofmann, Richard J.

A very general model for the computation of independent cluster solutions in factor analysis is presented. The model is discussed as being either orthogonal or oblique. Furthermore, it is demonstrated that for every orthogonal independent cluster solution there is an oblique analog. Using three illustrative examples, certain generalities are made…

Factors Affecting the Development of Analogical Reasoning in Young Children: A Review of Literature

ERIC Educational Resources Information Center

Abdellatif, Hanaa R.; Cummings, Rhoda; Maddux, Cleborne D.

2008-01-01

The ability to use analogical reasoning traditionally has been considered a higher-level ability characteristic of thinking of older children and adults. Such reasoning has not been thought to be accessible to younger children. However, recently, it has been suggested that younger children's ability to understand and solve analogical problems…

Involvement of human decidual cell-expressed tissue factor in uterine hemostasis and abruption.

PubMed

Lockwood, C J; Paidas, M; Murk, W K; Kayisli, U A; Gopinath, A; Huang, S J; Krikun, G; Schatz, F

2009-11-01

Vascular injury increases access and binding of plasma-derived factor VII to perivascular cell membrane-bound tissue factor (TF). The resulting TF/VIIa complex promotes hemostasis by cleaving pro-thrombin to thrombin leading to the fibrin clot. In human pregnancy, decidual cell-expressed TF prevents decidual hemorrhage (abruption). During placentation, trophoblasts remodel decidual spiral arteries into high conductance vessels. Shallow trophoblast invasion impedes decidual vascular conversion, producing an inadequate uteroplacental blood flow that elicits abruption-related placental ischemia. Thrombin induces several biological effects via cell surface protease activated receptors. In first trimester human DCs thrombin increases synthesis of sFlt-1, which elicits placental ischemia by impeding angiogenesis-related decidual vascular remodeling. During pregnacy, the fibrillar collagen-rich amnion and choriodecidua extracellular matrix (ECM) provides greater than additive tensile strength and structural integrity. Thrombin acts as an autocrine/paracrine mediator that degrades these ECMs by augmenting decidual cell expression of: 1) matrix metalloproteinases and 2) interleukin-8, a key mediator of abruption-associated decidual infiltration of neutrophils, which express several ECM degrading proteases. Among the cell types at the maternal fetal interface at term, TF expression is highest in decidual cells indicating that this TF meets the hemostatic demands of labor and delivery. TF expression in cultured term decidual cells is enhanced by progestin and thrombin suggesting that the maintenance of elevated circulating progesterone provides hemostatic protection and that abruption-generated thrombin acts in an autocrine/paracrine fashion on decidual cells to promote hemostasis via enhanced TF expression.

Discovery and evaluation of asymmetrical monocarbonyl analogs of curcumin as anti-inflammatory agents

PubMed Central

Zhang, Yali; Zhao, Chengguang; He, Wenfei; Wang, Zhe; Fang, Qilu; Xiao, Bing; Liu, Zhiguo; Liang, Guang; Yang, Shulin

2014-01-01

Sepsis is a systemic inflammatory response syndrome and is mainly caused by lipopolysaccharides (LPS) – a component of the cell walls of gram-negative bacteria, via toll-like receptor 4–mitogen-activated protein kinases/nuclear factor-kappa B-dependent proinflammatory signaling pathway. Here, we synthesized 26 asymmetric monocarbonyl analogs of curcumin and evaluated their anti-inflammatory activity by inhibiting the LPS-induced secretion of tumor necrosis factor-α and interleukin-6 in mouse RAW264.7 macrophages. Five active compounds (3a, 3c, 3d, 3j, and 3l) exhibited dose-dependent inhibition against the release of tumor necrosis factor-α and interleukin-6, and they also showed much higher chemical stability than curcumin in vitro. The anti-inflammatory activity of analogs 3a and 3c may be associated with their inhibition of the phosphorylation of extracellular signal-regulated kinase and the activation of nuclear factor-kappa B. In addition, 3c exhibited significant protection against LPS-induced septic death in vivo. These results indicate that asymmetrical monocarbonyl curcumin analogs may be utilized as candidates for the treatment of acute inflammatory diseases. PMID:24741294

RCS MEDDH-288 (R1), Annual Progress Report, 1 July 1972 - 30 June 1973

DTIC Science & Technology

1973-07-01

July 1972 - 30 June 1973 ?RI:XCtPAL INVESTIGATOR : Bryce C. Walton, COL, MSC ASSOC.IATE INVEcTIGATOR Larry D. Hendricks , CPT, MSC Af3SIS2A2:TS Michael...was obtained from adult worms maintained up to 14 days in mediur 199 containing 2,;5 penicillin -streptomycin and 0.550 armhotericin B. Crude antigen...Ackerman, MAJ, VC Larry D. Hendricks , CPT, MSC ýG. REPORT DAT- 7E. TOTAL NO. OF PAGES 7b. NO. OP REFS S+ viIa .. CONTHACT OR GRANT NO. 9a. ORIGINATOR’S

Combat Modeling Evaluation at the United States Military Academy.

DTIC Science & Technology

1985-06-01

Ti.s to a smil- ique eitew de = Smaleissei by doe S hefer Press. am rnr we ma@"e- even I - "-re is hso use mom a sly ente orders bring dartani, vphae... transported to the VIIA *yet= at MR., a proes* which to almeet complete. 2Me lepertmet of fts- tory will thee be able te evelse the Sharks, md Arfemme...danewa its we modified As mei mmr Ciaur. 6). &W mit thot sooogltoly esm~hts Its supply of inmoitIawl"q eoat is Smoediaboly de . ttopd. IM6 OSOMe WOW. U

Validity and reliability of the Rosenberg Self-Esteem Scale-Thai version as compared to the Self-Esteem Visual Analog Scale.

PubMed

Piyavhatkul, Nawanant; Aroonpongpaisal, Suwanna; Patjanasoontorn, Niramol; Rongbutsri, Somchit; Maneeganondh, Somchit; Pimpanit, Wijitra

2011-07-01

To compare the validity and reliability of the Thai version of the Rosenberg Self-Esteem Scale with the Self-Esteem Visual Analog Scale. The Rosenberg Self-Esteem Scale was translated into Thai and its content-validity checked by bacA translation. The reliability of the Rosenberg Self-Esteem Scale compared with the Self-Esteem Visual Analog Scale was ther tested between February and March 2008 on 270 volunteers, including 135 patients with psychiatric illness and 135 normal volunteers. The authors analyzed the internal consistency and factor structure of the Rosenberg Self-Esteem Scale-Thai version and the correlation between it and the Visual Analog Scale. The Cronbach's Alpha for the Rosenberg Self-Esteem scale-Thai version was 0.849 and the Pearson's correlation between it and the Self-Esteem Visual Analog Scale 0.618 (p = 0.01). Two factors, viz, the positively and negatively framea items, from the Rosenberg Self-Esteem Scale-Thai version accounted for 44.04% and 12.10% of the variance, respectively. The Rosenberg Self-Esteem Scale-Thai version has acceptable reliability. The Self-Esteem Visual Analog Scale provides an effective measure of self-esteem.

Fully human antibodies against the Protease-Activated Receptor-2 (PAR-2) with anti-inflammatory activity.

PubMed

Giblin, Patricia; Boxhammer, Rainer; Desai, Sudha; Kroe-Barrett, Rachel; Hansen, Gale; Ksiazek, John; Panzenbeck, Maret; Ralph, Kerry; Schwartz, Racheline; Zimmitti, Clare; Pracht, Catrin; Miller, Sandra; Magram, Jeanne; Litzenburger, Tobias

2011-01-01

PAR-2 belongs to a family of G-protein coupled Protease-Activated Receptors (PAR) which are activated by specific proteolytic cleavage in the extracellular N-terminal region. PAR-2 is activated by proteases such as trypsin, tryptase, proteinase 3, factor VIIa, factor Xa and is thought to be a mediator of inflammation and tissue injury, where elevated levels of proteases are found. Utilizing the HuCAL GOLD® phage display library we generated fully human antibodies specifically blocking the protease cleavage site in the N-terminal domain. In vitro affinity optimization resulted in antibodies with up to 1000-fold improved affinities relative to the original parental antibodies with dissociation constants as low as 100 pM. Corresponding increases in potency were observed in a mechanistic protease cleavage assay. The antibodies effectively inhibited PAR-2 mediated intracellular calcium release and cytokine secretion in various cell types stimulated with trypsin. In addition, the antibodies demonstrated potent inhibition of trypsin induced relaxation of isolated rat aortic rings ex vivo. In a short term mouse model of inflammation, the trans vivo DTH model, anti-PAR-2 antibodies showed inhibition of the inflammatory swelling response. In summary, potent inhibitors of PAR-2 were generated which allow further assessment of the role of this receptor in inflammation and evaluation of their potential as therapeutic agents.

Immune Function Changes during a Spaceflight-Analog Undersea Mission

NASA Technical Reports Server (NTRS)

Crucian, Brian; Stowe, Raymond; Mehta, Satish; Quiniarte, Heather; Yetman, Deborah; Pierson, Duane; Sams, Clarence

2008-01-01

There is ample evidence to suggest that space flight leads to immune system dysregulation. This may be a result of microgravity, confinement, physiological stress, radiation, environment or other mission-associated factors. It is attractive to utilize ground-based spaceflight analogs as appropriate to investigate this phenomenon. For spaceflight-associated immune dysregulation (SAID), the authors believe the most appropriate analogs might be NEEMO (short duration, Shuttle analog), Antarctic winter-over (long-duration, ISS analog) and the Haughton Mars Project in the Canadian Arctic (intermediate-duration). Each of these analogs replicate isolation, mission-associated stress, disrupted circadian rhythms, and other aspects of flight thought to contribute to SAID. To validate NEEMO as a flight analog with respect to SAID, a pilot study was conducted during the NEEMO-12 and 13 missions during 2007. Assays were performed that assessed immune status, physiological stress and latent viral reactivation. Blood and saliva samples were collected at pre-, mid-, and post-mission timepoints.

Crystallization and preliminary X-ray diffraction analysis of hemextin A: a unique anticoagulant protein from Hemachatus haemachatus venom

DOE Office of Scientific and Technical Information (OSTI.GOV)

Banerjee, Yajnavalka; Kumar, Sundramurthy; Jobichen, Chacko

2007-08-01

Crystals of hemextin A, a three-finger toxin isolated and purified from African Ringhals cobra (H. haemachatus), are orthorhombic, space group P2{sub 1}2{sub 1}2{sub 1}, with unit-cell parameters a = 49.27, b = 49.51, c = 57.87 Å, and diffract to 1.5 Å resolution. Hemextin A was isolated and purified from African Ringhals cobra (Hemachatus haemachatus). It is a three-finger toxin that specifically inhibits blood coagulation factor VIIa and clot formation and that also interacts with hemextin B to form a unique anticoagulant complex. Hemextin A was crystallized by the hanging-drop vapour-diffusion method by equilibration against 0.2 M ammonium acetate, 0.1more » M sodium acetate trihydrate pH 4.6 and 30% PEG 4000 as the precipitating agent. The crystals belong to space group P2{sub 1}2{sub 1}2{sub 1}, with unit-cell parameters a = 49.27, b = 49.51, c = 57.87 Å and two molecules in the asymmetric unit. They diffracted to 1.5 Å resolution at beamline X25 at BNL.« less

Analog synthetic biology.

PubMed

Sarpeshkar, R

2014-03-28

We analyse the pros and cons of analog versus digital computation in living cells. Our analysis is based on fundamental laws of noise in gene and protein expression, which set limits on the energy, time, space, molecular count and part-count resources needed to compute at a given level of precision. We conclude that analog computation is significantly more efficient in its use of resources than deterministic digital computation even at relatively high levels of precision in the cell. Based on this analysis, we conclude that synthetic biology must use analog, collective analog, probabilistic and hybrid analog-digital computational approaches; otherwise, even relatively simple synthetic computations in cells such as addition will exceed energy and molecular-count budgets. We present schematics for efficiently representing analog DNA-protein computation in cells. Analog electronic flow in subthreshold transistors and analog molecular flux in chemical reactions obey Boltzmann exponential laws of thermodynamics and are described by astoundingly similar logarithmic electrochemical potentials. Therefore, cytomorphic circuits can help to map circuit designs between electronic and biochemical domains. We review recent work that uses positive-feedback linearization circuits to architect wide-dynamic-range logarithmic analog computation in Escherichia coli using three transcription factors, nearly two orders of magnitude more efficient in parts than prior digital implementations.

Analogical scaffolding: Making meaning in physics through representation and analogy

NASA Astrophysics Data System (ADS)

Podolefsky, Noah Solomon

This work reviews the literature on analogy, introduces a new model of analogy, and presents a series of experiments that test and confirm the utility of this model to describe and predict student learning in physics with analogy. Pilot studies demonstrate that representations (e.g., diagrams) can play a key role in students' use of analogy. A new model of analogy, Analogical Scaffolding, is developed to explain these initial empirical results. This model will be described in detail, and then applied to describe and predict the outcomes of further experiments. Two large-scale (N>100) studies will demonstrate that: (1) students taught with analogies, according to the Analogical Scaffolding model, outperform students taught without analogies on pre-post assessments focused on electromagnetic waves; (2) the representational forms used to teach with analogy can play a significant role in student learning, with students in one treatment group outperforming students in other treatment groups by factors of two or three. It will be demonstrated that Analogical Scaffolding can be used to predict these results, as well as finer-grained results such as the types of distracters students choose in different treatment groups, and to describe and analyze student reasoning in interviews. Abstraction in physics is reconsidered using Analogical Scaffolding. An operational definition of abstraction is developed within the Analogical Scaffolding framework and employed to explain (a) why physicists consider some ideas more abstract than others in physics, and (b) how students conceptions of these ideas can be modeled. This new approach to abstraction suggests novel approaches to curriculum design in physics using Analogical Scaffolding.

Structural modulation of factor VIIa by full-length tissue factor (TF1-263): implication of novel interactions between EGF2 domain and TF.

PubMed

Prasad, Ramesh; Sen, Prosenjit

2018-02-01

Tissue factor (TF)-mediated factor VII (FVII) activation and a subsequent proteolytic TF-FVIIa binary complex formation is the key step initiating the coagulation cascade, with implications in various homeostatic and pathologic scenarios. TF binding allosterically modifies zymogen-like free FVIIa to its highly catalytically active form. As a result of unresolved crystal structure of the full-length TF 1-263 -FVIIa binary complex and free FVIIa, allosteric alterations in FVIIa following its binding to full-length TF and the consequences of these on function are not entirely clear. The present study aims to map and identify structural alterations in FVIIa and TF resulting from full-length TF binding to FVIIa and the key events responsible for enhanced FVIIa activity in coagulation. We constructed the full-length TF 1-263 -FVIIa membrane bound complex using computational modeling and subjected it to molecular dynamics (MD) simulations. MD simulations showed that TF alters the structure of each domain of FVIIa and these combined alterations contribute to enhanced TF-FVIIa activity. Detailed, domain-wise investigation revealed several new non-covalent interactions between TF and FVIIa that were not found in the truncated soluble TF-FVIIa crystal structure. The structural modulation of each FVIIa domain imparted by TF indicated that both inter and intra-domain communication is crucial for allosteric modulation of FVIIa. Our results suggest that these newly formed interactions can provide additional stability to the protease domain and regulate its activity profile by governing catalytic triad (CT) orientation and localization. The unexplored newly formed interactions between EGF2 and TF provides a possible explanation for TF-induced allosteric activation of FVIIa.

Involvement of human decidual cell-expressed tissue factor in uterine hemostasis and abruption

PubMed Central

Lockwood, C.J.; Paidas, M.; Murk, W.K.; Kayisli, U.A.; Gopinath, A.; Krikun, G.; Huang, S.J.; Schatz, F.

2009-01-01

Vascular injury increases access and binding of plasma-derived factor VII to perivascular cell membrane-bound tissue factor (TF). The resulting TF/VIIa complex promotes hemostasis by cleaving pro-thrombin to thrombin leading to the fibrin clot. In human pregnancy, decidual cell-expressed TF prevents decidual hemorrhage (abruption). During placentation, trophoblasts remodel decidual spiral arteries into high conductance vessels. Shallow trophoblast invasion impedes decidual vascular conversion, producing an inadequate uteroplacental blood flow that elicits abruption-related placental ischemia. Thrombin induces several biological effects via cell surface protease activated receptors. In first trimester human DCs thrombin increases synthesis of sFlt-1, which elicits placental ischemia by impeding angiogenesis-related decidual vascular remodeling. During pregnacy, the fibrillar collagen-rich amnion and choriodecidua extracellular matrix (ECM) provides greater than additive tensile strength and structural integrity. Thrombin acts as an autocrine/paracrine mediator that degrades these ECMs by augmenting decidual cell expression of: 1) matrix metalloproteinases and 2) interleukin-8, a key mediator of abruption-associated decidual infiltration of neutrophils, which express several ECM degrading proteases. Our recent observations that: 1) among the cell types at the maternal fetal interface at term TF expression is highest in decidual cells indicates that this TF meets the hemostatic demands of labor and delivery; 2) TF expression in cultured term decidual cells is enhanced by progestin and thrombin suggest that maintenance of elevated circulating progesterone at term provides hemostatic protection, whereas abruption-generated thrombin can act in autocrine/paracrine fashion on DCs to promote hemostasis via enhanced TF expression. PMID:19720393

Matriptase activation connects tissue factor-dependent coagulation initiation to epithelial proteolysis and signaling.

PubMed

Le Gall, Sylvain M; Szabo, Roman; Lee, Melody; Kirchhofer, Daniel; Craik, Charles S; Bugge, Thomas H; Camerer, Eric

2016-06-23

The coagulation cascade is designed to sense tissue injury by physical separation of the membrane-anchored cofactor tissue factor (TF) from inactive precursors of coagulation proteases circulating in plasma. Once TF on epithelial and other extravascular cells is exposed to plasma, sequential activation of coagulation proteases coordinates hemostasis and contributes to host defense and tissue repair. Membrane-anchored serine proteases (MASPs) play critical roles in the development and homeostasis of epithelial barrier tissues; how MASPs are activated in mature epithelia is unknown. We here report that proteases of the extrinsic pathway of blood coagulation transactivate the MASP matriptase, thus connecting coagulation initiation to epithelial proteolysis and signaling. Exposure of TF-expressing cells to factors (F) VIIa and Xa triggered the conversion of latent pro-matriptase to an active protease, which in turn cleaved the pericellular substrates protease-activated receptor-2 (PAR2) and pro-urokinase. An activation pathway-selective PAR2 mutant resistant to direct cleavage by TF:FVIIa and FXa was activated by these proteases when cells co-expressed pro-matriptase, and matriptase transactivation was necessary for efficient cleavage and activation of wild-type PAR2 by physiological concentrations of TF:FVIIa and FXa. The coagulation initiation complex induced rapid and prolonged enhancement of the barrier function of epithelial monolayers that was dependent on matriptase transactivation and PAR2 signaling. These observations suggest that the coagulation cascade engages matriptase to help coordinate epithelial defense and repair programs after injury or infection, and that matriptase may contribute to TF-driven pathogenesis in cancer and inflammation.

Pharmacodynamics and pharmacokinetics during the transition from warfarin to rivaroxaban: a randomized study in healthy subjects

PubMed Central

Kubitza, Dagmar; Becka, Michael; Mück, Wolfgang; Krätzschmar, Jöern

2014-01-01

Aims This study investigated relevant pharmacodynamic and pharmacokinetic parameters during the transition from warfarin to rivaroxaban in healthy male subjects. Methods Ninety-six healthy men were randomized into the following three groups: warfarin [international normalized ratio (INR) 2.0–3.0] transitioned to rivaroxaban 20 mg once daily (od; group A); warfarin (INR 2.0–3.0) followed by placebo od (group B); and rivaroxaban alone 20 mg od (group C) for 4 days. Anti-factor Xa activity, inhibition of factor Xa activity, prothrombin time (PT), activated partial thromboplastin time, HepTest, prothrombinase-induced clotting time, factor VIIa activity, factor IIa activity, endogenous thrombin potential and pharmacokinetics were measured. Results An additive effect was observed on the PT and PT/INR during the initial transition period. The mean maximal prolongation of PT was 4.39-fold [coefficient of variation (CV) 18.03%; range 3.39–6.50] of the baseline value in group A, compared with 1.88-fold (CV 10.35%; range 1.53–2.21) in group B and 1.57-fold (CV 9.98%; range 1.37–2.09) in group C. Rivaroxaban had minimal influence on the PT/INR at trough levels. Inhibition of factor Xa activity, activated partial thromboplastin time and endogenous thrombin potential were also enhanced, but to a lesser extent. In contrast, the effects of rivaroxaban on anti-factor Xa activity, HepTest and prothrombinase-induced clotting time were not affected by pretreatment with warfarin. Conclusions Changes in pharmacodynamics during the transition from warfarin to rivaroxaban vary depending on the test used. A supra-additive effect on PT/INR is expected during the initial period of transition, but pretreatment with warfarin does not influence the effect of rivaroxaban on anti-factor Xa activity. PMID:24528331

Equid Herpesvirus Type 1 Activates Platelets

PubMed Central

Stokol, Tracy; Yeo, Wee Ming; Burnett, Deborah; DeAngelis, Nicole; Huang, Teng; Osterrieder, Nikolaus; Catalfamo, James

2015-01-01

Equid herpesvirus type 1 (EHV-1) causes outbreaks of abortion and neurological disease in horses. One of the main causes of these clinical syndromes is thrombosis in placental and spinal cord vessels, however the mechanism for thrombus formation is unknown. Platelets form part of the thrombus and amplify and propagate thrombin generation. Here, we tested the hypothesis that EHV-1 activates platelets. We found that two EHV-1 strains, RacL11 and Ab4 at 0.5 or higher plaque forming unit/cell, activate platelets within 10 minutes, causing α-granule secretion (surface P-selectin expression) and platelet microvesiculation (increased small events double positive for CD41 and Annexin V). Microvesiculation was more pronounced with the RacL11 strain. Virus-induced P-selectin expression required plasma and 1.0 mM exogenous calcium. P-selectin expression was abolished and microvesiculation was significantly reduced in factor VII- or X-deficient human plasma. Both P-selectin expression and microvesiculation were re-established in factor VII-deficient human plasma with added purified human factor VIIa (1 nM). A glycoprotein C-deficient mutant of the Ab4 strain activated platelets as effectively as non-mutated Ab4. P-selectin expression was abolished and microvesiculation was significantly reduced by preincubation of virus with a goat polyclonal anti-rabbit tissue factor antibody. Infectious virus could be retrieved from washed EHV-1-exposed platelets, suggesting a direct platelet-virus interaction. Our results indicate that EHV-1 activates equine platelets and that α-granule secretion is a consequence of virus-associated tissue factor triggering factor X activation and thrombin generation. Microvesiculation was only partly tissue factor and thrombin-dependent, suggesting the virus causes microvesiculation through other mechanisms, potentially through direct binding. These findings suggest that EHV-1-induced platelet activation could contribute to the thrombosis that occurs in clinically infected horses and provides a new mechanism by which viruses activate hemostasis. PMID:25905776

Differential activity of 2-methylene-19-nor vitamin D analogs on growth factor gene expression in rhino mouse skin and comparison to all-trans retinoic acid.

PubMed

Ahrens, Jamie M; Jones, James D; Nieves, Nirca J; Mitzey, Ann M; DeLuca, Hector F; Clagett-Dame, Margaret

2017-01-01

While all 2-methylene-19-nor analogs of 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) tested produce an increase in epidermal thickness in the rhino mouse, only a subset reduce utricle size (comedolysis). All-trans retinoic acid (atRA) also causes epidermal thickening and a reduction in utricle size in the rhino mouse. We now report that 2-methylene-19-nor-(20S)-1α-hydroxybishomopregnacalciferol (2MbisP), a comedolytic analog, increases epidermal thickening more rapidly than does atRA, while both reduce utricle area at an equal rate. Whereas unlike atRA, 2MbisP does not alter the epidermal growth factor receptor ligand, heparin-binding epidermal growth factor-like growth factor, it does increase the expression of both amphiregulin and epigen mRNA, even after a single dose. In situ hybridization reveals an increase in these transcripts throughout the closing utricle as well as in the interfollicular epidermis. The mRNAs for other EGFR ligands including betacellulin and transforming growth factor-α, as well as the epidermal growth factor receptor are largely unaffected by 2MbisP. Another analog, 2-methylene-19-nor-(20S)-26,27-dimethylene-1α,25-dihydroxyvitamin D3 (CAGE-3), produces epidermal thickening but fails to reduce utricle size or increase AREG mRNA levels. CAGE-3 modestly increases epigen mRNA levels, but only after 5 days of dosing. Thus, 2-MbisP produces unique changes in epidermal growth factor receptor ligand mRNAs that may be responsible for both epidermal proliferation and a reduction in utricle size.

Analog synthetic biology

PubMed Central

Sarpeshkar, R.

2014-01-01

We analyse the pros and cons of analog versus digital computation in living cells. Our analysis is based on fundamental laws of noise in gene and protein expression, which set limits on the energy, time, space, molecular count and part-count resources needed to compute at a given level of precision. We conclude that analog computation is significantly more efficient in its use of resources than deterministic digital computation even at relatively high levels of precision in the cell. Based on this analysis, we conclude that synthetic biology must use analog, collective analog, probabilistic and hybrid analog–digital computational approaches; otherwise, even relatively simple synthetic computations in cells such as addition will exceed energy and molecular-count budgets. We present schematics for efficiently representing analog DNA–protein computation in cells. Analog electronic flow in subthreshold transistors and analog molecular flux in chemical reactions obey Boltzmann exponential laws of thermodynamics and are described by astoundingly similar logarithmic electrochemical potentials. Therefore, cytomorphic circuits can help to map circuit designs between electronic and biochemical domains. We review recent work that uses positive-feedback linearization circuits to architect wide-dynamic-range logarithmic analog computation in Escherichia coli using three transcription factors, nearly two orders of magnitude more efficient in parts than prior digital implementations. PMID:24567476

Discovery and evaluation of novel anti-inflammatory derivatives of natural bioactive curcumin

PubMed Central

Zhang, Yali; Jiang, Xin; Peng, Kesong; Chen, Chengwei; Fu, Lili; Wang, Zhe; Feng, Jianpeng; Liu, Zhiguo; Zhang, Huajie; Liang, Guang; Pan, Zheer

2014-01-01

Curcumin is a natural active product that has various pharmacological activities such as anti-inflammatory effects. Here, we report the synthesis and evaluation of 34 monocarbonyl curcumin analogs as novel anti-inflammatory agents. Among the analogs, the symmetrical heterocyclic type displayed the strongest inhibition of lipopolysaccharide (LPS)-stimulated expression of pro-inflammatory cytokines in macrophages. Analogs S1–S5 and AS29 reduced tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production in a dose-dependent manner and also displayed excellent stability and low cytotoxicity in vitro. In addition, analog S1 dose-dependently inhibited LPS-induced extracellular signal-regulated kinase (ERK) phosphorylation. Furthermore, analogs S1 and S4 displayed a significant protective effect on LPS-induced septic death in mouse models, with 40% and 50% survival rates, respectively. These data demonstrate that the heterocyclic monocarbonyl curcumin analogs have potential therapeutic effects in acute inflammatory diseases. PMID:25395833

Ultra-high-speed optical transmission using digital-preprocessed analog-multiplexed DAC

NASA Astrophysics Data System (ADS)

Yamazaki, Hiroshi; Nagatani, Munehiko; Hamaoka, Fukutaro; Horikoshi, Kengo; Nakamura, Masanori; Matsushita, Asuka; Kanazawa, Shigeru; Hashimoto, Toshikazu; Nosaka, Hideyuki; Miyamoto, Yutaka

2018-02-01

In advanced fiber transmission systems with digital signal processors (DSPs), analog bandwidths of digital-to-analog converters (DACs), which interface the DSPs and optics, are the major factors limiting the data rates. We have developed a technology to extend the DACs' bandwidth using a digital preprocessor, two sub-DACs, and an analog multiplexer. This technology enables us to generate baseband signals with bandwidths of up to around 60 GHz, which is almost twice that of signals generated by typical CMOS DACs. In this paper, we describe the principle of the bandwidth extension and review high-speed transmission experiments enabled by this technology.

Analogical Transfer from a Simulated Physical System

ERIC Educational Resources Information Center

Day, Samuel B.; Goldstone, Robert L.

2011-01-01

Previous research has consistently found that spontaneous analogical transfer is strongly tied to concrete and contextual similarities between the cases. However, that work has largely failed to acknowledge that the relevant factor in transfer is the similarity between individuals' mental representations of the situations rather than the overt…

Synthesis of 4-(3'-[125I]iodoanilino)-6,7-dialkoxyquinazolines:radiolabeled epidermal growth factor receptor tyrosine kinaseinhibitors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lim, John K.; Negash, Kitaw; Hanrahan, Stephen M.

1999-10-25

The preparation of two radioiodinated analogs of theepidermal growth factor receptor tyrosine kinase (EGFrTK) inhibitorPD153035(4-(3'-bromoanilino)-6,7-dimethoxyquinazoline) are reportedherein. The two analogs,4-(3'-[125I]iodoanilino)-6,7-dimethoxyquinazoline and4-(3'-[125I]iodoanilino)-6,7-diethoxyquinazoline, were synthesizedviaiododestannylation of the corresponding4-(3'-trimethylstannylanilino)-6,7-dialkoxyquinazolines to form thedesired I-125 labeled products in good yield and high radiochemicalpurity (>99 percent).

Thermodynamic Characterization of Hydration Sites from Integral Equation-Derived Free Energy Densities: Application to Protein Binding Sites and Ligand Series.

PubMed

Güssregen, Stefan; Matter, Hans; Hessler, Gerhard; Lionta, Evanthia; Heil, Jochen; Kast, Stefan M

2017-07-24

Water molecules play an essential role for mediating interactions between ligands and protein binding sites. Displacement of specific water molecules can favorably modulate the free energy of binding of protein-ligand complexes. Here, the nature of water interactions in protein binding sites is investigated by 3D RISM (three-dimensional reference interaction site model) integral equation theory to understand and exploit local thermodynamic features of water molecules by ranking their possible displacement in structure-based design. Unlike molecular dynamics-based approaches, 3D RISM theory allows for fast and noise-free calculations using the same detailed level of solute-solvent interaction description. Here we correlate molecular water entities instead of mere site density maxima with local contributions to the solvation free energy using novel algorithms. Distinct water molecules and hydration sites are investigated in multiple protein-ligand X-ray structures, namely streptavidin, factor Xa, and factor VIIa, based on 3D RISM-derived free energy density fields. Our approach allows the semiquantitative assessment of whether a given structural water molecule can potentially be targeted for replacement in structure-based design. Finally, PLS-based regression models from free energy density fields used within a 3D-QSAR approach (CARMa - comparative analysis of 3D RISM Maps) are shown to be able to extract relevant information for the interpretation of structure-activity relationship (SAR) trends, as demonstrated for a series of serine protease inhibitors.

Early experience with activated recombinant factor VII for intractable hemorrhage after cardiovascular surgery.

PubMed

Halkos, Michael E; Levy, Jerrold H; Chen, Edward; Reddy, V Seenu; Lattouf, Omar M; Guyton, Robert A; Song, Howard K

2005-04-01

Intractable hemorrhage after complex cardiovascular operations is a serious and potentially lethal complication. We report our experience with the use of activated recombinant factor VIIa (rFVIIa) as rescue therapy for patients with refractory postoperative hemorrhage. From April 2002 through December 2003, 9 patients received rFVIIa for intractable hemorrhage after cardiovascular surgery. Patients underwent aortic surgery (2), coronary artery bypass graft surgery (4), double valve operations (2), and mitral valve replacement (1). Four of these procedures were reoperations. Intraoperative aprotinin was used in all patients. All patients underwent standard heparinization (300 IU/kg) before cardiopulmonary bypass and reversal with protamine. Five patients underwent reexploration for mediastinal hemorrhage before treatment; 2 were reexplored twice. The average transfusion requirement before rFVIIa administration was 9 U of blood, 7 U of plasma, 22 U of platelets, and 19 U of cryoprecipitate. rFVIIa was administered as an intravenous bolus at 68 to 120 mug/kg. Mean time of administration from the first operation was 10.9 +/- 7.2 hours. At the time of activated rFVIIa administration, chest tube drainage averaged 640 mL/h. In all patients, chest tube drainage was dramatically reduced to less than 100 mL/h within 5 hours after drug delivery. None of the patients required reexploration after treatment. There were no postoperative neurologic or cardiovascular complications. When used as rescue therapy for intractable hemorrhage after cardiovascular surgery, rFVIIa may be effective in promoting hemostasis, preventing reexploration, and reducing transfusion requirements.

Coagulation activation by MC28 fibrosarcoma cells facilitates lung tumor formation.

PubMed

Amirkhosravi, M; Francis, J L

1995-01-01

Tumor cells interact with the hemostatic system in various ways and may thus influence malignant growth and spread. MC28 fibrosarcoma cells possess a potent procoagulant activity (PCA) and form lung tumors following intravenous injection. The aim of this work was to study the relationship between PCA, intravascular coagulation and lung seeding in the MC28 model. MC28 cells were injected into control, warfarinized and heparinized hooded Lister rats. Coagulation changes were monitored by thromboelastography (TEG) and Sonoclot analysis (SA), lung fibrin formation by light and electron microscopy, tumor seeding by macroscopic counting and tumor cell and platelet deposition in the lungs by radiolabelling. PCA was measured by chromogenic assay. MC28 PCA was characterized as a tissue factor-factor VIIa complex that probably arose during cell culture or disaggregation of solid tumors. Injection of tumor cells caused marked coagulopathy and was rapidly (within 30 min) followed by fibrin deposition in the lungs and accumulation of radiolabelled platelets. Heparin and warfarin significantly reduced lung seeding (p < 0.001) and reduced retention of radiolabelled tumor cells in the pulmonary circulation (p < 0.01). Inhibition of cellular PCA by prior treatment with concanavalin A markedly reduced intravascular coagulation and lung seeding. We conclude that MC28 cells cause intravascular coagulation as a direct result of their procoagulant activity. The data suggest that tumor cells form complexes with platelets and fibrin which are retained in the lungs long enough for extravasation and seeding to occur.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibacterial and Antibiofilm Activities of Makaluvamine Analogs

PubMed Central

Nijampatnam, Bhavitavya; Nadkarni, Dwayaja H.; Wu, Hui; Velu, Sadanandan E.

2014-01-01

Streptococcus mutans is a key etiological agent in the formation of dental caries. The major virulence factor is its ability to form biofilms. Inhibition of S. mutans biofilms offers therapeutic prospects for the treatment and the prevention of dental caries. In this study, 14 analogs of makaluvamine, a marine alkaloid, were evaluated for their antibacterial activity against S. mutans and for their ability to inhibit S. mutans biofilm formation. All analogs contained the tricyclic pyrroloiminoquinone core of makaluvamines. The structural variations of the analogs are on the amino substituents at the 7-position of the ring and the inclusion of a tosyl group on the pyrrole ring N of the makaluvamine core. The makaluvamine analogs displayed biofilm inhibition with IC50 values ranging from 0.4 μM to 88 μM. Further, the observed bactericidal activity of the majority of the analogs was found to be consistent with the anti-biofilm activity, leading to the conclusion that the anti-biofilm activity of these analogs stems from their ability to kill S. mutans. However, three of the most potent N-tosyl analogs showed biofilm IC50 values at least an order of magnitude lower than that of bactericidal activity, indicating that the biofilm activity of these analogs is more selective and perhaps independent of bactericidal activity. PMID:25767719

Cap analogs modified with 1,2-dithiodiphosphate moiety protect mRNA from decapping and enhance its translational potential

PubMed Central

Strenkowska, Malwina; Grzela, Renata; Majewski, Maciej; Wnek, Katarzyna; Kowalska, Joanna; Lukaszewicz, Maciej; Zuberek, Joanna; Darzynkiewicz, Edward; Kuhn, Andreas N.; Sahin, Ugur; Jemielity, Jacek

2016-01-01

Along with a growing interest in mRNA-based gene therapies, efforts are increasingly focused on reaching the full translational potential of mRNA, as a major obstacle for in vivo applications is sufficient expression of exogenously delivered mRNA. One method to overcome this limitation is chemically modifying the 7-methylguanosine cap at the 5′ end of mRNA (m7Gppp-RNA). We report a novel class of cap analogs designed as reagents for mRNA modification. The analogs carry a 1,2-dithiodiphosphate moiety at various positions along a tri- or tetraphosphate bridge, and thus are termed 2S analogs. These 2S analogs have high affinities for translation initiation factor 4E, and some exhibit remarkable resistance against the SpDcp1/2 decapping complex when introduced into RNA. mRNAs capped with 2S analogs combining these two features exhibit high translation efficiency in cultured human immature dendritic cells. These properties demonstrate that 2S analogs are potentially beneficial for mRNA-based therapies such as anti-cancer immunization. PMID:27903882

Coagulation factor VIIa-mediated protease-activated receptor 2 activation leads to β-catenin accumulation via the AKT/GSK3β pathway and contributes to breast cancer progression.

PubMed

Roy, Abhishek; Ansari, Shabbir A; Das, Kaushik; Prasad, Ramesh; Bhattacharya, Anindita; Mallik, Suman; Mukherjee, Ashis; Sen, Prosenjit

2017-08-18

Cell migration and invasion are very characteristic features of cancer cells that promote metastasis, which is one of the most common causes of mortality among cancer patients. Emerging evidence has shown that coagulation factors can directly mediate cancer-associated complications either by enhancing thrombus formation or by initiating various signaling events leading to metastatic cancer progression. It is well established that, apart from its distinct role in blood coagulation, coagulation factor FVIIa enhances aggressive behaviors of breast cancer cells, but the underlying signaling mechanisms still remain elusive. To this end, we investigated FVIIa's role in the migration and invasiveness of the breast cancer cell line MDA-MB-231. Consistent with previous observations, we observed that FVIIa increased the migratory and invasive potential of these cells. We also provide molecular evidence that protease-activated receptor 2 activation followed by PI3K-AKT activation and GSK3β inactivation is involved in these processes and that β-catenin, a well known tumor-regulatory protein, contributes to this signaling pathway. The pivotal role of β-catenin was further indicated by the up-regulation of its downstream targets cyclin D1, c-Myc, COX-2, MMP-7, MMP-14, and Claudin-1. β-Catenin knockdown almost completely attenuated the FVIIa-induced enhancement of breast cancer migration and invasion. These findings provide a new perspective to counteract the invasive behavior of breast cancer, indicating that blocking PI3K-AKT pathway-dependent β-catenin accumulation may represent a potential therapeutic approach to control breast cancer. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Concentration-dependent effect of hypocalcaemia on mortality of patients with critical bleeding requiring massive transfusion: a cohort study.

PubMed

Ho, K M; Leonard, A D

2011-01-01

Mortality of patients with critical bleeding requiring massive transfusion is high. Although hypothermia, acidosis and coagulopathy have been well described as important determinants of mortality in patients with critical bleeding requiring massive transfusion, the risk factors and outcome associated with hypocalcaemia in these patients remain uncertain. This cohort study assessed the relationship between the lowest ionised calcium concentration during the 24-hour period of critical bleeding and the hospital mortality of 352 consecutive patients, while adjusting for diagnosis, acidosis, coagulation results, transfusion requirements and use of recombinant factor VIIa. Hypocalcaemia was common (mean concentrations 0.77 mmol/l, SD 0.19) and had a linear; concentration-dependent relationship with mortality (odds ratio [OR] 1.25 per 0.1 mmol/l decrement, 95% confidence interval [CI]: 1.04 to 1.52; P = 0.02). Hypocalcaemia accounted for 12.5% of the variability and was more important than the lowest fibrinogen concentrations (10.8%), acidosis (7.9%) and lowest platelet counts (7.7%) in predicting hospital mortality. The amount of fresh frozen plasma transfused (OR 1.09 per unit, 95% CI: 1.02 to 1.17; P = 0.02) and acidosis (OR 1.45 per 0.1 decrement, 95% CI: 1.19 to 1.72; P = 0.01) were associated with the occurrence of severe hypocalcaemia (< 0.8 mmol/l). In conclusion, ionised calcium concentrations had an inverse concentration-dependent relationship with mortality of patients with critical bleeding requiring massive transfusion. Both acidosis and the amount of fresh frozen plasma transfused were the main risk factors for severe hypocalcaemia. Further research is needed to determine whether preventing ionised hypocalcaemia can reduce mortality of patients with critical bleeding requiring massive transfusion.

Development of a lectin binding assay to differentiate between recombinant and endogenous proteins in pharmacokinetic studies of protein-biopharmaceuticals.

PubMed

Weber, Alfred; Minibeck, Eva; Scheiflinger, Friedrich; Turecek, Peter L

2015-04-10

Human glycoproteins, expressed in hamster cell lines, show similar glycosylation patterns to naturally occurring human molecules except for a minute difference in the linkage of terminal sialic acid: both cell types lack α2,6-galactosyl-sialyltransferase, abundantly expressed in human hepatocytes and responsible for the α2,6-sialylation of circulating glycoproteins. This minute difference, which is currently not known to have any physiological relevance, was the basis for the selective measurement of recombinant glycoproteins in the presence of their endogenous counterparts. The assay is based on using the lectin Sambucus nigra agglutinin (SNA), selectively binding to α2,6-sialylated N-glycans. Using von Willebrand factor (VWF), factor IX (FIX), and factor VIIa (FVIIa), it was demonstrated that (i) the plasma-derived proteins, but not the corresponding recombinant proteins, specifically bind to SNA and (ii) this binding can be used to deplete the plasma-derived proteins. The feasibility of this approach was confirmed in spike-recovery studies for all three recombinant coagulation proteins in human plasma and for recombinant VWF (rVWF) in macaque plasma. Analysis of plasma samples from macaques after administration of recombinant and a plasma-derived VWF demonstrated the suitability and robustness of this approach. Data showed that rVWF could be selectively measured without changing the ELISAs and furthermore revealed the limitations of baseline adjustment using a single measurement of the predose concentration only. The SNA gel-based depletion procedure can easily be integrated in existing procedures as a specific sample pre-treatment step. While ELISA-based methods were used to measure the recombinant coagulation proteins in the supernatants obtained by depletion, this procedure is applicable for all biochemical analyses. Copyright © 2015 Elsevier B.V. All rights reserved.

Thromboprophylaxis and VTE rates in soldiers wounded in Operation Enduring Freedom and Operation Iraqi Freedom.

PubMed

Holley, Aaron B; Petteys, Sarah; Mitchell, Joshua D; Holley, Paul R; Collen, Jacob F

2013-09-01

US soldiers suffer catastrophic injuries during combat. We sought to define risk factors and rates for VTE in this population. We gathered data each hospital day on all patients injured in Afghanistan or Iraq who were admitted to the Walter Reed Army Medical Center (WRAMC). We analyzed prophylaxis rates and efficacy and identified risk factors for VTE. We recorded data on 506 combat casualties directly admitted to WRAMC after medical air evacuation. The average injury severity score for the group was 18.4 ± 11.7, and the most common reason for air evacuation was injury by improvised explosive device (65%). As part of the initial resuscitation, patients received 4.7 ± 9.0 and 4.00 ± 7.8 units of packed RBCs and fresh frozen plasma, respectively, and 42 patients received factor VIIa. Forty-six patients (9.1%) were given a diagnosis of VTE prior to discharge, 18 (3.6%) during air evacuation, and 28 (5.5%) during the hospital stay. In Cox regression analysis, administration of 1 unit of packed RBCs was associated with a hazard ratio (HR) of 1.04 (95% CI, 1.02-1.07; P = .002), and enoxaparin, 30 mg bid, administered subcutaneously for the majority of hospital days was associated with a HR of 0.31 (95% CI, 0.11-0.86; P = .02) for VTE during the hospitalization. Patients who suffer traumatic injuries in combat overseas are at high risk for VTE during evacuation and recovery. Those with large resuscitations are at particularly high risk, and low-molecular-weight heparin is associated with a decrease in VTE.

Differential effects of somatostatin on circulating tissue factor procoagulant activity and protein.

PubMed

Boden, Guenther; Vaidyula, Vijender; Homko, Carol; Mozzoli, Maria; Rao, A Koneti

2007-05-01

The tissue factor (TF) pathway is the primary mechanism for initiation of blood coagulation. Circulating blood contains TF, which originates mainly from monocytes and is thrombogenic. The presence of somatostatin (SMS) receptors on monocytes suggests the possibility that SMS may regulate TF synthesis and/or release. Circulating TF procoagulant activity (TF-PCA), factor VIIa activity (FVIIa; clotting assays), TF antigen (TF-Ag; ELISA), prothrombin fragment 1.2 (F1.2), thrombin-antithrombin complexes (ELISAs), CD40 ligand expression on platelets, and monocyte-platelet aggregates (flow cytometry) were determined in blood from normal volunteers undergoing 24 h of basal glucose/basal insulin (BG/BI) clamps and high-glucose/high-insulin (HG/HI) clamps with and without SMS. Infusions of SMS under basal conditions (BG/BI) raised TF-PCA 1.8-fold (P < 0.03), TF-Ag 2.3-fold (P < 0.001), and TF expression on monocytes by 36% (P < 0.001) and decreased plasma levels of FVIIa by 30% (P < 0.001). Infusion of SMS reduced the 8.6-fold HG/HI-induced increase in TF-Ag by 26% and the 8.6-fold increase in TF-PCA by 100%. SMS also prevented the 60% increase in TF expression on monocytes, the 2.2-fold increase in F1.2, the 40% increase in CD40L expression on platelets, and the 17% increase in monocyte-platelet aggregates seen during HG/HI. We conclude that SMS completely prevented HG/HI-induced TF activation in normal volunteers and may be of use to reduce the procoagulant state and acute vascular events in hyperinsulinemic insulin-resistant patients with type 2 diabetes.

Analysis of Several PLA2 mRNA in Human Meningiomas

PubMed Central

Denizot, Yves; De Armas, Rafael; Durand, Karine; Robert, Sandrine; Moreau, Jean-Jacques; Caire, François; Weinbreck, Nicolas; Labrousse, François

2009-01-01

In view of the important oncogenic action of phospholipase A2(PLA2) we investigated PLA2 transcripts in human meningiomas. Real-time PCR was used to investigate PLA2 transcripts in 26 human meningioma tumors. Results indicated that three Ca2+-dependent high molecular weight PLA2 (PLA2-IVA, PLA2-IVB, PLA2-IVC), one Ca2+-independent high molecular weight PLA2 (PLA2-VI) and five low molecular weight secreted forms of PLA2 (PLA2-IB, PLA2-IIA, PLA2-III, PLA2-V, and PLA2-XII) are expressed with PLA2-IVA, PLA2-IVB, PLA2-VI, and PLA2-XIIA as the major expressed forms. PLA2-IIE, PLA2-IIF, PLA2-IVD, and PLA2-XIIB are not detected. Plasma (PLA2-VIIA) and intracellular (PLA2-VIIB) platelet-activating factor acetylhydrolase transcripts are expressed in human meningiomas. However no difference was found for PLA2 transcript amounts in relation to the tumor grade, the subtype of meningiomas, the presence of inflammatory infiltrated cells, of an associated edema, mitosis, brain invasion, vascularisation or necrosis. In conclusion numerous genes encoding multiples forms of PLA2 are expressed in meningiomas where they might act on the phospholipid remodeling and on the local eicosanoid and/or cytokine networks. PMID:20339511

Establishment of a fluorescence-based method to evaluate endocytosis of desialylated glycoproteins in vitro.

PubMed

Luo, Cheng; Chen, Song; Xu, Na; Sai, Wen Bo; Zhao, Wei; Li, Ying Chun; Hu, Xiao Jing; Tian, Hong; Gao, Xiang Dong; Yao, Wen Bing

2017-04-01

Insufficient sialylation can result in rapid clearance of therapeutic glycoproteins by intracellular degradation, which is mainly mediated by asialoglycoprotein receptors (ASGPRs) on hepatic cells. In contrast, for glycoproteins, a long half-life is often related to high level of terminal sialic acid. These could be extremely important for insufficient sialylated biomedicines in clinic, and development of therapeutic glycoproteins in laboratory. However, how the desialylated glycoproteins are removed and how to evaluate the ASGPRs mediated endocytosis in vitro needs further investigate. Herein we described an integrative characterization of ASGPRs in vitro to elucidate its endocytosis properties. The endocytosis was determined by a fluorescence-based quantization method. The results showed that the ASGPRs could bind to poorly sialylated glycoproteins including asialofetuin and low sialylated recombinant Factor VIIa with a relatively higher ASGPRs binding affinity, and induce a more rapid endocytosis in vitro. Moreover, the mechanism under the internalization of ASGPRs was also investigated, which was found to depend on clathrin and caveolin. Utilizing the relative fluorescence quantification can be suitable for measurement of insufficient sialylated glycoprotein endocytosis and quality control of therapeutic glycoproteins, which could be useful for the understanding of the development of therapeutic glycoproteins. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Analysis of Complaints from Patients During Mechanical Ventilation After Cardiac Surgery: A Retrospective Study.

PubMed

Wang, Yi; Li, Hua; Zou, Honglin; Li, Yaxiong

2015-08-01

This study analyzed major complaints from patients during mechanical ventilation after cardiac surgery and identified the most common complaints to reduce adverse psychologic responses. Retrospective. A single tertiary university hospital. Patients with heart disease who were on mechanical ventilation after cardiac surgery (N = 800). The major complaints of the patients during mechanical ventilation after cardiac surgery were analyzed. Patients' comfort was evaluated using a visual analog scale, and the factors affecting comfort were analyzed. The average visual analog scale score in all patients was 5.8±2.0, and most patients presented moderate discomfort. The factors affecting comfort included dry mouth, thirst, tracheal intubation, aspiration of sputum, communication barriers, limited mobility, fear/anxiety, patient-ventilator dyssynchrony, and poor environmental conditions. Of these factors, 8 were independent predictors of the visual analog scale score. Patients considered mechanical ventilation to be the worst part of their hospitalization. The study identified 8 independent factors causing discomfort in patients during mechanical ventilation after cardiac surgery. Clinicians should take appropriate measures and implement nursing interventions to reduce suffering, physical and psychologic trauma, and adverse psychologic responses and to promote recovery. Copyright © 2015 Elsevier Inc. All rights reserved.

Early executive function predicts reasoning development.

PubMed

Richland, Lindsey E; Burchinal, Margaret R

2013-01-01

Analogical reasoning is a core cognitive skill that distinguishes humans from all other species and contributes to general fluid intelligence, creativity, and adaptive learning capacities. Yet its origins are not well understood. In the study reported here, we analyzed large-scale longitudinal data from the Study of Early Child Care and Youth Development to test predictors of growth in analogical-reasoning skill from third grade to adolescence. Our results suggest an integrative resolution to the theoretical debate regarding contributory factors arising from smaller-scale, cross-sectional experiments on analogy development. Children with greater executive-function skills (both composite and inhibitory control) and vocabulary knowledge in early elementary school displayed higher scores on a verbal analogies task at age 15 years, even after adjusting for key covariates. We posit that knowledge is a prerequisite to analogy performance, but strong executive-functioning resources during early childhood are related to long-term gains in fundamental reasoning skills.

Current prospects of synthetic curcumin analogs and chalcone derivatives against mycobacterium tuberculosis.

PubMed

Bukhari, Syed Nasir Abbas; Franzblau, Scott G; Jantan, Ibrahim; Jasamai, Malina

2013-11-01

Tuberculosis, caused by Mycobacterium tuberculosis, is amongst the foremost infectious diseases. Treatment of tuberculosis is a complex process due to various factors including a patient's inability to persevere with a combined treatment regimen, the difficulty in eradicating the infection in immune-suppressed patients, and multidrug resistance (MDR). Extensive research circumscribing molecules to counteract this disease has led to the identification of many inhibitory small molecules. Among these are chalcone derivatives along with curcumin analogs. In this review article, we summarize the reported literature regarding anti tubercular activity of chalcone derivatives and synthetic curcumin analogs. Our goal is to provide an analysis of research to date in order to facilitate the synthesis of superior antitubercular chalcone derivatives and curcumin analogs.

Differential Stability of Dimeric and Monomeric Cytochrome c Oxidase Exposed to Elevated Hydrostatic Pressure†

PubMed Central

Staničová, Jana; Sedlák, Erik; Musatov, Andrej; Robinson, Neal C.

2007-01-01

Detergent-solubilized dimeric and monomeric cytochrome c oxidase (CcO) have significantly different quaternary stability when exposed to 2−3 kbar of hydrostatic pressure. Dimeric, dodecyl maltoside-solubilized cytochrome c oxidase is very resistant to elevated hydrostatic pressure with almost no perturbation of its quaternary structure or functional activity after release of pressure. In contrast to the stability of dimeric CcO, 3 kbar of hydrostatic pressure triggers multiple structural and functional alterations within monomeric cytochrome c oxidase. The perturbations are either irreversible or slowly reversible since they persist after the release of high pressure. Therefore, standard biochemical analytical procedures could be used to quantify the pressure-induced changes after the release of hydrostatic pressure. The electron transport activity of monomeric cytochrome c oxidase decreases by as much as 60% after exposure to 3 kbar of hydrostatic pressure. The irreversible loss of activity occurs in a time- and pressure-dependent manner. Coincident with the activity loss is a sequential dissociation of four subunits as detected by sedimentation velocity, high-performance ion-exchange chromatography, and reversed-phase and SDS–PAGE subunit analysis. Subunits VIa and VIb are the first to dissociate followed by subunits III and VIIa. Removal of subunits VIa and VIb prior to pressurization makes the resulting 11-subunit form of CcO even more sensitive to elevated hydrostatic pressure than monomeric CcO containing all 13 subunits. However, dimeric CcO, in which the association of VIa and VIb is stabilized, is not susceptible to pressure-induced inactivation. We conclude that dissociation of subunit III and/or VIIa must be responsible for pressure-induced inactivation of CcO since VIa and VIb can be removed from monomeric CcO without significant activity loss. These results are the first to clearly demonstrate an important structural role for the dimeric form of cytochrome c oxidase, i.e., stabilization of its quaternary structure. PMID:17530783

Spontaneous nucleotide exchange in low molecular weight GTPases by fluorescently labeled γ-phosphate-linked GTP analogs

PubMed Central

Korlach, Jonas; Baird, Daniel W.; Heikal, Ahmed A.; Gee, Kyle R.; Hoffman, Gregory R.; Webb, Watt W.

2004-01-01

Regulated guanosine nucleotide exchange and hydrolysis constitute the fundamental activities of low molecular weight GTPases. We show that three guanosine 5′-triphosphate analogs with BODIPY fluorophores coupled via the gamma phosphate bind to the GTPases Cdc42, Rac1, RhoA, and Ras and displace guanosine 5′-diphosphate with high intrinsic exchange rates in the presence of Mg2+ ions, thereby acting as synthetic, low molecular weight guanine nucleotide exchange factors. The accompanying large fluorescence enhancements (as high as 12-fold), caused by a reduction in guanine quenching of the environmentally sensitive BODIPY dye fluorescence on protein binding, allow for real-time monitoring of this spontaneous nucleotide exchange in the visible spectrum with high signal-to-noise ratios. Binding affinities increased with longer aliphatic linkers connecting the nucleotide and BODIPY fluorophore and were in the 10–100 nM range. Steady-state and time-resolved fluorescence spectroscopy showed an inverse relationship between linker length and fluorescence enhancement factors and differences in protein-bound fluorophore mobilities, providing optimization criteria for future applications of such compounds as efficient elicitors and reporters of nucleotide exchange. EDTA markedly enhanced nucleotide exchange, enabling rapid loading of GTPases with these probes. Differences in active site geometries, in the absence of Mg2+, caused qualitatively different reporting of the bound state by the different analogs. The BODIPY analogs also prevented the interaction of Cdc42 with p21 activated kinase. Together, these results validate the use of these analogs as valuable tools for studying GTPase functions and for developing potent synthetic nucleotide exchange factors for this important class of signaling molecules. PMID:14973186

Evaluation of the Therapeutic Potential of a CNP Analog in a Fgfr3 Mouse Model Recapitulating Achondroplasia

PubMed Central

Lorget, Florence; Kaci, Nabil; Peng, Jeff; Benoist-Lasselin, Catherine; Mugniery, Emilie; Oppeneer, Todd; Wendt, Dan J.; Bell, Sean M.; Bullens, Sherry; Bunting, Stuart; Tsuruda, Laurie S.; O'Neill, Charles A.; Di Rocco, Federico; Munnich, Arnold; Legeai-Mallet, Laurence

2012-01-01

Achondroplasia (ACH), the most common form of dwarfism, is an inherited autosomal-dominant chondrodysplasia caused by a gain-of-function mutation in fibroblast-growth-factor-receptor 3 (FGFR3). C-type natriuretic peptide (CNP) antagonizes FGFR3 downstream signaling by inhibiting the pathway of mitogen-activated protein kinase (MAPK). Here, we report the pharmacological activity of a 39 amino acid CNP analog (BMN 111) with an extended plasma half-life due to its resistance to neutral-endopeptidase (NEP) digestion. In ACH human growth-plate chondrocytes, we demonstrated a decrease in the phosphorylation of extracellular-signal-regulated kinases 1 and 2, confirming that this CNP analog inhibits fibroblast-growth-factor-mediated MAPK activation. Concomitantly, we analyzed the phenotype of Fgfr3Y367C/+ mice and showed the presence of ACH-related clinical features in this mouse model. We found that in Fgfr3Y367C/+ mice, treatment with this CNP analog led to a significant recovery of bone growth. We observed an increase in the axial and appendicular skeleton lengths, and improvements in dwarfism-related clinical features included flattening of the skull, reduced crossbite, straightening of the tibias and femurs, and correction of the growth-plate defect. Thus, our results provide the proof of concept that BMN 111, a NEP-resistant CNP analog, might benefit individuals with ACH and hypochondroplasia. PMID:23200862

Reversal of coagulopathy in critically ill patients with traumatic brain injury: recombinant factor VIIa is more cost-effective than plasma.

PubMed

Stein, Deborah M; Dutton, Richard P; Kramer, Mary E; Scalea, Thomas M

2009-01-01

Traumatic brain injury (TBI) is the leading cause of death and disability after trauma. Coagulopathy is common in this patient population and requires rapid reversal to allow for safe neurosurgical intervention and prevent worsening of the primary injury. Typically reversal of coagulopathy is accomplished with the use of plasma. Recombinant factor VIIa (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) has become increasingly used "off-label" in patients with neurosurgical emergencies to rapidly reverse coagulopathy. We hypothesized that the use of rFVIIa in this patient population would prove to be cost-effective as well as demonstrate clinical benefit. The trauma registry at the R Adams Cowley Shock Trauma Center was used to identify all coagulopatic trauma patients admitted between January 2002 and December 2007 with relatively isolated TBI (head Abbreviated Injury Scale score of >or=4). The medical records of patients were reviewed and demographics, injury-specific data, medications administered, laboratory values, blood product utilization, neurosurgical procedures, length of stay (LOS), discharge disposition, and outcome data were abstracted. Patients who received rFVIIa for reversal of coagulopathy were compared against those who did not receive rFVIIa. t Tests were used to compare differences between continuous variables, and chi2 analysis was used to compare categorical variables. A p value of <0.05 was considered significant for all statistical tests. During a 6-year period, there were 179 patients who met inclusion criteria. One hundred eleven patients (62.0%) were treated with conventional therapy alone whereas 68 (38.0%) received rFVIIa. Baseline characteristics between the two groups were similar except that Injury Severity Score and admission International normalized ratio were higher in the rFVIIa group and the rFVIIa group had a higher percentage of patients with head Abbreviated Injury Scale score of 5 injuries, patients who underwent neurosurgical procedures and patients with preinjury warfarin use. There was no difference in total charges between these groups (mean US $63,403 in the conventionally treated group vs. $66,086). When patients who required admission to the intensive care unit were analyzed (n = 110, 50% received rFVIIa), total mean charges and costs were significantly lower in the group that received rFVIIa (mean US $108,900 vs. $77,907). Hospital LOS, days of mechanical ventilation, and plasma utilization were lower in the rFVIIa group. Mortality and thromboembolic complication rates were not different between the two groups. In this study, we were able to demonstrate a significant economic benefit of the use of rFVIIa for reversal of coagulopathy in severely injured patients with TBI. Not all patients with coagulopathy and an anatomic brain injury benefit, but in patients who are neurologically or physiologically compromised, using rFVIIa decreases total charges and costs of hospitalization. This decrease in overall cost is directly attributable to the significant decrease in LOS and decrease in the need for mechanical ventilation. This study demonstrates that in coagulopathic patients with TBI who require intensive care unit admission, rFVIIa is cost-effective and safe. Prospective studies are needed to confirm these findings and establish clinical effectiveness.

Antarctica as a testing ground for manned missions to the Moon and Mars

NASA Astrophysics Data System (ADS)

Demidov, N. E.; Lukin, V. V.

2017-03-01

This paper is concerned with the study of expedition activity in Antarctica as a part of the search for useful analogies and solutions which can be taken into account in planning manned missions to the Moon and Mars. The following is considered: natural analogies, human factors, station facilities, means of transportation, scientific programs, safety issues, and historical and political analogies. A rationalization is given for the idea of creating a testing ground in Antarctica (stations Vostok, Novolazarevskaya, Jetty Oasis) for ground-based simulation of functioning of a lunar and Martian base.

The Relationship between American Sign Language Vocabulary and the Development of Language-Based Reasoning Skills in Deaf Children

ERIC Educational Resources Information Center

Henner, Jonathan

2016-01-01

The language-based analogical reasoning abilities of Deaf children are a controversial topic. Researchers lack agreement about whether Deaf children possess the ability to reason using language-based analogies, or whether this ability is limited by a lack of access to vocabulary, both written and signed. This dissertation examines factors that…

Analyzing the effectiveness of teaching and factors in clinical decision-making.

PubMed

Hsieh, Ming-Chen; Lee, Ming-Shinn; Chen, Tsung-Ying; Tsai, Tsuen-Chiuan; Pai, Yi-Fong; Sheu, Min-Muh

2017-01-01

The aim of this study is to prepare junior physicians, clinical education should focus on the teaching of clinical decision-making. This research is designed to explore teaching of clinical decision-making and to analyze the benefits of an "Analogy guide clinical decision-making" as a learning intervention for junior doctors. This study had a "quasi-experimental design" and was conducted in a medical center in eastern Taiwan. Participants and Program Description: Thirty junior doctors and three clinical teachers were involved in the study. The experimental group (15) received 1 h of instruction from the "Analogy guide for teaching clinical decision-making" every day for 3 months. Program Evaluation: A "Clinical decision-making self-evaluation form" was used as the assessment tool to evaluate participant learning efficiency before and after the teaching program. Semi-structured qualitative research interviews were also conducted. We found using the analogy guide for teaching clinical decision-making could help enhance junior doctors' self-confidence. Important factors influencing clinical decision-making included workload, decision-making, and past experience. Clinical teaching using the analogy guide for clinical decision-making may be a helpful tool for training and can contribute to a more comprehensive understanding of decision-making.

FERM proteins in animal morphogenesis.

PubMed

Tepass, Ulrich

2009-08-01

Proteins containing a FERM domain are ubiquitous components of the cytocortex of animal cells where they are engaged in structural, transport, and signaling functions. Recent years have seen a wealth of genetic studies in model organisms that explore FERM protein function in development and tissue organization. In addition, mutations in several FERM protein-encoding genes have been associated with human diseases. This review will provide a brief overview of the FERM domain structure and the FERM protein superfamily and then discuss recent advances in our understanding of the mechanism of function and developmental requirement of several FERM proteins including Moesin, Myosin-VIIA, Myosin-XV, Coracle/Band4.1 as well as Yurt and its vertebrate homologs Mosaic Eyes and EPB41L5/YMO1/Limulus.

Increased recombinant activated factor VII use and need for surgical reexploration following a switch from aprotinin to epsilon-aminocaproic acid in infant cardiac surgery.

PubMed

Scott, John P; Costigan, Daniel J; Hoffman, George M; Simpson, Pippa M; Dasgupta, Mahua; Punzalan, Rowena; Berens, Richard J; Tweddell, James S; Stuth, Eckehard A E

2014-05-01

To evaluate whether conversion from aprotinin to epsilon-aminocaproic acid (EACA) during infant cardiac surgery was associated with increased perioperative bleeding. Structured retrospective chart review. University-affiliated large congenital cardiac surgery program. Records from 145 infants (age < 1 yr) receiving aprotinin as antifibrinolytic therapy for cardiac surgery between 6/1/2006 and 12/31/2006 were compared with a cohort of infants receiving EACA for cardiac surgery between 6/1/2008 and 12/31/2008. Sixty-eight infants received aprotinin and 77 infants received EACA. Measured indicators of perioperative bleeding included transfusion volumes, recombinant activated clotting factor VIIa (rFVIIa) administration, need for reexploration, and perioperative chest tube output. EACA treated patients received significantly more rFVIIa for uncontrolled bleeding (19/77 [25%] vs 3/68 [4%]; P < 0.001) and required surgical reexploration more frequently (21/77 [27%] vs 7/68 [10%]; P = 0.01]. Median (25th-75th percentiles) intraoperative platelet transfusion requirements were also increased after the switch to EACA (28 mL [0-58 mL] vs 0 mL [0 mL - 34.5 mL]), but this difference did not reach statistical significance (P = 0.06). Bleeding in infant cardiac surgery increased following the change in antifibrinolytic therapy from aprotinin to EACA. Given the potential for major harm, especially thrombotic complications, from rFVIIa use, prospective studies examining the safety of postcardiopulmonary bypass rFVIIa administration in infants are necessary before the routine off-label use may be recommended. Copyright © 2014 Elsevier Inc. All rights reserved.

Factor (F)VIII/VIIa enhances global haemostatic function in the co-presence of bypassing agents and FVIII among patients with haemophilia A with inhibitor.

PubMed

Nogami, Keiji; Matsumoto, Tomoko; Yada, Koji; Ogiwara, Kenichi; Furukawa, Shoko; Shida, Yasuaki; Takeyama, Masahiro; Shima, Midori

2018-05-01

Bypassing therapy is essential for the haemostatic management of patients with haemophilia A with inhibitor (PWHA-inh), but the therapeutic effects are inconsistent. We previously reported that activated prothrombin complex concentrates (aPCC) activated factor (F)VIIIin vitro, and was mediated mainly by the activated FVII (FVIIa) contained in aPCC. We have extended those studies to assess global coagulation in whole blood from 18 PWHA-inh in the co-presence of aPCC and FVIII using Ca 2+ -triggered rotational thromboelastometry. The clot times (CTs) in the presence of both aPCC (0·05 iu/ml) and recombinant (r)FVIII (1 iu/ml) ex vivo were shortened compared to the aPCC alone (P < 0·01). These enhancing effects of rFVIII were observed, irrespective of recognizing inhibitor epitopes; however, the clot formation time and 'α'-angle were not significantly different. In samples from 7 PWHA-inh post-infusion of aPCC (70-80 iu/kg), only the CTs were shortened in the presence of rFVIIIex vivo compared to its absence (P < 0·05), indicating that the enhanced activity centred on the initiation phase of coagulation. Furthermore, experiments in the co-presence of rFVIIa and rFVIII demonstrated that FVIII accelerated only the CTs. We concluded that FVIII/FVIIa-related coagulation mechanism enhanced global haemostatic function by the co-presence of bypassing agents and FVIII in PWHA-inh. © 2018 John Wiley & Sons Ltd.

Cost Assessment of Implementation of Immune Tolerance Induction in Iran.

PubMed

Cheraghali, Abdol Majid; Eshghi, Peyman

2012-05-01

A number of hemophilia A patients who receive clotting factors may develop antibodies (inhibitors) against clotting factors. The immune tolerance induction (ITI) method has proved to be a very cost-effective alternative to bypassing agents. Iran's national health authority is interested in implementing the ITI method for the management of hemophilia patients with inhibitors. The objective of this study was to calculate the breakeven point between costs attributed to the ITI method and the use of bypassing agents for the management of high-responder hemophilia patients with inhibitors. This study assessed costs attributed to the implementation of ITI for the management of Iranian hemophilia patients with costs of high-titer and high-responding inhibitors from the perspective of the national health system. The main objective was to find the breakeven point for the ITI method in comparison with the use of bypassing medicine, recombinant factor VIIa (Novoseven). Based on the sensitivity analysis performed, the breakeven point mainly depends on costs of factor VIII, Novoseven, and the success rate of the ITI intervention. According to this analysis, the breakeven point of ITI and Novoseven methods varies between 16 and 34 months posttreatment. The optimized point is about 17 months posttreatment. Iran's national health system spends more than 24 million euros for providing bypassing agents to about 124 hemophilia patients with inhibitors. Because of limited resources available in Iran's health sector, this is a huge burden. Results of this study show that the implementation of the ITI method for the management of Iranian hemophilia patients with inhibitors is a cost-saving method and Iran's health system will recover all the expenditure related to the implementation of ITI in less than 2 years and will make a considerable saving along with providing standard care for these patients. Copyright © 2012 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Differences in the incorporation of bromodeoxyuridine by human lymphoblastoid cell lines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Henderson, E.E.; Strauss, B.

1975-08-01

Long term human lymphoblastoid lines differ in their ability to grow in medium containing bromodeoxyuridine (BrdU) and to incorporate analog into their DNA. Eight Burkitts' lymphoma cell lines divided at least twice in BrdU-containing medium and made DNA in which over 90 percent of the thymidine residues were substituted with analog in both strands. Three infectious mononucleosis-derived lines and 24 lines transformed in vitro were inhibited by BrdU after one cell division and made only hybrid DNA in which one strand was substituted with analog. One out of eight normal individuals from whom long term lines were prepared gave cellmore » lines which divided at least twice in BrdU and gave DNA in which both strands were substituted with analog. It would appear that intrinsic cellular factors regulate the response to BrdU and that Burkitt's tumor lines are characterized by their ability to make stable doubly substituted DNA containing a high proportion of halogenated analog.« less

Inhibition of Delta-induced Notch signaling using fucose analogs

PubMed Central

Schneider, Michael; Kumar, Vivek; Nordstrøm, Lars Ulrik; Feng, Lei; Takeuchi, Hideyuki; Hao, Huilin; Luca, Vincent C.; Garcia, K. Christopher; Stanley, Pamela; Wu, Peng; Haltiwanger, Robert S.

2017-01-01

Notch is a cell-surface receptor that controls cell fate decisions and is regulated by O-glycans attached to epidermal growth factor-like (EGF) repeats in its extracellular domain. Protein O-fucosyltransferase 1 (Pofut1) modifies EGF repeats with O-fucose and is essential for Notch signaling. Constitutive activation of Notch signaling has been associated with a variety of human malignancies. Therefore, tools for inhibiting Notch activity are being developed as cancer therapeutics. Towards this end, we screened L-fucose analogs for their effects on Notch signaling. Two analogs, 6-alkynyl and 6-alkenyl fucose, were substrates of Pofut1 and were incorporated directly into Notch EGF repeats in cells. Both analogs were potent inhibitors of binding to and activation of Notch1 by Notch ligands Dll1 and Dll4, but not by Jag1. Mutagenesis and modeling studies suggest that incorporation of the analogs into EGF8 of Notch1 markedly reduces the ability of Delta ligands to bind and activate Notch1. PMID:29176671

Relation Education Index Norms for 500 Picture Pairs and 10 Relations: High School Sample. Technical Report No. 6.

ERIC Educational Resources Information Center

Haynes, James L.; And Others

Mode of presentation (word vs. picture) is said to be a factor in social class differences in performance on analogy tests. To investigate this contention, data were needed on equivalent word and picture analogy test performance. This report presents data on relation education index (REI) norms for 500 picture pairs collected in the process of…

The Pulley Analogy Does Not Work for Every Siphon

ERIC Educational Resources Information Center

Planinsic, Gorazd; Slisko, Josip

2010-01-01

How do siphons work? Some see atmospheric pressure, explicitly or implicitly, as a crucial factor in siphon action. Others explain that a siphon works due to a difference of water weights in unequal arms. According to the latter view, siphon action is analogous to the action of a pulley or to the behaviour of a chain that is moving over a tube. In…

Immunomodulatory effects of thalidomide analogs on LPS-induced plasma and hepatic cytokines in the rat.

PubMed

Fernández-Martínez, Eduardo; Morales-Ríos, Martha S; Pérez-Alvarez, Víctor; Muriel, Pablo

2004-10-01

Thalidomide has shown to inhibit, selectively and mainly the cytokine tumor necrosis factor-alpha (TNF-alpha), thus, thalidomide has inhibitory consequences on other cytokines; this is ascribed as an immunomodulatory effect. Novel thalidomide analogs are reported with immunomodulatory activity. The aim of this work was to synthesize some of these analogs and to assess them as immunomodulatory agents in an acute model of LPS-induced septic challenge in rat. Animal groups received orally twice a day vehicle carboxymethylcellulose (0.9%), or thalidomide in suspension (100mg/kg), or analogs in an equimolar dose. Two hours after last dose, rats were injected with saline (NaCl, 0.9%, i.p.) or LPS (5mg/kg, i.p.). Groups were sacrificed 2h after injection and samples of blood and liver were obtained. TNF-alpha, interleukin-6, -1beta, and -10 (IL-6, IL-1beta, IL-10) were quantified by enzyme linked immunosorbent assay (ELISA) and studied in plasma and liver. After 2h of LPS-induction, different patterns of measured cytokines were observed with thalidomide analogs administration evidencing their immunomodulatory effects. Interestingly, some analogs decreased significantly plasma and hepatic levels of LPS-induced proinflammatory TNF-alpha and others increased plasma concentration of anti-inflammatory IL-10. Thalidomide analogs also showed slight effects on the remaining proinflammatory cytokines. Differences among immunomodulatory effects of analogs can be related to potency, mechanism of action, and half lives. Thalidomide analogs could be used as a pharmacological tool and in therapeutics in the future.

The Role of Transporters in the Toxicity of Nucleoside and Nucleotide Analogs

PubMed Central

Koczor, Christopher A; Torres, Rebecca A

2013-01-01

Introduction Two families of nucleoside analogs have been developed to treat viral infections and cancer, but these compounds can cause tissue and cell-specific toxicity related to their uptake and subcellular activity which are dictated by host enzymes and transporters. Cellular uptake of these compounds requires nucleoside transporters that share functional similarities but differ in substrate specificity. Tissue-specific cellular expression of these transporters enables nucleoside analogs to produce their tissue specific toxic effects, a limiting factor in the treatment of retroviruses and cancer. Areas Covered This review discusses the families of nucleoside transporters and how they mediate cellular uptake of nucleoside analogs. Specific focus is placed on examples of known cases of transporter-mediated cellular toxicity and classification of the toxicities resulting. Efflux transporters are also explored as a contributor to analog toxicity and cell-specific effects. Expert Opinion Efforts to modulate transporter uptake/clearance remain long-term goals of oncologists and virologists. Accordingly, subcellular approaches that either increase or decrease intracellular nucleoside analog concentrations are eagerly sought and include transporter inhibitors and targeting transporter expression. However, additional understanding of nucleoside transporter kinetics, tissue expression, and genetic polymorphisms are required to design better molecules and better therapies. PMID:22509856

Instrumentation for Verification of Bomb Damage Repair Computer Code.

DTIC Science & Technology

1981-09-01

record the data, a conventional 14-track FM analog tape recorder was retained. The unknown factors of signal duration, test duration, and signal ...Kirtland Air Force Base computer centers for more detailed analyses. In addition to the analog recorder, signal conditioning equipment and amplifiers were...necessary to allow high quality data to be recorded. An Interrange Instrumentation Group (IRIG) code generator/reader placed a coded signal on the tape

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) with chronic cough and preserved muscle stretch reflexes: evidence for selective sparing of afferent Ia fibres.

PubMed

Infante, Jon; García, Antonio; Serrano-Cárdenas, Karla M; González-Aguado, Rocío; Gazulla, José; de Lucas, Enrique M; Berciano, José

2018-06-01

The aim of this study was to describe five patients with cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) with chronic cough and preserved limb muscle stretch reflexes. All five patients were in the seventh decade of age, their gait imbalance having been initiated in the fifth decade. In four patients cough antedated gait imbalance between 15 and 29 years; cough was spasmodic and triggered by variable factors. Established clinical picture included severe hypopallesthesia predominating in the lower limbs with postural imbalance, and variable degree of cerebellar axial and appendicular ataxia, dysarthria and horizontal gaze-evoked nystagmus. Upper- and lower-limb tendon jerks were preserved, whereas jaw jerk was absent. Vestibular function testing showed bilateral impairment of the vestibulo-ocular reflex. Nerve conduction studies demonstrated normal motor conduction parameters and absence or severe attenuation of sensory nerve action potentials. Somatosensory evoked potentials were absent or severely attenuated. Biceps and femoral T-reflex recordings were normal, while masseter reflex was absent or attenuated. Sympathetic skin responses were normal. Cranial MRI showed vermian and hemispheric cerebellar atrophy predominating in lobules VI, VII and VIIa. We conclude that spasmodic cough may be an integral part of the clinical picture in CANVAS, antedating the appearance of imbalance in several decades and that sparing of muscle spindle afferents (Ia fibres) is probably the pathophysiological basis of normoreflexia.

Synthesis and conformation analysis of 3-substituted derivatives of 1H,3H-pyrido[2,3-d] pyrimidin-4-one of expected depressive nervous system. Part III.

PubMed

Chodkowski, Andrzej; Herold, Franciszek; Kleps, Jerzy

2004-01-01

Four series of new 1-aryl (heteroaryl) piperazinylacetyl derivatives of 1H,3H-pyrido[2,3-d] pyrimidin-4-one VIIa-o were synthesised. Substrates for the synthesis of VIa-d were obtained from the respective 3H-pyrido[2.3-d]pyrimidines IVa-d in the reaction with NaBH4. Compounds VIa-d were prepared by chloroacetylation. The obtained 1-chloroacetyl derivatives in the reaction with respective aryl (heteroaryl) piperazine formed 1-aminoacetyl derivatives of 2-phenyl-1 H.3H-pyrido[2.3-d]pyrimidin-4-one compounds VII1a-n. The structure ol compounds was analysed by 1H, 13C NMR spectroscopy.

The molecular genetics of Usher syndrome.

PubMed

Ahmed, Z M; Riazuddin, S; Riazuddin, S; Wilcox, E R

2003-06-01

Association of sensorineural deafness and progressive retinitis pigmentosa with and without a vestibular abnormality is the hallmark of Usher syndrome and involves at least 12 loci among three different clinical subtypes. Genes identified for the more commonly inherited loci are USH2A (encoding usherin), MYO7A (encoding myosin VIIa), CDH23 (encoding cadherin 23), PCDH15 (encoding protocadherin 15), USH1C (encoding harmonin), USH3A (encoding clarin 1), and USH1G (encoding SANS). Transcripts from all these genes are found in many tissues/cell types other than the inner ear and retina, but all are uniquely critical for retinal and cochlear cell function. Many of these protein products have been demonstrated to have direct interactions with each other and perform an essential role in stereocilia homeostasis.

The Robustness of Acoustic Analogies

NASA Technical Reports Server (NTRS)

Freund, J. B.; Lele, S. K.; Wei, M.

2004-01-01

Acoustic analogies for the prediction of flow noise are exact rearrangements of the flow equations N(right arrow q) = 0 into a nominal sound source S(right arrow q) and sound propagation operator L such that L(right arrow q) = S(right arrow q). In practice, the sound source is typically modeled and the propagation operator inverted to make predictions. Since the rearrangement is exact, any sufficiently accurate model of the source will yield the correct sound, so other factors must determine the merits of any particular formulation. Using data from a two-dimensional mixing layer direct numerical simulation (DNS), we evaluate the robustness of two analogy formulations to different errors intentionally introduced into the source. The motivation is that since S can not be perfectly modeled, analogies that are less sensitive to errors in S are preferable. Our assessment is made within the framework of Goldstein's generalized acoustic analogy, in which different choices of a base flow used in constructing L give different sources S and thus different analogies. A uniform base flow yields a Lighthill-like analogy, which we evaluate against a formulation in which the base flow is the actual mean flow of the DNS. The more complex mean flow formulation is found to be significantly more robust to errors in the energetic turbulent fluctuations, but its advantage is less pronounced when errors are made in the smaller scales.

Satellite analog FDMA/FM to digital TDMA conversion

NASA Technical Reports Server (NTRS)

Driggers, T.; Nguyen, T.; Kolavennu, V.

1987-01-01

The results of a study which investigated design issues regarding the use of analog to digital (A/D) conversion on board a satellite are presented. The need for A/D, and of course D/A as well, conversion arose from a satellite design which required analog FDMA/FM up and down links to/from a digitally modulated intersatellite link. There are also some advantages when one must interconnect a large number of various spot beams which are using analog, and therefore cannot take advantage of SS/TDMA switching among the beams, thus resulting in low fill factors. Various tradeoffs were performed regarding the implementation of on-board A/D processing, including mass, power, and costs. The various technologies which were considered included flash ADCs, surface acoustic wave (SAW) devices, and digital signal processing (DSP) chips. Impact analyses were also performed to determine the effect on ground stations to convert to digital if the A/D approach were not implemented.

Analysis of Experimental Sea-level Transient Data and Analog Method of Obtaining Altitude Response for Turbine-propeller Engine with Relay-type Speed Control

NASA Technical Reports Server (NTRS)

Vasu, George; Pack, George J

1951-01-01

Correlation has been established between transient engine and control data obtained experimentally and data obtained by simulating the engine and control with an analog computer. This correlation was established at sea-level conditions for a turbine-propeller engine with a relay-type speed control. The behavior of the controlled engine at altitudes of 20,000 and 35,000 feet was determined with an analog computer using the altitude pressure and temperature generalization factors to calculate the new engine constants for these altitudes. Because the engine response varies considerably at altitude some type of compensation appears desirable and four methods of compensation are discussed.

Quality of Service Metrics in Wireless Sensor Networks: A Survey

NASA Astrophysics Data System (ADS)

Snigdh, Itu; Gupta, Nisha

2016-03-01

Wireless ad hoc network is characterized by autonomous nodes communicating with each other by forming a multi hop radio network and maintaining connectivity in a decentralized manner. This paper presents a systematic approach to the interdependencies and the analogy of the various factors that affect and constrain the wireless sensor network. This article elaborates the quality of service parameters in terms of methods of deployment, coverage and connectivity which affect the lifetime of the network that have been addressed, till date by the different literatures. The analogy of the indispensable rudiments was discussed that are important factors to determine the varied quality of service achieved, yet have not been duly focused upon.

Apparatus for measuring internal friction Q factors in brittle materials. [applied to lunar samples

NASA Technical Reports Server (NTRS)

Tittmann, B. R.; Curnow, J. M.

1976-01-01

A flexural analog of the torsion pendulum for measuring the Young's modulus and the internal friction Q factor of brittle materials has been developed for Q greater than 10 to the 3rd measurements at a zero static stress and at 10 to the -7th strains of brittle materials in the Hz frequency range. The present design was motivated by the desire to measure Q in fragile lunar return samples at zero static stress to shed light on the anomalously low attenuation of seismic waves on the moon. The use of the apparatus is demonstrated with data on fused silica and on a terrestrial analog of lunar basalt.

BASALT A: Basaltic Terrains in Idaho and Hawaii as Planetary Analogs for Mars Geology and Astrobiology

NASA Technical Reports Server (NTRS)

Hughes, Scott S.; Haberle, Christopher W.; Nawotniak, Shannon E. Kobs; Sehlke, Alexander; Garry, W. Brent; Elphic, Richard C.; Payler, Sam J.; Stevens, Adam H.; Cockell, Charles S.; Brady, Allyson L.;

Synthesis of isosteric selenium analog of the PPARbeta/delta agonist GW501516 and comparison of biological activity.

PubMed

Sharma, Arun K; Sk, Ugir Hossain; He, Pengfei; Peters, Jeffrey M; Amin, Shantu

2010-07-15

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors and members of the nuclear hormone receptor superfamily. Herein, we describe an efficient synthesis of a novel isosteric selenium analog of the highly specific PPARbeta/delta ligand 2-methyl-4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl)-methylsulfanyl)phenoxy-acetic acid (GW501516; 1). The study examined the efficiency of the novel selenium analog 2-methyl-4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-selenazol-5-yl)-methylsulfanyl)phenoxy-acetic acid (2) to activate PPARbeta/delta and the effect of ligand activation of PPARbeta/delta on cell proliferation and target gene expression in human HaCaT keratinocytes. The results showed that similar to GW501516, the Se-analog 2 increased expression of the known PPARbeta/delta target gene angiopoietin-like protein 4 (ANGPTL4); the compound 2 was comparable in efficacy as compared to GW501516. Consistent with a large body of evidence, the Se-analog inhibited cell proliferation in HaCaT keratinocytes similar to that observed with GW501516. In summary, the novel Se-analog 2 has been developed as a potent PPARbeta/delta ligand that may possess additional anti-cancer properties of selenium. 2010 Elsevier Ltd. All rights reserved.

Overview of the Human Exploration Research Analog (HERA)

NASA Technical Reports Server (NTRS)

Neigut, J.

2015-01-01

In 2013, the Human Research Program at NASA began developing a new confinement analog specifically for conducting research to investigate the effects of confinement on the human system. The HERA (Human Exploration Research Analog) habitat has been used for both 7 and 14 day missions to date to examine and mitigate exploration risks to enable safe, reliable and productive human space exploration. This presentation will describe how the Flight Analogs Project developed the HERA facility and the infrastructure to suit investigator requirements for confinement research and in the process developed a new approach to analog utilization and a new state of the art analog facility. Details regarding HERA operations will be discussed including specifics on the mission simulation utilized for the current 14-day campaign, the specifics of the facility (total volume, overall size, hardware), and the capabilities available to researchers. The overall operational philosophy, mission fidelity including timeline, schedule pressures and cadence, and development and implementation of mission stressors will be presented. Research conducted to date in the HERA has addressed risks associated with behavioral health and performance, human physiology, as well as human factors. This presentation will conclude with a discussion of future research plans for the HERA, including infrastructure improvements and additional research capabilities planned for the upcoming 30-day missions in 2016.

Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2-mediated heparin-binding EGF signaling in endothelial cells.

PubMed

Svensson, Katrin J; Kucharzewska, Paulina; Christianson, Helena C; Sköld, Stefan; Löfstedt, Tobias; Johansson, Maria C; Mörgelin, Matthias; Bengzon, Johan; Ruf, Wolfram; Belting, Mattias

2011-08-09

Highly malignant tumors, such as glioblastomas, are characterized by hypoxia, endothelial cell (EC) hyperplasia, and hypercoagulation. However, how these phenomena of the tumor microenvironment may be linked at the molecular level during tumor development remains ill-defined. Here, we provide evidence that hypoxia up-regulates protease-activated receptor 2 (PAR-2), i.e., a G-protein-coupled receptor of coagulation-dependent signaling, in ECs. Hypoxic induction of PAR-2 was found to elicit an angiogenic EC phenotype and to specifically up-regulate heparin-binding EGF-like growth factor (HB-EGF). Inhibition of HB-EGF by antibody neutralization or heparin treatment efficiently counteracted PAR-2-mediated activation of hypoxic ECs. We show that PAR-2-dependent HB-EGF induction was associated with increased phosphorylation of ERK1/2, and inhibition of ERK1/2 phosphorylation attenuated PAR-2-dependent HB-EGF induction as well as EC activation. Tissue factor (TF), i.e., the major initiator of coagulation-dependent PAR signaling, was substantially induced by hypoxia in several types of cancer cells, including glioblastoma; however, TF was undetectable in ECs even at prolonged hypoxia, which precludes cell-autonomous PAR-2 activation through TF. Interestingly, hypoxic cancer cells were shown to release substantial amounts of TF that was mainly associated with secreted microvesicles with exosome-like characteristics. Vesicles derived from glioblastoma cells were found to trigger TF/VIIa-dependent activation of hypoxic ECs in a paracrine manner. We provide evidence of a hypoxia-induced signaling axis that links coagulation activation in cancer cells to PAR-2-mediated activation of ECs. The identified pathway may constitute an interesting target for the development of additional strategies to treat aggressive brain tumors.

Evolutionary divergence of phytochrome protein function in Zea mays PIF3 signaling.

PubMed

Kumar, Indrajit; Swaminathan, Kankshita; Hudson, Karen; Hudson, Matthew E

2016-07-01

Two maize phytochrome-interacting factor (PIF) basic helix-loop-helix (bHLH) family members, ZmPIF3.1 and ZmPIF3.2, were identified, cloned and expressed in vitro to investigate light-signaling interactions. A phylogenetic analysis of sequences of the maize bHLH transcription factor gene family revealed the extent of the PIF family, and a total of seven predicted PIF-encoding genes were identified from genes encoding bHLH family VIIa/b proteins in the maize genome. To investigate the role of maize PIFs in phytochrome signaling, full-length cDNAs for phytochromes PhyA2, PhyB1, PhyB2 and PhyC1 from maize were cloned and expressed in vitro as chromophorylated holophytochromes. We showed that ZmPIF3.1 and ZmPIF3.2 interact specifically with the Pfr form of maize holophytochrome B1 (ZmphyB1), showing no detectable affinity for the Pr form. Maize holophytochrome B2 (ZmphyB2) showed no detectable binding affinity for PIFs in either Pr or Pfr forms, but phyB Pfr from Arabidopsis interacted with ZmPIF3.1 similarly to ZmphyB1 Pfr. We conclude that subfunctionalization at the protein-protein interaction level has altered the role of phyB2 relative to that of phyB1 in maize. Since the phyB2 mutant shows photomorphogenic defects, we conclude that maize phyB2 is an active photoreceptor, without the binding of PIF3 seen in other phyB family proteins. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology.

Use of recombinant factor VIIA for control of combat-related haemorrhage.

PubMed

Woodruff, Susan I; Dougherty, Amber L; Dye, Judy L; Mohrle, Charlene R; Galarneau, Michael R

2010-02-01

Recombinant activated human coagulation factor VII (rFVIIa), an intravascular strategy to promote clotting, is being used as an adjunct to surgical control of bleeding in combat trauma patients. To describe the initial experiences with rFVIIa administered to combat casualties at US Navy-Marine Corps medical treatment facilities in Iraq, and to compare survival outcomes of those treated with rFVIIa to controls not receiving rFVIIa. Medical encounter data from the US Navy-Marine Corps Combat Trauma Registry were retrospectively reviewed to identify all battle-injured patients documented as having received rFVIIa during the period May 2004 to January 2006 of Operation Iraqi Freedom. Available clinical and injury related data are presented to characterise the patients. To assess effects of rFVIIa on survival outcomes, rFVIIa cases were matched to controls on injury severity and age. 22 battle-injured patients from the Combat Trauma Registry received rFVIIa. Primarily young US Marines, these patients typically had penetrating injuries from improvised explosive devices and gunshot wounds. Injuries were often abdominal. The average dose used was similar to that reported in another study of civilian trauma patients, although dosing varies widely in the existing experimental and anecdotal literature. Over two-thirds (68%) of the rFVIIa patients survived-an identical outcome seen for a matched control group of 22 patients. Survival of seriously injured combat casualties was good, although identical to that of a control group. Methodological limitations of this retrospective study preclude making firm conclusions about the effectiveness of rFVIIa. Future controlled studies are needed for safety and efficacy testing of rFVIIa in combat trauma patients.

Effect of a Rapidly Degrading Presolidified 10 kDa Chitosan/Blood Implant and Subchondral Marrow Stimulation Surgical Approach on Cartilage Resurfacing in a Sheep Model.

PubMed

Bell, Angela D; Hurtig, Mark B; Quenneville, Eric; Rivard, Georges-Étienne; Hoemann, Caroline D

2017-10-01

Objective This study tested the hypothesis that presolidified chitosan-blood implants are retained in subchondral bone channels perforated in critical-size sheep cartilage defects, and promote bone repair and hyaline-like cartilage resurfacing versus blood implant. Design Cartilage defects (10 × 10 mm) with 3 bone channels (1 drill, 2 Jamshidi biopsy, 2 mm diameter), and 6 small microfracture holes were created bilaterally in n = 11 sheep knee medial condyles. In one knee, 10 kDa chitosan-NaCl/blood implant (presolidified using recombinant factor VIIa or tissue factor), was inserted into each drill and Jamshidi hole. Contralateral knee defects received presolidified whole blood clot. Repair tissues were assessed histologically, biochemically, biomechanically, and by micro-computed tomography after 1 day ( n = 1) and 6 months ( n = 10). Results Day 1 defects showed a 60% loss of subchondral bone plate volume fraction along with extensive subchondral hematoma. Chitosan implant was resident at day 1, but had no effect on any subsequent repair parameter compared with blood implant controls. At 6 months, bone defects exhibited remodeling and hypomineralized bone repair and were partly resurfaced with tissues containing collagen type II and scant collagen type I, 2-fold lower glycosaminoglycan and fibril modulus, and 4.5-fold higher permeability compared with intact cartilage. Microdrill holes elicited higher histological ICRS-II overall assessment scores than Jamshidi holes (50% vs. 30%, P = 0.041). Jamshidi biopsy holes provoked sporadic osteonecrosis in n = 3 debrided condyles. Conclusions Ten kilodalton chitosan was insufficient to improve repair. Microdrilling is a feasible subchondral marrow stimulation surgical approach with the potential to elicit poroelastic tissues with at least half the compressive modulus as intact articular cartilage.

Safety and effectiveness of room temperature stable recombinant factor VIIa in patients with haemophilia A or B and inhibitors: Results of a multinational, prospective, observational study.

PubMed

Kavakli, K; Demartis, F; Karimi, M; Eshghi, P; Neme, D; Chambost, H; Sommer, L; Zak, M; Benson, G

2017-07-01

A room temperature stable formulation of recombinant activated factor VII (NovoSeven ® ), allowing convenient storage and therefore improved treatment access, has been developed. Bioequivalence to the previous NovoSeven ® was demonstrated in healthy humans, leading to European approval (2008). Although no confirmed cases of neutralising antibodies to rFVIIa in patients with haemophilia A or B have been observed with the original formulation, changes in formulation or storage condition may alter immunogenicity. SMART-7™ was designed to investigate the safety of NovoSeven ® in a real-world setting in patients with haemophilia A or B with inhibitors. Study medication was not provided by the sponsor, and treatment was at the discretion of the treating physician, in accordance with the local label. Patient baseline information was collected at enrolment. Information on safety, drug exposure and bleeding episodes was collected and FVII antibody screening was encouraged at baseline and performed at the investigator's discretion. Fifty-one patients were enrolled and 31 completed the study. Forty-one adverse events (AEs) were reported in 23 patients; 25 AEs in 14 patients were serious. No thromboembolic events were observed. Although four cases of reduced therapeutic response were reported, FVII antibody screening was negative. Forty-eight patients experienced 618 bleeding episodes and 93.4% of 609 evaluated bleeds were stopped by treatment. Of the 538 bleeding episodes treated with NovoSeven ® monotherapy, 94.2% stopped by end of treatment. Data collected during the SMART-7™ study revealed no treatment-related safety issues and no FVII-binding antibodies for patients treated with NovoSeven ® under real-world conditions. © 2017 John Wiley & Sons Ltd.

Management of Bleeding With Non-Vitamin K Antagonist Oral Anticoagulants in the Era of Specific Reversal Agents.

PubMed

Ruff, Christian T; Giugliano, Robert P; Antman, Elliott M

2016-07-19

Vitamin K antagonists are commonly used by clinicians to provide anticoagulation to patients who have or are at risk of having thrombotic events. In addition to familiarity with the dosing and monitoring of vitamin K antagonists, clinicians are accustomed to using vitamin K if there is a need to reverse the anticoagulant effect of vitamin K antagonists. There are now 4 new non-vitamin K antagonist oral anticoagulants (NOACs) that are attractive alternatives to vitamin K antagonists. Despite similar or lower rates of serious bleeding with NOACs in comparison with warfarin, there is a pressing need for strategies to manage bleeding when it does occur with NOACs and to reverse the pharmacological effect of these agents if needed. Important steps in minimizing bleeding risks with NOACs include dose adjustment of the agents in the setting of renal dysfunction and avoidance of the concomitant use of other antithrombotic agents if feasible. Laboratory measurement of the anticoagulant effect of NOACs is best accomplished with specialized assays, although some of the more widely available coagulation tests can provide information that is potentially useful to clinicians. Nonspecific hemostatic agents such as prothrombin complex concentrates and recombinant factor VIIa can be used to reverse the effect of NOACs. More specific reversing agents include the approved humanized monoclonal antibody fragment idarucizumab for reversing the effects of dabigatran, the investigational factor Xa decoy andexanet alfa, and the synthetic small molecule ciraparantag. Both andexanet and ciraparantag have been reported to reverse the effects of the anti-Xa NOACs (rivaroxaban, apixaban, and edoxaban), and a number of other anticoagulant agents in common clinical use, as well. © 2016 American Heart Association, Inc.

Effect of a Rapidly Degrading Presolidified 10 kDa Chitosan/Blood Implant and Subchondral Marrow Stimulation Surgical Approach on Cartilage Resurfacing in a Sheep Model

PubMed Central

Bell, Angela D.; Hurtig, Mark B.; Quenneville, Eric; Rivard, Georges-Étienne; Hoemann, Caroline D.

2016-01-01

Objective This study tested the hypothesis that presolidified chitosan-blood implants are retained in subchondral bone channels perforated in critical-size sheep cartilage defects, and promote bone repair and hyaline-like cartilage resurfacing versus blood implant. Design Cartilage defects (10 × 10 mm) with 3 bone channels (1 drill, 2 Jamshidi biopsy, 2 mm diameter), and 6 small microfracture holes were created bilaterally in n = 11 sheep knee medial condyles. In one knee, 10 kDa chitosan–NaCl/blood implant (presolidified using recombinant factor VIIa or tissue factor), was inserted into each drill and Jamshidi hole. Contralateral knee defects received presolidified whole blood clot. Repair tissues were assessed histologically, biochemically, biomechanically, and by micro–computed tomography after 1 day (n = 1) and 6 months (n = 10). Results Day 1 defects showed a 60% loss of subchondral bone plate volume fraction along with extensive subchondral hematoma. Chitosan implant was resident at day 1, but had no effect on any subsequent repair parameter compared with blood implant controls. At 6 months, bone defects exhibited remodeling and hypomineralized bone repair and were partly resurfaced with tissues containing collagen type II and scant collagen type I, 2-fold lower glycosaminoglycan and fibril modulus, and 4.5-fold higher permeability compared with intact cartilage. Microdrill holes elicited higher histological ICRS-II overall assessment scores than Jamshidi holes (50% vs. 30%, P = 0.041). Jamshidi biopsy holes provoked sporadic osteonecrosis in n = 3 debrided condyles. Conclusions Ten kilodalton chitosan was insufficient to improve repair. Microdrilling is a feasible subchondral marrow stimulation surgical approach with the potential to elicit poroelastic tissues with at least half the compressive modulus as intact articular cartilage. PMID:28934884

The combination of recombinant factor VIIa and fibrinogen correct clotting ex vivo in patient samples obtained following cardiopulmonary bypass surgery.

PubMed

Sørensen, Benny; Asvaldsdottir, Hanna S; Gudmundsdottir, Brynja R; Onundarson, Pall T

2009-12-01

Cardiac surgery involving cardio pulmonary bypass (CPB) may be associated with development of a coagulopathy that increases risk of bleeding. In the present ex vivo study we investigated the influence of fibrinogen and rFVIIa, alone or in combination, on whole blood coagulation thromboelastometry using pre- and postoperative blood samples from 18 consecutive adult patients undergoing CPB surgery. Dynamic thromboelastometric clotting profiles were recorded using citrated whole blood activated with trace amounts of tissue factor (Innovin, final dilution 1:17000). Blood samples were collected before surgery (control) and postoperative samples were obtained following in vivo neutralization of heparin with protamine sulphate. All blood samples were treated with heparinase to ensure neutralization of possible residual heparin effect. The post-operative blood samples were spiked with buffer, rFVIIa (2 microg/mL), fibrinogen (1 mg/mL), or the combination of rFVIIa and fibrinogen. Despite neutralization of heparin, CPB surgery left a measurable coagulopathy that was thromboelastometrically characterized by prolonged onset of clotting, reduced maximum velocity of clot formation (MaxVel), and decreased maximum clot firmness (MCF). Ex vivo spiking of the postoperative samples with rFVIIa shortened the clotting time. Fibrinogen also shortened the clotting time and, in addition, improved the MaxVel, and MCF. Finally, adding the combination of rFVIIa and fibrinogen to the postoperative samples corrected all thromboelastometric parameters to the preoperative range. In conclusion, the correction of whole blood clotting abnormalities that occurs with rFVIIa and/or fibrinogen suggests that future clinical trials on treatment of bleeding during CPB surgery should study the haemostatic effect of fibrinogen or possibly the combination of rFVIIa and fibrinogen.

Cyclic Nucleotide-gated Channel α-3 (CNGA3) Interacts with Stereocilia Tip-Link Cadherin 23 + Exon 68 or Alternatively with Myosin VIIa, Two Proteins Required for Hair Cell Mechanotransduction*

PubMed Central

Selvakumar, Dakshnamurthy; Drescher, Marian J.; Drescher, Dennis G.

2013-01-01

Previously, we obtained evidence for a photoreceptor/olfactory type of CNGA3 transcript in a purified teleost vestibular hair cell preparation with immunolocalization of CNGA3 protein to stereocilia of teleost vestibular and mammalian cochlear hair cells. The carboxyl terminus of highly Ca2+-permeable CNGA3 expressed in the mammalian organ of Corti and saccular hair cells was found to interact with an intracellular domain of microfibril interface-located protein 1 (EMILIN 1), a member of the elastin superfamily, also immunolocalizd to hair cell stereocilia (Selvakumar, D., Drescher, M. J., Dowdall, J. R., Khan, K. M., Hatfield, J. S., Ramakrishnan, N. A., and Drescher, D. G. (2012) Biochem. J. 443, 463–476). Here, we provide evidence for organ of Corti proteins, of Ca2+-dependent binding of the amino terminus of CNGA3 specifically to the carboxyl terminus of stereocilia tip-link protein CDH23 +68 (cadherin 23 with expressed exon 68) by yeast two-hybrid mating and co-transformation protocols, pulldown assays, and surface plasmon resonance analysis. Myosin VIIa, required for adaptation of hair cell mechanotransduction (MET) channel(s), competed with CDH23 +68, with direct Ca2+-dependent binding to the amino terminus of CNGA3. Based upon the premise that hair cell stereocilia tip-link proteins are closely coupled with MET, these results are consistent with the possibility that CNGA3 participates in hair-cell MET. Together with the demonstration of protein-protein interaction between HCN1 and tip-link protein protocadherin 15 CD3 (Ramakrishnan, N. A., Drescher, M. J., Barretto, R. L., Beisel, K. W., Hatfield, J. S., and Drescher, D. G. (2009) J. Biol. Chem. 284, 3227–3238; Ramakrishnan, N. A., Drescher, M. J., Khan, K. M., Hatfield, J. S., and Drescher, D. G. (2012) J. Biol. Chem. 287, 37628–37646), a protein-protein interaction for CNGA3 and a second tip-link protein, CDH23 +68, further suggests possible association of two different channels with a single stereocilia tip link. PMID:23329832

Cyclic nucleotide-gated channel α-3 (CNGA3) interacts with stereocilia tip-link cadherin 23 + exon 68 or alternatively with myosin VIIa, two proteins required for hair cell mechanotransduction.

PubMed

Selvakumar, Dakshnamurthy; Drescher, Marian J; Drescher, Dennis G

2013-03-08

Previously, we obtained evidence for a photoreceptor/olfactory type of CNGA3 transcript in a purified teleost vestibular hair cell preparation with immunolocalization of CNGA3 protein to stereocilia of teleost vestibular and mammalian cochlear hair cells. The carboxyl terminus of highly Ca(2+)-permeable CNGA3 expressed in the mammalian organ of Corti and saccular hair cells was found to interact with an intracellular domain of microfibril interface-located protein 1 (EMILIN 1), a member of the elastin superfamily, also immunolocalizd to hair cell stereocilia (Selvakumar, D., Drescher, M. J., Dowdall, J. R., Khan, K. M., Hatfield, J. S., Ramakrishnan, N. A., and Drescher, D. G. (2012) Biochem. J. 443, 463-476). Here, we provide evidence for organ of Corti proteins, of Ca(2+)-dependent binding of the amino terminus of CNGA3 specifically to the carboxyl terminus of stereocilia tip-link protein CDH23 +68 (cadherin 23 with expressed exon 68) by yeast two-hybrid mating and co-transformation protocols, pulldown assays, and surface plasmon resonance analysis. Myosin VIIa, required for adaptation of hair cell mechanotransduction (MET) channel(s), competed with CDH23 +68, with direct Ca(2+)-dependent binding to the amino terminus of CNGA3. Based upon the premise that hair cell stereocilia tip-link proteins are closely coupled with MET, these results are consistent with the possibility that CNGA3 participates in hair-cell MET. Together with the demonstration of protein-protein interaction between HCN1 and tip-link protein protocadherin 15 CD3 (Ramakrishnan, N. A., Drescher, M. J., Barretto, R. L., Beisel, K. W., Hatfield, J. S., and Drescher, D. G. (2009) J. Biol. Chem. 284, 3227-3238; Ramakrishnan, N. A., Drescher, M. J., Khan, K. M., Hatfield, J. S., and Drescher, D. G. (2012) J. Biol. Chem. 287, 37628-37646), a protein-protein interaction for CNGA3 and a second tip-link protein, CDH23 +68, further suggests possible association of two different channels with a single stereocilia tip link.

Design of a fiber-optic transmitter for microwave analog transmission with high phase stability

NASA Technical Reports Server (NTRS)

Logan, R. T., Jr.; Lutes, G. F.; Primas, L. E.; Maleki, L.

1990-01-01

The principal considerations in the design of fiber-optic transmitters for highly phase-stable radio frequency and microwave analog transmission are discussed. Criteria for a fiber-optic transmitter design with improved amplitude and phase-noise performance are developed through consideration of factors affecting the phase noise, including low-frequency laser-bias supply noise, the magnitude and proximity of external reflections into the laser, and temperature excursions of the laser-transmitter package.

Analog self-powered harvester achieving switching pause control to increase harvested energy

NASA Astrophysics Data System (ADS)

Makihara, Kanjuro; Asahina, Kei

2017-05-01

In this paper, we propose a self-powered analog controller circuit to increase the efficiency of electrical energy harvesting from vibrational energy using piezoelectric materials. Although the existing synchronized switch harvesting on inductor (SSHI) method is designed to produce efficient harvesting, its switching operation generates a vibration-suppression effect that reduces the harvested levels of electrical energy. To solve this problem, the authors proposed—in a previous paper—a switching method that takes this vibration-suppression effect into account. This method temporarily pauses the switching operation, allowing the recovery of the mechanical displacement and, therefore, of the piezoelectric voltage. In this paper, we propose a self-powered analog circuit to implement this switching control method. Self-powered vibration harvesting is achieved in this study by attaching a newly designed circuit to an existing analog controller for SSHI. This circuit aims to effectively implement the aforementioned new switching control strategy, where switching is paused in some vibration peaks, in order to allow motion recovery and a consequent increase in the harvested energy. Harvesting experiments performed using the proposed circuit reveal that the proposed method can increase the energy stored in the storage capacitor by a factor of 8.5 relative to the conventional SSHI circuit. This proposed technique is useful to increase the harvested energy especially for piezoelectric systems having large coupling factor.

Somatostatin analogs regress endometriotic implants in rats by decreasing implant levels of vascular endothelial growth factor and matrix metaloproteinase 9.

PubMed

Sevket, Osman; Sevket, Asli; Molla, Taner; Buyukpınarbasılı, Nur; Uysal, Omer; Yılmaz, Bulent; Dane, Banu; Kelekcı, Sefa

2013-06-01

To examine the effect of somatostatin analogs on surgically induced endometriosis in rat models. Endometrial tissue was implanted onto the abdominal peritoneum of 26 rats that were randomized into 3 groups. The rats in group 1(n = 9) were subcutaneously administered with 0.02 mg/kg/d of octreotide (a short-acting analog)for 28 days . The rats in group 2 (n = 8) were subcutaneously injected with 20 mg/kg of a single dose of a long-acting analogue lanreotide The rats in group 3 were given no medication and served as controls (n = 9). Mean volume and histologic score of implants in groups 1 (P < .01 and P < .05, respectively) and 2 (P < .01and P < .05, respectively) were significantly lower than that in group 3. There were significant reductions in vascular endothelial growth factor (VEGF) and matrix metalloproteinase 9 (MMP-9) immunoreactivities in group 1 (0.67 ± 0.50 and 1.22 ± 0.44, respectively; both P < .01) and group 2 (0.71 ± 0.48 and 0.86 ± 0.69, respectively; both P < .01) when compared with the control group (1.78 ± 0.83 and 2.11 ± 0.78, respectively). Somatostatin analogs has regressed significantly the size of the endometriotic implants and caused atrophy of these lesions in rats by decreasing explant levels of VEGF and MMP-9.

Costs and utilization of hemophilia A and B patients with and without inhibitors.

PubMed

Armstrong, Edward P; Malone, Daniel C; Krishnan, Sangeeta; Wessler, Maj Jacob

2014-11-01

To evaluate the health system costs among patients with hemophilia A and B with and without inhibitors over 5 years. This was a retrospective, observational study utilizing medical and pharmacy electronic medical records and administrative encounters/claims data tracking US patients between 2006-2011. Patients with diagnosis codes for hemophilia A and B were identified. Patients with inhibitors were characterized by utilization of bypassing agents activated prothrombin complex concentrate or factor VIIa on two or more distinct dates. Severity was classified as mild, moderate, or severe based on laboratory tests of clotting factor. There were 160 hemophilia A patients and 54 hemophilia B patients identified. From this group, seven were designated as patients with inhibitors (five with hemophilia A and two with hemophilia B). Hemophilia A patients without inhibitors reported 65 (41.9%) as being severe, 19 (12.3%) as moderate, and 71 (45.8%) as mild. Hemophilia B patients without inhibitors reported nine (17.3%) had severe, 13 (25.0%) had moderate, and 30 (57.7%) had mild hemophilia. All patients with inhibitors had been hospitalized in the previous 5 years compared to 64 (41.3%) with hemophilia A without inhibitors and 22 (42.3%) with hemophilia B without inhibitors. The median aggregate cost per year (including factor and health resource use) was $325,780 for patients with inhibitors compared to $98,334 for hemophilia A patients without inhibitors and $23,265 for hemophilia B patients without inhibitors. The results suggest that, while the frequency of inhibitors within the hemophilia cohort was low, there was a higher frequency of hospitalizations, and the associated median aggregate costs per year were 3-fold higher than those patients without inhibitors. In contrast, hemophilia B patients experience less severe disease and account for lower aggregate yearly costs compared to either patients with hemophilia A or patients with inhibitors.

Embryotrophic factor-3 from human oviductal cells affects the messenger RNA expression of mouse blastocyst.

PubMed

Lee, Y L; Lee, K F; Xu, J S; Kwok, K L; Luk, J M; Lee, W M; Yeung, W S B

2003-02-01

Our previous results showed that embryotrophic factor-3 (ETF-3) from human oviductal cells increased the size and hatching rate of mouse blastocysts in vitro. The present study investigated the production of ETF-3 by an immortalized human oviductal cell line (OE-E6/E7) and the effects of ETF-3 on the mRNA expression of mouse embryos. The ETF-3 was purified from primary oviductal cell conditioned media using sequential liquid chromatographic systems, and antiserum against ETF-3 was raised. The ETF-3-supplemented Chatot-Ziomek-Bavister medium was used to culture Day 1 MF1 x BALB/c mouse embryos for 4 days. The ETF-3 treatment significantly enhanced the mouse embryo blastulation and hatching rate. The antiserum, at concentrations of 0.03-3%, abolished the embryotrophic effect of ETF-3. Positive ETF-3 immunoreactivity was detected in the primary oviductal cells, OE-E6/E7, and blastocysts derived from ETF-3 treatment. Vero cells (African Green Monkey kidney cell line), fibroblasts, and embryos cultured in control medium did not possess ETF-3 immunoreactivity. The mRNA expression patterns of the treated embryos were studied at the blastocyst stage by mRNA differential display reverse transcription-polymerase chain reaction (DDRT-PCR). The DDRT-PCR showed that some of the mRNAs were differentially expressed after ETF-3 treatment. Twelve of the differentially expressed mRNAs that had high homology with cDNA sequences in the GenBank were selected for further characterization. The differential expression of seven of these mRNAs (ezrin, heat shock 70-kDa protein, cytochrome c oxidase subunit VIIa-L precursor, proteinase-activated receptor 2, eukaryotic translation initiation factor 2beta, cullin 1, and proliferating cell nuclear antigen) was confirmed by semiquantitative RT-PCR. In conclusion, immortalized oviductal cells produce ETF-3, which influences mRNA expression of mouse blastocyst.

Correcting thrombin generation ex vivo using different haemostatic agents following cardiac surgery requiring the use of cardiopulmonary bypass.

PubMed

Percy, Charles L; Hartmann, Rudolf; Jones, Rhidian M; Balachandran, Subramaniam; Mehta, Dheeraj; Dockal, Michael; Scheiflinger, Friedrich; O'Donnell, Valerie B; Hall, Judith E; Collins, Peter W

2015-06-01

Recently, lower thrombin generation has been associated with excess bleeding post-cardiopulmonary bypass (CPB). Therefore, treatment to correct thrombin generation is a potentially important aspect of management of bleeding in this group of patients. The objective of the present study was to investigate the effects of fresh frozen plasma (FFP), recombinant factor VIIa (rFVIIa), prothrombin complex concentrate (PCC) and tissue factor pathway inhibitor (TFPI) inhibition on thrombin generation when added ex vivo to the plasma of patients who had undergone cardiac surgery requiring CPB. Patients undergoing elective cardiac surgery were recruited. Blood samples were collected before administration of heparin and 30 min after its reversal. Thrombin generation was measured in the presence and absence of different concentrations of FFP, rFVIIa, PCC and an anti-TFPI antibody. A total of 102 patients were recruited. Thrombin generation following CPB was lower compared with pre-CPB (median endogenous thrombin potential pre-CPB 339 nmol/l per min, post-CPB 155 nmol/l per min, P < 0.0001; median peak thrombin pre-CPB 35 nmol/l, post-CPB 11 nmol/l, P < 0.0001). Coagulation factors and anticoagulants decreased, apart from total TFPI, which increased (55-111 ng/ml, P < 0.0001), and VWF (144-170 IU/dl, P < 0.0001). Thrombin generation was corrected to pre-CPB levels by the equivalent of 15 ml/kg FFP, 45 μg/kg rFVIIa and 25 U/kg of PCC. Inhibition of TFPI resulted in an enhancement of thrombin generation significantly beyond pre-CPB levels. This study shows that FFP, rFVIIa, PCC and inhibition of TFPI correct thrombin generation in the plasma of patients who have undergone surgery requiring CPB. Inhibition of TFPI may be a further potential therapeutic strategy for managing bleeding in this group of patients.

The ESA-NASA 'CHOICE' Study: Winterover at Concordia Station, Interior Antarctica, as an Analog for Spaceflight-Associated Immune Dysregu1ation

NASA Technical Reports Server (NTRS)

Crucian, Brian E,; Feuerecker, M.; Salam, A. P.; Rybka, A.; Stowe, R. P.; Morrels, M.; Mehta, S. K.; Quiriarte, H.; Quintens, Roel; Thieme, U.;

75 FR 26904 - Mandatory Reporting of Greenhouse Gases: Notice of Data Availability; Default Emission Factors...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-13

... mass of each fluorinated GHG by-product formed as a fraction of the mass of the dominant fluorinated... factors that account for gas utilization and by-product formation for multi-gas chemistries. X The...-product formation factors. X Alternatives to the analogies EPA used to assign gas utilization and by...

Synthesis, properties, and biological activity of boranophosphate analogs of the mRNA cap: versatile tools for manipulation of therapeutically relevant cap-dependent processes

PubMed Central

Kowalska, Joanna; Wypijewska del Nogal, Anna; Darzynkiewicz, Zbigniew M.; Buck, Janina; Nicola, Corina; Kuhn, Andreas N.; Lukaszewicz, Maciej; Zuberek, Joanna; Strenkowska, Malwina; Ziemniak, Marcin; Maciejczyk, Maciej; Bojarska, Elzbieta; Rhoads, Robert E.; Darzynkiewicz, Edward; Sahin, Ugur; Jemielity, Jacek

2014-01-01

Modified mRNA cap analogs aid in the study of mRNA-related processes and may enable creation of novel therapeutic interventions. We report the synthesis and properties of 11 dinucleotide cap analogs bearing a single boranophosphate modification at either the α-, β- or γ-position of the 5′,5′-triphosphate chain. The compounds can potentially serve either as inhibitors of translation in cancer cells or reagents for increasing expression of therapeutic proteins in vivo from exogenous mRNAs. The BH3-analogs were tested as substrates and binding partners for two major cytoplasmic cap-binding proteins, DcpS, a decapping pyrophosphatase, and eIF4E, a translation initiation factor. The susceptibility to DcpS was different between BH3-analogs and the corresponding analogs containing S instead of BH3 (S-analogs). Depending on its placement, the boranophosphate group weakened the interaction with DcpS but stabilized the interaction with eIF4E. The first of the properties makes the BH3-analogs more stable and the second, more potent as inhibitors of protein biosynthesis. Protein expression in dendritic cells was 2.2- and 1.7-fold higher for mRNAs capped with m27,2′-OGppBH3pG D1 and m27,2′-OGppBH3pG D2, respectively, than for in vitro transcribed mRNA capped with m27,3′-OGpppG. Higher expression of cancer antigens would make mRNAs containing m27,2′-OGppBH3pG D1 and m27,2′-OGppBH3pG D2 favorable for anticancer immunization. PMID:25150148

Associations of activated coagulation factor VII and factor VIIa-antithrombin levels with genome-wide polymorphisms and cardiovascular disease risk.

PubMed

Olson, N C; Raffield, L M; Lange, L A; Lange, E M; Longstreth, W T; Chauhan, G; Debette, S; Seshadri, S; Reiner, A P; Tracy, R P

2018-01-01

Essentials A fraction of coagulation factor VII circulates in blood as an activated protease (FVIIa). We evaluated FVIIa and FVIIa-antithrombin (FVIIa-AT) levels in the Cardiovascular Health Study. Polymorphisms in the F7 and PROCR loci were associated with FVIIa and FVIIa-AT levels. FVIIa may be an ischemic stroke risk factor in older adults and FVIIa-AT may assess mortality risk. Background A fraction of coagulation factor (F) VII circulates as an active protease (FVIIa). FVIIa also circulates as an inactivated complex with antithrombin (FVIIa-AT). Objective Evaluate associations of FVIIa and FVIIa-AT with genome-wide single nucleotide polymorphisms (SNPs) and incident coronary heart disease, ischemic stroke and mortality. Patients/Methods We measured FVIIa and FVIIa-AT in 3486 Cardiovascular Health Study (CHS) participants. We performed a genome-wide association scan for FVIIa and FVIIa-AT in European-Americans (n = 2410) and examined associations of FVII phenotypes with incident cardiovascular disease. Results In European-Americans, the most significant SNP for FVIIa and FVIIa-AT was rs1755685 in the F7 promoter region on chromosome 13 (FVIIa, β = -25.9 mU mL -1 per minor allele; FVIIa-AT, β = -26.6 pm per minor allele). Phenotypes were also associated with rs867186 located in PROCR on chromosome 20 (FVIIa, β = 7.8 mU mL -1 per minor allele; FVIIa-AT, β = 9.9 per minor allele). Adjusted for risk factors, a one standard deviation higher FVIIa was associated with increased risk of ischemic stroke (hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.01, 1.23). Higher FVIIa-AT was associated with mortality from all causes (HR, 1.08; 95% CI, 1.03, 1.12). Among European-American CHS participants the rs1755685 minor allele was associated with lower ischemic stroke (HR, 0.69; 95% CI, 0.54, 0.88), but this association was not replicated in a larger multi-cohort analysis. Conclusions The results support the importance of the F7 and PROCR loci in variation in circulating FVIIa and FVIIa-AT. The findings suggest FVIIa is a risk factor for ischemic stroke in older adults, whereas higher FVIIa-AT may reflect mortality risk. © 2017 International Society on Thrombosis and Haemostasis.

The use of UV, FT-IR and Raman spectra for the identification of the newest penem analogs: solutions based on mathematic procedure and the density functional theory.

PubMed

Cielecka-Piontek, J; Lewandowska, K; Barszcz, B; Paczkowska, M

2013-02-15

The application of ultraviolet, FT-IR and Raman spectra was proposed for identification studies of the newest penem analogs (doripenem, biapenem and faropenem). An identification of the newest penem analogs based on their separation from related substances was achieved after the application of first derivative of direct spectra in ultraviolet which permitted elimination of overlapping effects. A combination of experimental and theoretical studies was performed for analyzing the structure and vibrational spectra (FT-IR and Raman spectra) of doripenem, biapenem and faropenem. The calculations were conducted using the density functional theory with the B3LYP hybrid functional and 6-31G(d,p) basis set. The confirmation of the applicability of the DFT methodology for interpretation of vibrational IR and Raman spectra of the newest penem analogs contributed to determination of changes of vibrations in the area of the most labile bonds. By employing the theoretical approach it was possible to eliminate necessity of using reference standards which - considering the instability of penem analogs - require that correction coefficients are factored in. Copyright © 2012 Elsevier B.V. All rights reserved.

In vivo testing of Renilla luciferase substrate analogs in an orthotopic murine model of human glioblastoma.

PubMed

Otto-Duessel, Maya; Khankaldyyan, Vazgen; Gonzalez-Gomez, Ignacio; Jensen, Michael C; Laug, Walter E; Rosol, Michael

2006-01-01

In vivo bioluminescent imaging using cells expressing Renilla luciferase is becoming increasingly common. Hindrances to the more widespread use of Renilla luciferase are the high autoluminescence of its natural substrate, coelenterazine, in plasma, the relatively high absorbance by tissue of the light emitted by the enzyme-substrate reaction; rapid clearance of the substrate; and significant cost. These factors, save for the cost, which has its own limiting effect on use, can combine to reduce the sensitivity of in vivo assays utilizing this reporter system, and methods of increasing light output or decreasing autoluminescence could be of great benefit. A number of analogs of coelenterazine are being investigated may accomplish one or both of these goals. In this study that we report on the testing of two new substrate analogs, EnduRen and ViViren, manufactured by Promega Corporation, in an orthotopic murine model of human glioblastoma expressing Renilla luciferase. We have tested these analogs in this cell line both in vitro and in vivo, and find that the substrate viviren results in significantly greater light output than the natural substrate or the other analog EnduRen. This new substrate could be valuable for studies where greater sensitivity is important.

Digitally controlled analog proportional-integral-derivative (PID) controller for high-speed scanning probe microscopy

NASA Astrophysics Data System (ADS)

Dukic, Maja; Todorov, Vencislav; Andany, Santiago; Nievergelt, Adrian P.; Yang, Chen; Hosseini, Nahid; Fantner, Georg E.

2017-12-01

Nearly all scanning probe microscopes (SPMs) contain a feedback controller, which is used to move the scanner in the direction of the z-axis in order to maintain a constant setpoint based on the tip-sample interaction. The most frequently used feedback controller in SPMs is the proportional-integral (PI) controller. The bandwidth of the PI controller presents one of the speed limiting factors in high-speed SPMs, where higher bandwidths enable faster scanning speeds and higher imaging resolution. Most SPM systems use digital signal processor-based PI feedback controllers, which require analog-to-digital and digital-to-analog converters. These converters introduce additional feedback delays which limit the achievable imaging speed and resolution. In this paper, we present a digitally controlled analog proportional-integral-derivative (PID) controller. The controller implementation allows tunability of the PID gains over a large amplification and frequency range, while also providing precise control of the system and reproducibility of the gain parameters. By using the analog PID controller, we were able to perform successful atomic force microscopy imaging of a standard silicon calibration grating at line rates up to several kHz.

Digitally controlled analog proportional-integral-derivative (PID) controller for high-speed scanning probe microscopy.

PubMed

Dukic, Maja; Todorov, Vencislav; Andany, Santiago; Nievergelt, Adrian P; Yang, Chen; Hosseini, Nahid; Fantner, Georg E

2017-12-01

Nearly all scanning probe microscopes (SPMs) contain a feedback controller, which is used to move the scanner in the direction of the z-axis in order to maintain a constant setpoint based on the tip-sample interaction. The most frequently used feedback controller in SPMs is the proportional-integral (PI) controller. The bandwidth of the PI controller presents one of the speed limiting factors in high-speed SPMs, where higher bandwidths enable faster scanning speeds and higher imaging resolution. Most SPM systems use digital signal processor-based PI feedback controllers, which require analog-to-digital and digital-to-analog converters. These converters introduce additional feedback delays which limit the achievable imaging speed and resolution. In this paper, we present a digitally controlled analog proportional-integral-derivative (PID) controller. The controller implementation allows tunability of the PID gains over a large amplification and frequency range, while also providing precise control of the system and reproducibility of the gain parameters. By using the analog PID controller, we were able to perform successful atomic force microscopy imaging of a standard silicon calibration grating at line rates up to several kHz.

Compact SPAD-Based Pixel Architectures for Time-Resolved Image Sensors

PubMed Central

Perenzoni, Matteo; Pancheri, Lucio; Stoppa, David

2016-01-01

This paper reviews the state of the art of single-photon avalanche diode (SPAD) image sensors for time-resolved imaging. The focus of the paper is on pixel architectures featuring small pixel size (<25 μm) and high fill factor (>20%) as a key enabling technology for the successful implementation of high spatial resolution SPAD-based image sensors. A summary of the main CMOS SPAD implementations, their characteristics and integration challenges, is provided from the perspective of targeting large pixel arrays, where one of the key drivers is the spatial uniformity. The main analog techniques aimed at time-gated photon counting and photon timestamping suitable for compact and low-power pixels are critically discussed. The main features of these solutions are the adoption of analog counting techniques and time-to-analog conversion, in NMOS-only pixels. Reliable quantum-limited single-photon counting, self-referenced analog-to-digital conversion, time gating down to 0.75 ns and timestamping with 368 ps jitter are achieved. PMID:27223284

Chronobiology of Takotsubo Syndrome and Myocardial Infarction: Analogies and Differences.

PubMed

Manfredini, Roberto; Manfredini, Fabio; Fabbian, Fabio; Salmi, Raffaella; Gallerani, Massimo; Bossone, Eduardo; Deshmukh, Abhishek J

2016-10-01

Several pathophysiologic factors, not harmful if taken alone, are capable of triggering unfavorable events when presenting together within the same temporal window (chronorisk), and the occurrence of many cardiovascular events is not evenly distributed in time. Both acute myocardial infarction and takotsubo syndrome seem to exhibit a temporal preference in their onset, characterized by variations according to time of day, day of the week, and month of the year, although with both analogies and differences. Copyright © 2016 Elsevier Inc. All rights reserved.

Impact of Linearity and Write Noise of Analog Resistive Memory Devices in a Neural Algorithm Accelerator

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jacobs-Gedrim, Robin B.; Agarwal, Sapan; Knisely, Kathrine E.

Resistive memory (ReRAM) shows promise for use as an analog synapse element in energy-efficient neural network algorithm accelerators. A particularly important application is the training of neural networks, as this is the most computationally-intensive procedure in using a neural algorithm. However, training a network with analog ReRAM synapses can significantly reduce the accuracy at the algorithm level. In order to assess this degradation, analog properties of ReRAM devices were measured and hand-written digit recognition accuracy was modeled for the training using backpropagation. Bipolar filamentary devices utilizing three material systems were measured and compared: one oxygen vacancy system, Ta-TaO x, andmore » two conducting metallization systems, Cu-SiO 2, and Ag/chalcogenide. Analog properties and conductance ranges of the devices are optimized by measuring the response to varying voltage pulse characteristics. Key analog device properties which degrade the accuracy are update linearity and write noise. Write noise may improve as a function of device manufacturing maturity, but write nonlinearity appears relatively consistent among the different device material systems and is found to be the most significant factor affecting accuracy. As a result, this suggests that new materials and/or fundamentally different resistive switching mechanisms may be required to improve device linearity and achieve higher algorithm training accuracy.« less

Impact of Linearity and Write Noise of Analog Resistive Memory Devices in a Neural Algorithm Accelerator

DOE PAGES

Jacobs-Gedrim, Robin B.; Agarwal, Sapan; Knisely, Kathrine E.; ...

2017-12-01

Resistive memory (ReRAM) shows promise for use as an analog synapse element in energy-efficient neural network algorithm accelerators. A particularly important application is the training of neural networks, as this is the most computationally-intensive procedure in using a neural algorithm. However, training a network with analog ReRAM synapses can significantly reduce the accuracy at the algorithm level. In order to assess this degradation, analog properties of ReRAM devices were measured and hand-written digit recognition accuracy was modeled for the training using backpropagation. Bipolar filamentary devices utilizing three material systems were measured and compared: one oxygen vacancy system, Ta-TaO x, andmore » two conducting metallization systems, Cu-SiO 2, and Ag/chalcogenide. Analog properties and conductance ranges of the devices are optimized by measuring the response to varying voltage pulse characteristics. Key analog device properties which degrade the accuracy are update linearity and write noise. Write noise may improve as a function of device manufacturing maturity, but write nonlinearity appears relatively consistent among the different device material systems and is found to be the most significant factor affecting accuracy. As a result, this suggests that new materials and/or fundamentally different resistive switching mechanisms may be required to improve device linearity and achieve higher algorithm training accuracy.« less

Not So Fast: Inflation in Impact Factors Contributes to Apparent Improvements in Journal Quality

ERIC Educational Resources Information Center

Neff, Bryan D.; Olden, Julian D.

2010-01-01

The Institute for Scientific Information (ISI) impact factor has become an important standard for assessing journal quality. Here we propose that impact factors may be subject to inflation analogous to changes in monetary prices in economics. The possibility of inflation came to light as a result of the observation that papers published today tend…

The Kinetic Effects on Thymidine Kinase 2 by Enzyme-Bound dTTP May Explain the Mitochondrial Side Effects of Antiviral Thymidine Analogs▿†

PubMed Central

Wang, Liya; Sun, Ren; Eriksson, Staffan

2011-01-01

Mitochondrial thymidine kinase 2 (TK2) is a key enzyme in the salvage of pyrimidine deoxynucleosides needed for mitochondrial DNA synthesis. TK2 phosphorylates thymidine (dThd), deoxycytidine (dCyd), and many other antiviral pyrimidine nucleoside analogs. Zidovudine (AZT) is the first nucleoside analog approved for anti-HIV therapy, and it is still used in combination with other drugs. One of the side effects of long-term treatment with nucleoside analogs is mitochondrial DNA depletion, which has been ascribed to competition by AZT for the endogenous dThd phosphorylation carried out by TK2. Here we studied the kinetics of AZT and 3′-fluorothymidine phosphorylation by recombinant human TK2 and the effects of these and other pyrimidine nucleoside analogs on the phosphorylation of dThd and dCyd. Thymidine analogs strongly inhibited dThd phosphorylation but not dCyd phosphorylation, which instead was stimulated ∼30%. We found that recombinant human TK2 contained the feedback inhibitor dTTP in a 1:1 molar ratio and that incubation with dThd and AZT could completely remove the enzyme-bound dTTP, but dCyd was less efficient in this regard. The release of feedback inhibitor by dThd and dThd analogs most likely accounts for the observed kinetics. Similar effects were also observed with native rat liver mitochondrial TK2, strongly indicating a physiologic role for this process, which most likely is an important factor in the mitochondrial toxicity observed with antiviral nucleoside analogs. PMID:21444706

Assessing Underreporting Response Bias on the MMPI-2

ERIC Educational Resources Information Center

Bagby, R. Michael; Marshall, Margarita B.

2004-01-01

The authors assess the replicability of the two-factor model of underreporting response style. They then examine the relative performance of scales measuring these styles in analog (ARD) and differential prevalence group (DPG) designs. Principal components analysis produced a two-factor structure corresponding to self-deceptive (SD) and impression…

Andrographolide, a New Hope in the Prevention and Treatment of Metabolic Syndrome.

PubMed

Islam, Muhammad T

2017-01-01

Recently, the use of plant-derived medicines is increasing interest in the prevention and treatment of a variety of disorders including metabolic syndromes. Metabolic syndrome is one of the major risk factors for cardiovascular diseases (CVDs) and incidence of mortality worldwide. Scientific evidence suggests that Andrographis paniculata and its derived components, especially andrographolide (AGL) and its analogs/derivatives have a broad spectrum of biological activities. This review aims to sketch the activity of AGL and its analogs/derivatives against the components of metabolic syndromes such as diabetes, hyperlipidemia, hypertension, and obesity. Additionally, AGL activity against CVDs is also summarized. The finding suggests that AGL and its analogs/derivatives have a potential role in the management of metabolic syndrome; however, more studies should be conducted to evaluate their effectiveness.

A Budget Impact Model of Hemophilia Bypassing Agent Prophylaxis Relative to Recombinant Factor VIIa On-Demand.

PubMed

Mehta, Darshan A; Oladapo, Abiola O; Epstein, Joshua D; Novack, Aaron R; Neufeld, Ellis J; Hay, Joel W

2016-02-01

Hemophilia patients use factor-clotting concentrates (factor VIII for hemophilia A and factor IX for hemophilia B) for improved blood clotting. These products are used to prevent or stop bleeding episodes. However, some hemophilia patients develop inhibitors (i.e., the patient's immune system develops antibodies against these factor concentrates). Hence, these patients do not respond well to the factor concentrates. A majority of hemophilia patients with inhibitors are managed on-demand with the following bypassing agents: recombinant factor VIIa (rFVIIa) and activated prothrombin complex concentrate (aPCC). The recently published U.S. registries Dosing Observational Study in Hemophilia (DOSE) and Hemostasis and Thrombosis Research Society (HTRS) reported higher rFVIIa on-demand use for bleed management than previously described. To estimate aPCC and rFVIIa prophylaxis costs relative to rFVIIa on-demand treatment cost based on rFVIIa doses reported in U.S. registries. A literature-based cost model was developed assuming a base case on-demand annual bleed rate (ABR) of 28.7 per inhibitor patient, which was taken from a randomized phase 3 clinical trial. The doses for rFVIIa on-demand were taken from the median dose per bleed reported by the DOSE and HTRS registries. Model inputs for aPCC and rFVIIa prophylaxis (i.e., dosing and efficacy) were derived from respective randomized clinical trials. Cost analysis was from the U.S. payer perspective, and only direct drug costs were considered. The drug cost was based on the Medicare Part B 2014 average sale price (ASP). Two-way sensitivity and threshold analyses were performed by simultaneously varying on-demand ABR, prophylaxis efficacy, and unit drug cost. In addition to studying relative costs associated with on-demand and prophylaxis treatments, relative cost per bleeding episode avoided were also calculated for aPCC and rFVIIa prophylaxis treatments. The prophylaxis efficacy reported in the trials were used to determine the number of bleeding episodes avoided. Based on the median on-demand dose of 695 mcg per kg per bleed, reported by the DOSE registry, the annual rFVIIa on-demand cost was $34,009 per kg of body weight. The annual rFVIIa on-demand cost was $22,020 per kg of body weight when the median dose of 450 mcg per kg per bleed reported by the HTRS registry was considered. The annual cost rose to $38,461 per kg of body weight when the rFVIIa on-demand dose of 786 mcg per kg per bleed among patients infusing an initial dose ≥ 250 mcg per kg was considered. The aPCC (85 units per kg per every other day) and rFVIIa (90 mcg per kg per every day) annual prophylaxis costs were $26,536 and $60,700, respectively. Also, aPCC and rFVIIa prophyaxis treatments were estimated to prevent a total of 20.8 and 12.9 annual bleeding episodes, respectively. When compared with the on-demand dose of 695 mcg per kg per bleed (DOSE registry), the annual aPCC and rFVIIa prophylaxis costs were 21.9% lower and 78.4% higher, respectively. Additionally, aPCC prophylaxis saved $360 per kg for each bleeding episode avoided. rFVIIa prophylaxis cost $2,066 per kg for each bleeding episode avoided. Compared with the on-demand dose of 450 mcg per kg per bleed (HTRS registry), aPCC and rFVIIa prophylaxis costs were 20.5% and 174.9% higher, respectively. In this case, aPCC and rFVIIa prophylaxis treatment costs were $217 per kg and $2,995 per kg, respectively, for each bleeding episode avoided. aPCC and rFVIIa prophylaxis costs were 31.0% lower and 57.8% higher, respectively, when compared with the rFVIIa on-demand dose of 786 mcg per kg per bleed, among patients infusing an initial dose ≥ 250 mcg per kg (HTRS registry). In this case, aPCC prophylaxis saved $573 per kg for each bleeding episode avoided, while rFVIIa prophylaxis costs $1,724 per kg for each bleeding episode avoided. Results of the 2-way sensitivity analyses were robust in the majority of the scenarios considered. aPCC prophylaxis may be cost saving for managing hemophilia patients with inhibitors who bleed frequently and infuse significant quantities of rFVIIa on-demand.

Assessing efficacy and therapeutic claims in emerging indications for recombinant factor VIIa: regulatory perspectives.

PubMed

Farrugia, Albert

2006-01-01

When compared with the evidence-based, cost-effectiveness criteria underpinning most government reimbursement schemes in the social market economies, the three regulatory hurdles of safety, quality and efficacy are probably of modest impact in influencing increased usage of recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark). Nevertheless, efficacy claims must be supported if regulatory approval is to be granted for the wider range of indications that have been proposed for rFVIIa. With the refinement of clinical trial designs over the past 40 years, the randomized controlled trial (RCT) has assumed the role of gold standard, providing the highest level of evidence for therapeutic efficacy. However, it is incorrect to assume that regulatory authorities give sole credence to RCTs in assessing claims. It is noteworthy that the indications already accepted for rFVIIa by international regulatory authorities--including the treatment of inhibitors to factor VIII and factor IX, substitution for FVII deficiency, and treatment of Glanzmann's thrombasthenia--were supported not by RCTs but by studies conventionally considered to provide modest evidence levels. Therefore, the use of studies other than RCTs for the more recently proposed indications for rFVIIa in a range of conditions requiring hemostatic correction is perfectly feasible. What regulators expect are well-conducted and well-described studies adhering to principles of good clinical practice, which can be scrutinized for evidence of clinical efficacy and which are based on the initially proven principle for the drug. This paper discusses the regulatory history of rFVIIa in the major regulatory authorities and assesses the route needed to support claims being made in the mainstream literature. Recent episodes where post-market events have forced regulators to be more than usually cautious will be used as examples to suggest possible pitfalls to the extension of approved claims for rFVIIa. The major paths for enhancing access for indications in small patient numbers, where RCTs are even more difficult to perform, will be described and their use for possible extension of rFVIIa indications will be discussed.

Insulin analog preparations and their use in children and adolescents with type 1 diabetes mellitus.

PubMed

Miles, Harriet L; Acerini, Carlo L

2008-01-01

Standard or 'traditional' human insulin preparations such as regular soluble insulin and neutral protamine Hagedorn (NPH) insulin have shortcomings in terms of their pharmacokinetic and pharmacodynamic properties that limit their clinical efficacy. Structurally modified insulin molecules or insulin 'analogs' have been developed with the aim of delivering insulin replacement therapy in a more physiological manner. In the last 10 years, five insulin analog preparations have become commercially available for clinical use in patients with type 1 diabetes mellitus: three 'rapid' or fast-acting analogs (insulin lispro, aspart, and glulisine) and two long-acting analogs (insulin glargine and detemir). This review highlights the specific pharmacokinetic properties of these new insulin analog preparations and focuses on their potential clinical advantages and disadvantages when used in children and adolescents with type 1 diabetes mellitus. The fast-acting analogs specifically facilitate more flexible insulin injection timing with regard to meals and activities, whereas the long-acting analogs have a more predictable profile of action and lack a peak effect. To date, clinical trials in children and adolescents have been few in number, but the evidence available from these and from other studies carried out in adults with type 1 diabetes suggest that they offer significant benefits in terms of reduced frequency of nocturnal hypoglycemia, better postprandial blood glucose control, and improved quality of life when compared with traditional insulins. In addition, insulin detemir therapy is unique in that patients may benefit from reduced risk of excessive weight, particularly during adolescence. Evidence for sustained long-term improvements in glycosylated hemoglobin, on the other hand, is modest. Furthermore, alterations to insulin/insulin-like growth factor I receptor binding characteristics have also raised theoretical concerns that insulin analogs may have an increased mitogenic potential and risk of tumor development, although evidence from both in vitro and in vivo animal studies do not support this assertion. Long-term surveillance has been recommended and further carefully designed prospective studies are needed to evaluate the overall benefits and clinical efficacy of insulin analog therapy in children and adolescents with type 1 diabetes.

Consensus recommendations for preventing and managing bleeding complications associated with novel oral anticoagulants in singapore.

PubMed

Ng, Heng Joo; Chee, Yen Lin; Ponnudurai, Kuperan; Lim, Lay Cheng; Tan, Daryl; Tay, Jam Chin; Handa, Pankaj Kumar; Akbar Ali, Mufeedha; Lee, Lai Heng

2013-11-01

Novel oral anticoagulants (NOACs) have at least equivalent efficacy compared to standard anticoagulants with similar bleeding risk. Optimal management strategies for bleeding complications associated with NOACs are currently unestablished. A working group comprising haematologists and vascular medicine specialists representing the major institutions in Singapore was convened to produce this consensus recommendation. A Medline and EMBASE search was conducted for articles related to the 3 available NOACs (dabigatran, rivaroxaban, apixaban), bleeding and its management. Additional information was obtained from the product monographs and bibliographic search of articles identified. The NOACs still has substantial interactions with a number of drugs for which concomitant administration should best be avoided. As they are renally excreted, albeit to different degrees, NOACs should not be prescribed to patients with creatinine clearance of <30 mLs/min. Meticulous consideration of risk versus benefits should be exercised before starting a patient on a NOAC. In patients presenting with bleeding, risk stratification of the severity of bleeding as well as identification of the source of bleeding should be performed. In life-threatening bleeds, recombinant activated factor VIIa and prothrombin complex may be considered although their effectiveness is currently unsupported by firm clinical evidence. The NOACs have varying effect on the prothrombin time and activated partial thromboplastin time which has to be interpreted with caution. Routine monitoring of drug level is not usually required. NOACs are an important advancement in antithrombotic management and careful patient selection and monitoring will permit optimisation of their potential and limit bleeding events.

[Syndromic hereditary deafness. Usher's syndrome. Oto-neurologic and genetic factors].

PubMed

Espinós, C; Pérez-Garrigues, H; Beneyto, M; Vilela, C; Rodrigo, O; Nájera, C

1999-01-01

Usher syndrome (USH) is an autosomal recessive hereditary disorder characterized by congenital bilateral sensorineural hearing loss and progressive loss of vision due to retinitis pigmentosa (RP). The prevalence of Usher syndrome is estimated to be 3-4.4 cases per 100.000 people. Several clinical types have been distinguished by age at onset, rate of progression, and severity of symptoms. Type I (USH1) is characterized by a congenital, severe-to-profound deafness and absent vestibular function. Type II (USH2) shows a congenital and moderate-to-severe hearing loss and normal vestibular response. It is also suggested a third type (USH3), clinically similar to USH2, but with progressive hearing loss. Genetic heterogeneity of USH is quite extensive. Up to now, seven different loci responsible for the defect are known: 14q, 11q, 11p, 10q and 21q for USH1; 1q for USH2 and 3q for USH3. Moreover, there are USH1 and USH2 families that fail to show linkage to these candidate regions demonstrating that should exist other loci causing USH, although their ubications are unknown. To date, only two genes involved in the USH pathology are known, although together they are responsibles of about the 80% of total USH cases: myosin VIIA, an unconventional myosin, involved in the USH1b phenotype and a protein similar to the laminina, responsible for the USH2a phenotype.

An investigation of reasoning by analogy in schizophrenia and autism spectrum disorder

PubMed Central

Krawczyk, Daniel C.; Kandalaft, Michelle R.; Didehbani, Nyaz; Allen, Tandra T.; McClelland, M. Michelle; Tamminga, Carol A.; Chapman, Sandra B.

2014-01-01

Relational reasoning ability relies upon by both cognitive and social factors. We compared analogical reasoning performance in healthy controls (HC) to performance in individuals with Autism Spectrum Disorder (ASD), and individuals with schizophrenia (SZ). The experimental task required participants to find correspondences between drawings of scenes. Participants were asked to infer which item within one scene best matched a relational item within the second scene. We varied relational complexity, presence of distraction, and type of objects in the analogies (living or non-living items). We hypothesized that the cognitive differences present in SZ would reduce relational inferences relative to ASD and HC. We also hypothesized that both SZ and ASD would show lower performance on living item problems relative to HC due to lower social function scores. Overall accuracy was higher for HC relative to SZ, consistent with prior research. Across groups, higher relational complexity reduced analogical responding, as did the presence of non-living items. Separate group analyses revealed that the ASD group was less accurate at making relational inferences in problems that involved mainly non-living items and when distractors were present. The SZ group showed differences in problem type similar to the ASD group. Additionally, we found significant correlations between social cognitive ability and analogical reasoning, particularly for the SZ group. These results indicate that differences in cognitive and social abilities impact the ability to infer analogical correspondences along with numbers of relational elements and types of objects present in the problems. PMID:25191240

Openness to Experience Rather than Overexcitabilities: Call It Like It Is

ERIC Educational Resources Information Center

Vuyk, M. Alexandra; Krieshok, Thomas S.; Kerr, Barbara A.

2016-01-01

Openness to experience is a personality factor in the five-factor model of personality, and it is composed of six facets. Facets of openness appear conceptually analogous to overexcitabilities (OEs), which are displays of inner energy guiding individuals toward advanced potential according to the theory of positive disintegration. This study…

Analysis of ligand-receptor cross-linked fragments by mass spectrometry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Son, C.D.; Sargsyan, H.; Hurst, Gregory

G-protein coupled receptors (GPCRs) are a class of integral membrane receptor proteins that are characterized by a signature seven-transmembrane (7-TM) configuration. The a-factor receptor (Ste2p) from Saccharomyces cerevisiae is a GPCR that, upon binding of a peptide ligand, transduces a signal to initiate a cascade of events leading to the mating of haploid yeast cells. This study summarizes the application of affinity purification and of matrix-assisted laser-desorption ionization time-of-flight (MALDI-TOF) experiments using biotinylated photoactivatable a-factor analogs. Affinity purification and enrichment of biotinylated peptides by monomeric avidin beads resulted in mass spectrometric detection of specific signals corresponding to crosslinked fragments ofmore » Ste2p. Data obtained from cyanogen bromide (CNBr) fragments of receptor cross-linked to an a-factor analog with the photoaffinity group p-benzoyl-L-phenylalanine on position 1 were in agreement with the previous results reported by our laboratory suggesting the cross-linking between position 1 of a-factor and a region of Ste2p covering residues 251 294.« less

N,N'-dihydroxyamidines: a new prodrug principle to improve the oral bioavailability of amidines.

PubMed

Reeh, Christiane; Wundt, Judith; Clement, Bernd

2007-12-27

N, N'-dihydroxybenzamdine represents a model compound for a new prodrug principle to improve the oral bioavailability of drugs containing amidine functions. The activation of the prodrug could be demonstrated in vitro by porcine and human subcellular enzyme fractions, the mitochondrial benzamidoxime reducing system, and porcine hepatocytes. In vivo, the bioavailability of benzamidine after oral application of N, N'-dihydroxybenzamidine was about 91% and exceeded that of benzamidine after oral application of benzamidoxime, being about 74% (Liu, L.; Ling, Y.; Havel, C.; Bashnick, L.; Young, W.; Rai, R.; Vijaykumar, D.; Riggs, J. R.; Ton, T.; Shaghafi, M.; Graupe, D.; Mordenti, J.; Sukbuntherng, J. Species comparison of in vitro and in vivo conversion of five N-hydroxyamidine prodrugs of fVIIA inhibitors to their corresponding active amidines. Presented at the 13th North America ISSX Meeting, Maui, HI, 2005).

Genetic heterogeneity in Usher syndrome.

PubMed

Keats, Bronya J B; Savas, Sevtap

2004-09-15

Mutations in seven different genes have been associated with Usher syndrome, and an additional four loci have been mapped. The identified genes encode myosin VIIa, harmonin (a PDZ-domain protein), cadherin 23, protocadherin 15, sans (a scaffold-like protein), usherin and clarin. Three clinical types of Usher syndrome have been described: USH1 patients have severe to profound congenital hearing loss, vestibular dysfunction, and retinal degeneration beginning in childhood, those with USH2 have moderate to severe congenital hearing loss, normal vestibular function, and later onset of retinitis pigmentosa, and USH3 patients have progressive hearing loss, which distinguishes them from the other two types. The shaker-1, waltzer, Ames waltzer, and Jackson shaker mice provide murine models for four of the genetic forms of Usher syndrome. Ongoing studies are enabling early diagnosis of Usher syndrome in children who present with hearing loss, thus providing time to prepare for the onset of visual loss. Copyright 2004 Wiley-Liss, Inc.

New Verapamil Analogs Inhibit Intracellular Mycobacteria without Affecting the Functions of Mycobacterium-Specific T Cells

PubMed Central

Ruminiski, Peter G.; Kumar, Malkeet; Singh, Kawaljit; Hamzabegovic, Fahreta; Hoft, Daniel F.; Eickhoff, Christopher S.; Selimovic, Asmir; Campbell, Mary; Chibale, Kelly

2015-01-01

There is a growing interest in repurposing mycobacterial efflux pump inhibitors, such as verapamil, for tuberculosis (TB) treatment. To aid in the design of better analogs, we studied the effects of verapamil on macrophages and Mycobacterium tuberculosis-specific T cells. Macrophage activation was evaluated by measuring levels of nitric oxide, tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and gamma interferon (IFN-γ). Since verapamil is a known autophagy inducer, the roles of autophagy induction in the antimycobacterial activities of verapamil and norverapamil were studied using bone marrow-derived macrophages from ATG5flox/flox (control) and ATG5flox/flox Lyz-Cre mice. Our results showed that despite the well-recognized effects of verapamil on calcium channels and autophagy, its action on intracellular M. tuberculosis does not involve macrophage activation or autophagy induction. Next, the effects of verapamil and norverapamil on M. tuberculosis-specific T cells were assessed using flow cytometry following the stimulation of peripheral blood mononuclear cells from TB-skin-test-positive donors with M. tuberculosis whole-cell lysate for 7 days in the presence or absence of drugs. We found that verapamil and norverapamil inhibit the expansion of M. tuberculosis-specific T cells. Additionally, three new verapamil analogs were found to inhibit intracellular Mycobacterium bovis BCG, and one of the three analogs (KSV21) inhibited intracellular M. tuberculosis replication at concentrations that did not inhibit M. tuberculosis-specific T cell expansion. KSV21 also inhibited mycobacterial efflux pumps to the same degree as verapamil. More interestingly, the new analog enhances the inhibitory activities of isoniazid and rifampin on intracellular M. tuberculosis. In conclusion, KSV21 is a promising verapamil analog on which to base structure-activity relationship studies aimed at identifying more effective analogs. PMID:26643325

In vitro monoamine oxidase inhibition potential of alpha-methyltryptamine analog new psychoactive substances for assessing possible toxic risks.

PubMed

Wagmann, Lea; Brandt, Simon D; Kavanagh, Pierce V; Maurer, Hans H; Meyer, Markus R

2017-04-15

Tryptamines have emerged as new psychoactive substances (NPS), which are distributed and consumed recreationally without preclinical studies or safety tests. Within the alpha-methylated tryptamines, some of the psychoactive effects of the prototypical alpha-methyltryptamine (AMT) have been described decades ago and a contributing factor of its acute toxicity appears to involve the inhibition of monoamine oxidase (MAO). However, detailed information about analogs is scarce. Therefore, thirteen AMT analogs were investigated for their potential to inhibit MAO. An in vitro assay analyzed using hydrophilic interaction liquid chromatography-high resolution-tandem mass spectrometry was developed and validated. The AMT analogs were incubated with recombinant human MAO-A or B and kynuramine, a non-selective MAO substrate to determine the IC 50 values. The known MAO-A inhibitors 5-(2-aminopropyl)indole (5-IT), harmine, harmaline, yohimbine, and the MAO-B inhibitor selegiline were tested for comparison. AMT and all analogs showed MAO-A inhibition properties with IC 50 values between 0.049 and 166μM, whereas four analogs inhibited also MAO-B with IC 50 values between 82 and 376μM. 7-Me-AMT provided the lowest IC 50 value against MAO-A comparable to harmine and harmaline and was identified as a competitive MAO-A inhibitor. Furthermore, AMT, 7-Me-AMT, and nine further analogs inhibited MAO activity in human hepatic S9 fraction used as model for the human liver which expresses both isoforms. The obtained results suggested that MAO inhibition induced by alpha-methylated tryptamines might be clinically relevant concerning possible serotonergic and adrenergic effects and interactions with drugs (of abuse) particularly acting as monoamine reuptake inhibitors. However, as in vitro assays have only limited conclusiveness, further studies are needed. Copyright © 2017 Elsevier B.V. All rights reserved.

Glucagon-like peptide-1 analogs against antipsychotic-induced weight gain: potential physiological benefits

PubMed Central

2012-01-01

Background Antipsychotic-induced weight gain constitutes a major unresolved clinical problem which may ultimately be associated with reducing life expectancy by 25 years. Overweight is associated with brain deterioration, cognitive decline and poor quality of life, factors which are already compromised in normal weight patients with schizophrenia. Here we outline the current strategies against antipsychotic-induced weight gain, and we describe peripheral and cerebral effects of the gut hormone glucagon-like peptide-1 (GLP-1). Moreover, we account for similarities in brain changes between schizophrenia and overweight patients. Discussion Current interventions against antipsychotic-induced weight gain do not facilitate a substantial and lasting weight loss. GLP-1 analogs used in the treatment of type 2 diabetes are associated with significant and sustained weight loss in overweight patients. Potential effects of treating schizophrenia patients with antipsychotic-induced weight gain with GLP-1 analogs are discussed. Conclusions We propose that adjunctive treatment with GLP-1 analogs may constitute a new avenue to treat and prevent metabolic and cerebral deficiencies in schizophrenia patients with antipsychotic-induced weight gain. Clinical research to support this idea is highly warranted. PMID:22891821

An analog integrated circuit beamformer for high-frequency medical ultrasound imaging.

PubMed

Gurun, Gokce; Zahorian, Jaime S; Sisman, Alper; Karaman, Mustafa; Hasler, Paul E; Degertekin, F Levent

2012-10-01

We designed and fabricated a dynamic receive beamformer integrated circuit (IC) in 0.35-μm CMOS technology. This beamformer IC is suitable for integration with an annular array transducer for high-frequency (30-50 MHz) intravascular ultrasound (IVUS) imaging. The beamformer IC consists of receive preamplifiers, an analog dynamic delay-and-sum beamformer, and buffers for 8 receive channels. To form an analog dynamic delay line we designed an analog delay cell based on the current-mode first-order all-pass filter topology, as the basic building block. To increase the bandwidth of the delay cell, we explored an enhancement technique on the current mirrors. This technique improved the overall bandwidth of the delay line by a factor of 6. Each delay cell consumes 2.1-mW of power and is capable of generating a tunable time delay between 1.75 ns to 2.5 ns. We successfully integrated the fabricated beamformer IC with an 8-element annular array. Experimental test results demonstrated the desired buffering, preamplification and delaying capabilities of the beamformer.

International Space Station Medical Projects - Full Services to Mars

NASA Technical Reports Server (NTRS)

Pietrzyk, R. A.; Primeaux, L. L.; Wood, S. J.; Vessay, W. B.; Platts, S. H.

2018-01-01

The International Space Station Medical Projects (ISSMP) Element provides planning, integration, and implementation services for HRP research studies for both spaceflight and flight analog research. Through the implementation of these two efforts, ISSMP offers an innovative way of guiding research decisions to meet the unique challenges of understanding the human risks to space exploration. Flight services provided by ISSMP include leading informed consent briefings, developing and validating in-flight crew procedures, providing ISS crew and ground-controller training, real-time experiment monitoring, on-orbit experiment and hardware operations and facilitating data transfer to investigators. For analog studies at the NASA Human Exploration Research Analog (HERA), the ISSMP team provides subject recruitment and screening, science requirements integration, data collection schedules, data sharing agreements, mission scenarios and facilities to support investigators. The ISSMP also serves as the HRP interface to external analog providers including the :envihab bed rest facility (Cologne, Germany), NEK isolation chamber (Moscow, Russia) and the Antarctica research stations. Investigators working in either spaceflight or analog environments requires a coordinated effort between NASA and the investigators. The interdisciplinary nature of both flight and analog research requires investigators to be aware of concurrent research studies and take into account potential confounding factors that may impact their research objectives. Investigators must define clear research requirements, participate in Investigator Working Group meetings, obtain human use approvals, and provide study-specific training, sample and data collection and procedures all while adhering to schedule deadlines. These science requirements define the technical, functional and performance operations to meet the research objectives. The ISSMP maintains an expert team of professionals with the knowledge and experience to guide investigators science through all aspects of mission planning, crew operations, and research integration. During this session, the ISSMP team will discuss best-practices approaches for successfully preparing and conducting studies in both the flight and analog environments. Critical tips and tricks will be shown to greatly improve your chances of successfully completing your research aboard the International Space Station and in Spaceflight Analogs.

In silico designing of hyper-glycosylated analogs for the human coagulation factor IX.

PubMed

Ghasemi, Fahimeh; Zomorodipour, Alireza; Karkhane, Ali Asghar; Khorramizadeh, M Reza

2016-07-01

N-glycosylation is a process during which a glycan moiety attaches to the asparagine residue in the N-glycosylation consensus sequence (Asn-Xxx-Ser/Thr), where Xxx can be any amino acid except proline. Introduction of a new N-glycosylation site into a protein backbone leads to its hyper-glycosylation, and may improve the protein properties such as solubility, folding, stability, and secretion. Glyco-engineering is an approach to facilitate the hyper-glycosylation of recombinant proteins by application of the site-directed mutagenesis methods. In this regard, selection of a suitable location on the surface of a protein for introduction of a new N-glycosylation site is a main concern. In this work, a computational approach was conducted to select suitable location(s) for introducing new N-glycosylation sites into the human coagulation factor IX (hFIX). With this aim, the first 45 residues of mature hFIX were explored to find out suitable positions for introducing either Asn or Ser/Thr residues, to create new N-glycosylation site(s). Our exploration lead to detection of five potential positions, for hyper-glycosylation. For each suggested position, an analog was defined and subjected for N-glycosylation efficiency prediction. After generation of three-dimensional structures, by homology-based modeling, the five designed analogs were examined by molecular dynamic (MD) simulations, to predict their stability levels and probable structural distortions caused by amino acid substitutions, relative to the native counterpart. Three out of five suggested analogs, namely; E15T, K22N, and R37N, reached equilibration state with relatively constant Root Mean Square Deviation values. Additional analysis on the data obtained during MD simulations, lead us to conclude that, R37N is the only qualified analog with the most similar structure and dynamic behavior to that of the native counterpart, to be considered for further experimental investigations. Copyright © 2016 Elsevier Inc. All rights reserved.

Immunoconjugates in the management of hairy cell leukemia

PubMed Central

Kreitman, Robert J.; Pastan, Ira

2015-01-01

Hairy cell leukemia (HCL) is an indolent B-cell malignancy effectively treated but not often cured by purine analog therapy; after multiple courses of purine analogs, patients can become purine analog resistant and in need of alternative therapies. Complete remission to single-agent purine analog is often accompanied by minimal residual disease (MRD), residual HCL cells detectable by immunologic methods, considered a risk factor for eventual relapse. Several different non-chemotherapy approaches are being used to target relapsed and refractory HCL, including inhibitors of BRAF, but so far only monoclonal antibody (MAb)-based approaches have been reported to eliminate MRD in a high percentage of patients. One of the MAb-based options for HCL currently under clinical investigation involves recombinant immunotoxins, containing a fragment of a MAb and a bacterial toxin. The bacterial toxin, a highly potent fragment from Pseudomonas exotoxin, catalytically ADP-ribosylates elongation factor 2 (EF2), resulting in protein synthesis inhibition and apoptotic cell death. Recombinant immunotoxins tested in HCL patients include LMB-2, targeting CD25, and BL22, targeting CD22. An affinity matured version of BL22, termed moxetumomab pasudotox (formerly HA22 or CAT-8015) achieved high CR rates in phase I, and is currently undergoing multicenter Phase 3 testing. Phase I testing was without dose-limiting toxicity, although 2 patients had grade 2 hemolytic uremic syndrome (HUS) with transient grade 1 abnormalities in platelets and creatinine. Preclinical work is underway to identify residues on moxetumomab pasudotox leading to immunogenicity. Moxetumomab pasudotox is undergoing pivotal testing for relapsed and refractory HCL. PMID:26614902

Geometric Theory of Reduction of Nonlinear Control Systems

NASA Astrophysics Data System (ADS)

Elkin, V. I.

2018-02-01

The foundations of a differential geometric theory of nonlinear control systems are described on the basis of categorical concepts (isomorphism, factorization, restrictions) by analogy with classical mathematical theories (of linear spaces, groups, etc.).

Air Force Officer Qualifying Test Form T: Initial Item-, Test-, Factor-, and Composite-Level Analyses

DTIC Science & Technology

2016-12-01

five lower-order factors representing verbal, math , spatial, perceptual speed, and aviation knowledge, and a hierarchical general factor showed the...Academic Aptitude Verbal Quant. Verbal Analogies 25 X X X Arithmetic Reasoning 25 X X Word Knowledge 25 X X X Math Knowledge 25 X X...Reasoning (AR) uses word problems to assess the ability to understand arithmetic relations. Math Knowledge (MK) assesses the ability to use

Therapeutic drug monitoring in patients with inflammatory bowel disease

PubMed Central

Yarur, Andres J; Abreu, Maria T; Deshpande, Amar R; Kerman, David H; Sussman, Daniel A

2014-01-01

Thiopurine analogs and anti-tumor necrosis factor (TNF) agents have dramatically changed the therapeutics of inflammatory bowel diseases (IBD), improving short and long-term outcomes. Unfortunately some patients do not respond to therapy and others lose response over time. The pharmacokinetic properties of these drugs are complex, with high inter-patient variability. Thiopurine analogs are metabolized through a series of pathways, which vary according to the patients’ pharmacogenetic profile. This profile largely determines the ratios of metabolites, which are in turn associated with likelihoods of clinical efficacy and/or toxicity. Understanding these mechanisms allows for manipulation of drug dose, aiming to reduce the development of toxicity while improving the efficacy of treatment. The efficacy of anti-TNF drugs is influenced by many pharmacodynamic variables. Several factors may alter drug clearance, including the concomitant use of immunomodulators (thiopurine analogs and methotrexate), systemic inflammation, the presence of anti-drug antibodies, and body mass. The treatment of IBD has evolved with the understanding of the pharmacologic profiles of immunomodulating and TNF-inhibiting medications, with good evidence for improvement in patient outcomes observed when measuring metabolic pathway indices. The role of routine measurement of metabolite/drug levels and antibodies warrants further prospective studies as we enter the era of personalized IBD care. PMID:24707130

In vitro evaluation of nicotinamide riboside analogs against Haemophilus influenzae.

PubMed Central

Godek, C P; Cynamon, M H

1990-01-01

Exogenous NAD, nicotinamide mononucleotide, or nicotinamide riboside is required for the growth of Haemophilus influenzae. These compounds have been defined as the V-factor growth requirement. We have previously shown that the internalization of nicotinamide riboside is energy dependent and carrier mediated with saturation kinetics. Thionicotinamide riboside, 3-pyridinealdehyde riboside, 3-acetylpyridine riboside, and 3-aminopyridine riboside were prepared from their corresponding NAD analogs. These compounds and several other nicotinamide riboside analogs were evaluated for their ability to support the growth of H. influenzae and for their ability to block the uptake of [carbonyl-14C]nicotinamide riboside by H. influenzae. 3-Aminopyridine riboside blocked the uptake of [carbonyl-14C]nicotinamide riboside and inhibited the growth of H. influenzae when NAD, nicotinamide mononucleotide, or nicotinamide riboside served as the V factor. The antibacterial activity of 3-aminopyridine riboside was found to be specific for H. influenzae but had no effect on the growth of Staphylococcus aureus or Escherichia coli. In additional experiments by reversed-phase high-performance liquid chromatography, it was determined that whole cells of H. influenzae degrade 3-aminopyridine adenine dinucleotide to 3-aminopyridine riboside, which is then internalized. Inside the cell, 3-aminopyridine riboside has the ability to interfere with the growth of H. influenzae by an undetermined mechanism. Images PMID:2145800

In vitro evaluation of nicotinamide riboside analogs against Haemophilus influenzae.

PubMed

Godek, C P; Cynamon, M H

1990-08-01

Exogenous NAD, nicotinamide mononucleotide, or nicotinamide riboside is required for the growth of Haemophilus influenzae. These compounds have been defined as the V-factor growth requirement. We have previously shown that the internalization of nicotinamide riboside is energy dependent and carrier mediated with saturation kinetics. Thionicotinamide riboside, 3-pyridinealdehyde riboside, 3-acetylpyridine riboside, and 3-aminopyridine riboside were prepared from their corresponding NAD analogs. These compounds and several other nicotinamide riboside analogs were evaluated for their ability to support the growth of H. influenzae and for their ability to block the uptake of [carbonyl-14C]nicotinamide riboside by H. influenzae. 3-Aminopyridine riboside blocked the uptake of [carbonyl-14C]nicotinamide riboside and inhibited the growth of H. influenzae when NAD, nicotinamide mononucleotide, or nicotinamide riboside served as the V factor. The antibacterial activity of 3-aminopyridine riboside was found to be specific for H. influenzae but had no effect on the growth of Staphylococcus aureus or Escherichia coli. In additional experiments by reversed-phase high-performance liquid chromatography, it was determined that whole cells of H. influenzae degrade 3-aminopyridine adenine dinucleotide to 3-aminopyridine riboside, which is then internalized. Inside the cell, 3-aminopyridine riboside has the ability to interfere with the growth of H. influenzae by an undetermined mechanism.

Immune System Dysregulation and Latent Herpesvirus Reactivation During Winterover at Concordia Station, Dome C, Antarctica

NASA Technical Reports Server (NTRS)

Crucian, B. E.; Feuerecker, M.; Salam, A. P.; Rybka, A.; Stowe, R. P.; Morrels, M.; Meta, S. K.; Quiriarte, H.; Quintens, Roel; Thieme, U.;

Detector signal correction method and system

DOEpatents

Carangelo, Robert M.; Duran, Andrew J.; Kudman, Irwin

1995-07-11

Corrective factors are applied so as to remove anomalous features from the signal generated by a photoconductive detector, and to thereby render the output signal highly linear with respect to the energy of incident, time-varying radiation. The corrective factors may be applied through the use of either digital electronic data processing means or analog circuitry, or through a combination of those effects.

Detector signal correction method and system

DOEpatents

Carangelo, R.M.; Duran, A.J.; Kudman, I.

1995-07-11

Corrective factors are applied so as to remove anomalous features from the signal generated by a photoconductive detector, and to thereby render the output signal highly linear with respect to the energy of incident, time-varying radiation. The corrective factors may be applied through the use of either digital electronic data processing means or analog circuitry, or through a combination of those effects. 5 figs.

Enhanced factoring with a bose-einstein condensate.

PubMed

Sadgrove, Mark; Kumar, Sanjay; Nakagawa, Ken'ichi

2008-10-31

We present a novel method to realize analog sum computation with a Bose-Einstein condensate in an optical lattice potential subject to controlled phase jumps. We use the method to implement the Gauss sum algorithm for factoring numbers. By exploiting higher order quantum momentum states, we are able to improve the algorithm's accuracy beyond the limits of the usual classical implementation.

Molecular-like hierarchical self-assembly of monolayers of mixtures of particles

PubMed Central

Singh, P.; Hossain, M.; Gurupatham, S. K.; Shah, K.; Amah, E.; Ju, D.; Janjua, M.; Nudurupati, S.; Fischer, I.

2014-01-01

We present a technique that uses an externally applied electric field to self-assemble monolayers of mixtures of particles into molecular-like hierarchical arrangements on fluid-liquid interfaces. The arrangements consist of composite particles (analogous to molecules) which are arranged in a pattern. The structure of a composite particle depends on factors such as the relative sizes of the particles and their polarizabilities, and the electric field intensity. If the particles sizes differ by a factor of two or more, the composite particle has a larger particle at its core and several smaller particles form a ring around it. The number of particles in the ring and the spacing between the composite particles depend on their polarizabilities and the electric field intensity. Approximately same sized particles form chains (analogous to polymeric molecules) in which positively and negatively polarized particles alternate. PMID:25510331

Effects of nucleoside analog incorporation on DNA binding to the DNA binding domain of the GATA-1 erythroid transcription factor.

PubMed

Foti, M; Omichinski, J G; Stahl, S; Maloney, D; West, J; Schweitzer, B I

1999-02-05

We investigate here the effects of the incorporation of the nucleoside analogs araC (1-beta-D-arabinofuranosylcytosine) and ganciclovir (9-[(1,3-dihydroxy-2-propoxy)methyl] guanine) into the DNA binding recognition sequence for the GATA-1 erythroid transcription factor. A 10-fold decrease in binding affinity was observed for the ganciclovir-substituted DNA complex in comparison to an unmodified DNA of the same sequence composition. AraC substitution did not result in any changes in binding affinity. 1H-15N HSQC and NOESY NMR experiments revealed a number of chemical shift changes in both DNA and protein in the ganciclovir-modified DNA-protein complex when compared to the unmodified DNA-protein complex. These changes in chemical shift and binding affinity suggest a change in the binding mode of the complex when ganciclovir is incorporated into the GATA DNA binding site.

Synthetic analog computation in living cells.

PubMed

Daniel, Ramiz; Rubens, Jacob R; Sarpeshkar, Rahul; Lu, Timothy K

2013-05-30

A central goal of synthetic biology is to achieve multi-signal integration and processing in living cells for diagnostic, therapeutic and biotechnology applications. Digital logic has been used to build small-scale circuits, but other frameworks may be needed for efficient computation in the resource-limited environments of cells. Here we demonstrate that synthetic analog gene circuits can be engineered to execute sophisticated computational functions in living cells using just three transcription factors. Such synthetic analog gene circuits exploit feedback to implement logarithmically linear sensing, addition, ratiometric and power-law computations. The circuits exhibit Weber's law behaviour as in natural biological systems, operate over a wide dynamic range of up to four orders of magnitude and can be designed to have tunable transfer functions. Our circuits can be composed to implement higher-order functions that are well described by both intricate biochemical models and simple mathematical functions. By exploiting analog building-block functions that are already naturally present in cells, this approach efficiently implements arithmetic operations and complex functions in the logarithmic domain. Such circuits may lead to new applications for synthetic biology and biotechnology that require complex computations with limited parts, need wide-dynamic-range biosensing or would benefit from the fine control of gene expression.

Methyl phenlactonoates are efficient strigolactone analogs with simple structure

PubMed Central

Jamil, Muhammad; Kountche, Boubacar A; Haider, Imran; Guo, Xiujie; Ntui, Valentine O; Jia, Kun-Peng; Hameed, Umar S; Nakamura, Hidemitsu; Lyu, Ying; Jiang, Kai; Hirabayashi, Kei; Tanokura, Masaru; Arold, Stefan T; Asami, Tadao

2018-01-01

abstract Strigolactones (SLs) are a new class of phytohormones that also act as germination stimulants for root parasitic plants, such as Striga spp., and as branching factors for symbiotic arbuscular mycorrhizal fungi. Sources for natural SLs are very limited. Hence, efficient and simple SL analogs are needed for elucidating SL-related biological processes as well as for agricultural applications. Based on the structure of the non-canonical SL methyl carlactonoate, we developed a new, easy to synthesize series of analogs, termed methyl phenlactonoates (MPs), evaluated their efficacy in exerting different SL functions, and determined their affinity for SL receptors from rice and Striga hermonthica. Most of the MPs showed considerable activity in regulating plant architecture, triggering leaf senescence, and inducing parasitic seed germination. Moreover, some MPs outperformed GR24, a widely used SL analog with a complex structure, in exerting particular SL functions, such as modulating Arabidopsis roots architecture and inhibiting rice tillering. Thus, MPs will help in elucidating the functions of SLs and are promising candidates for agricultural applications. Moreover, MPs demonstrate that slight structural modifications clearly impact the efficiency in exerting particular SL functions, indicating that structural diversity of natural SLs may mirror a functional specificity. PMID:29300919

Impact of device engineering on analog/RF performances of tunnel field effect transistors

NASA Astrophysics Data System (ADS)

Vijayvargiya, V.; Reniwal, B. S.; Singh, P.; Vishvakarma, S. K.

2017-06-01

The tunnel field effect transistor (TFET) and its analog/RF performance is being aggressively studied at device architecture level for low power SoC design. Therefore, in this paper we have investigated the influence of the gate-drain underlap (UL) and different dielectric materials for the spacer and gate oxide on DG-TFET (double gate TFET) and its analog/RF performance for low power applications. Here, it is found that the drive current behavior in DG-TFET with a UL feature while implementing dielectric material for the spacer is different in comparison to that of DG-FET. Further, hetero gate dielectric-based DG-TFET (HGDG-TFET) is more resistive against drain-induced barrier lowering (DIBL) as compared to DG-TFET with high-k (HK) gate dielectric. Along with that, as compared to DG-FET, this paper also analyses the attributes of UL and dielectric material on analog/RF performance of DG-TFET in terms of transconductance (gm ), transconductance generation factor (TGF), capacitance, intrinsic resistance (Rdcr), cut-off frequency (F T), and maximum oscillation frequency (F max). The LK spacer-based HGDG-TFET with a gate-drain UL has the potential to improve the RF performance of device.

Determination of Roles of Microgravity and Ionizing Radiation on the Reactivation of Epstein-Barr Virus In Vitro

NASA Technical Reports Server (NTRS)

Mehta, Satish K; Renner, Ashlie; Stowe, Raymond; Bloom, David; Pierson, Duane

2015-01-01

Astronauts experience symptomatic and asymptomatic herpes virus reactivation during spaceflight. We have shown increases in reactivation of Epstein-Barr virus (EBV), cytomegalovirus (CMV) and varicella zoster virus (VZV) and shedding in body fluids (saliva and urine) in astronauts during space travel. Alterations in immunity, increased stress hormone levels, microgravity, increased radiation, and other conditions unique to spaceflight may promote reactivation of latent herpes viruses. Unique mechanico-physico forces associated with spaceflight can have profound effects on cellular function, especially immune cells. In space flight analog studies such as Antarctica, bed rest studies, and NASA's undersea habitat (Aquarius), reactivation of these viruses occurred, but to a lesser extent than spaceflight. Spaceflight analogs model some spaceflight factors, but none of the analogs recreates all factors experienced in space. Most notably, microgravity and radiation are not included in many analogs. Stress, processed through the HPA axis and SAM systems, induces viral reactivation. However, the respective roles of microgravity and increased space radiation levels or if any synergy exists are not known. Therefore, we studied the effect of modeled space radiation and/or microgravity, independent of the immune system on the changes in cellular gene expression that results in viral (EBV) reactivation. The effects of modeled microgravity and low shear on EBV replication and cellular and EBV gene expression were studied in human B-lymphocyte cell cultures. Latently infected B-lymphocytes were propagated in the rotating wall bioreactor and irradiated with the various dosages of gamma irradiation. At specific time intervals following exposure to modeled microgravity, the cells and supernatant were harvested and reactivation of EBV were assessed by measuring EBV and gene expression, DNA methylation, and infectious virus production.

Presence of organophosphorus pesticide oxygen analogs in air samples

NASA Astrophysics Data System (ADS)

Armstrong, Jenna L.; Fenske, Richard A.; Yost, Michael G.; Galvin, Kit; Tchong-French, Maria; Yu, Jianbo

2013-02-01

A number of recent toxicity studies have highlighted the increased potency of oxygen analogs (oxons) of several organophosphorus (OP) pesticides. These findings were a major concern after environmental oxons were identified in environmental samples from air and surfaces following agricultural spray applications in California and Washington State. This paper reports on the validity of oxygen analog measurements in air samples for the OP pesticide, chlorpyrifos. Controlled environmental and laboratory experiments were used to examine artificial formation of chlorpyrifos-oxon using OSHA Versatile Sampling (OVS) tubes as recommended by NIOSH method 5600. Additionally, we compared expected chlorpyrifos-oxon attributable to artificial transformation to observed chlorpyrifos-oxon in field samples from a 2008 Washington State Department of Health air monitoring study using non-parametric statistical methods. The amount of artificially transformed oxon was then modeled to determine the amount of oxon present in the environment. Toxicity equivalency factors (TEFs) for chlorpyrifos-oxon were used to calculate chlorpyrifos-equivalent air concentrations. The results demonstrate that the NIOSH-recommended sampling matrix (OVS tubes with XAD-2 resin) was found to artificially transform up to 30% of chlorpyrifos to chlorpyrifos-oxon, with higher percentages at lower concentrations (<30 ng m-3) typical of ambient or residential levels. Overall, the 2008 study data had significantly greater oxon than expected by artificial transformation, but the exact amount of environmental oxon in air remains difficult to quantify with the current sampling method. Failure to conduct laboratory analysis for chlorpyrifos-oxon may result in underestimation of total pesticide concentration when using XAD-2 resin matrices for occupational or residential sampling. Alternative methods that can accurately measure both OP pesticides and their oxygen analogs should be used for air sampling, and a toxicity equivalent factor approach should be used to determine potential health risks from exposures.

The molar hydrodynamic volume changes of factor VIIa due to GlycoPEGylation.

PubMed

Plesner, Bitten; Westh, Peter; Hvidt, Søren; Nielsen, Anders D

2011-06-01

The effects of GlycoPEGylation on the molar hydrodynamic volume of recombinant human rFVIIa were investigated using rFVIIa and two GlycoPEGylated recombinant human FVIIa derivatives, a linear 10kDa PEG and a branched 40kDa PEG, respectively. Molar hydrodynamic volumes were determined by capillary viscometry and mass spectrometry. The intrinsic viscosities of rFVIIa, its two GlycoPEGylated compounds, and of linear 8kDa, 10kDa, 20kDa and branched 40kDa PEG polymers were determined. The measured intrinsic viscosity of rFVIIa is 6.0mL/g, while the intrinsic viscosities of 10kDa PEG-rFVIIa and 40kDa PEG-rFVIIa are 29.5mL/g and 79.0mL/g, respectively. The intrinsic viscosities of the linear PEG polymers are 20, 22.6 and 41.4mL/g for 8, 10, and 20kDa, respectively, and 61.1mL/g for the branched 40kDa PEG. From the results of the intrinsic viscosity and MALDI-TOF measurements it is evident, that the molar hydrodynamic volume of the conjugated protein is not just an addition of the molar hydrodynamic volume of the PEG and the protein. The molar hydrodynamic volume of the GlycoPEGylated protein is larger than the volume of its composites. These results suggest that both the linear and the branched PEG are not wrapped around the surface of rFVIIa but are chains that are significantly stretched out when attached to the protein. Copyright © 2011 Elsevier B.V. All rights reserved.

Gateways to clinical trials.

PubMed

Tomillero, A; Moral, M A

2010-01-01

(-)-Epigallocatechin gallate, Abafungin, ACE-031, Adapalene/benzoyl peroxide, AE-37, Aflibercept, AGS-003, Albiglutide, Alemtuzumab, Aliskiren fumarate, ALT-801, AN-2728, Anacetrapib, API, Aprepitant, ARQ-197, Ascorbic acid, Atazanavir sulfate, ATN-224, AVI-4658, Azacitidine, Azelnidipine; Belinostat, Bevacizumab, BI-2536, Biphasic insulin aspart, Bortezomib, Bovine lactoferrin, Bryostatin 1, Budesonide/formoterol fumarate; cAC10, Canfosfamide hydrochloride, Cediranib, Clofarabine, Cocaine conjugate vaccine; Darbepoetin alfa, Dasatinib, Denosumab, Disomotide, Doripenem, Dovitinib Lactate, Dronedarone hydrochloride, Drospirenone/estradiol, Dutasteride; Ecogramostim, Entinostat, Enzastaurin hydrochloride, Erlotinib hydrochloride, Everolimus, Exenatide, Ezetimibe, Ezetimibe/simvastatin; Fampridine, Fenretinide LXS, FFR-factor VIIa, Fingolimod hydrochloride, Frovatriptan; Gefitinib, Gimatecan, GP-2/GM-CSF; Iloperidone, Imatinib mesylate, Indibulin, Ipilimumab, Ivabradine hydrochloride; Lactobacillus rhamnosus, Lapatinib ditosylate, LC-07, Lenalidomide, Linifanib, Liposomal doxorubicin, Liposomal vincristine, Litenimod, Lutein; M-118, MDX-1401, MEDI-528, Midostaurin, Miglustat, MK-0657; Natalizumab, Nesiritide, NGR-TNF, Niacin/simvastatin; Obatoclax mesylate, Olaparib, Omacetaxine mepesuccinate; Paclitaxel nanoparticles, Paclitaxel-eluting stent, Palonosetron hydrochloride, Pazopanib hydrochloride, Pegfilgrastim, Pemetrexed disodium, PER.C-flu, Perifosine, PF-02341066, Pimecrolimus, Pitrakinra, Plerixafor hydrochloride, Posaconazole; Rasburicase, Recombinant human relaxin H2, ReoT3D, Retaspimycin hydrochloride, Riferminogene pecaplasmid, Rindopepimut, Romiplostim, Ronacaleret hydrochloride, Rosuvastatin calcium, Rotigotine; Sagopilone, sALP-FcD10, SAR-245409, SCH-697243, Selumetinib, Sirolimus-eluting stent, SIR-Spheres, Sitagliptin phosphate monohydrate, Sitaxentan sodium, Sorafenib, Sunitinib malate; Tadalafil, Tandutinib, Tasimelteon, Temsirolimus, Teriparatide, Tiotropium bromide, TIV, Trabectedin, Tremelimumab, TRU-016; Vadimezan, Val8-GLP-1(7-37)OH, Vandetanib, Vernakalant hydrochloride, Voreloxin, Voriconazole, Vorinostat, Yttrium 90 (90Y) ibritumomab tiuxetan; Zeaxanthin, Ziprasidone hydrochloride, Zosuquidar trihydrochloride. Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.

A Synthetic Serine Protease Inhibitor, Nafamostat Mesilate, Is a Drug Potentially Applicable to the Treatment of Ebola Virus Disease.

PubMed

Nishimura, Hidekazu; Yamaya, Mutsuo

2015-09-01

Ebola virus disease (EVD) has been a great concern worldwide because of its high mortality. EVD usually manifests with fever, diarrhea and vomiting, as well as disseminated intravascular coagulation (DIC). To date, there is neither a licensed Ebola vaccine nor a promising therapeutic agent, although clinical trials are ongoing. For replication inside the cell, Ebola virus (EBOV) must undergo the proteolytic processing of its surface glycoprotein in the endosome by proteases including cathepsin B (CatB), followed by the fusion of the viral membrane and host endosome. Thus, the proteases have been considered as potential targets for drugs against EVD. However, no protease inhibitor has been presented as effective clinical drug against it. A synthetic serine protease inhibitor, nafamostat mesilate (NM), reduced the release of CatB from the rat pancreas. Furthermore, it has anticoagulant activities, such as inhibition of the factor VIIa complex, and has been used for treating DIC in Japan. Thus, NM could be considered as a drug candidate for the treatment of DIC induced by EBOV infection, as well as for the possible CatB-related antiviral action. Moreover, the drug has a history of large-scale production and clinical use, and the issues of safety and logistics might have been cleared. We advocate in vitro and in vivo experiments using active EBOV to examine the activities of NM against the infection and the DIC induced by the infection. In addition, we suggest trials for comparison among anti-DIC drugs including the NM in EVD patients, in parallel with the experiments.

The acute management of intracerebral hemorrhage: a clinical review.

PubMed

Elliott, Justine; Smith, Martin

2010-05-01

Intracerebral hemorrhage (ICH) is a devastating disease with high rates of mortality and morbidity. The major risk factors for ICH include chronic arterial hypertension and oral anticoagulation. After the initial hemorrhage, hematoma expansion and perihematoma edema result in secondary brain damage and worsened outcome. A rapid onset of focal neurological deficit with clinical signs of increased intracranial pressure is strongly suggestive of a diagnosis of ICH, although cranial imaging is required to differentiate it from ischemic stroke. ICH is a medical emergency and initial management should focus on urgent stabilization of cardiorespiratory variables and treatment of intracranial complications. More than 90% of patients present with acute hypertension, and there is some evidence that acute arterial blood pressure reduction is safe and associated with slowed hematoma growth and reduced risk of early neurological deterioration. However, early optimism that outcome might be improved by the early administration of recombinant factor VIIa (rFVIIa) has not been substantiated by a large phase III study. ICH is the most feared complication of warfarin anticoagulation, and the need to arrest intracranial bleeding outweighs all other considerations. Treatment options for warfarin reversal include vitamin K, fresh frozen plasma, prothrombin complex concentrates, and rFVIIa. There is no evidence to guide the specific management of antiplatelet therapy-related ICH. With the exceptions of placement of a ventricular drain in patients with hydrocephalus and evacuation of a large posterior fossa hematoma, the timing and nature of other neurosurgical interventions is also controversial. There is substantial evidence that management of patients with ICH in a specialist neurointensive care unit, where treatment is directed toward monitoring and managing cardiorespiratory variables and intracranial pressure, is associated with improved outcomes. Attention must be given to fluid and glycemic management, minimizing the risk of ventilator-acquired pneumonia, fever control, provision of enteral nutrition, and thromboembolic prophylaxis. There is an increasing awareness that aggressive management in the acute phase can translate into improved outcomes after ICH.

The Corfu Landslide: Analog to Giant Landslides on Mars

NASA Technical Reports Server (NTRS)

Lewis, S. W.; Baker, V. R.

1984-01-01

In an analog to the great landslides of the Vales Marineris, Mars, a detailed study was made of the Corfu Landslide in south-central Washington. This prehistoric slide is located on the northern flank of the Saddle Mountains, southwest of Othello, Washington. The slide covers a 13 square km area centered on section 11 of T.15N., R.27E., Willamette Meridian, adjacent to the Corfu townsite. Approximately 1 cubic km of material is involved in sliding that was probably initiated by Missoula flooding through the Channeled Scabland. It is concluded that there were four primary factors involved in the initiation of the Corfu landsliding: (1) A slip surface was present at the right orientation; (2) Glacial flooding undercut the slope; (3) Wetter climatic conditions prevailed during that time period; and (4) Some seismic vibrations, known to occur locally, probably acted as a trigger. These factors show that special conditions were required in conjunction to produce landsliding. Studies in progress of the Vales Marieneris suggest that the same factors probably contributed to landsliding there.

Virulence Factor-activity Relationships: Workshop Summary

EPA Science Inventory

The concept or notion of virulence factor–activity relationships (VFAR) is an approach for identifying an analogous process to the use of qualitative structure–activity relationships (QSAR) for identifying new microbial contaminants. In QSAR, it is hypothesized that, for new chem...

21 CFR 522.1083 - Gonadotropin releasing factor analog-diphtheria toxoid conjugate.

Code of Federal Regulations, 2014 CFR

2014-04-01

... castration (suppression of testicular function) and reduction of boar taint in intact male pigs intended for... veterinarian. Pigs should be slaughtered no earlier than 3 weeks and no later than 10 weeks after the second...

Enhancement of the anti-inflammatory activity of temporin-1Tl-derived antimicrobial peptides by tryptophan, arginine and lysine substitutions.

PubMed

Rajasekaran, Ganesan; Kamalakannan, Radhakrishnan; Shin, Song Yub

2015-10-01

Temporin-1Tl (TL) is a 13-residue frog antimicrobial peptide (AMP) exhibiting potent antimicrobial and anti-inflammatory activity. To develop novel AMP with improved anti-inflammatory activity and antimicrobial selectivity, we designed and synthesized a series of TL analogs by substituting Trp, Arg and Lys at selected positions. Except for Escherichia coli and Staphylococcus epidermidis, all TL analogs exhibited retained or increased antimicrobial activity against seven bacterial strains including three methicillin-resistant Staphylococcus aureus strains compared with TL. TL-1 and TL-4 showed a little increase in antimicrobial selectivity, while TL-2 and TL-3 displayed slightly decreased antimicrobial selectivity because of their about twofold increased hemolytic activity. All TL analogs demonstrated greatly increased anti-inflammatory activity, evident by their higher inhibition of the production tumor necrosis factor-α (TNF-α) and nitric oxide and the mRNA expression of inducible nitric oxide synthase and TNF-α in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells, compared with TL. Taken together, the peptide anti-inflammatory activity is as follows: TL-2 ≈ TL-3 ≈ TL-4 > TL-1 > TL. In addition, LPS binding ability of the peptides corresponded with their anti-inflammatory activity. These results apparently suggest that the anti-inflammatory activity of TL analogs is associated with the direct binding ability between these peptides and LPS. Collectively, our designed TL analogs possess improved anti-inflammatory activity and retain antimicrobial activity without a significant increase in hemolysis. Therefore, it is evident that our TL analogs constitute promising candidates for the development of peptide therapeutics for gram-negative bacterial infection. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.

Applying Human Factors Evaluation and Design Guidance to a Nuclear Power Plant Digital Control System

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thomas Ulrich; Ronald Boring; William Phoenix

2012-08-01

The United States (U.S.) nuclear industry, like similar process control industries, has moved toward upgrading its control rooms. The upgraded control rooms typically feature digital control system (DCS) displays embedded in the panels. These displays gather information from the system and represent that information on a single display surface. In this manner, the DCS combines many previously separate analog indicators and controls into a single digital display, whereby the operators can toggle between multiple windows to monitor and control different aspects of the plant. The design of the DCS depends on the function of the system it monitors, but revolvesmore » around presenting the information most germane to an operator at any point in time. DCSs require a carefully designed human system interface. This report centers on redesigning existing DCS displays for an example chemical volume control system (CVCS) at a U.S. nuclear power plant. The crucial nature of the CVCS, which controls coolant levels and boration in the primary system, requires a thorough human factors evaluation of its supporting DCS. The initial digital controls being developed for the DCSs tend to directly mimic the former analog controls. There are, however, unique operator interactions with a digital vs. analog interface, and the differences have not always been carefully factored in the translation of an analog interface to a replacement DCS. To ensure safety, efficiency, and usability of the emerging DCSs, a human factors usability evaluation was conducted on a CVCS DCS currently being used and refined at an existing U.S. nuclear power plant. Subject matter experts from process control engineering, software development, and human factors evaluated the DCS displays to document potential usability issues and propose design recommendations. The evaluation yielded 167 potential usability issues with the DCS. These issues should not be considered operator performance problems but rather opportunities identified by experts to improve upon the design of the DCS. A set of nine design recommendations was developed to address these potential issues. The design principles addressed the following areas: (1) color, (2) pop-up window structure, (3) navigation, (4) alarms, (5) process control diagram, (6) gestalt grouping, (7) typography, (8) terminology, and (9) data entry. Visuals illustrating the improved DCS displays accompany the design recommendations. These nine design principles serve as the starting point to a planned general DCS style guide that can be used across the U.S. nuclear industry to aid in the future design of effective DCS interfaces.« less

Solid State Research

DTIC Science & Technology

1997-08-15

superconducting resonators that have been demonstrated use microstrip circuits of YBCO at 77 K and niobium at 4 K coupled to polycrystalline magnetic garnet... demagnetizing factor in plane along the direction of propagation, and Ny is the effective demagnetizing factor of the rf magnetization component normal to...Geiger-Mode Avalanche Photodiode Arrays for Imaging Laser Radar 31 6. ANALOG DEVICE TECHNOLOGY 35 6.1 Tunable Superconducting Resonators Using Ferrite

Method and system for photoconductive detector signal correction

DOEpatents

Carangelo, Robert M.; Hamblen, David G.; Brouillette, Carl R.

1992-08-04

A corrective factor is applied so as to remove anomalous features from the signal generated by a photoconductive detector, and to thereby render the output signal highly linear with respect to the energy of incident, time-varying radiation. The corrective factor may be applied through the use of either digital electronic data processing means or analog circuitry, or through a combination of those effects.

Method and system for photoconductive detector signal correction

DOEpatents

Carangelo, R.M.; Hamblen, D.G.; Brouillette, C.R.

1992-08-04

A corrective factor is applied so as to remove anomalous features from the signal generated by a photoconductive detector, and to thereby render the output signal highly linear with respect to the energy of incident, time-varying radiation. The corrective factor may be applied through the use of either digital electronic data processing means or analog circuitry, or through a combination of those effects. 5 figs.

The influence of a prediction display on the quasi-linear describing function and remnant measured with an adaptive analog-pilot in a closed loop

NASA Technical Reports Server (NTRS)

Dey, D.

1972-01-01

The effect of a prediction display on the human transfer characteristics is explained with the aid of a quasi-linear model. The prediction display causes an increase of the gain factor and the lead factor, a diminishing of the lag factor and a decrease of the remnant. Altogether, these factors yield a smaller mean square value of the control deviation and a simultaneous decrease of the mean square value of the stick signal.

Design of 90×8 ROIC with pixel level digital TDI implementation for scanning type LWIR FPAs

NASA Astrophysics Data System (ADS)

Ceylan, Omer; Kayahan, Huseyin; Yazici, Melik; Gurbuz, Yasar

2013-06-01

Design of a 90×8 CMOS readout integrated circuit (ROIC) based on pixel level digital time delay integration (TDI) for scanning type LWIR focal plane arrays (FPAs) is presented. TDI is implemented on 8 pixels which improves the SNR of the system with a factor of √8. Oversampling rate of 3 improves the spatial resolution of the system. TDI operation is realized with a novel under-pixel analog-to-digital converter, which improves the noise performance of ROIC with a lower quantization noise. Since analog signal is converted to digital domain in-pixel, non-uniformities and inaccuracies due to analog signal routing over large chip area is eliminated. Contributions of each pixel for proper TDI operation are added in summation counters, no op-amps are used for summation, hence power consumption of ROIC is lower than its analog counterparts. Due to lack of multiple capacitors or summation amplifiers, ROIC occupies smaller chip area compared to its analog counterparts. ROIC is also superior to its digital counterparts due to novel digital TDI implementation in terms of power consumption, noise and chip area. ROIC supports bi-directional scan, multiple gain settings, bypass operation, automatic gain adjustment, pixel select/deselect, and is programmable through serial or parallel interface. Input referred noise of ROIC is less than 750 rms electrons, while power consumption is less than 20mW. ROIC is designed to perform both in room and cryogenic temperatures.

Stability and Performance of Rapid-Acting Insulin Analogs Used for Continuous Subcutaneous Insulin Infusion: A Systematic Review

PubMed Central

Kerr, David; Wizemann, Erik; Senstius, Jakob; Zacho, Mette; Ampudia-Blasco, Francisco Javier

2013-01-01

Aim: We review and summarize the literature on the safety and stability of rapid-acting insulin analogs used for continuous subcutaneous insulin infusion (CSII) in patients with diabetes. Methods Two predefined search strategies were systematically implemented to search Medline and the Cochrane Register of Clinical Trials for publications between 1996 and 2012. Results Twenty studies were included in the review: 13 in vitro studies and 7 clinical studies. In vitro studies investigated the effects of extreme CSII conditions (high temperature and mechanical agitation) on the risk of catheter occlusions and insulin stability factors, such as potency, purity, high molecular weight protein content, pH stability, and preservative content (m-cresol, phenol). Under these conditions, the overall stability of rapid-acting insulin analogs was similar for insulin lispro, insulin aspart, and insulin glulisine, although insulin glulisine showed greater susceptibility to insulin precipitation and catheter occlusions. A limited number of clinical trials were identified; this evidence-based information suggests that the rate of catheter occlusions in patients with type 1 diabetes using CSII treatment may vary depending on the rapid-acting analog used. Conclusions Based on a limited amount of available data, the safety, stability, and performance of the three available rapid-acting insulin analogs available for use with CSII were similar. However, there is limited evidence suggesting that the risk of occlusion may vary with the insulin preparation under certain circumstances. PMID:24351186

Severe Hemophilia A in a Male Old English Sheep Dog with a C→T Transition that Created a Premature Stop Codon in Factor VIII

PubMed Central

Lozier, Jay N; Kloos, Mark T; Merricks, Elizabeth P; Lemoine, Nathaly; Whitford, Margaret H; Raymer, Robin A; Bellinger, Dwight A; Nichols, Timothy C

2016-01-01

Animals with hemophilia are models for gene therapy, factor replacement, and inhibitor development in humans. We have actively sought dogs with severe hemophilia A that have novel factor VIII mutations unlike the previously described factor VIII intron 22 inversion. A male Old English Sheepdog with recurrent soft-tissue hemorrhage and hemarthrosis was diagnosed with severe hemophilia A (factor VIII activity less than 1% of normal). We purified genomic DNA from this dog and ruled out the common intron 22 inversion; we then sequenced all 26 exons. Comparing the results with the normal canine factor VIII sequence revealed a C→T transition in exon 12 of the factor VIII gene that created a premature stop codon at amino acid 577 in the A2 domain of the protein. In addition, 2 previously described polymorphisms that do not cause hemophilia were present at amino acids 909 and 1184. The hemophilia mutation creates a new TaqI site that facilitates rapid genotyping of affected offspring by PCR and restriction endonuclease analyses. This mutation is analogous to the previously described human factor VIII mutation at Arg583, which likewise is a CpG dinucleotide transition causing a premature stop codon in exon 12. Thus far, despite extensive treatment with factor VIII, this dog has not developed neutralizing antibodies (‘inhibitors’) to the protein. This novel mutation in a dog gives rise to severe hemophilia A analogous to a mutation seen in humans. This model will be useful for studies of the treatment of hemophilia. PMID:27780008

Quantitative PET Imaging of Tissue Factor Expression Using 18F-Labeled Active Site-Inhibited Factor VII.

PubMed

Nielsen, Carsten H; Erlandsson, Maria; Jeppesen, Troels E; Jensen, Mette M; Kristensen, Lotte K; Madsen, Jacob; Petersen, Lars C; Kjaer, Andreas

2016-01-01

Tissue factor (TF) is upregulated in many solid tumors, and its expression is linked to tumor angiogenesis, invasion, metastasis, and prognosis. A noninvasive assessment of tumor TF expression status is therefore of obvious clinical relevance. Factor VII is the natural ligand to TF. Here we report the development of a new PET tracer for specific imaging of TF using an (18)F-labeled derivative of factor VII. Active site-inhibited factor VIIa (FVIIai) was obtained by inactivation with phenylalanine-phenylalanine-arginine-chloromethyl ketone. FVIIai was radiolabeled with N-succinimidyl 4-(18)F-fluorobenzoate and purified. The corresponding product, (18)F-FVIIai, was injected into nude mice with subcutaneous human pancreatic xenograft tumors (BxPC-3) and investigated using small-animal PET/CT imaging 1, 2, and 4 h after injection. Ex vivo biodistribution was performed after the last imaging session, and tumor tissue was preserved for molecular analysis. A blocking experiment was performed in a second set of mice. The expression pattern of TF in the tumors was visualized by immunohistochemistry and the amount of TF in tumor homogenates was measured by enzyme-linked immunosorbent assay and correlated with the uptake of (18)F-FVIIai in the tumors measured in vivo by PET imaging. The PET images showed high uptake of (18)F-FVIIai in the tumor regions, with a mean uptake of 2.5 ± 0.3 percentage injected dose per gram (%ID/g) (mean ± SEM) 4 h after injection of 7.3-9.3 MBq of (18)F-FVIIai and with an average maximum uptake in the tumors of 7.1 ± 0.7 %ID/g at 4 h. In comparison, the muscle uptake was 0.2 ± 0.01 %ID/g at 4 h. At 4 h, the tumors had the highest uptake of any organ. Blocking with FVIIai significantly reduced the uptake of (18)F-FVIIai from 2.9 ± 0.1 to 1.4 ± 0.1 %ID/g (P < 0.001). The uptake of (18)F-FVIIai measured in vivo by PET imaging correlated (r = 0.72, P < 0.02) with TF protein level measured ex vivo. (18)F-FVIIai is a promising PET tracer for specific and noninvasive imaging of tumor TF expression. The tracer merits further development and clinical translation, with potential to become a companion diagnostics for emerging TF-targeted therapies. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Evaluating The Global Inventory of Planetary Analog Environments on Earth: An Ontological Approach

NASA Astrophysics Data System (ADS)

Conrad, P. G.

2010-12-01

Introduction: Field sites on Earth are routinely used to simulate planetary environments so that we can try to understand the evidence of processes such as sedimentary deposition, weathering, evolution of habitable environments, and behavior of spacecraft and instrumentation prior to selection of mission architectures, payload investigations and landing sites for in situ exploration of other planets. The rapid evolution of astrobiology science drivers for space exploration as well as increasing capability to explore planetary surfaces in situ has led to a proliferation of declarations that various Earth environments are analogs for less accessible planetary environments. We have not yet progressed to standardized measures of analog fidelity, and the analog value of field sites can be variable de-pending upon a variety of factors. Here we present a method of evaluating the fidelity and hence utility of analog environments by using an ontological approach to evaluating how well the analogs work. The use of ontologies as specification constructs is now quite common in artificial intelligence, systems engineering, business development and various informatics systems. We borrow from these developments just as they derive from the original use of ontology in philosophy, where it was meant as a systematic approach to describing the fundamental elements that define “being,” or existence [1]. An ontology is a framework for the specification of a concept or domain of interest. The knowledge regarding that domain, eg., inventory of objects, hierarchical classes, relationships and functions is what describes and defines the domain as a declarative formalism [2]. In the case of planetary environments, one can define a list of fundamen-tal attributes without which the domain (environment) in question must be defined (classified) otherwise. In particu-lar this is problematic when looking at ancient environments because of their alteration over time. In other words, their fundamental attributes may no longer exist and have to be reconstructed. In the case of Earth analogs for Mars, there are important distinctions that cannot be duplicated in contemporary Earth environments—we cannot produce the same surface conditions with respect to thermal fluctuation, ionizing radiation and extremely oxidizing chemistry. Mars analogs on Earth: We have studied the habitability of several desert environments on Earth by measuring their chemical, physical and biological features. These locations, which include Battleship Promontory in the McMurdo Dry Valleys, Antarctica; several sites in Svalbard, the arctic; the Imperial Dunes in southern California and Amboy Crater in the Mojave Desert, CA, form the basis for a trial ontology of analog environments which have varying degrees of analogy to potential environments of interest on Mars for exploration of its habitability potential. We present a trial taxonomy for Mars analog environments to which we can add the attributes of other environments advocated as Earth analogs for Mars. References: [1] Bunge,M.,Treatise on Basic Philosophy: Ontology I, The Furniture of the World, Reidel, 1977. [2] Gruber, T. R., (1993). Knowledge Acquisition, 5(2):199-220.

Antarctic Space Analog Program

NASA Technical Reports Server (NTRS)

Palinkas, Lawrence A; Gunderson, E. K. Eric; Johnson, Jeffrey C.; Holland, Albert W.

1998-01-01

The primary aim of this project was to examine group dynamics and individual performance in extreme, isolated environments and identify human factors requirements for long-duration space missions using data collected in an analog environment. Specifically, we wished to determine: 1) the characteristics of social relations in small groups of individuals living and working together in extreme, isolated environments, and 2) the environmental, social and psychological determinants of performance effectiveness in such groups. These two issues were examined in six interrelated studies using data collected in small, isolated research stations in Antarctica from 1963 to the present. Results from these six studies indicated that behavior and performance on long-duration space flights is likely to be seasonal or cyclical, situational, social, and salutogenic in nature. The project responded to two NASA program emphases for FY 1997 as described in the NRA: 1) the primary emphasis of the Behavior and Performance Program on determining long-term individual and group performance responses to space, identifying critical factors affecting those responses and understanding underlying mechanisms involved in behavior and performance, and developing and using ground-based models and analogs for studying space-related behavior and performance; and 2) the emphasis of the Data Analysis Program on extended data analysis. Results from the study were used to develop recommendations for the design and development of pre-flight crew training and in-flight psychological countermeasures for long-duration manned space missions.

Analog phase lock between two lasers at LISA power levels

NASA Astrophysics Data System (ADS)

Diekmann, Christian; Steier, Frank; Sheard, Benjamin; Heinzel, Gerhard; Danzmann, Karsten

2009-03-01

This paper presents the implementation of an analog optical phase-locked-loop with an offset frequency of about 20MHz between two lasers, where the detected light powers were of the order of 31 pW and 200 μW. The goal of this setup was the design and characterization of a photodiode transimpedance amplifier for application in LISA. By application of a transimpedance amplifier designed to have low noise and low power consumption, the phase noise between the two lasers was a factor of two above the shot noise limit down to 60mHz. The achievable phase sensitivity depends ultimately on the available power of the highly attenuated master laser and on the input current noise of the transimpedance amplifier of the photodetector. The limiting noise source below 60mHz was the analog phase measurement system that was used in this experiment. A digital phase measurement system that is currently under development at the AEI will be used in the near future. Its application should improve the sensitivity.

Exobiology site selection for future Mars missions: Martian paleolake sediments and terrestrial analogs

NASA Technical Reports Server (NTRS)

Wharton, Robert A., Jr.

1989-01-01

This research was conducted to establish the scientific framework for the exobiological study of sediments on Mars and to encourage the selection of these sedimentary deposits as sampling sites for future Mars missions. A study was completed on the Antarctic Dry Valley Lakes (terrestrial analogs of the purported Martian paleolakes) and their sediments that allowed the development of quantitative models relating environmental factors to the nature of the biological community and sediment forming processes. The publications presented include: (1) Diversity of micro-fungi isolated in an Antarctic dry valley; (2) Lake Hoare, Antarctica--sedimentation through a thick perennial ice cover; (3) The possibility of life on Mars during a water-rich past; (4) An Antarctic research outpost as a model for planetary exploration; (5) Early Martian environments--the Antarctic and other terrestrial analogs; (6) Lipophilic pigments from the benthos of a perennially ice-covered Antarctic lake; and (7) Perennially ice-covered Lake Hoare, Antarctica--physical environment, biology, and sedimentation.

Using analogy role-play activity in an undergraduate biology classroom to show central dogma revision.

PubMed

Takemura, Masaharu; Kurabayashi, Mario

2014-01-01

For the study of biology in an undergraduate classroom, a classroom exercise was developed: an analogy role-play to learn mechanisms of gene transcription and protein translation (central dogma). To develop the central dogma role-play exercise, we made DNA and mRNA using paper sheets, tRNA using a wire dress hanger, and amino acids using Lego® blocks (Lego System A/S, Denmark). Students were studying in the course of mathematics, physics, or chemistry, so biology was not among their usual studies. In this exercise, students perform the central dogma role-play and respectively act out nuclear matrix proteins, a transcription factor, an RNA polymerase II, an mRNA transport protein, nuclear pore proteins, a large ribosomal subunit, a small ribosomal subunit, and several amino-acyl tRNA synthetases. Questionnaire results obtained after the activity show that this central dogma role-play analogy holds student interest in the practical molecular biological processes of transcription and translation. © 2014 The International Union of Biochemistry and Molecular Biology.

Comparison of protocols for measuring and calculating postmortem submersion intervals for human analogs in fresh water.

PubMed

Humphreys, Michael K; Panacek, Edward; Green, William; Albers, Elizabeth

2013-03-01

Protocols for determining postmortem submersion interval (PMSI) have long been problematic for forensic investigators due to the wide variety of factors affecting the rate of decomposition of submerged carrion. Likewise, it has been equally problematic for researchers to develop standardized experimental protocols to monitor underwater decomposition without artificially affecting the decomposition rate. This study compares two experimental protocols: (i) underwater in situ evaluation with photographic documentation utilizing the Heaton et al. total aquatic decomposition (TAD) score and (ii) weighing the carrion before and after submersion. Complete forensic necropsies were performed as a control. Perinatal piglets were used as human analogs. The results of this study indicate that in order to objectively measure decomposition over time, the human analog should be examined at depth using the TAD scoring system rather than utilizing a carrion weight evaluation. The acquired TAD score can be used to calculate an approximate PMSI. © 2012 American Academy of Forensic Sciences.

Structure-Activity Relationships of 6- and 8-Gingerol Analogs as Anti-Biofilm Agents.

PubMed

Choi, Hyunsuk; Ham, So-Young; Cha, Eunji; Shin, Yujin; Kim, Han-Shin; Bang, Jeong Kyu; Son, Sang-Hyun; Park, Hee-Deung; Byun, Youngjoo

2017-12-14

Pseudomonas aeruginosa is a causative agent of chronic infections in immunocompromised patients. Disruption of quorum sensing circuits is an attractive strategy for treating diseases associated with P. aeruginosa infection. In this study, we designed and synthesized a series of gingerol analogs targeting LasR, a master regulator of quorum sensing networks in P. aeruginosa. Structure-activity relationship studies showed that a hydrogen-bonding interaction in the head section, stereochemistry and rotational rigidity in the middle section, and optimal alkyl chain length in the tail section are important factors for the enhancement of LasR-binding affinity and for the inhibition of biofilm formation. The most potent compound 41, an analog of (R)-8-gingerol with restricted rotation, showed stronger LasR-binding affinity and inhibition of biofilm formation than the known LasR antagonist (S)-6-gingerol. This new LasR antagonist can be used as an early lead compound for the development of anti-biofilm agents to treat P. aeruginosa infections.

A CMOS image sensor with programmable pixel-level analog processing.

PubMed

Massari, Nicola; Gottardi, Massimo; Gonzo, Lorenzo; Stoppa, David; Simoni, Andrea

2005-11-01

A prototype of a 34 x 34 pixel image sensor, implementing real-time analog image processing, is presented. Edge detection, motion detection, image amplification, and dynamic-range boosting are executed at pixel level by means of a highly interconnected pixel architecture based on the absolute value of the difference among neighbor pixels. The analog operations are performed over a kernel of 3 x 3 pixels. The square pixel, consisting of 30 transistors, has a pitch of 35 microm with a fill-factor of 20%. The chip was fabricated in a 0.35 microm CMOS technology, and its power consumption is 6 mW with 3.3 V power supply. The device was fully characterized and achieves a dynamic range of 50 dB with a light power density of 150 nW/mm2 and a frame rate of 30 frame/s. The measured fixed pattern noise corresponds to 1.1% of the saturation level. The sensor's dynamic range can be extended up to 96 dB using the double-sampling technique.

Nonsyndromic recessive deafness DFNB18 and Usher syndrome type IC are allelic mutations of USHIC.

PubMed

Ahmed, Zubair M; Smith, Tenesha N; Riazuddin, Saima; Makishima, Tomoko; Ghosh, Manju; Bokhari, Sirosh; Menon, Puthezhath S N; Deshmukh, Dilip; Griffith, Andrew J; Riazuddin, Sheikh; Friedman, Thomas B; Wilcox, Edward R

2002-06-01

Human chromosome 11 harbors two Usher type I loci, USHIB and USHIC, which encode myosin VIIA and harmonin, respectively. The USHIC locus overlaps the reported critical interval for nonsyndromic deafness locus DFNB18. We found an IVS12+5G-->C mutation in the USHIC gene, which is associated with nonsyndromic recessive deafness ( DFNB18) segregating in the original family, S-11/12. No other disease-associated mutation was found in the other 27 exons or in the intron-exon boundaries, and the IVS12+5G-->C mutation was not present in 200 representative unaffected individuals ascertained from the same area of India. An exon-trapping assay with a construct harboring IVS12+5G-->C generated wildtype spliced mRNA having exons 11 and 12 and mRNA that skipped exon 12. We conclude that mutations of USHIC can cause both Usher syndrome type IC and nonsyndromic recessive deafness DFNB18.

Mutations in myosin VIIA (MYO7A) and usherin (USH2A) in Spanish patients with Usher syndrome types I and II, respectively.

PubMed

Nájera, Carmen; Beneyto, Magdalena; Blanca, José; Aller, Elena; Fontcuberta, Ana; Millán, José María; Ayuso, Carmen

2002-07-01

Usher syndrome is an autosomal recessive disorder characterized by congenital hearing impairment and retinitis pigmentosa. Three clinical types are known (USH1, USH2 and USH3), and there is an extensive genetic heterogeneity, with at least ten genes implicated. The most frequently mutated genes are MYO7A, which causes USH1B, and usherin, which causes USH2A. We carried out a mutation analysis of these two genes in the Spanish population. Analysis of the MYO7A gene in patients from 30 USH1 families and sporadic cases identified 32% of disease alleles, with mutation Q821X being the most frequent. Most of the remaining variants are private mutations. With regard to USH2, mutation 2299delG was detected in 25% of the Spanish patients. Altogether the mutations detected in USH2A families account for 23% of the disease alleles. Copyright 2002 Wiley-Liss, Inc.

Facilitating Problem Solving in High School Chemistry.

ERIC Educational Resources Information Center

Gabel, Dorothy L.; Sherwood, Robert D.

1983-01-01

Investigated superiority of instructional strategies (factor-label method, proportionality, use of analogies, use of diagrams) in teaching problem-solving related to mole concept, gas laws, stoichiometry, and molarity. Also investigated effectiveness of strategies for students (N=609) with different verbal-visual preferences, proportional…

A Natural Language for AdS/CFT Correlators

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fitzpatrick, A.Liam; /Boston U.; Kaplan, Jared

2012-02-14

We provide dramatic evidence that 'Mellin space' is the natural home for correlation functions in CFTs with weakly coupled bulk duals. In Mellin space, CFT correlators have poles corresponding to an OPE decomposition into 'left' and 'right' sub-correlators, in direct analogy with the factorization channels of scattering amplitudes. In the regime where these correlators can be computed by tree level Witten diagrams in AdS, we derive an explicit formula for the residues of Mellin amplitudes at the corresponding factorization poles, and we use the conformal Casimir to show that these amplitudes obey algebraic finite difference equations. By analyzing the recursivemore » structure of our factorization formula we obtain simple diagrammatic rules for the construction of Mellin amplitudes corresponding to tree-level Witten diagrams in any bulk scalar theory. We prove the diagrammatic rules using our finite difference equations. Finally, we show that our factorization formula and our diagrammatic rules morph into the flat space S-Matrix of the bulk theory, reproducing the usual Feynman rules, when we take the flat space limit of AdS/CFT. Throughout we emphasize a deep analogy with the properties of flat space scattering amplitudes in momentum space, which suggests that the Mellin amplitude may provide a holographic definition of the flat space S-Matrix.« less

77 FR 67007 - Federal Reserve Bank Services Private Sector Adjustment Factor

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-08

... had characteristics most analogous to correspondent banks, clearing balances held by depository institutions at Reserve Banks were a primary component in computing the PSAF. The clearing balance program was largely modeled after similar programs offered by correspondent banks, wherein banks maintain balances...

Dialkoxyquinazolines: Screening Epidermal Growth Factor ReceptorTyrosine Kinase Inhibitors for Potential Tumor Imaging Probes

DOE Office of Scientific and Technical Information (OSTI.GOV)

VanBrocklin, Henry F.; Lim, John K.; Coffing, Stephanie L.

2005-09-01

The epidermal growth factor receptor (EGFR), a long-standingdrug development target, is also a desirable target for imaging. Sixteendialkoxyquinazoline analogs, suitable for labeling with positron-emittingisotopes, have been synthesized and evaluated in a battery of in vitroassays to ascertain their chemical and biological properties. Thesecharacteristics provided the basis for the adoption of a selection schemato identify lead molecules for labeling and in vivo evaluation. A newEGFR tyrosine kinase radiometric binding assay revealed that all of thecompounds possessed suitable affinity (IC50 = 0.4 - 51 nM) for the EGFRtyrosine kinase. All of the analogs inhibited ligand-induced EGFRtyrosine phosphorylation (IC50 = 0.8 - 20more » nM). The HPLC-estimatedoctanol/water partition coefficients ranged from 2.0-5.5. Four compounds,4-(2'-fluoroanilino)- and 4-(3'-fluoroanilino)-6,7-diethoxyquinazoline aswell as 4-(3'-chloroanilino)- and4-(3'-bromoanilino)-6,7-dimethoxyquinazoline, possess the bestcombination of characteristics that warrant radioisotope labeling andfurther evaluation in tumor-bearing mice.« less

Deep Space Mission Trend Analyses: A Briefing to the Next Generation EBRE Study Team

NASA Technical Reports Server (NTRS)

Abraham, Douglas S.

2012-01-01

Determination of stakeholder needs for next generation implementations necessitates a multi ]pronged approach. . Future mission set analyses provide a lower gbound h for some of these needs. . Earth ]based analogies provide an upper gbound h for some of these needs. . Interpreting the results requires being mindful of both the near ]term contextual factors and long ]term factors that are in play. . In the context of last year fs analyses, the current budget environment, the potential Pu ]238 shortage, and SMD fs gsingle 34m only h policy may, collectively, create a future deep space mission set that, from a capacity and end ]to ]end link difficulty standpoint, is no more challenging than it is today. . Nonetheless, data rates and volumes continue to increase, suggesting capability and spectrum challenges ahead. These results agree with the results from the Earthbased analogies. . Emerging developments such as smallsats and distributed spacecraft could significantly change the capacity and end ]to ]end link difficulty picture.

Network-Physics(NP) Bec DIGITAL(#)-VULNERABILITY Versus Fault-Tolerant Analog

NASA Astrophysics Data System (ADS)

Alexander, G. K.; Hathaway, M.; Schmidt, H. E.; Siegel, E.

2011-03-01

Siegel[AMS Joint Mtg.(2002)-Abs.973-60-124] digits logarithmic-(Newcomb(1881)-Weyl(1914; 1916)-Benford(1938)-"NeWBe"/"OLDbe")-law algebraic-inversion to ONLY BEQS BEC:Quanta/Bosons= digits: Synthesis reveals EMP-like SEVERE VULNERABILITY of ONLY DIGITAL-networks(VS. FAULT-TOLERANT ANALOG INvulnerability) via Barabasi "Network-Physics" relative-``statics''(VS.dynamics-[Willinger-Alderson-Doyle(Not.AMS(5/09)]-]critique); (so called)"Quantum-computing is simple-arithmetic(sans division/ factorization); algorithmic-complexities: INtractibility/ UNdecidability/ INefficiency/NONcomputability / HARDNESS(so MIScalled) "noise"-induced-phase-transitions(NITS) ACCELERATION: Cook-Levin theorem Reducibility is Renormalization-(Semi)-Group fixed-points; number-Randomness DEFINITION via WHAT? Query(VS. Goldreich[Not.AMS(02)] How? mea culpa)can ONLY be MBCS "hot-plasma" versus digit-clumping NON-random BEC; Modular-arithmetic Congruences= Signal X Noise PRODUCTS = clock-model; NON-Shor[Physica A,341,586(04)] BEC logarithmic-law inversion factorization:Watkins number-thy. U stat.-phys.); P=/=NP TRIVIAL Proof: Euclid!!! [(So Miscalled) computational-complexity J-O obviation via geometry.

Designing Agent Collectives For Systems With Markovian Dynamics

NASA Technical Reports Server (NTRS)

Wolpert, David H.; Lawson, John W.

2004-01-01

The Collective Intelligence (COIN) framework concerns the design of collectives of agents so that as those agents strive to maximize their individual utility functions, their interaction causes a provided world utility function concerning the entire collective to be also maximized. Here we show how to extend that framework to scenarios having Markovian dynamics when no re-evolution of the system from counter-factual initial conditions (an often expensive calculation) is permitted. Our approach transforms the (time-extended) argument of each agent's utility function before evaluating that function. This transformation has benefits in scenarios not involving Markovian dynamics of an agent's utility function are observable. We investigate this transformation in simulations involving both hear and quadratic (nonlinear) dynamics. In addition, we find that a certain subset of these transformations, which result in utilities that have low opacity (analogous to having high signal to noise) but are not factored (analogous to not being incentive compatible), reliably improve performance over that arising with factored utilities. We also present a Taylor Series method for the fully general nonlinear case.

Genetic analysis of Bacillus stearothermophilus by protoplast fusion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Z.; Wojcik, S.F.; Welker, N.E.

1986-03-01

Efficient and reliable protoplasting, regeneration, and fusion techniques were established for the prototrophic strain Bacillus stearothermophilus NUB36. Auxotrophic mutants were isolated, and protoplast fusion was used to construct isogenic mutant strains and for chromosomal mapping. Markers were mapped using two-, three-, and four-factor crosses. The order of the markers was hom-1-thr-1-his-1-(gly-1 or gly-2)-pur-1-pur-2. These markers may be analogous to hom, thrA, hisA, glyC, and purA markers on the Bacillus subtilis chromosome. No analogous pur-1 marker has been reported in B. subtilis. The relative order of three of the markers (hom-1-thr-1-gly-1) was independently confirmed by transduction.

Inflight characterization and correction of Planck/HFI analog to digital converter nonlinearity

NASA Astrophysics Data System (ADS)

Sauvé, A.; Couchot, F.; Patanchon, G.; Montier, L.

2016-07-01

The Planck Satellite launched in 2009 was targeted to observe the anisotropies of the Cosmic Microwave Back-ground (CMB) to an unprecedented sensitivity. While the Analog to Digital Converter of the HFI (High Frequency Instrument) readout electronics had not been properly characterized on ground, it has been shown to add a systematic nonlinearity effect up to 2% of the cosmological signal. This was a limiting factor for CMB science at large angular scale. We will present the in-flight analysis and method used to characterize and correct this effect down to 0.05% level. We also discuss how to avoid this kind of complex issue for future missions.

Mars inflatable greenhouse analog.

PubMed

Sadler, Philip D; Giacomelli, Gene A

2002-01-01

Light intensities on the Martian surface can possibly support a bioregenerative life support system (BLSS) utilizing natural sunlight for hydroponic crop production, if a suitable controlled environment can be provided. Inflatable clear membrane structures offer low mass, are more easily transported than a rigid structure, and are good candidates for providing a suitable controlled environment for crop production. Cable culture is one hydroponic growing system that can take advantage of the beneficial attributes of the inflatable structure. An analog of a Mars inflatable greenhouse can provide researchers data on issues such as crew time requirements for operation, productivity for BLSS, human factors, and much more at a reasonable cost. This is a description of one such design.

Preliminary evaluation of an analog procedure to assess acceptability of intimate partner violence against women: the Partner Violence Acceptability Movie Task

PubMed Central

Gracia, Enrique; Rodriguez, Christina M.; Lila, Marisol

2015-01-01

Acceptability of partner violence against women is a risk factor linked to its perpetration, and to public, professionals’ and victims’ responses to this behavior. Research on the acceptability of violence in intimate partner relationships is, however, limited by reliance solely on self-reports that often provide distorted or socially desirable accounts that may misrepresent respondents’ attitudes. This study presents data on the development and initial validation of a new analog task assessing respondents’ acceptability of physical violence toward women in intimate relationships: the Partner Violence Acceptability Movie Task (PVAM). This new analog task is intended to provide a more implicit measure of the acceptability of partner violence against women. For this analog task, clips were extracted from commercially available films (90-s segments) portraying partner violence. Two independent samples were used to develop and evaluate the PVAM: a sample of 245 undergraduate students and a sample of 94 male intimate partner violence offenders. This new analog task demonstrated acceptable internal consistency. Results also indicated adequate construct validity. Both perpetrators and undergraduates scoring high in the PVAM also scored higher in self-reported justifications of partner abuse. Perpetrators of partner violence scored significantly higher in acceptability of partner violence than the undergraduate sample (both male and female students), and male students scored higher than females. These preliminary results suggest that the PVAM may be a promising tool to assess the acceptability of violence in intimate partner relationships, highlighting the need to consider alternatives to self-report to evaluate potential beliefs about partner violence. PMID:26528220

Proverb Comprehension as a Function of Reading Proficiency in Preadolescents.

PubMed

Nippold, Marilyn A; Allen, Melissa M; Kirsch, Dixon I

2001-04-01

Proverb comprehension through reading was examined in 42 preadolescents (mean age=12:2 [years:months]) attending a rural public middle school. The study was designed to learn about individual differences with respect to reading, word knowledge, and analogical reasoning skills. The 42 students were assigned to subgroups of proficient and less proficient readers based on their scores on a school-administered achievement test. Reading tasks were presented to examine their comprehension of unfamiliar concrete (e.g., every bird must hatch its own eggs) and abstract (e.g., gratitude is a heavy burden) proverbs, and their knowledge of nouns contained in the expressions. A nonverbal analogical reasoning task also was administered. Proverb comprehension was found to be associated with reading proficiency, word knowledge, and analogical reasoning. Although all students were considered by their school to be typical achievers, they demonstrated wide individual differences in their ability to interpret unfamiliar concrete and abstract proverbs. Proficient readers outperformed less proficient readers on comprehension of both types of proverbs, knowledge of abstract nouns contained in proverbs, and analogical reasoning. They did not differ, however, on knowledge of concrete nouns, with both subgroups having mastered those words. Educational Implications: The results support the view that reading is an important language modality in older children, significantly related to their understanding of words and figurative expressions. Implications for instruction in proverb comprehension as part of a language arts curriculum are offered for speech-language pathologists working collaboratively with classroom teachers. These guidelines reflect the view that multiple factors (i.e., reading, word knowledge, analogical reasoning) promote proverb comprehension in youth.

Performance Effects of Display Incogruity in a Digital and Analog Clock Reading Task

NASA Technical Reports Server (NTRS)

Comstock, J. Raymond, Jr.; Derks, Peter L.

2004-01-01

In an era of increasing automation, it is important to design displays and input devices that minimize human error. In this context, information concerning the human response to the detection of incongruous information is important. Such incongruous information can be operationalized as unexpected (perhaps erroneous) information on which a decision by the human or operation by an automated system is based. In the aviation environment, decision making when faced with inadequate, incomplete, or incongruous information may occur in a failure scenario. An additional challenge facing the human operator in automated environments is maintaining alertness or vigilance. The vigilance issue is of particular concern as a factor that may interact with performance when faced with inadequate, incomplete, or incongruous information. From the literature on eye-scan behavior we know that the time spent looking at a particular display or indicator is a function of the type of information one is trying to discern from the display. For example, quick glances are all it takes for confirming that an indicator is in a normal position or range, whereas a continuous look of several seconds may be required for confirmation that a complex control input is having the desired effect. Important to consider is that while an extended look takes place, visual input from other sources may be missed. Much like an extended look, the interpretation of incongruous information may require extra time. The present experiment was designed to explore the performance consequences of a decision making task when incongruous information was presented. For this experiment a display incongruity was created on a subset of trials of a clock reading laboratory task. Display incongruity was made possible through presentation of 'impossible' times (e.g. 1:65 or 11:90). Subjects made 'same' 'different' decisions and keyboard responses to pairings of Analog-Analog (AA), Digital-Digital (DD), and Analog- Digital (AD), display combinations. For trials during which display incongruities were not presented, based on prior research comparing digital and analog clock displays, it would be expected that the Digital-Digital condition would result in the shortest response times and the Analog-Analog and Analog-Digital conditions would have longer response times. The performance consequence expected on trials with incongruous times would be very long response times.

HEAT TRANSFER FROM SURFACES OF NON-UNIFORM TEMPERATURE DISTRIBUTION. PART II. TURBULENT TRANSFER FROM ISOTHERMAL SPANWISE STRIPS ON A FLAT PLATE

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sogin, H.H.; Goldstein, R.J.

1960-02-01

Experiments were performed on mass transfer by forced convection from naphthalene strips on a flat plate to an air stream at ordinary temperature and pressure. Turbulence was induced in the boundary layer by means of a wire strip. In all cases there was a hydrodynamic starting length upstream of the strips. The ratio of this inert length to the total length was varied from about 0.80 to 0.96. The flow was practically incompressible with Reynolds number, based on the total length, varying from 175,000 to 486,000. The Schmidt number was 2.5. The experimental results fell in proximity to the Sebanmore » step function factor when they were reduced after the massmomentum analysis of Deissler and Loeffler for a surface of uniform vapor pressure. When Karman's formulation of the mass- momentum analogy was assumed, the data fell between the values predicted by the Seban and by the Rubesin expression for the step function factor. The results were well correlated by the Colburn analogy in conjunction with the Rubesin step function factor. (auth)« less

Efficient audio signal processing for embedded systems

NASA Astrophysics Data System (ADS)

Chiu, Leung Kin

As mobile platforms continue to pack on more computational power, electronics manufacturers start to differentiate their products by enhancing the audio features. However, consumers also demand smaller devices that could operate for longer time, hence imposing design constraints. In this research, we investigate two design strategies that would allow us to efficiently process audio signals on embedded systems such as mobile phones and portable electronics. In the first strategy, we exploit properties of the human auditory system to process audio signals. We designed a sound enhancement algorithm to make piezoelectric loudspeakers sound ”richer" and "fuller." Piezoelectric speakers have a small form factor but exhibit poor response in the low-frequency region. In the algorithm, we combine psychoacoustic bass extension and dynamic range compression to improve the perceived bass coming out from the tiny speakers. We also developed an audio energy reduction algorithm for loudspeaker power management. The perceptually transparent algorithm extends the battery life of mobile devices and prevents thermal damage in speakers. This method is similar to audio compression algorithms, which encode audio signals in such a ways that the compression artifacts are not easily perceivable. Instead of reducing the storage space, however, we suppress the audio contents that are below the hearing threshold, therefore reducing the signal energy. In the second strategy, we use low-power analog circuits to process the signal before digitizing it. We designed an analog front-end for sound detection and implemented it on a field programmable analog array (FPAA). The system is an example of an analog-to-information converter. The sound classifier front-end can be used in a wide range of applications because programmable floating-gate transistors are employed to store classifier weights. Moreover, we incorporated a feature selection algorithm to simplify the analog front-end. A machine learning algorithm AdaBoost is used to select the most relevant features for a particular sound detection application. In this classifier architecture, we combine simple "base" analog classifiers to form a strong one. We also designed the circuits to implement the AdaBoost-based analog classifier.

An evolutionary perspective on the history of flap reconstruction in the upper extremity.

PubMed

Fang, Frank; Chung, Kevin C

2014-05-01

Examining the evolution of flap reconstruction of the upper extremity is similar to studying the evolution of biological species. This analogy provides a perspective to appreciate the contributing factors that led to the development of the current arsenal of techniques. It shows the trajectory for the future and provides a glimpse of the factors that that will be influential in the future. Copyright © 2014 Elsevier Inc. All rights reserved.

Fast controller for a unity-power-factor PWM rectifier

DOE Office of Scientific and Technical Information (OSTI.GOV)

Eissa, M.O.; Leeb, S.B.; Verghese, G.C.

1996-01-01

This paper presents an analog implementation of a fast controller for a unity-power-factor (UPF) PWM rectifier. The best settling times of many popular controllers for this type of converter are on the order of a few line cycles, corresponding to bandwidths under 20 Hz. The fast controller demonstrated in this paper can exercise control action at a rate comparable to the switching frequency rather than the line frequency. In order to accomplish this while maintaining unity power factor during steady-state operation, the fast controller employs a ripple-feedback cancellation scheme.

Using Internet Audio to Enhance Online Accessibility

ERIC Educational Resources Information Center

Schwartz, Linda Matula

2004-01-01

Accessibility to online education programs is an important factor that requires continued research, improvement, and regulation. Particularly valuable in the enhancement of online accessibility is the Voice-over Internet Protocol (VOIP) medium. VOIP compresses analog voice data and converts it into digital packets for transmission over the…

A Planar Calculus for Infinite Index Subfactors

NASA Astrophysics Data System (ADS)

Penneys, David

2013-05-01

We develop an analog of Jones' planar calculus for II 1-factor bimodules with arbitrary left and right von Neumann dimension. We generalize to bimodules Burns' results on rotations and extremality for infinite index subfactors. These results are obtained without Jones' basic construction and the resulting Jones projections.

Who's at Risk in Reading?

ERIC Educational Resources Information Center

Vacca, Richard T.; Padak, Nancy D.

1990-01-01

Draws an analogy between the insurance business and at-risk students. Argues that being at-risk in reading means a failure to gain control over reading and reading to learn, leading to learned helplessness. Discusses factors associated with learned helplessness. Outlines what teachers can do for at-risk students. (RS)

Pharmacokinetics, pharmacodynamics and safety of recombinant canine FVIIa in a study dosing one haemophilia A and one haemostatically normal dog.

PubMed

Knudsen, T; Kristensen, A T; Nichols, T C; Agersø, H; Jensen, A L; Kjalke, M; Ezban, M; Tranholm, M

2011-11-01

Recombinant human FVIIa (rhFVIIa) corrects the coagulopathy in hemophilia A and B as well as FVII deficiency. This is also the case in dogs until canine anti-human FVIIa antibodies develop (~2 weeks). Recombinant canine factor VIIa (rcFVIIa), successfully over-expressed by gene transfer in haemophilia dogs, has provided long-term haemostasis (>2 years). However, pharmacokinetics (PK), pharmacodynamics (PD) and safety of rcFVIIa after pharmacological administration have not been reported. We therefore wanted to explore the safety, PK and PD of rcFVIIa in dogs. A pilot study was set up to evaluate the safety as well as PK and PD of rcFVIIa after a single intravenous dose of 270 μg kg(-1) to one HA and one haemostatically normal dog and to directly compare rcFVIIa with rhFVIIa in these two dogs. Single doses of rcFVIIa and rhFVIIa were well tolerated. No adverse events were observed. Pharmacokinetic characteristics including half-life (FVIIa activity: 1.2-1.8 h; FVIIa antigen 2.8-3.7 h) and clearance were comparable for rcFVIIa and rhFVIIa. Kaolin-activated thromboelastography approached normal in the HA dog with the improvement being most pronounced after rcFVIIa. This study provided the first evidence that administering rcFVIIa intravenously is feasible, safe, well tolerated and efficacious in correcting the haemophilic coagulopathy in canine HA and that rcFVIIa exhibits pharmacokinetic characteristics comparable to rhFVIIa in haemophilic and haemostatically competent dogs. This strengthens the hypothesis that rcFVIIa can be administered to dogs to mimic the administration of rhFVIIa to humans. © 2011 Blackwell Publishing Ltd.

Interaction of antithrombin with sulfated, low molecular weight lignins: opportunities for potent, selective modulation of antithrombin function.

PubMed

Henry, Brian L; Connell, Justin; Liang, Aiye; Krishnasamy, Chandravel; Desai, Umesh R

2009-07-31

Antithrombin, a major regulator of coagulation and angiogenesis, is known to interact with several natural sulfated polysaccharides. Previously, we prepared sulfated low molecular weight variants of natural lignins, called sulfated dehydrogenation polymers (DHPs) (Henry, B. L., Monien, B. H., Bock, P. E., and Desai, U. R. (2007) J. Biol. Chem. 282, 31891-31899), which have now been found to exhibit interesting antithrombin binding properties. Sulfated DHPs represent a library of diverse noncarbohydrate aromatic scaffolds that possess structures completely different from heparin and heparan sulfate. Fluorescence binding studies indicate that sulfated DHPs bind to antithrombin with micromolar affinity under physiological conditions. Salt dependence of binding affinity indicates that the antithrombin-sulfated DHP interaction involves a massive 80-87% non-ionic component to the free energy of binding. Competitive binding studies with heparin pentasaccharide, epicatechin sulfate, and full-length heparin indicate that sulfated DHPs bind to both the pentasaccharide-binding site and extended heparin-binding site of antithrombin. Affinity capillary electrophoresis resolves a limited number of peaks of antithrombin co-complexes suggesting preferential binding of selected DHP structures to the serpin. Computational genetic algorithm-based virtual screening study shows that only one sulfated DHP structure, out of the 11 present in a library of plausible sequences, bound in the heparin-binding site with a high calculated score supporting selectivity of recognition. Enzyme inhibition studies indicate that only one of the three sulfated DHPs studied is a potent inhibitor of free factor VIIa in the presence of antithrombin. Overall, the chemo-enzymatic origin and antithrombin binding properties of sulfated DHPs present novel opportunities for potent and selective modulation of the serpin function, especially for inhibiting the initiation phase of hemostasis.

Elevated expression of the metabolic regulator receptor-interacting protein 140 results in cardiac hypertrophy and impaired cardiac function.

PubMed

Fritah, Asmaà; Steel, Jennifer H; Nichol, Donna; Parker, Nadeene; Williams, Sharron; Price, Anthony; Strauss, Leena; Ryder, Timothy A; Mobberley, Margaret A; Poutanen, Matti; Parker, Malcolm; White, Roger

2010-06-01

Receptor-interacting protein 140 (RIP140) is a ligand-dependent cofactor for nuclear receptors that regulate networks of genes involved in cellular processes, including metabolism. An important role for RIP140 in metabolic control has been identified in RIP140 null mice, whose phenotypes include derepression of genes involved in energy mobilization or catabolism in adipocytes and a switch to more oxidative fibres in skeletal muscle. We hypothesized that ubiquitous expression of RIP140 would suppress metabolic processes, leading to defects in development or cellular function. The primary effect of exogenous expression of RIP140 mRNA (real-time PCR) and protein (western blotting) in transgenic mice is impaired postnatal heart function. There was rapid onset of cardiac hypertrophy and ventricular fibrosis, detected microscopically, in male RIP140 transgenic mice from 4 weeks of age, resulting in 25% mortality by 5 months. RIP140 exogenous expression in the heart leads to decreased mitochondria state III and state IV membrane potential and oxygen consumption. Quantitative PCR showed more than 50% reduced expression of genes involved in mitochondrial activity and fatty acid metabolism, including mitochondrial transcription factor A, cytochrome oxidase VIIa, cytochrome XII, CD36, medium-chain acyl dehydrogenase, and fatty acid transport protein, many of which are known targets for nuclear receptors, including peroxisome proliferator-activated receptors PPARalpha and PPARdelta and oestrogen-related receptors ERRalpha and ERRgamma. This study demonstrates that RIP140 is an important cofactor in postnatal cardiac function and that inhibition of the action of RIP140 may provide a model system to investigate specific interventions designed to prevent or delay the onset of cardiac disease.

Quantifying Uncertainty of Wind Power Production Through an Analog Ensemble

NASA Astrophysics Data System (ADS)

Shahriari, M.; Cervone, G.

2016-12-01

The Analog Ensemble (AnEn) method is used to generate probabilistic weather forecasts that quantify the uncertainty in power estimates at hypothetical wind farm locations. The data are from the NREL Eastern Wind Dataset that includes more than 1,300 modeled wind farms. The AnEn model uses a two-dimensional grid to estimate the probability distribution of wind speed (the predictand) given the values of predictor variables such as temperature, pressure, geopotential height, U-component and V-component of wind. The meteorological data is taken from the NCEP GFS which is available on a 0.25 degree grid resolution. The methodology first divides the data into two classes: training period and verification period. The AnEn selects a point in the verification period and searches for the best matching estimates (analogs) in the training period. The predictand value at those analogs are the ensemble prediction for the point in the verification period. The model provides a grid of wind speed values and the uncertainty (probability index) associated with each estimate. Each wind farm is associated with a probability index which quantifies the degree of difficulty to estimate wind power. Further, the uncertainty in estimation is related to other factors such as topography, land cover and wind resources. This is achieved by using a GIS system to compute the correlation between the probability index and geographical characteristics. This study has significant applications for investors in renewable energy sector especially wind farm developers. Lower level of uncertainty facilitates the process of submitting bids into day ahead and real time electricity markets. Thus, building wind farms in regions with lower levels of uncertainty will reduce the real-time operational risks and create a hedge against volatile real-time prices. Further, the links between wind estimate uncertainty and factors such as topography and wind resources, provide wind farm developers with valuable information regarding wind farm siting.

Human Factor Investigation of Waste Processing System During the HI-SEAS 4 Month Mars Analog Mission in Support of NASA's Logistic Reduction and Repurposing Project: Trash to Gas

NASA Technical Reports Server (NTRS)

Caraccio, Anne; Hintze, Paul; Miles, John D.

2014-01-01

NASAs Logistics Reduction and Repurposing (LRR) project is a collaborative effort in which NASA is tasked with reducing total logistical mass through reduction, reuse and recycling of various wastes and components of long duration space missions and habitats. Trash to Gas (TtG) is a sub task to LRR with efforts focused on development of a technology that converts wastes generated during long duration space missions into high-value products such as methane, water for life support, raw material production feedstocks, and other energy sources. The reuse of discarded materials is a critical component to reducing overall mission mass. The 120 day Hawaii Space Exploration and Analog Simulation provides a unique opportunity to answer questions regarding crew interface and system analysis for designing and developing future flight-like versions of a TtG system. This paper will discuss the human factors that would affect the design of a TtG or other waste processing systems. An overview of the habitat, utility usage, and waste storage and generation is given. Crew time spent preparing trash for TtG processing was recorded. Gas concentrations were measured near the waste storage locations and at other locations in the habitat. In parallel with the analog mission, experimental processing of waste materials in a TtG reactor was performed in order to evaluate performance with realistic waste materials.

Human Factor Investigation of Waste Processing System During the HI-SEAS 4-month Mars Analog Mission in Support of NASA's Logistic Reduction and Repurposing Project: Trash to Gas

NASA Technical Reports Server (NTRS)

Caraccio, Anne; Hintze, Paul E.; Miles, John D.

2014-01-01

NASA's Logistics Reduction and Repurposing (LRR) project is a collaborative effort in which NASA is tasked with reducing total logistical mass through reduction, reuse and recycling of various wastes and components of long duration space missions and habitats. Trash to Gas (TtG) is a sub task to LRR with efforts focused on development of a technology that converts wastes generated during long duration space missions into high-value products such as methane, water for life support, raw material production feedstocks, and other energy sources. The reuse of discarded materials is a critical component to reducing overall mission mass. The 120 day Hawaii Space Exploration and Analog Simulation provides a unique opportunity to answer questions regarding crew interface and system analysis for designing and developing future flight-like versions of a TtG system. This paper will discuss the human factors that would affect the design of a TtG or other waste processing systems. An overview of the habitat, utility usage, and waste storage and generation is given. Crew time spent preparing trash for TtG processing was recorded. Gas concentrations were measured near the waste storage locations and at other locations in the habitat. In parallel with the analog mission, experimental processing of waste materials in a TtG reactor was performed in order to evaluate performance with realistic waste materials.

Perspectives on New Synthetic Curcumin Analogs and their Potential Anticancer Properties

PubMed Central

Vyas, Alok; Dandawate, Prasad; Padhye, Subhash; Ahmad, Aamir; Sarkar, Fazlul

2013-01-01

Curcumin is the active component of dried rhizome of Curcuma longa, a perennial herb belonging to ginger family, cultivated extensively in south and southeastern tropical Asia. It is widely consumed in the Indian subcontinent, south Asia and Japan in traditional food recipes. Extensive research over last few decades has shown that curcumin is a potent anti-inflammatory agent with powerful therapeutic potential against a variety of cancers. It suppresses proliferation and metastasis of human tumors through regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases and other enzymes. It induces apoptotic cell death and also inhibits proliferation of cancer cells by cell cycle arrest. Pharmacokinetic data has shown that curcumin undergoes rapid metabolism leading to glucuronidation and sulfation in the liver and excretion in the feces, which accounts for its poor systemic bioavailability. The compound has, therefore, been formulated and administered using different drug delivery systems such as liposomes, micelles, polysaccharides, phospholipid complexes and nanoparticles that can overcome the limitation of bioavailability to some extent. Attempts to avoid rapid metabolism of curcumin until now have been met with limited success. This has prompted researchers to look for new synthetic curcumin analogs in order to overcome the drawbacks of limited bioavailability and rapid metabolism, and gain efficacy with reduced toxicity. In this review we provide a summarized account of novel synthetic curcumin formulations and analogs, and the recent progress in the field of cancer prevention and treatment. PMID:23116312

Perspectives on new synthetic curcumin analogs and their potential anticancer properties.

PubMed

Vyas, Alok; Dandawate, Prasad; Padhye, Subhash; Ahmad, Aamir; Sarkar, Fazlul

2013-01-01

Curcumin is the active component of dried rhizome of Curcuma longa, a perennial herb belonging to ginger family, cultivated extensively in south and southeastern tropical Asia. It is widely consumed in the Indian subcontinent, south Asia and Japan in traditional food recipes. Extensive research over last few decades has shown that curcumin is a potent anti-inflammatory agent with powerful therapeutic potential against a variety of cancers. It suppresses proliferation and metastasis of human tumors through regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases and other enzymes. It induces apoptotic cell death and also inhibits proliferation of cancer cells by cell cycle arrest. Pharmacokinetic data has shown that curcumin undergoes rapid metabolism leading to glucuronidation and sulfation in the liver and excretion in the feces, which accounts for its poor systemic bioavailability. The compound has, therefore, been formulated and administered using different drug delivery systems such as liposomes, micelles, polysaccharides, phospholipid complexes and nanoparticles that can overcome the limitation of bioavailability to some extent. Attempts to avoid rapid metabolism of curcumin until now have been met with limited success. This has prompted researchers to look for new synthetic curcumin analogs in order to overcome the drawbacks of limited bioavailability and rapid metabolism, and gain efficacy with reduced toxicity. In this review we provide a summarized account of novel synthetic curcumin formulations and analogs, and the recent progress in the field of cancer prevention and treatment.

PROBLEM OF FORMING IN A MAN-OPERATOR A HABIT OF TRACKING A MOVING TARGET,

DTIC Science & Technology

Cybernetics stimulated the large-scale use of the method of functional analogy which makes it possible to compare technical and human activity systems...interesting and highly efficient human activity because of the psychological control factor involved in its operation. The human tracking system is

Facilitating Problem Solving in High School Chemistry.

ERIC Educational Resources Information Center

Gabel, Dorothy L.

The major purpose of this study was to determine whether certain types of instructional strategies (factor-label method, use of analogies, use of diagrams, and proportionality) were superior to others in teaching problem solving in four topics (mole concept, gas laws, stoichiometry, and molarity). Also of major interest was whether particular…

Therapist Effects on Functional Analysis Outcomes with Young Children

ERIC Educational Resources Information Center

Huete, John M.; Kurtz, Patricia F.

2010-01-01

Analog functional analyses (FAs) are commonly used to assess factors that maintain problem behavior of individuals with intellectual disabilities. These analyses are usually conducted by trained staff in clinic settings. However, recent research suggests that FAs conducted by unfamiliar individuals, such as hospital or clinic staff, may result in…

The Tapestry of Language Learning: The Individual in the Communicative Classroom.

ERIC Educational Resources Information Center

Scarcella, Robin C.; Oxford, Rebecca L.

The analogy of a tapestry is used to provide instructional techniques and practices to help teachers of English as a Second Language (ESL) "weave" together environmental factors (classroom interaction, input) and learner cognitive, affective, and social characteristics (learning styles, strategies, motivation) according to the needs of the…

Visualizing Mixed Variable-Type Multidimensional Data Using Tree Distances

DTIC Science & Technology

2015-09-01

24 1. The Regression Method .................................................. 25 2. Maximum Deviance Ratio Method... Deviance Change as a Factor of the Amount of Correlation? ................................................... 50 B. A PROPOSED SOLUTION...Splice mapping using d1 ...................... 36 Figure 18. Reduction in 2R analog ( deviance ratio-DevRat) per variable for the Splice data

Modeling the initial mechanical response and yielding behavior of gelled crude oil

NASA Astrophysics Data System (ADS)

Lei, Chen; Gang, Liu; Xingguo, Lu; Minghai, Xu; Yuannan, Tang

2018-05-01

The initial mechanical response and yielding behavior of gelled crude oil under constant shear rate conditions were investigated. By putting the Maxwell mechanical analog and a special dashpot in parallel, a quasi-Jeffreys model was obtained. The kinetic equation of the structural parameter in the Houska model was simplified reasonably so that a simplified constitutive equation of the special dashpot was expressed. By introducing a damage factor into the constitutive equation of the special dashpot and the Maxwell mechanical analog, we established a constitutive equation of the quasi-Jeffreys model. Rheological tests of gelled crude oil were conducted by imposing constant shear rates and the relationship between the shear stress and shear strain under different shear rates was plotted. It is found that the constitutive equation can fit the experimental data well under a wide range of shear rates. Based on the fitted parameters in the quasi-Jeffreys model, the shear stress changing rules of the Maxwell mechanical analog and the special dashpot were calculated and analyzed. It is found that the critical yield strain and the corresponding shear strain where shear stress of the Maxwell analog is the maximum change slightly under different shear rates. And then a critical damage softening strain which is irrelevant to the shearing conditions was put forward to describe the yielding behavior of gelled crude oil.

A two-dimensional (2D) analytical subthreshold swing and transconductance model of underlap dual-material double-gate (DMDG) MOSFET for analog/RF applications

NASA Astrophysics Data System (ADS)

Narendar, Vadthiya; Rai, Saurabh; Tiwari, Siddharth; Mishra, R. A.

2016-12-01

The double-gate (DG) metal-oxide-semiconductor field effect transistors (MOSFETs) are the choice of technology in sub -100 nm regime of leading microelectronics industry. To enhance the analog and RF performance of DG MOSFET, an underlap dual-material (DM) DG MOSFET device structure has been considered because, it has the advantages of both underlap as well as that of dual-material gate (DMG). A 2D analytical surface potential, subthreshold current, subthreshold swing as well as transconductance modelling of underlap DMDG MOSFET has been done by solving the Poisson's equation. It has also been found that, numerically simulated data approves the analytically modelled data with commendable accuracy. As underlap length (Lun) increases, a substantial reduction of subthreshold current due to enhanced gate control over channel regime is observed. DMG structure facilitates to improve the average velocity of carriers which leads to superior drive current of the device. The underlap DMDG MOSFET device structure demonstrates an ameliorated subthreshold characteristic. The analog figure of merits (FOMs) such as transconductance (gm), transconductance generation factor (TGF), output conductance (gd), early voltage (VEA), intrinsic gain (AV) and RF FOMs namely cut-off frequency (fT), gain frequency product (GFP), transconductance frequency product (TFP) and gain transconductance frequency product (GTFP) have been evaluated. The aforesaid analysis revels that, the device is best suited for communication related Analog/RF applications.

A hybrid analog-digital phase-locked loop for frequency mode non-contact scanning probe microscopy.

PubMed

Mehta, M M; Chandrasekhar, V

2014-01-01

Non-contact scanning probe microscopy (SPM) has developed into a powerful technique to image many different properties of samples. The conventional method involves monitoring the amplitude, phase, or frequency of a cantilever oscillating at or near its resonant frequency as it is scanned across the surface of a sample. For high Q factor cantilevers, monitoring the resonant frequency is the preferred method in order to obtain reasonable scan times. This can be done by using a phase-locked-loop (PLL). PLLs can be obtained as commercial integrated circuits, but these do not have the frequency resolution required for SPM. To increase the resolution, all-digital PLLs requiring sophisticated digital signal processors or field programmable gate arrays have also been implemented. We describe here a hybrid analog/digital PLL where most of the components are implemented using discrete analog integrated circuits, but the frequency resolution is provided by a direct digital synthesis chip controlled by a simple peripheral interface controller (PIC) microcontroller. The PLL has excellent frequency resolution and noise, and can be controlled and read by a computer via a universal serial bus connection.

A hybrid analog-digital phase-locked loop for frequency mode non-contact scanning probe microscopy

NASA Astrophysics Data System (ADS)

Mehta, M. M.; Chandrasekhar, V.

2014-01-01

Non-contact scanning probe microscopy (SPM) has developed into a powerful technique to image many different properties of samples. The conventional method involves monitoring the amplitude, phase, or frequency of a cantilever oscillating at or near its resonant frequency as it is scanned across the surface of a sample. For high Q factor cantilevers, monitoring the resonant frequency is the preferred method in order to obtain reasonable scan times. This can be done by using a phase-locked-loop (PLL). PLLs can be obtained as commercial integrated circuits, but these do not have the frequency resolution required for SPM. To increase the resolution, all-digital PLLs requiring sophisticated digital signal processors or field programmable gate arrays have also been implemented. We describe here a hybrid analog/digital PLL where most of the components are implemented using discrete analog integrated circuits, but the frequency resolution is provided by a direct digital synthesis chip controlled by a simple peripheral interface controller (PIC) microcontroller. The PLL has excellent frequency resolution and noise, and can be controlled and read by a computer via a universal serial bus connection.

Menaquinone analogs inhibit growth of bacterial pathogens.

PubMed

Schlievert, Patrick M; Merriman, Joseph A; Salgado-Pabón, Wilmara; Mueller, Elizabeth A; Spaulding, Adam R; Vu, Bao G; Chuang-Smith, Olivia N; Kohler, Petra L; Kirby, John R

2013-11-01

Gram-positive bacteria cause serious human illnesses through combinations of cell surface and secreted virulence factors. We initiated studies with four of these organisms to develop novel topical antibacterial agents that interfere with growth and exotoxin production, focusing on menaquinone analogs. Menadione, 1,4-naphthoquinone, and coenzymes Q1 to Q3 but not menaquinone, phylloquinone, or coenzyme Q10 inhibited the growth and to a greater extent exotoxin production of Staphylococcus aureus, Bacillus anthracis, Streptococcus pyogenes, and Streptococcus agalactiae at concentrations of 10 to 200 μg/ml. Coenzyme Q1 reduced the ability of S. aureus to cause toxic shock syndrome in a rabbit model, inhibited the growth of four Gram-negative bacteria, and synergized with another antimicrobial agent, glycerol monolaurate, to inhibit S. aureus growth. The staphylococcal two-component system SrrA/B was shown to be an antibacterial target of coenzyme Q1. We hypothesize that menaquinone analogs both induce toxic reactive oxygen species and affect bacterial plasma membranes and biosynthetic machinery to interfere with two-component systems, respiration, and macromolecular synthesis. These compounds represent a novel class of potential topical therapeutic agents.

Detecting peptidic drugs, drug candidates and analogs in sports doping: current status and future directions.

PubMed

Thevis, Mario; Thomas, Andreas; Schänzer, Wilhelm

2014-12-01

With the growing availability of mature systems and strategies in biotechnology and the continuously expanding knowledge of cellular processes and involved biomolecules, human sports drug testing has become a considerably complex field in the arena of analytical chemistry. Proving the exogenous origin of peptidic drugs and respective analogs at lowest concentration levels in biological specimens (commonly blood, serum and urine) of rather limited volume is required to pursue an action against cheating athletes. Therefore, approaches employing chromatographic-mass spectrometric, electrophoretic, immunological and combined test methods have been required and developed. These allow detecting the misuse of peptidic compounds of lower (such as growth hormone-releasing peptides, ARA-290, TB-500, AOD-9604, CJC-1295, desmopressin, luteinizing hormone-releasing hormones, synacthen, etc.), intermediate (e.g., insulins, IGF-1 and analogs, 'full-length' mechano growth factor, growth hormone, chorionic gonadotropin, erythropoietin, etc.) and higher (e.g., stamulumab) molecular mass with desired specificity and sensitivity. A gap between the technically possible detection and the day-to-day analytical practice, however, still needs to be closed.

The design of CMOS general-purpose analog front-end circuit with tunable gain and bandwidth for biopotential signal recording systems.

PubMed

Chen, Wei-Ming; Yang, Wen-Chia; Tsai, Tzung-Yun; Chiueh, Herming; Wu, Chung-Yu

2011-01-01

In this paper an 8-channel CMOS general-purpose analog front-end (AFE) circuit with tunable gain and bandwidth for biopotential signal recording systems is presented. The proposed AFE consists of eight chopper stabilized pre-amplifiers, an 8-to-1 analog multiplexer, and a programmable gain amplifier. It can be used to sense and amplify different kinds of biopotential signals, such as electrocorticogram (ECoG), electrocardiogram (ECG) and electromyogram (EMG). The AFE chip is designed and fabricated in 0.18-μm CMOS technology. The measured maximum gain of AFE is 60.8 dB. The low cutoff frequency can achieve as low as 0.8 Hz and high cutoff frequency can be adjusted from 200 Hz to 10 kHz to suit for different kinds of biopotential signals. The measured input-referred noise is 0.9 μV(rms), with the power consumption of 18μW per channel at 1.8-V power supply. And the noise efficiency factor (NEF) is only 1.3 for pre-amplifier.

Automating CapCom: Pragmatic Operations and Technology Research for Human Exploration of Mars

NASA Technical Reports Server (NTRS)

Clancey, William J.

2003-01-01

During the Apollo program, NASA and the scientific community used terrestrial analog sites for understanding planetary features and for training astronauts to be scientists. More recently, computer scientists and human factors specialists have followed geologists and biologists into the field, learning how science is actually done on expeditions in extreme environments. Research stations have been constructed by the Mars Society in the Arctic and American southwest, providing facilities for hundreds of researchers to investigate how small crews might live and work on Mars. Combining these interests-science, operations, and technology-in Mars analog field expeditions provides tremendous synergy and authenticity to speculations about Mars missions. By relating historical analyses of Apollo and field science, engineers are creating experimental prototypes that provide significant new capabilities, such as a computer system that automates some of the functions of Apollo s CapCom. Thus, analog studies have created a community of practice-a new collaboration between scientists and engineers-so that technology begins with real human needs and works incrementally towards the challenges of the human exploration of Mars.

A 4 μW/Ch analog front-end module with moderate inversion and power-scalable sampling operation for 3-D neural microsystems.

PubMed

Al-Ashmouny, Khaled M; Chang, Sun-Il; Yoon, Euisik

2012-10-01

We report an analog front-end prototype designed in 0.25 μm CMOS process for hybrid integration into 3-D neural recording microsystems. For scaling towards massive parallel neural recording, the prototype has investigated some critical circuit challenges in power, area, interface, and modularity. We achieved extremely low power consumption of 4 μW/channel, optimized energy efficiency using moderate inversion in low-noise amplifiers (K of 5.98 × 10⁸ or NEF of 2.9), and minimized asynchronous interface (only 2 per 16 channels) for command and data capturing. We also implemented adaptable operations including programmable-gain amplification, power-scalable sampling (up to 50 kS/s/channel), wide configuration range (9-bit) for programmable gain and bandwidth, and 5-bit site selection capability (selecting 16 out of 128 sites). The implemented front-end module has achieved a reduction in noise-energy-area product by a factor of 5-25 times as compared to the state-of-the-art analog front-end approaches reported to date.

Analog and RF performance of a multigate FinFET at nano scale

NASA Astrophysics Data System (ADS)

Kumar, Abhishek

2016-12-01

In this paper, analog and RF performance of the Fin field effect transistor (FET) at Nano scale is observed through 3D simulation. FinFET devices like rectangular gate all around (RE-GAA) FinFET, cylindrical gate all around (CY-GAA) FinFET and triple gate (TG) FinFET are observed. The figure of merit (FOMs) such as input-output characteristics, trans-conductance (gm), output-conductance (gd), intrinsic gain (gm/gd), gate capacitance (gate to source and total gate capacitance), unity gain cut-off frequency (ft), trans-conductance generation factor (TGF), gain frequency product (GFP), gain bandwidth product (GBP) and gain transconductance frequency product (GTFP) are observed. The analog performance of a FinFETs are observed by realising source follower circuit with NMOS transistor as a current source. The source follower circuit gain is observed. It has been observed that maximum capacitance is observed in case gate all around condition. Rectangular gate all around has the highest transconductance. In the source follower circuit, the gain curve (Vout/Vin) is sharper for TG-FinFET.

A Mathematical Model for Alternation of Polygamy and Parthenogenesis: Stability Versus Efficiency and Analogy with Parasitism.

PubMed

Sanchez-Palencia, Evariste; Lherminier, Philippe; Françoise, Jean-Pierre

2016-12-01

The present work is a contribution to the understanding of the sempiternal problem of the "burden of factor two" implied by sexual reproduction versus asexual one, as males are energy consumers not contributing to the production of offspring. We construct a deterministic mathematical model in population dynamics where a species enjoys both sexual and parthenogenetic capabilities of reproduction and lives on a limited resource. We then show how polygamy implies instability of a parthenogenetic population with a small number of sexually born males. This instability implies evolution of the system towards an attractor involving both (sexual and asexual) populations (which does not imply optimality of the population). We also exhibit the analogy with a parasite/host system.

An essential amino acid induces epithelial β-defensin expression

PubMed Central

Fehlbaum, Pascale; Rao, Meena; Zasloff, Michael; Anderson, G. Mark

2000-01-01

Antimicrobial peptides constitute an important component of the mammalian innate immune response. Several types of antimicrobial peptides, including the β-defensins, are produced at epithelial surfaces in response to infectious threats. Here we show that a class of small molecules, including l-isoleucine and several of its analogs, can specifically induce epithelial β-defensin expression. This induction is transcriptional in nature and involves activation of the NF-κB/rel family of trans-activating factors. We hypothesize that these substances represent unique markers for the presence of pathogens and are recognized by innate immune pattern recognition receptors. Isoleucine or its analogs ultimately may have clinical utility as novel immunostimulants that could bolster the barrier defenses of mucosal surfaces. PMID:11058160

Extension of transonic flow computational concepts in the analysis of cavitated bearings

NASA Technical Reports Server (NTRS)

Vijayaraghavan, D.; Keith, T. G., Jr.; Brewe, D. E.

1990-01-01

An analogy between the mathematical modeling of transonic potential flow and the flow in a cavitating bearing is described. Based on the similarities, characteristics of the cavitated region and jump conditions across the film reformation and rupture fronts are developed using the method of weak solutions. The mathematical analogy is extended by utilizing a few computational concepts of transonic flow to numerically model the cavitating bearing. Methods of shock fitting and shock capturing are discussed. Various procedures used in transonic flow computations are adapted to bearing cavitation applications, for example, type differencing, grid transformation, an approximate factorization technique, and Newton's iteration method. These concepts have proved to be successful and have vastly improved the efficiency of numerical modeling of cavitated bearings.

Biomedical sensor design using analog compressed sensing

NASA Astrophysics Data System (ADS)

Balouchestani, Mohammadreza; Krishnan, Sridhar

2015-05-01

The main drawback of current healthcare systems is the location-specific nature of the system due to the use of fixed/wired biomedical sensors. Since biomedical sensors are usually driven by a battery, power consumption is the most important factor determining the life of a biomedical sensor. They are also restricted by size, cost, and transmission capacity. Therefore, it is important to reduce the load of sampling by merging the sampling and compression steps to reduce the storage usage, transmission times, and power consumption in order to expand the current healthcare systems to Wireless Healthcare Systems (WHSs). In this work, we present an implementation of a low-power biomedical sensor using analog Compressed Sensing (CS) framework for sparse biomedical signals that addresses both the energy and telemetry bandwidth constraints of wearable and wireless Body-Area Networks (BANs). This architecture enables continuous data acquisition and compression of biomedical signals that are suitable for a variety of diagnostic and treatment purposes. At the transmitter side, an analog-CS framework is applied at the sensing step before Analog to Digital Converter (ADC) in order to generate the compressed version of the input analog bio-signal. At the receiver side, a reconstruction algorithm based on Restricted Isometry Property (RIP) condition is applied in order to reconstruct the original bio-signals form the compressed bio-signals with high probability and enough accuracy. We examine the proposed algorithm with healthy and neuropathy surface Electromyography (sEMG) signals. The proposed algorithm achieves a good level for Average Recognition Rate (ARR) at 93% and reconstruction accuracy at 98.9%. In addition, The proposed architecture reduces total computation time from 32 to 11.5 seconds at sampling-rate=29 % of Nyquist rate, Percentage Residual Difference (PRD)=26 %, Root Mean Squared Error (RMSE)=3 %.

Extension of volcanic forcing data back to 100 BC using the Analog method

NASA Astrophysics Data System (ADS)

Wagner, Sebastian; Zorita, Eduardo

2013-04-01

Present reconstructions of volcanic forcing to be used for climate simulations so far extend back until 500 AD for stratospheric aerosol sulphate injection (Gao et al., 2008), and back until 800 AD for aerosol optical depth and effective radius (Crowley et al. 2012; ICI5 data set). Here, we aim to extent the volcanic data set of Crowley et al. (2012) back to 100 BC. This data sets originally starts in 800 AD, for aerosol optical depth and effective radius. The method we apply is the Analog method, using information in the already existing reconstruction and extending it back in time by using information of long volcanic sulphate contained in Greenland and Antarctic Ice cores published in previous studies. The reconstruction of the volcanic forcing in first millennium is based on the search of analogs in the second millennium. The pool of analogs includes the ICI5 data set for the period 800-2000 AD. The basic philosophy is to find volcanic events with the same or similar magnitude in terms of volcanic sulphate deposition in Greenland and Antarctic ice cores. For the Northern Hemisphere the estimated maximum total stratospheric sulphate loading from Zielinski (1995) is used. For the Southern Hemisphere the Plummer et al. (2012) data set and the Ferris et al. (2011) data set are used in terms of sulphate deposition. To ensure that the volcanic event was large enough in magnitude, a certain threshold is applied to the analog selection. The extension, i.e. the analog search, is carried out separately for the four different latitudinal bands of the ICI5 data set. The method can be applied when better records than the Zielinski et al. (1995), record for the Northern Hemisphere become available. The analogs are selected based on the comparison between the information contained in the ice cores in the pre-800 AD period and post-800 AD period. For each event in the pre-800 AD period (the target), the most similar event (the analog) in the post-800 AD pool in terms of ice-core sulphate is identified. The forcing data (effective radius and aerosol optical depth) of the ICI5 data set for that analog event is then used as a surrogate for the target event. In the case that the analog does not exactly match the amplitude of the pre-800 AD event a scaling correction factor is applied, taking into account the relative difference of ice-core sulphate between the analog and the target. Although the method does not take into account the specific structure of each volcanic event, the basic patterns are reproduced reasonably well for a validation period in the second millennium AD. The largest uncertainties relate to the dating of each volcanic event, including the season of the eruption, the synchronization of hemispheric versus global eruptions and the translation of the ice core volcanic sulphate concentrations into stratospheric aerosol loadings. However, these uncertainties will essentially remain using different methods based on the sulphate information contained in Antarctic and Greenland ice cores.

Methods to decrease blood loss and transfusion requirements for liver transplantation.

PubMed

Gurusamy, Kurinchi Selvan; Pissanou, Theodora; Pikhart, Hynek; Vaughan, Jessica; Burroughs, Andrew K; Davidson, Brian R

2011-12-07

Excessive blood loss and increased blood transfusion requirements may have significant impact on the short-term and long-term outcomes after liver transplantation. To compare the potential benefits and harms of different methods of decreasing blood loss and blood transfusion requirements during liver transplantation. We searched The Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and metaRegister of Controlled Trials until September 2011. We included all randomised clinical trials that were performed to compare various methods of decreasing blood loss and blood transfusion requirements during liver transplantation. Two authors independently identified the trials and extracted the data. We analysed the data with both the fixed-effect and the random-effects model using RevMan Analysis. For each outcome we calculated the risk ratio (RR), mean difference (MD), or standardised mean difference (SMD) with 95% confidence intervals (CI) based on available data analysis. We also conducted network meta-analysis. We included 33 trials involving 1913 patients. The sample size in the trials varied from 8 to 209 participants. The interventions included pharmacological interventions (aprotinin, tranexamic acid, epsilon amino caproic acid, antithrombin 3, recombinant factor (rFvIIa), oestrogen, prostaglandin, epinephrine), blood substitutes (blood components rather than whole blood, hydroxy-ethyl starch, thromboelastography), and cardiovascular interventions (low central venous pressure). All the trials were of high risk of bias. Primary outcomes were reported in at least two trials for the following comparisons: aprotinin versus control, tranexamic acid versus control, recombinant factor VIIa (rFVIIa) versus control, and tranexamic acid versus aprotinin. There were no significant differences in the 60-day mortality (3 trials; 6/161 (3.7%) in the aprotinin group versus 8/119 (6.7%) in the control group; RR 0.52; 95% CI 0.18 to 1.45), primary graft non-function (2 trials; 0/128 (0.0%) in the aprotinin group versus 4/89 (4.5%) in the control group; RR 0.15; 95% CI 0.02 to 1.25), retransplantation (3 trials; 2/256 (0.8%) in the aprotinin group versus 12/178 (6.7%) in the control group; RR 0.21; 95% CI 0.02 to 1.79), or thromboembolic episodes (3 trials; 4/161 (2.5%) in the aprotinin group versus 5/119 (4.2%) in the control group; RR 0.59; 95% CI 0.19 to 1.84) between the aprotinin and control groups. There were no significant differences in the 60-day mortality (3 trials; 4/83 (4.8%) in the tranexamic acid group versus 5/56 (8.9%) in the control group; RR 0.55; 95% CI 0.17 to 1.76), retransplantation (2 trials; 3/41 (7.3%) in the tranexamic acid group versus 3/36 (8.3%) in the control group; RR 0.79; 95% CI 0.18 to 3.48), or thromboembolic episodes (5 trials; 5/103 (4.9%) in the tranexamic acid group versus 1/76 (1.3%) in the control group; RR 2.20; 95% CI 0.38 to 12.64) between the tranexamic acid and control groups. There were no significant differences in the 60-day mortality (3 trials; 8/195 (4.1%) in the recombinant factor VIIa (rFVIIa) group versus 2/91 (2.2%) in the control group; RR 1.51; 95% CI 0.33 to 6.95), thromboembolic episodes (2 trials; 24/185 (13.0%) in the rFVIIa group versus 8/81 (9.9%) in the control group; RR 1.38; 95% CI 0.65 to 2.91), or serious adverse events (2 trials; 90/185 (48.6%) in the rFVIIa group versus 30/81 (37.0%) in the control group; RR 1.30; 95% CI 0.94 to 1.78) between the rFVIIa and control groups. There were no significant differences in the 60-day mortality (2 trials; 6/91 (6.6%) in the tranexamic acid group versus 1/87 (1.1%) in the aprotinin group; RR 4.12; 95% CI 0.71 to 23.76) or thromboembolic episodes (2 trials; 4/91 (4.4%) in the tranexamic acid group versus 2/87 (2.3%) in the aprotinin group; RR 1.97; 95% CI 0.37 to 10.37) between the tranexamic acid and aprotinin groups. The remaining outcomes in the above comparisons and the remaining comparisons included only only trial under the primary outcome or the outcome was not reported at all in the trials. There were no significant differences in the mortality, primary graft non-function, graft failure, retransplantation, thromboembolic episodes, or serious adverse events in any of these comparisons. However, the confidence intervals were wide, and it is not possible to reach any conclusion on the safety of the interventions. None of the trials reported the quality of life in patients.Secondary outcomes were reported in at least two trials for the following comparisons - aprotinin versus control, tranexamic acid versus control, rFVIIa versus control, thromboelastography versus control, and tranexamic acid versus aprotinin. There was significantly lower allogeneic blood transfusion requirements in the aprotinin group than the control group (8 trials; 185 patients in aprotinin group and 190 patients in control group; SMD -0.61; 95% CI -0.82 to -0.40). There were no significant differences in the allogeneic blood transfusion requirements between the tranexamic acid and control groups (4 trials; 93 patients in tranexamic acid group and 66 patients in control group; SMD -0.27; 95% CI -0.59 to 0.06); rFVIIa and control groups (2 trials; 141 patients in rFVIIa group and 80 patients in control group; SMD -0.05; 95% CI -0.32 to 0.23); thromboelastography and control groups (2 trials; 31 patients in thromboelastography group and 31 patients in control group; SMD -0.73; 95% CI -1.69 to 0.24); or between the tranexamic acid and aprotinin groups (3 trials; 101 patients in tranexamic acid group and 97 patients in aprotinin group; SMD -0.09; 95% CI -0.36 to 0.19). The remaining outcomes in the above comparisons and the remaining comparisons included only only trial under the primary outcome or the outcome was not reported at all in the trials. There were no significant differences in the blood loss, transfusion requirements, hospital stay, or intensive care unit stay in most of the comparisons. Aprotinin, recombinant factor VIIa, and thromboelastography groups may potentially reduce blood loss and transfusion requirements. However, risks of systematic errors (bias) and risks of random errors (play of chance) hamper the confidence in this conclusion. We need further well-designed randomised trials with low risk of systematic error and low risk of random errors before these interventions can be supported or refuted.

High-yield production of herbicidal thaxtomins and analogs in a nonpathogenic Streptomyces strain.

PubMed

Jiang, Guangde; Zhang, Yucheng; Powell, Magan M; Zhang, Peilan; Zuo, Ran; Zhang, Yi; Kallifidas, Dimitrios; Tieu, Albert M; Luesch, Hendrik; Loria, Rosemary; Ding, Yousong

2018-03-30

Thaxtomins are virulence factors of most plant pathogenic Streptomyces strains. Due to their potent herbicidal activity, attractive environmental compatibility and inherent biodegradability, thaxtomins are key active ingredients of bioherbicides approved by the United States Environmental Protection Agency. However, the low yield of thaxtomins in native Streptomyces producers limits their wide agricultural applications. Here, we describe the high-yield production of thaxtomins in a heterologous host. The thaxtomin gene cluster from S. scabiei 87.22 was cloned and expressed in S. albus J1074 after chromosomal integration. The production of thaxtomins and nitro-tryptophan analogs were observed using LC-MS analysis. When culturing the engineered S. albus J1074 in the minimal medium TMDc, the yield of the most abundant and herbicidal analog, thaxtomin A, was 10 times higher than S. scabiei 87.22, and optimization of the medium resulted in the highest yield of thaxtomin analogs at about 222 mg/L. Further engineering of the thaxtomin biosynthetic gene cluster through gene deletion led to the production of multiple biosynthetic intermediates important to the chemical synthesis of new analogs. Additionally, the versatility of the thaxtomin biosynthetic system in S. albus J1074 was capitalized to produce one unnatural fluorinated analog 5-F-thaxtomin A, whose structure was elucidated by a combination of MS and 1D and 2D NMR analyses. Natural and unnatural thaxtomins demonstrated potent herbicidal activity in radish seedling assays. These results indicated that S. albus J1074 has the potential to produce thaxtomins and thereof with high yield, fostering their agricultural applications. IMPORTANCE Thaxtomins are agriculturally valuable herbicidal natural products but the productivity of native producers is limiting. Heterologous expression of thaxtomin gene cluster in S. albus J1074 resulted in the highest yield of thaxtomins ever reported, representing a significant leap forward in its wide agricultural use. Furthermore, current synthetic routes to thaxtomins and analogs are lengthy, and two thaxtomin biosynthetic intermediates produced at high yields in this work can provide precursors and building blocks to advanced synthetic routes. Importantly, the production of 5-F-thaxtomin A in engineered S. albus J1074 demonstrated a viable alternative to chemical methods in the synthesis of new thaxtomin analogs. Moreover, our work presents an attractive synthetic biology strategy to improve the supply of herbicidal thaxtomins, likely finding general applications in the discovery and production of many other bioactive natural products. Copyright © 2018 American Society for Microbiology.

The yeast genome may harbor hypoxia response elements (HRE).

PubMed

Ferreira, Túlio César; Hertzberg, Libi; Gassmann, Max; Campos, Elida Geralda

2007-01-01

The hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor activated when cells are submitted to hypoxia. The heterodimer is composed of two subunits, HIF-1alpha and the constitutively expressed HIF-1beta. During normoxia, HIF-1alpha is degraded by the 26S proteasome, but hypoxia causes HIF-1alpha to be stabilized, enter the nucleus and bind to HIF-1beta, thus forming the active complex. The complex then binds to the regulatory sequences of various genes involved in physiological and pathological processes. The specific regulatory sequence recognized by HIF-1 is the hypoxia response element (HRE) that has the consensus sequence 5'BRCGTGVBBB3'. Although the basic transcriptional regulation machinery is conserved between yeast and mammals, Saccharomyces cerevisiae does not express HIF-1 subunits. However, we hypothesized that baker's yeast has a protein analogous to HIF-1 which participates in the response to changes in oxygen levels by binding to HRE sequences. In this study we screened the yeast genome for HREs using probabilistic motif search tools. We described 24 yeast genes containing motifs with high probability of being HREs (p-value<0.1) and classified them according to biological function. Our results show that S. cerevisiae may harbor HREs and indicate that a transcription factor analogous to HIF-1 may exist in this organism.

The development of novel inhibitors of tumor necrosis factor-alpha production based on substituted [5,5]-bicyclic pyrozolones

DOE Office of Scientific and Technical Information (OSTI.GOV)

Laufersweiler, Matthew; Brugel, Todd; Clark, Michael

Novel substituted [5,5]-bicyclic pyrzazolones are presented as inhibitors of tumor necrosis factor-{alpha} (TNF-{alpha}) production. Many of these compounds show low nanomolar activity against lipopolysaccaride (LPS)-induced TNF-{alpha} production in THP-1 cells. This class of molecules was co-crystallized with mutated p38, and several analogs showed good oral bioavailability in the rat. Oral activity of these compounds in the rat iodoacetate model for osteoarthritis is discussed.

Regulatory Mechanisms Involved in the Expression of Brain-Derived Neurotrophic Factor and Glial Cell Line-Derived Neurotrophic Factor

DTIC Science & Technology

1996-03-01

neurotoxic dopamine analog that is taken up by nigral dopaminergic cells where it is metabolized to highly reactive oxygen free radicals that cause ...brain regions is elevated after other types of brain insults, including ischemia and hypoglycemia (see Lindvall et al. 1994 for review). Lindvall et a1...with kainic acid were also reported. These investigators also reported significant increases in BDNF mRNA levels in cultures of neonatal astrocytes

One amino acid in mouse activated factor VII defines its endothelial protein C receptor (EPCR) binding and modulates its EPCR-dependent hemostatic activity in vivo.

PubMed

Pavani, G; Zintner, S M; Ivanciu, L; Small, J C; Stafford, K A; Szeto, J H; Margaritis, P

2017-03-01

Essentials The lack of factor (F) VIIa-endothelial protein C receptor (EPCR) binding in mice is unresolved. A single substitution of Leu4 to Phe in mouse FVIIa (mFVIIa) enables its interaction with EPCR. mFVIIa with a Phe4 shows EPCR binding-dependent enhanced hemostatic function in vivo vs. mFVIIa. Defining the FVIIa-EPCR interaction in mice allows for further investigating its biology in vivo. Background Human activated factor VII (hFVIIa), which is used in hemophilia treatment, binds to the endothelial protein C (PC) receptor (EPCR) with unclear hemostatic consequences. Interestingly, mice lack the activated FVII (FVIIa)-EPCR interaction. Therefore, to investigate the hemostatic consequences of this interaction in hemophilia, we previously engineered a mouse FVIIa (mFVIIa) molecule that bound mouse EPCR (mEPCR) by using three substitutions from mouse PC (mPC), i.e. Leu4→Phe, Leu8→Met, and Trp9→Arg. The resulting molecule, mFVIIa-FMR, modeled the EPCR-binding properties of hFVIIa and showed enhanced hemostatic capacity in hemophilic mice versus mFVIIa. These data implied a role of EPCR in the action of hFVIIa in hemophilia treatment. However, the substitutions in mFVIIa-FMR only broadly defined the sequence determinants for its mEPCR interaction and enhanced function in vivo. Objectives To determine the individual contributions of mPC Phe4, Met8 and Arg9 to the in vitro/in vivo properties of mFVIIa-FMR. Methods The mEPCR-binding properties of single amino acid variants of mFVIIa or mPC at position 4, 8 or 9 were investigated. Results and conclusions Phe4 in mFVIIa or mPC was solely critical for interaction with mEPCR. In hemophilic mice, administration of mFVIIa harboring a Phe4 resulted in a 1.9-2.5-fold increased hemostatic capacity versus mFVIIa that was EPCR binding-dependent. This recapitulated previous observations made with triple-mutant mFVIIa-FMR. As Leu8 is crucial for hFVIIa-EPCR binding, we describe the sequence divergence of this interaction in mice, now allowing its further characterization in vivo. We also illustrate that modulation of the EPCR-FVIIa interaction may lead to improved FVIIa therapeutics. © 2016 International Society on Thrombosis and Haemostasis.

Factors That Attenuate the Correlation Coefficient and Its Analogs.

ERIC Educational Resources Information Center

Dolenz, Beverly

The correlation coefficient is an integral part of many other statistical techniques (analysis of variance, t-tests, etc.), since all analytic methods are actually correlational (G. V. Glass and K. D. Hopkins, 1984). The correlation coefficient is a statistical summary that represents the degree and direction of relationship between two variables.…

Nitrogen excess in North American ecosystems: predisposing factors, ecosystem responses, and management strategies

Treesearch

Mark E. Fenn; Mark A. Poth; John D. Aber; Jill S. Baron; Bernard T. Bormann; Dale W. Johnson; A. Dennis Lemly; Steven G. McNulty; Douglas F. Ryan; Robert Stottlemyer

1998-01-01

Most forests in North America remain nitrogen limited, although recent studies have identified forested areas that exhibit symptoms of N excess, analogous to overfertilization of arable land. Nitrogen excess in watersheds is detrimental because of disruptions in plantlsoil nutrient relations, increased soil acidification and aluminum mobility, increased emissions of...

Nitrogen Excess in North American Ecosystems: Predisposing Factors, Ecosystem Responses, and Management Strategies

Treesearch

Mark E. Fenn; Mark A. Poth; John D. Aber; Jill S. Baron; Bernard T. Bormann; Dale W. Johnson; A. Dennis Lemly; Steven G. McNulty; Douglas F. Ryan; Robert Stottlemyer

1998-01-01

Most forests in North America remain nitrogen limited, although recent studies have identified forested areas that exhibit symptoms of N excess, analogous to overfertilization of arable land. Nitrogen excess in watersheds is detrimental because of disruptions in plant/soil nutrient relations, increased soil acidification and aluminum mobility, increased emissions of...

Rhyme and Analogy in Beginning Reading: Conceptual and Methodological Issues.

ERIC Educational Resources Information Center

Goswami, Usha; East, Martin

2000-01-01

Two experiments replicated an earlier study on the causal connection between rhyming skills and reading development found in English. Different results were found from the first study. Argues that methodological and instructional factors may be very important for the conceptual interpretation of studies attempting to pit small units (phonemes)…

Delivery Pain and the Development of Mother-Infant Interaction

ERIC Educational Resources Information Center

Ferber, Sari Goldstein; Feldman, Ruth

2005-01-01

This study examined delivery pain as a possible risk factor for the development of mother-infant interaction. Eighty-one mothers completed the Pain Catastrophizing Scale, the State-Trait Anxiety Inventory, and the Edinburgh Postnatal Depression Scale. A retrospective evaluation of labor pain was performed using the Visual Analog Scale at 2 days…

Role of reservoir engineering in the assessment of undiscovered oil and gas resources in the National Petroleum Reserve, Alaska

USGS Publications Warehouse

Verma, M.K.; Bird, K.J.

2005-01-01

The geology and reservoir-engineering data were integrated in the 2002 U.S. Geological Survey assessment of the National Petroleum Reserve in Alaska (NPRA). VVhereas geology defined the analog pools and fields and provided the basic information on sizes and numbers of hypothesized petroleum accumulations, reservoir engineering helped develop necessary equations and correlations, which allowed the determination of reservoir parameters for better quantification of in-place petroleum volumes and recoverable reserves. Seismic- and sequence-stratigraphic study of the NPRA resulted in identification of 24 plays. Depth ranges in these 24 plays, however, were typically greater than depth ranges of analog plays for which there were available data, necessitating the need for establishing correlations. The basic parameters required were pressure, temperature, oil and gas formation volume factors, liquid/gas ratios for the associated and nonassociated gas, and recovery factors. Finally, the re sults of U.S. Geological Survey deposit simulation were used in carrying out an economic evaluation, which has been separately published. Copyright ?? 2005. The American Association of Petroleum Geologists. All rights reserved.

Activity ranking of synthetic analogs targeting vascular endothelial growth factor receptor 2 by an integrated cell membrane chromatography system.

PubMed

Wang, Dongyao; Lv, Diya; Chen, Xiaofei; Liu, Yue; Ding, Xuan; Jia, Dan; Chen, Langdong; Zhu, Zhenyu; Cao, Yan; Chai, Yifeng

2015-12-01

Evaluating the biological activities of small molecules represents an important part of the drug discovery process. Cell membrane chromatography (CMC) is a well-developed biological chromatographic technique. In this study, we have developed combined SMMC-7721/CMC and HepG2/CMC with high-performance liquid chromatography and time-of-flight mass spectrometry to establish an integrated screening platform. These systems was subsequently validated and used for evaluating the activity of quinazoline compounds, which were designed and synthesized to target vascular endothelial growth factor receptor 2. The inhibitory activities of these compounds towards this receptor were also tested using a classical caliper mobility shift assay. The results revealed a significant correlation between these two methods (R(2) = 0.9565 or 0.9420) for evaluating the activities of these compounds. Compared with traditional methods of evaluating the activities analogous compounds, this integrated cell membrane chromatography screening system took less time and was more cost effective, indicating that it could be used as a practical method in drug discovery. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Vitamin D receptor signaling and its therapeutic implications: Genome-wide and structural view.

PubMed

Carlberg, Carsten; Molnár, Ferdinand

2015-05-01

Vitamin D3 is one of the few natural compounds that has, via its metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) and the transcription factor vitamin D receptor (VDR), a direct effect on gene regulation. For efficiently applying the therapeutic and disease-preventing potential of 1,25(OH)2D3 and its synthetic analogs, the key steps in vitamin D signaling need to be understood. These are the different types of molecular interactions with the VDR, such as (i) the complex formation of VDR with genomic DNA, (ii) the interaction of VDR with its partner transcription factors, (iii) the binding of 1,25(OH)2D3 or its synthetic analogs within the ligand-binding pocket of the VDR, and (iv) the resulting conformational change on the surface of the VDR leading to a change of the protein-protein interaction profile of the receptor with other proteins. This review will present the latest genome-wide insight into vitamin D signaling, and will discuss its therapeutic implications.

Lipophilicity-related inhibition of blood platelet aggregation by nipecotic acid anilides.

PubMed

De Marco, Agostino; De Candia, Modesto; Carotti, Andrea; Cellamare, Saverio; De Candia, Erica; Altomare, Cosimo

2004-06-01

Using N-[4-(hexyloxy)phenyl]piperidine-3-carboxamide (17c) as a structural lead, a number of isomers, derivatives, and ring-opened analogs were synthesized and tested for their ability to block the in vitro aggregation of human platelets induced by adenosine 5'-diphosphate (ADP). For the most active compounds, inhibition of the platelet aggregation triggered by arachidonic acid (AA) and ADP-induced intraplatelet calcium mobilization was also demonstrated. Based on quantitative structure-activity relationships (QSARs), we proved the impact of hydrophobicity on antiplatelet activity by a nonlinear (parabolic or bilinear) relationship between pIC(50) and lipophilicity, as assessed by RP-HPLC capacity factors and ClogP (i.e. calculated 1-octanol-water partition coefficients). This study highlighted the following additional SARs: quasi-isolipophilic isomers of 17c (isonipecotanilides and pipecolinanilides) and ring-opened analogs (e.g. anilide of beta-alanine) exhibited lower antiplatelet activity; methylation of the piperidine nitrogen of 17c has no effect, whereas alkylation with an n-propyl group decreases the activity by a factor of approximately 2, most likely due to a conformation-dependent decrease in lipophilicity.

Designing Agent Collectives For Systems With Markovian Dynamics

NASA Technical Reports Server (NTRS)

Wolpert, David H.; Lawson, John W.; Clancy, Daniel (Technical Monitor)

2001-01-01

The "Collective Intelligence" (COIN) framework concerns the design of collectives of agents so that as those agents strive to maximize their individual utility functions, their interaction causes a provided "world" utility function concerning the entire collective to be also maximized. Here we show how to extend that framework to scenarios having Markovian dynamics when no re-evolution of the system from counter-factual initial conditions (an often expensive calculation) is permitted. Our approach transforms the (time-extended) argument of each agent's utility function before evaluating that function. This transformation has benefits in scenarios not involving Markovian dynamics, in particular scenarios where not all of the arguments of an agent's utility function are observable. We investigate this transformation in simulations involving both linear and quadratic (nonlinear) dynamics. In addition, we find that a certain subset of these transformations, which result in utilities that have low "opacity (analogous to having high signal to noise) but are not "factored" (analogous to not being incentive compatible), reliably improve performance over that arising with factored utilities. We also present a Taylor Series method for the fully general nonlinear case.

Cryogenic Calcite: A Morphologic and Isotopic Analog to the ALH84001 Carbonates

NASA Technical Reports Server (NTRS)

Niles, P. B.; Leshin, L. A.; Socki, R. A.; Guan, Y.; Ming, D. W.; Gibson, E. K.

2004-01-01

Martian meteorite ALH84001 carbonates preserve large and variable microscale isotopic compositions, which in some way reflect their formation environment. These measurements show large variations (>20%) in the carbon and oxygen isotopic compositions of the carbonates on a 10-20 micron scale that are correlated with chemical composition. However, the utilization of these data sets for interpreting the formation conditions of the carbonates is complex due to lack of suitable terrestrial analogs and the difficulty of modeling under non-equilibrium conditions. Thus, the mechanisms and processes are largely unknown that create and preserve large microscale isotopic variations in carbonate minerals. Experimental tests of the possible environments and mechanisms that lead to large microscale isotopic variations can help address these concerns. One possible mechanism for creating large carbon isotopic variations in carbonates involves the freezing of water. Carbonates precipitate during extensive CO2 degassing that occurs during the freezing process as the fluid s decreasing volume drives CO2 out. This rapid CO2 degassing results in a kinetic isotopic fractionation where the CO2 gas has a much lighter isotopic composition causing an enrichment of 13C in the remaining dissolved bicarbonate. This study seeks to determine the suitability of cryogenically formed carbonates as analogs to ALH84001 carbonates. Specifically, our objective is to determine how accurately models using equilibrium fractionation factors approximate the isotopic compositions of cryogenically precipitated carbonates. This includes determining the accuracy of applying equilibrium fractionation factors during a kinetic process, and determining how isotopic variations in the fluid are preserved in microscale variations in the precipitated carbonates.

Evolution of carbon isotope signatures during reactive transport of hydrocarbons in heterogeneous aquifers.

PubMed

Höyng, Dominik; Prommer, Henning; Blum, Philipp; Grathwohl, Peter; D'Affonseca, Fernando Mazo

2015-03-01

Compound-specific isotope analysis (CSIA) of organic pollutants has become a well-established tool for assessing the occurrence and extent of biodegradation processes in contaminated aquifers. However, the precision of CSIA is influenced by the degree to which assumptions underlying CSIA data interpretation hold under realistic field-scale conditions. For the first time this study demonstrates how aquifer analogs combined with reactive transport models offer an underexplored way to develop generic process understanding, evaluate monitoring and quantification strategies in highly heterogeneous subsurface settings. Data from high-resolution aquifer analogs were used in numerical experiments to track the propagation of a representative oxidizable organic compound (toluene) within a variety of realistic heterogeneous aquifers and to investigate its detailed fate. The simulations were used to analyze (1) the effects of physical aquifer heterogeneities on spatiotemporal patterns of contaminant concentrations and isotope signatures, (2) the performance of the commonly applied Rayleigh equation and (3) the applicability of an extension of the Rayleigh equation for complex hydrogeological conditions. The results indicate that if field-derived enrichment factors are applied without corrections for dilution, the conventional Rayleigh equation is inaccurate and estimates for biodegradation are typically overestimated and unreliable in heterogeneous aquifers. Underestimations can occur due to the partial source zone depletion. In contrast, if dilution can be accurately accounted for, field-derived enrichment factors comprise a suitable alternative to laboratory-derived and redox-specific enrichment factors. The study also examines to what extent variations in monitoring/sampling strategies influence the obtained results. Especially measurements from long-screened wells (>1 m) reveal to be inappropriate for the application of the Rayleigh equation in the investigated aquifer analogs, as low resolution data sampled from the simulated scenarios only enable a qualitative assessment of biodegradation. Measurements from both long- and short-screened wells employing the Rayleigh equation streamline approach are only partly viable for in situ biodegradation measurements in heterogeneous systems. Copyright © 2015 Elsevier B.V. All rights reserved.

Effects of the somatostatin analog lanreotide on the circulating levels of chromogranin-A, prostate-specific antigen, and insulin-like growth factor-1 in advanced prostate cancer patients.

PubMed

Berruti, A; Dogliotti, L; Mosca, A; Tarabuzzi, R; Torta, M; Mari, M; Gorzegno, G; Fontana, D; Angeli, A

2001-05-15

The concept that neuroendocrine cells detected within prostate adenocarcinoma produce paracrine factors, that may exert a proliferative effect on exocrine prostate tumor cells, provides a rationale for the use of somatostatin analogs with the aim to counteract or delay the tumor progression. This study was designed to provide preliminary information on the effect of the administration of a long-acting somatostatin analog, lanreotide, on plasma levels of chromogranin A (CgA). Secondary aims were the evaluation of changes in circulating prostate-specific antigen (PSA) and insulin-like growth factor-1 (IGF-1). Lanreotide (Ipstyl 30 mg; Ipsen, Milan, Italy) was administered intramuscularly every 14 days for 2 months to nine heavily pretreated prostate cancer patients with hormone refractory disease. All patients had, at baseline conditions, CgA values above the normal range. Androgen deprivation was maintained during the study period, while other concomitant antineoplastic treatments were not allowed. Serum PSA levels and plasma CgA and IGF-1 values were measured every week. Lanreotide treatment was very well tolerated and no patient experienced major toxicity. Plasma CgA values at baseline: mean 109 U/liter, standard deviation +/- 85 decreased significantly after treatment as follows: 42 U/liter, +/- 17.8; 27.2 U/liter +/- 13.6; 31.4 U/liter, +/- 17.8 and 27.6 U/liter, +/- 17.0; after 7, 14, 21, and 28 days, respectively (P < 0.01, Friedman ANOVA). Serum PSA did not change. Baseline IGF-1 was found to be above the detection limit in four cases, all of them showing a decrease after lanreotide. Lanreotide administration to prostate cancer patients induces a decrease in plasma CgA and IGF-1 levels, without any influence on serum PSA values. Prostate 47:205-211, 2001. Copyright 2001 Wiley-Liss, Inc.

Chemistry of transuranium elements in salt-base repository

DOE Office of Scientific and Technical Information (OSTI.GOV)

Borkowski, Marian; Reed, Donald T; Lucchini, Jean - Francois

2010-12-02

The mobility and potential release of actinides into the accessible environment continues to be the key performance assessment concern of nuclear repositories. Actinide, in particular plutonium speciation under the wide range of conditions that can exist in the subsurface is complex and depends strongly on the coupled effects of redox conditions, inorganic/organic complexation, and the extent/nature of aggregation. Understanding the key factors that define the potential for actinide migration is, in this context, an essential and critical part of making and sustaining a licensing case for a nuclear repository. Herein we report on recent progress in a concurrent modeling andmore » experimental study to determine the speciation of plutonium, uranium and americium in high ionic strength Na-CI-Mg brines. This is being done as part of the ongomg recertification effort m the Waste Isolation Pilot Plant (WIPP). The oxidation-state specific solubility of actinides were established in brine as function of pC{sub H+}, brine composition and the presence and absence of organic chelating agents and carbonate. An oxidation-state invariant analog approach using Nd{sup 3+} and Th{sup 4+} was used for An{sup 3+} and An{sup 4+} respectively. These results show that organic ligands and hydrolysis are key factors for An(III) solubility, hydrolysis at pC{sub H+} above 8 is predominate for An(IV) and carbonates are the key factor for U(VI) solubility. The effect of high ionic strength and brine components measured in absence of carbonates leads to measurable increased in overall solubility over analogous low ionic strength groundwater. Less is known about the bioreduction of actinides by halo-tolerant microorganisms, but there is now evidence that bioreduction does occur and is analogous, in many ways, to what occurs with soil bacteria. Results of solubility studies that focus on Pitzer parameter corrections, new species (e.g. borate complexation), and the thermodynamic parameters for modeling are discussed.« less

Localization of Usher 1 proteins to the photoreceptor calyceal processes, which are absent from mice.

PubMed

Sahly, Iman; Dufour, Eric; Schietroma, Cataldo; Michel, Vincent; Bahloul, Amel; Perfettini, Isabelle; Pepermans, Elise; Estivalet, Amrit; Carette, Diane; Aghaie, Asadollah; Ebermann, Inga; Lelli, Andrea; Iribarne, Maria; Hardelin, Jean-Pierre; Weil, Dominique; Sahel, José-Alain; El-Amraoui, Aziz; Petit, Christine

2012-10-15

The mechanisms underlying retinal dystrophy in Usher syndrome type I (USH1) remain unknown because mutant mice lacking any of the USH1 proteins-myosin VIIa, harmonin, cadherin-23, protocadherin-15, sans-do not display retinal degeneration. We found here that, in macaque photoreceptor cells, all USH1 proteins colocalized at membrane interfaces (i) between the inner and outer segments in rods and (ii) between the microvillus-like calyceal processes and the outer segment basolateral region in rods and cones. This pattern, conserved in humans and frogs, was mediated by the formation of an USH1 protein network, which was associated with the calyceal processes from the early embryonic stages of outer segment growth onwards. By contrast, mouse photoreceptors lacked calyceal processes and had no USH1 proteins at the inner-outer segment interface. We suggest that USH1 proteins form an adhesion belt around the basolateral region of the photoreceptor outer segment in humans, and that defects in this structure cause the retinal degeneration in USH1 patients.

Localization of Usher 1 proteins to the photoreceptor calyceal processes, which are absent from mice

PubMed Central

Sahly, Iman; Dufour, Eric; Schietroma, Cataldo; Michel, Vincent; Bahloul, Amel; Perfettini, Isabelle; Pepermans, Elise; Estivalet, Amrit; Carette, Diane; Aghaie, Asadollah; Ebermann, Inga; Lelli, Andrea; Iribarne, Maria; Hardelin, Jean-Pierre; Weil, Dominique; Sahel, José-Alain

2012-01-01

The mechanisms underlying retinal dystrophy in Usher syndrome type I (USH1) remain unknown because mutant mice lacking any of the USH1 proteins—myosin VIIa, harmonin, cadherin-23, protocadherin-15, sans—do not display retinal degeneration. We found here that, in macaque photoreceptor cells, all USH1 proteins colocalized at membrane interfaces (i) between the inner and outer segments in rods and (ii) between the microvillus-like calyceal processes and the outer segment basolateral region in rods and cones. This pattern, conserved in humans and frogs, was mediated by the formation of an USH1 protein network, which was associated with the calyceal processes from the early embryonic stages of outer segment growth onwards. By contrast, mouse photoreceptors lacked calyceal processes and had no USH1 proteins at the inner–outer segment interface. We suggest that USH1 proteins form an adhesion belt around the basolateral region of the photoreceptor outer segment in humans, and that defects in this structure cause the retinal degeneration in USH1 patients. PMID:23045546

Ages of subsurface stratigraphic intervals in the Quaternary of Enewetak Atoll, Marshall Islands

USGS Publications Warehouse

Szabo, B. J.; Tracey, J.I.; Goter, E.R.

1985-01-01

Drill cores of Enewetak Atoll, Marshall Islands, reveal six stratigraphic intervals, numbered in downward sequence, which represent vertical coral growth during Quaternary interglaciations. Radiocarbon dates indicate that the Holocene sea transgressed the emergent reef platform by about 8000 yr B.P. The reef grew rapidly upward (about 5 to 10 mm/yr) until about 6500 yr B.P. Afterward vertical growth slowed to about 0.5 mm/yr, then lateral development became dominant during the last several thousand years. The second interval is dated at 131,000 ?? 3000 yr B.P. by uranium series. This unit correlates with oxygen-isotope substage 5e and with terrace VIIa of Huon Peninsula, New Guinea, and of Main Reef-2 terrace at Atauro Island. The third interval is not dated because corals were recrystallized and it is tentatively correlated with either oxygen-isotope stages 7 or 9. The age of the fourth interval is estimated at 454,000 ?? 100,000 yr B.P. from measured 234U 238U activity ratios. This unit is correlated with either oxygen-isotope stage 9, 11, or 13. ?? 1985.

The Desire for Amputation or Paralyzation: Evidence for Structural Brain Anomalies in Body Integrity Identity Disorder (BIID).

PubMed

Blom, Rianne M; van Wingen, Guido A; van der Wal, Sija J; Luigjes, Judy; van Dijk, Milenna T; Scholte, H Steven; Denys, Damiaan

2016-01-01

Body Integrity Identity Disorder (BIID) is a condition in which individuals perceive a mismatch between their internal body scheme and physical body shape, resulting in an absolute desire to be either amputated or paralyzed. The condition is hypothesized to be of congenital nature, but evidence for a neuro-anatomical basis is sparse. We collected T1-weighted structural magnetic resonance imaging scans on a 3T scanner in eight individuals with BIID and 24 matched healthy controls, and analyzed the data using voxel-based morphometry. The results showed reduced grey matter volume in the left dorsal and ventral premotor cortices and larger grey matter volume in the cerebellum (lobule VIIa) in individuals with BIID compared to controls. The premotor cortex and cerebellum are thought to be crucial for the experience of body-ownership and the integration of multisensory information. Our results suggest that BIID is associated with structural brain anomalies and might result from a dysfunction in the integration of multisensory information, leading to the feeling of disunity between the mental and physical body shape.

First-Principles Prediction of Thermodynamically Stable Two-Dimensional Electrides

DOE PAGES

Ming, Wenmei; Yoon, Mina; Univ. of Tennessee, Knoxville, TN; ...

2016-10-21

Two-dimensional (2D) electrides, emerging as a new type of layered material whose electrons are confined in interlayer spaces instead of at atomic proximities, are receiving interest for their high performance in various (opto)electronics and catalytic applications. Experimentally, however, 2D electrides have been only found in a couple of layered nitrides and carbides. We report new thermodynamically stable alkaline-earth based 2D electrides by using a first-principles global structure optimization method, phonon spectrum analysis, and molecular dynamics simulation. The method was applied to binary compounds consisting of alkaline-earth elements as cations and group VA, VIA, or VIIA nonmetal elements as anions. Wemore » also revealed that the stability of a layered 2D electride structure is closely related to the cation/anion size ratio; stable 2D electrides possess a sufficiently large cation/anion size ratio to minimize electrostatic energy among cations, anions, and anionic electrons. This work demonstrates a new avenue to the discovery of thermodynamically stable 2D electrides beyond experimental material databases and provides new insight into the principles of electride design.« less

PDZD7-MYO7A complex identified in enriched stereocilia membranes

PubMed Central

Morgan, Clive P; Krey, Jocelyn F; Grati, M'hamed; Zhao, Bo; Fallen, Shannon; Kannan-Sundhari, Abhiraami; Liu, Xue Zhong; Choi, Dongseok; Müller, Ulrich; Barr-Gillespie, Peter G

2016-01-01

While more than 70 genes have been linked to deafness, most of which are expressed in mechanosensory hair cells of the inner ear, a challenge has been to link these genes into molecular pathways. One example is Myo7a (myosin VIIA), in which deafness mutations affect the development and function of the mechanically sensitive stereocilia of hair cells. We describe here a procedure for the isolation of low-abundance protein complexes from stereocilia membrane fractions. Using this procedure, combined with identification and quantitation of proteins with mass spectrometry, we demonstrate that MYO7A forms a complex with PDZD7, a paralog of USH1C and DFNB31. MYO7A and PDZD7 interact in tissue-culture cells, and co-localize to the ankle-link region of stereocilia in wild-type but not Myo7a mutant mice. Our data thus describe a new paradigm for the interrogation of low-abundance protein complexes in hair cell stereocilia and establish an unanticipated link between MYO7A and PDZD7. DOI: http://dx.doi.org/10.7554/eLife.18312.001 PMID:27525485

Plasma transfusion for patients with severe hemorrhage: what is the evidence?

PubMed

Callum, Jeannie L; Rizoli, Sandro

2012-05-01

The following review will detail the current knowledge in massive hemorrhage with regard to the pathophysiology of the coagulation disturbance, the role of plasma, the role of alternatives to plasma, and the clinical value of having a massive transfusion protocol. The coagulation disturbance in trauma patients is more than just the result of consumption of clotting factors at sites of injury and dilution from the infusion of intravenous fluids and red blood cells (RBCs). Even before substantial amounts of fluid resuscitation and RBC transfusion, one-quarter of trauma patients already have abnormal coagulation variables. There is an apparent role for the activation of protein C, hypofibrinogenemia, and fibrin(gen)olysis in the coagulation disturbance after trauma and massive hemorrhage. None of these three disturbances would be completely mitigated by the use of plasma alone, suggesting that there may be an opportunity to improve care of these patients with alternative strategies, such as fibrinogen concentrates and antifibrinolytics. Despite numerous retrospective cohort studies evaluating 1:1 plasma to RBC formula-driven resuscitation, the overall clinical value of this approach is unclear. Studies have even raised concerns regarding a potential increase in morbidity associated with this approach, particularly for patients overtriaged to 1:1 where a massive transfusion is unlikely. We also do not have sufficient evidence to recommend either goal-directed therapy with thromboelastography or early use of fibrinogen replacement, with either cryoprecipitate or fibrinogen concentrates. We have high-quality data that argue against the role for recombinant Factor VIIa that should prompt removal of this strategy from existing protocols. In contrast, we have high-level evidence that all bleeding trauma patients should receive tranexamic acid as soon as possible after injury. This therapy must be included in hemorrhage protocols. If we are to improve the care of massively bleeding patients on a firm scientific ground, we will need large-scale randomized trials to delineate the role of coagulation replacement and the utility of laboratory monitoring. But even until these trials are completed, it is clear that a massive transfusion protocol is needed in all hospitals that manage bleeding patients, to ensure a prompt and coordinated response to hemorrhage. © 2012 American Association of Blood Banks.

Origin and heterogeneity of HDL subspecies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nichols, A.V.; Gong, E.L.; Blanche, P.J.

1987-09-01

A major determinant of mature HDL particle size and apolar core content, in the absence of remodeling factors, is most likely the size and apolipoprotein content of the precursor particle. Depending on the number of apoA-I molecules per analog particle, the LCAT-induced transformation follows either a fusion pathway (for precursors with 2 apoA-I per particle) or a pathway (for precursors with more than 2 apoA-I per particle) that conserves the apolipoprotein number. According to our analog results, small nascent HDL probably serve as precursors to the major (apoA-I without apoA-II)-subpopulation in the size interval. Our studies with the large discoidalmore » analog suggest that HDL/sub 2/ (apoA-I without apoA-II)-subpopulations probably originate from the large discoidal nascent HDL that contain a higher number of apolipoprotein molecules per particle than the small nascent HDL. Intermediate transformation products of the large discoidal analog, described in the present study, resemble deformable species found in human lymph and are characterized by a relatively high surface-to-core lipid ratio. Whether large discoidal precursors containing apoE transform in comparable manner but with eventual interchange of apoA-I for apoE (10,15) is under investigation in our laboratory. Likewise, detailed delineation of pathways whereby the (apoA-I with apoA-II)-HDL subpopulations are formed is yet to be accomplished. 23 refs., 6 figs., 2 tabs.« less

(D-Phe/sup 12/)bombesin analogues: a new class of bombesin receptor antagonists

DOE Office of Scientific and Technical Information (OSTI.GOV)

Heinz-Erian, P.; Coy, D.H.; Tamura, M.

1987-03-01

Previous attempts to develop analogues of bombesin that function as specific receptor antagonists have been unsuccessful. Alteration of the histidine in luteinizing hormone releasing factor has resulted in analogues that function as competitive antagonists. In the present study the authors have used a similar strategy and altered the histidine in bombesin. (D-Phe/sup 12/)bombesin, (D-Phe/sup 12/,Leu/sup 14/)bombesin, and (Try/sup 4/, D-)je/sup 12/) bombesin did not stimulate amylase release from guinea pig pancreatic acini when present alone, but each analog inhibited bombesin-stimulated secretion. For each analog, detectable inhibition occurred at 1 ..mu..M and half-maximal inhibition at 4 ..mu..M. Each analog inhibited amylasemore » release by bombesin and other agonists that stimulate secretion by interacting with bombesin receptors. The analogues of bombesin did not alter stimulation by substance P or other agonists that interact with other receptors. The inhibition of the action of bombesin was competitive with Schild plots having slopes of 1.0. Each analog also inhibited binding of /sup 125/I-labeled (Try/sup 4/) bombesin but not /sup 125/I-labeled substance P. These results demonstrate that (D-Phe/sup 12/) analogues of bombesin function as bombesin receptor antagonists and are the only bombesin receptor antagonists that interact only with the bombesin receptor. Because of their specificity, these analogues may prove useful for defining the role of bombesin in various physiological or pathological processes.« less

Analog of parental empathy: association with physical child abuse risk and punishment intentions.

PubMed

Rodriguez, Christina M

2013-08-01

Current research has been inconsistent in corroborating that parents' compromised empathy is associated with elevated physical child abuse risk, perhaps in part because of an emphasis on dispositional empathy rather than empathy directed at their own children. Research has also relied on self-reports of empathy that are susceptible to participant misrepresentation. The present study utilized an analog task of parental empathy to investigate the association of parental empathy toward one's own child with physical child abuse potential and with their tendency to punish perceived child misbehavior. A sample of 135 mothers and their 4-9 year old children were recruited, with mothers estimating their children's emotional reactions using a behavioral simulation of parental empathy. Mothers also provided self-reports on two measures of child abuse potential, a measure of negative attributions and expected punishment of children using vignettes, as well as a traditional measure of dispositional empathic concern and perspective-taking. Findings suggest that parental demonstration of poorer empathic ability on the analog task was significantly related to increased physical abuse potential, likelihood to punish, and negative child attributions. However, self-reported dispositional empathy exhibited the pattern of inconsistent associations previously observed in the literature. Parental empathy appears to be a relevant target for prevention and intervention programs. Future research should also consider similar analog approaches to investigate such constructs to better uncover the factors that elevate abuse risk. Copyright © 2012 Elsevier Ltd. All rights reserved.

Graphene Quantum Capacitors for High Frequency Tunable Analog Applications.

PubMed

Moldovan, Clara F; Vitale, Wolfgang A; Sharma, Pankaj; Tamagnone, Michele; Mosig, Juan R; Ionescu, Adrian M

2016-08-10

Graphene quantum capacitors (GQC) are demonstrated to be enablers of radio-frequency (RF) functions through voltage-tuning of their capacitance. We show that GQC complements MEMS and MOSFETs in terms of performance for high frequency analog applications and tunability. We propose a CMOS compatible fabrication process and report the first experimental assessment of their performance at microwaves frequencies (up to 10 GHz), demonstrating experimental GQCs in the pF range with a tuning ratio of 1.34:1 within 1.25 V, and Q-factors up to 12 at 1 GHz. The figures of merit of graphene variable capacitors are studied in detail from 150 to 350 K. Furthermore, we describe a systematic, graphene specific approach to optimize their performance and predict the figures of merit achieved if such a methodology is applied.

Does sufficient evidence exist to support a causal association between vitamin D status and cardiovascular disease risk? An assessment using Hill's criteria for causality.

PubMed

Weyland, Patricia G; Grant, William B; Howie-Esquivel, Jill

2014-09-02

Serum 25-hydroxyvitamin D (25(OH)D) levels have been found to be inversely associated with both prevalent and incident cardiovascular disease (CVD) risk factors; dyslipidemia, hypertension and diabetes mellitus. This review looks for evidence of a causal association between low 25(OH)D levels and increased CVD risk. We evaluated journal articles in light of Hill's criteria for causality in a biological system. The results of our assessment are as follows. Strength of association: many randomized controlled trials (RCTs), prospective and cross-sectional studies found statistically significant inverse associations between 25(OH)D levels and CVD risk factors. Consistency of observed association: most studies found statistically significant inverse associations between 25(OH)D levels and CVD risk factors in various populations, locations and circumstances. Temporality of association: many RCTs and prospective studies found statistically significant inverse associations between 25(OH)D levels and CVD risk factors. Biological gradient (dose-response curve): most studies assessing 25(OH)D levels and CVD risk found an inverse association exhibiting a linear biological gradient. Plausibility of biology: several plausible cellular-level causative mechanisms and biological pathways may lead from a low 25(OH)D level to increased risk for CVD with mediators, such as dyslipidemia, hypertension and diabetes mellitus. Experimental evidence: some well-designed RCTs found increased CVD risk factors with decreasing 25(OH)D levels. Analogy: the association between serum 25(OH)D levels and CVD risk is analogous to that between 25(OH)D levels and the risk of overall cancer, periodontal disease, multiple sclerosis and breast cancer. all relevant Hill criteria for a causal association in a biological system are satisfied to indicate a low 25(OH)D level as a CVD risk factor.

DNA-inorganic hybrid nanovaccine for cancer immunotherapy

NASA Astrophysics Data System (ADS)

Zhu, Guizhi; Liu, Yijing; Yang, Xiangyu; Kim, Young-Hwa; Zhang, Huimin; Jia, Rui; Liao, Hsien-Shun; Jin, Albert; Lin, Jing; Aronova, Maria; Leapman, Richard; Nie, Zhihong; Niu, Gang; Chen, Xiaoyuan

2016-03-01

Cancer evolves to evade or compromise the surveillance of the immune system, and cancer immunotherapy aims to harness the immune system in order to inhibit cancer development. Unmethylated CpG dinucleotide-containing oligonucleotides (CpG), a class of potent adjuvants that activate the toll-like receptor 9 (TLR9) located in the endolysosome of many antigen-presenting cells (APCs), are promising for cancer immunotherapy. However, clinical application of synthetic CpG confronts many challenges such as suboptimal delivery into APCs, unfavorable pharmacokinetics caused by limited biostability and short in vivo half-life, and side effects associated with leaking of CpG into the systemic circulation. Here we present DNA-inorganic hybrid nanovaccines (hNVs) for efficient uptake into APCs, prolonged tumor retention, and potent immunostimulation and cancer immunotherapy. hNVs were self-assembled from concatemer CpG analogs and magnesium pyrophosphate (Mg2PPi). Mg2PPi renders hNVs resistant to nuclease degradation and thermal denaturation, both of which are demanding characteristics for effective vaccination and the storage and transportation of vaccines. Fluorophore-labeled hNVs were tracked to be efficiently internalized into the endolysosomes of APCs, where Mg2PPi was dissolved in an acidic environment and thus CpG analogs were exposed to hNVs. Internalized hNVs in APCs led to (1) elevated secretion of proinflammatory factors, and (2) elevated expression of co-stimulatory factors. Compared with molecular CpG, hNVs dramatically prolonged the tissue retention of CpG analogs and reduced splenomegaly, a common side effect of CpG. In a melanoma mouse model, two injections of hNVs significantly inhibited the tumor growth and outperformed the molecular CpG. These results suggest hNVs are promising for cancer immunotherapy.Cancer evolves to evade or compromise the surveillance of the immune system, and cancer immunotherapy aims to harness the immune system in order to inhibit cancer development. Unmethylated CpG dinucleotide-containing oligonucleotides (CpG), a class of potent adjuvants that activate the toll-like receptor 9 (TLR9) located in the endolysosome of many antigen-presenting cells (APCs), are promising for cancer immunotherapy. However, clinical application of synthetic CpG confronts many challenges such as suboptimal delivery into APCs, unfavorable pharmacokinetics caused by limited biostability and short in vivo half-life, and side effects associated with leaking of CpG into the systemic circulation. Here we present DNA-inorganic hybrid nanovaccines (hNVs) for efficient uptake into APCs, prolonged tumor retention, and potent immunostimulation and cancer immunotherapy. hNVs were self-assembled from concatemer CpG analogs and magnesium pyrophosphate (Mg2PPi). Mg2PPi renders hNVs resistant to nuclease degradation and thermal denaturation, both of which are demanding characteristics for effective vaccination and the storage and transportation of vaccines. Fluorophore-labeled hNVs were tracked to be efficiently internalized into the endolysosomes of APCs, where Mg2PPi was dissolved in an acidic environment and thus CpG analogs were exposed to hNVs. Internalized hNVs in APCs led to (1) elevated secretion of proinflammatory factors, and (2) elevated expression of co-stimulatory factors. Compared with molecular CpG, hNVs dramatically prolonged the tissue retention of CpG analogs and reduced splenomegaly, a common side effect of CpG. In a melanoma mouse model, two injections of hNVs significantly inhibited the tumor growth and outperformed the molecular CpG. These results suggest hNVs are promising for cancer immunotherapy. Electronic supplementary information (ESI) available: ESI materials and methods, characterization of hNVs. See DOI: 10.1039/c5nr08821f

A Surrogate for Debye-Waller Factors from Dynamic Stokes Shifts

PubMed Central

Zhong, Qin; Johnson, Jerainne; Aamer, Khaled A.; Tyagi, Madhusudan

2011-01-01

We show that the short-time behavior of time-resolved fluorescence Stokes shifts (TRSS) are similar to that of the intermediate scattering function obtained from neutron scattering at q near the peak in the static structure factor for glycerol. This allows us to extract a Debye-Waller (DW) factor analog from TRSS data at times as short as 1 ps in a relatively simple way. Using the time-domain relaxation data obtained by this method we show that DW factors evaluated at times ≥ 40 ps can be directly influenced by α relaxation and thus should be used with caution when evaluating relationships between fast and slow dynamics in glassforming systems. PMID:21701673

Identifying factors associated with perceived success in the transition from hospital to home after brain injury.

PubMed

Nalder, Emily; Fleming, Jennifer; Foster, Michele; Cornwell, Petrea; Shields, Cassandra; Khan, Asad

2012-01-01

: To identify the factors associated with perceived success of the transition from hospital to home after traumatic brain injury (TBI). : Prospective longitudinal cohort design with data collection at discharge and 1, 3, and 6 months postdischarge. : A total of 127 individuals with TBI discharged to the community and 83 significant others. : An analog scale (0-100) of perceived success of the transition from hospital to home rated by individuals and significant others; Sentinel Events Questionnaire; EuroQol Group Quality-of-Life measure visual analog scale; Sydney Psychosocial Reintegration Scale; Mayo-Portland Adaptability Inventory-4; short form of the Depression, Anxiety, Stress Scales; Craig Hospital Inventory of Environmental Factors; and Caregiver Strain Index. : Greater perceived success of transition for individuals with a TBI was associated with higher levels of health-related quality of life, level of community integration, and more severe injury. Among survivors, sentinel events such as returning to work and independent community access and changing living situation were associated with greater perceived success; financial strain and difficulty accessing therapy services were associated with less success. Among significant others, lower ratings of transition success were associated with higher significant other stress levels as well as lower levels of community integration and changes in the living situation of the individual with TBI. : A combination of sentinel events and personal and environmental factors influences the perceptions of individuals and their families regarding the success of the transition from hospital to home.

[The methods of Western medicine in on ancient medicine].

PubMed

Ban, Deokjin

2010-06-30

The treatise On Ancient Medicine attests that questions of method were being debated both in medicine and in philosophy and is important evidence of cross-discipline methodological controversy. The treatise On Ancient Medicine is the first attempt in the history of Greek thought to provide a detailed account of the development of a science from a starting point in observation and experience. The author of it criticizes philosophical physicians who attempt to systematized medicine by reducing it to the interaction of one or more of the opposites hot, cold, wet, and dry, factors. He regards the theory of his opponents as hypothesis(hypothesis). Medicine has long been in possession of both an archē and a hodos, a principle and a method, which have enabled it to make discoveries over a long period of time. As far as method is concerned, the traditional science of medicine attained the knowledge of the visible by starting from observation and experience, but it recommended the use of reasoning and analogies with familiar objects as a means of learning about the invisible. It also utilized inference from the visible to the visible(epilogismos) and inference from the visible to the invisible(analogismos). The use of analogy as a means of learning about the obscure was also part of the common heritage of early philosophy and medicine. But the author's use of the analogical method distinguishes it from Empedocles' well-known analogy comparisons of the eye to a lantern and the process of respiration to the operations of a clepsydra. According to the author, traditional science of medicine used functional analogy like wine example and cheese example to know the function of humors within the body and utilized structured analogy like a tube example and a cupping instrument example to acknowledge an organ or structure within the body. But the author didn't distinguish between the claim that medicine has a systematic method of making discoveries and very different claim that it has a systematic method of treatment. The reason for this is that he thought that discoveries are the end point of the method of investigation and the starting point of the procedures used in treatment.

Through-the-earth radio

DOEpatents

Reagor, David [Los Alamos, NM; Vasquez-Dominguez, Jose [Los Alamos, NM

2006-05-09

A method and apparatus for effective through-the-earth communication involves a signal input device connected to a transmitter operating at a predetermined frequency sufficiently low to effectively penetrate useful distances through-the earth, and having an analog to digital converter receiving the signal input and passing the signal input to a data compression circuit that is connected to an encoding processor, the encoding processor output being provided to a digital to analog converter. An amplifier receives the analog output from the digital to analog converter for amplifying said analog output and outputting said analog output to an antenna. A receiver having an antenna receives the analog output passes the analog signal to a band pass filter whose output is connected to an analog to digital converter that provides a digital signal to a decoding processor whose output is connected to an data decompressor, the data decompressor providing a decompressed digital signal to a digital to analog converter. An audio output device receives the analog output form the digital to analog converter for producing audible output.

Mars Analog Mission: Glacier Simulation AMADEE-15 by Austrian Space Forum

NASA Astrophysics Data System (ADS)

Groemer, Gernot; Losiak, Anna; Soucek, Alexander; Plank, Clemens; Zanardini, Laura; Sejkora, Nina; Sams, Sebastian

2016-04-01

Austrian Space Forum: The Austrian Space Forum (OeWF, Österreichisches Weltraum Forum) is a non-profit, citizen-science organization of aerospace specialists and enthusiasts. One of its specialisations is Mars analog research. Analog studies and analog instrument validation supported all planetary surface missions so far [1] and are considered as an effective tool to prepare for future missions to Mars [2,3,4,5,6,7]. Since 2006, OeWF has conducted 11 Mars analog field campaigns in diverse locations that represented: 1) average current Mars conditions (the Mars Desert Research Station (MDRS) in Utah in 2006 [8] and the Northern Sahara near Erfoud, Morocco in 2013 [9]); 2) the early and wet Mars (analog site of Rio Tinto Spain in 2011 [10]); and 3) subsurface exploration (Dachstein Ice Caves in 2012). During these campaigns, 68 experiments and major engineering tests were performed, whichwere mostly focused on astrobiology, robotics, human factors, geoscience and spacesuit operations. Major assets of OeWF include two advanced spacesuit simulators Aouda [11], an increasingly evolving Mission Support Center, a dedicated Remote Science Support team [12], and a growing set of Standard Operating Procedures defining major workflows within a mission team. The spacesuit simulators were operated by a total of 18 analog astronauts, who were selected and trained during a >6 month program. Total EVA time is nearly 600 hours, leading to a significant experience in analog field simulations. AMADEE-15: The mission took place between August 2nd and 14th 2015 at the Kaunertal Glacier in Tyrol, Austria. This glacier was selected as a study site because of its accessibility and high number of micro-landscapes analogous to those expected on Mars in locations where abundant water ice is present. As such it is considered a first-tier Mars analog [13]. The Base station was located at N 46.86320, E 10.71401 at 2800 masl, the highest reached location was on elevation of 2887 m. Eleven experiments were conducted by a field crew at the test site under simulated Martian surface exploration conditions, coordinated by the Mission Support Center in Innsbruck, Austria. A 10-minute satellite communication delay and other limitations pertinent to human planetary surface activities were introduced. A detailed description of the mission should be soon published in [14]. References: [1] Preston & Dartnell 2014. Int. J. Astrobiol. 13:81-98. [2] Drake et al. 2009. NASA-SP-2009-566.pdf. [3] Ross et al. 2013. Act. Astronaut. 90:182-202. [4] Abercromby et al. 2013. Act. Astronaut. 91:34-48. [5] Binstead et al. 2015. Human Research Program Investigators Workshop. [6] Imhof et al. 2015. AIAA SPACE 2015 Conference and Exposition. [7] Bessone et al. 2015. 10.1007/978-3-319-15982-9_37. [8] Groemer et al. 2007. AustroMars Sci. Worksh.:4-12. [9] Groemer et al. 2014. Astrobiol. 14:360-376. [10] Orgel et al. 2013. Act. Astronaut. 94:736-748. [11] Groemer et al. 2012. Astrobiol. 12(2):125-134. [12] Losiak et al. 2014. Astrobiol. 14:417-430. [13] Soare et al. 2001. EOS82, 501. [14] Gernot et al. 2016. Act. Astronaut. (in review).

Detecting Analogies Unconsciously

PubMed Central

Reber, Thomas P.; Luechinger, Roger; Boesiger, Peter; Henke, Katharina

2014-01-01

Analogies may arise from the conscious detection of similarities between a present and a past situation. In this functional magnetic resonance imaging study, we tested whether young volunteers would detect analogies unconsciously between a current supraliminal (visible) and a past subliminal (invisible) situation. The subliminal encoding of the past situation precludes awareness of analogy detection in the current situation. First, participants encoded subliminal pairs of unrelated words in either one or nine encoding trials. Later, they judged the semantic fit of supraliminally presented new words that either retained a previously encoded semantic relation (“analog”) or not (“broken analog”). Words in analogs versus broken analogs were judged closer semantically, which indicates unconscious analogy detection. Hippocampal activity associated with subliminal encoding correlated with the behavioral measure of unconscious analogy detection. Analogs versus broken analogs were processed with reduced prefrontal but enhanced medial temporal activity. We conclude that analogous episodes can be detected even unconsciously drawing on the episodic memory network. PMID:24478656

Synthesis of N-(β-D-glycuronopyranosyl)alkanamides and 1-(β-D-glycuronopyranosyl)-4-phenyl-[1,2,3]-triazoles as N-glycoprotein linkage region analogs: examination of the effect of C5 substituent on the N-glycosidic torsion (ΦN) based on X-ray crystallography.

PubMed

Mathiselvam, Manoharan; Loganathan, Duraikkannu; Varghese, Babu

2013-10-18

The torsion angle around the N-glycoprotein linkage region (GlcNAc-Asn) is an important factor for presenting sugar on the cell surface which is crucial for many biological processes. Earlier studies using model and analogs showed that this important torsion angle is greatly influenced by substitutions in the sugar part. In the present work, uronic acid alkanamides and triazole derivatives have been designed and synthesized as newer analogs of N-glycoprotein linkage region to understand the influence of the carboxylic group on linkage region torsion as well as on molecular packing. Crystal structure of N-(β-D-galacturonopyranosyl)acetamide is solved with the space group of P22121. Comparison of the torsion angle and molecular packing of this compound with N-(β-D-galactopyranosyl)acetamide showed that changing the C6-hydoxymethyl group to the carboxylic acid group has minimum influence on the N-glycosidic torsion angle, ΦN and significant influence on the molecular packing. Copyright © 2013 Elsevier Ltd. All rights reserved.

Fast Rotational Diffusion of Water Molecules in a 2D Hydrogen Bond Network at Cryogenic Temperatures

NASA Astrophysics Data System (ADS)

Prisk, T. R.; Hoffmann, C.; Kolesnikov, A. I.; Mamontov, E.; Podlesnyak, A. A.; Wang, X.; Kent, P. R. C.; Anovitz, L. M.

2018-05-01

Individual water molecules or small clusters of water molecules contained within microporous minerals present an extreme case of confinement where the local structure of hydrogen bond networks are dramatically altered from bulk water. In the zinc silicate hemimorphite, the water molecules form a two-dimensional hydrogen bond network with hydroxyl groups in the crystal framework. Here, we present a combined experimental and theoretical study of the structure and dynamics of water molecules within this network. The water molecules undergo a continuous phase transition in their orientational configuration analogous to a two-dimensional Ising model. The incoherent dynamic structure factor reveals two thermally activated relaxation processes, one on a subpicosecond timescale and another on a 10-100 ps timescale, between 70 and 130 K. The slow process is an in-plane reorientation of the water molecule involving the breaking of hydrogen bonds with a framework that, despite the low temperatures involved, is analogous to rotational diffusion of water molecules in the bulk liquid. The fast process is a localized motion of the water molecule with no apparent analogs among known bulk or confined phases of water.

Pleistocene Lake Bonneville as an analog for extraterrestrial lakes and oceans: Chapter 21

USGS Publications Warehouse

Chan, M.A.; Jewell, P.; Parker, T.J.; Ormo, J.; Okubo, Chris; Komatsu, G.

2016-01-01

Geomorphic confirmation for a putative ancient Mars ocean relies on analog comparisons of coastal-like features such as shoreline feature attributes and temporal scales of process formation. Pleistocene Lake Bonneville is one of the few large, geologically young, terrestrial lake systems that exemplify well-preserved shoreline characteristics that formed quickly, on the order of a thousand years or less. Studies of Lake Bonneville provide two essential analog considerations for interpreting shorelines on Mars: (1) morphological variations in expression depend on constructional vs erosional processes, and (2) shorelines are not always correlative at an equipotential elevation across a basin due to isostasy, heat flow, wave setup, fetch, and other factors. Although other large terrestrial lake systems display supporting evidence for geomorphic comparisons, Lake Bonneville encompasses the most integrated examples of preserved coastal features related to basin history, sediment supply, climate, and fetch, all within the context of a detailed hydrograph. These collective terrestrial lessons provide a framework to evaluate possible boundary conditions for ancient Mars hydrology and large water body environmental feedbacks. This knowledge of shoreline characteristics, processes, and environments can support explorations of habitable environments and guide future mission explorations.

Suited versus unsuited analog astronaut performance using the Aouda.X space suit simulator: the DELTA experiment of MARS2013.

PubMed

Soucek, Alexander; Ostkamp, Lutz; Paternesi, Roberta

2015-04-01

Space suit simulators are used for extravehicular activities (EVAs) during Mars analog missions. Flight planning and EVA productivity require accurate time estimates of activities to be performed with such simulators, such as experiment execution or traverse walking. We present a benchmarking methodology for the Aouda.X space suit simulator of the Austrian Space Forum. By measuring and comparing the times needed to perform a set of 10 test activities with and without Aouda.X, an average time delay was derived in the form of a multiplicative factor. This statistical value (a second-over-second time ratio) is 1.30 and shows that operations in Aouda.X take on average a third longer than the same operations without the suit. We also show that activities predominantly requiring fine motor skills are associated with larger time delays (between 1.17 and 1.59) than those requiring short-distance locomotion or short-term muscle strain (between 1.10 and 1.16). The results of the DELTA experiment performed during the MARS2013 field mission increase analog mission planning reliability and thus EVA efficiency and productivity when using Aouda.X.

Excess Noise Depletion of a Bose-Einstein Condensate in an Optical Cavity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Szirmai, G.; Nagy, D.; Domokos, P.

2009-02-27

Quantum fluctuations of a cavity field coupled into the motion of ultracold bosons can be strongly amplified by a mechanism analogous to the Petermann excess noise factor in lasers with unstable cavities. For a Bose-Einstein condensate in a stable optical resonator, the excess noise effect amounts to a significant depletion on long time scales.

Reading between the Lines: Implicit Assessment of the Association of Parental Attributions and Empathy with Abuse Risk

ERIC Educational Resources Information Center

Rodriguez, Christina M.; Cook, Anne E.; Jedrziewski, Chezlie T.

2012-01-01

Objective: Researchers in the child maltreatment field have traditionally relied on explicit self-reports to study factors that may exacerbate physical child abuse risk. The current investigation evaluated an implicit analog task utilizing eye tracking technology to assess both parental attributions of child misbehavior and empathy. Method: Based…

Missing Rings, Synchronous Growth, and Ecological Disturbance in a 36-Year Pitch Pine (Pinus rigida) Provenance Study

Treesearch

Caroline Leland; John Hom; Nicholas Skowronski; F. Thomas Ledig; Paul J. Krusic; Edward R. Cook; Dario Martin-Benito; Javier Martin-Fernandez; Neil Pederson; Dusan Gomory

2016-01-01

Provenance studies are an increasingly important analog for understanding how trees adapted to particular climatic conditions might respond to climate change. Dendrochronological analysis can illuminate differences among trees from different seed sources in terms of absolute annual growth and sensitivity to external growth factors. We analyzed annual radial growth of...

Representability of METT-TC Factors in JC3IEDM

DTIC Science & Technology

2007-06-01

of scenarios with Simulations and other applications. The scope of MSDL is bounded by the situation at one instant in time combined with the COA...analogous to being able to say that one boiled the noodles and heated the sauce in order to cook the spaghetti but not be able to say why one cooked the

Pedagogising Poverty Alleviation: A Discourse Analysis of Educational and Social Policies in Argentina and Chile

ERIC Educational Resources Information Center

Rambla, Xavier; Veger, Antoni

2009-01-01

For the past decades international organisations and governments have promoted and implemented analogous education policies on the grounds that education is the key factor to foster development and fight poverty. This article sets the context of these educational programmes and analyses their discourse on poverty in Argentina and Chile. Then, it…

21 CFR 522.1083 - Gonadotropin releasing factor analog-diphtheria toxoid conjugate.

Code of Federal Regulations, 2012 CFR

2012-04-01

... castration (suppression of testicular function) and reduction of boar taint in intact male pigs intended for slaughter. (3) Limitations. Not approved for use in female pigs and barrows. Do not use in intact male pigs... to use by or on the order of a licensed veterinarian. Pigs should be slaughtered no earlier than 3...

21 CFR 522.1083 - Gonadotropin releasing factor analog-diphtheria toxoid conjugate.

Code of Federal Regulations, 2013 CFR

2013-04-01

... castration (suppression of testicular function) and reduction of boar taint in intact male pigs intended for slaughter. (3) Limitations. Not approved for use in female pigs and barrows. Do not use in intact male pigs... to use by or on the order of a licensed veterinarian. Pigs should be slaughtered no earlier than 3...

Analogies: Explanatory Tools in Web-Based Science Instruction

ERIC Educational Resources Information Center

Glynn, Shawn M.; Taasoobshirazi, Gita; Fowler, Shawn

2007-01-01

This article helps designers of Web-based science instruction construct analogies that are as effective as those used in classrooms by exemplary science teachers. First, the authors explain what analogies are, how analogies foster learning, and what form analogies should take. Second, they discuss science teachers' use of analogies. Third, they…

Measurements in Vacuum of the Complex Permittivity of Planetary Regolith Analog Materials in Support of the OSIRIS-REx Mission

NASA Astrophysics Data System (ADS)

Boivin, A.; Hickson, D. C.; Cunje, A.; Tsai, C. A.; Ghent, R. R.; Daly, M. G.

2017-12-01

In preparation for the OSIRIS-REx sample return mission, ground based radar data have been used to help characterize the carbonaceous asteroid (101955) Bennu as well as to produce a 3-D shape model. Radar data have also been used to derive the near-surface bulk density of the asteroid, a key engineering factor for sample acquisition and return. The relationship between radar albedo and bulk density of the nearsurface depends on the relative permittivity of the material, in this case regolith. The relative permittivity is complex such that ɛ r = ɛ r' + i ɛ r'', where ɛ r' is the dielectric constant and ɛ r'' is the loss factor. Laboratory permittivity measurements have been made in the past on a myriad of samples including Earth materials, lunar Apollo and analog samples, Mars soil analog samples, some meteorites, and cometary analog samples in support of the Rosetta mission. These measurements have been made in different frequency bands and in various conditions; however, no measurements to date have systematically explored the effect of changes in mineralogy on the complex permittivity, and particularly the loss tangent (tanδ , the ratio of ɛ r'' to ɛ r'). The loss tangent controls the absorption of the signal by the material. Continuing our investigation of the effects of mineralogy on these properties, we will present for the first time results of complex permittivity measurements of the UCF/DSI-CI-2 CI asteroid regolith simulant produced by Deep Space Industries Inc. The simulant is mineralogically similar to the CI meteorite Orgueil. CI meteorites are the most spectrally similar meteorites to (101955) Bennu. Since the simulant has been provided to us un-mixed, several sub-samples will be created containing different amounts of carbon, thus allowing us to systematically investigate the effects of carbon content on the permittivity. In order to remove moisture from our samples, powders are baked at 250°C for 48hrs prior to being loaded into a coaxial transmission line and measured under vacuum. Measurements are made using a sweep of frequencies from 300 KHz to 8.5 GHz.

Insulin therapy in diabetes and cancer risk: current understanding and implications for future study: proceedings from a meeting of a European Insulin Safety Consensus Panel, convened and sponsored by Novo Nordisk, held Tuesday October 5, 2010 at The Radisson Edwardian Heathrow Hotel, Hayes, Middlesex, UK.

PubMed

Gough, Stephen C L; Belda-Iniesta, Cristóbal; Poole, Christopher; Weber, Matthias; Russell-Jones, David; Hansen, Bo Falck; Mannucci, Edoardo; Tuomilehto, Jaakko

2011-09-01

Interest in the possibility of certain insulin treatments having the potential to modify cancer development and prognosis was reawakened in 2009, following publication of several epidemiological studies addressing this issue. This interest extends to how diabetes itself and cancer might be linked, and makes desirable an exchange of expert views and knowledge to enhance understanding in this subject among those treating diabetes and cancer, or those developing diabetes therapies. A European meeting was convened with participants invited based on known relevant interests in endocrinology, oncology, epidemiology, and insulin analog design and investigation. Experts in these fields were invited to present on relevant topics, with open discussions held after each presentation. Concern over the potential mitogenic properties of certain insulin analogs has arisen from some (but not all) epidemiological studies, although confounding factors render interpretation controversial. Future epidemiological studies are likely to strengthen confidence in drawing conclusions. Meanwhile, pharmacological studies, and a consideration of cancer pathophysiology, implicate increased insulin-like growth factor-1 receptor affinity, and/or deranged insulin receptor interaction/signaling properties as possible a priori causes for concern with some insulin analogs. Again, interpretation of the body of pharmacological evidence is confounded by the array of test systems and methodologies used, and by studies frequently succumbing to methodological pitfalls. Reassuringly, most available insulin analogs do not differ in their receptor interaction response profile to human insulin, and for those that do there are reasons to question any potential clinical relevance. Nevertheless, it is desirable that new experimental models are devised that can better determine the likely clinical consequences of any variance in receptor response profile versus human insulin. More data are required to increase our understanding of this issue. To facilitate and disseminate such understanding, close cooperation and communication between diabetologists, epidemiologists, oncologists, and insulin engineers will be essential.

Inhibition of the NF-κB signaling pathway by the curcumin analog, 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31): anti-inflammatory and anti-cancer properties.

PubMed

Olivera, Anlys; Moore, Terry W; Hu, Fang; Brown, Andrew P; Sun, Aiming; Liotta, Dennis C; Snyder, James P; Yoon, Younghyoun; Shim, Hyunsuk; Marcus, Adam I; Miller, Andrew H; Pace, Thaddeus W W

2012-02-01

Nuclear factor kappa B (NF-κB) is a key signaling molecule in the elaboration of the inflammatory response. Data indicate that curcumin, a natural ingredient of the curry spice turmeric, acts as a NF-κB inhibitor and exhibits both anti-inflammatory and anti-cancer properties. Curcumin analogs with enhanced activity on NF-κB and other inflammatory signaling pathways have been developed including the synthetic monoketone compound 3,5-Bis(2-fluorobenzylidene)-4-piperidone (EF24). 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31) is a structurally-related curcumin analog whose potency for NF-κB inhibition has yet to be determined. To examine the activity of EF31 compared to EF24 and curcumin, mouse RAW264.7 macrophages were treated with EF31, EF24, curcumin (1-100 μM) or vehicle (DMSO 1%) for 1h. NF-κB pathway activity was assessed following treatment with lipopolysaccharide (LPS) (1 μg/mL). EF31 (IC(50)~5 μM) exhibited significantly more potent inhibition of LPS-induced NF-κB DNA binding compared to both EF24 (IC(50)~35 μM) and curcumin (IC(50) >50 μM). In addition, EF31 exhibited greater inhibition of NF-κB nuclear translocation as well as the induction of downstream inflammatory mediators including pro-inflammatory cytokine mRNA and protein (tumor necrosis factor-α, interleukin-1β, and interleukin-6). Regarding the mechanism of these effects on NF-κB, EF31 (IC(50)~1.92 μM) exhibited significantly greater inhibition of IκB kinase β compared to EF24 (IC(50)~131 μM). Finally, EF31 demonstrated potent toxicity in NF-κB-dependent cancer cell lines while having minimal and reversible toxicity in RAW264.7 macrophages. These data indicate that EF31 is a more potent inhibitor of NF-κB activity than either EF24 or curcumin while exhibiting both anti-inflammatory and anticancer activities. Thus, EF31 represents a promising curcumin analog for further therapeutic development. Copyright © 2011 Elsevier B.V. All rights reserved.

Optical domain analog to digital conversion methods and apparatus

DOEpatents

Vawter, Gregory A

2014-05-13

Methods and apparatus for optical analog to digital conversion are disclosed. An optical signal is converted by mapping the optical analog signal onto a wavelength modulated optical beam, passing the mapped beam through interferometers to generate analog bit representation signals, and converting the analog bit representation signals into an optical digital signal. A photodiode receives an optical analog signal, a wavelength modulated laser coupled to the photodiode maps the optical analog signal to a wavelength modulated optical beam, interferometers produce an analog bit representation signal from the mapped wavelength modulated optical beam, and sample and threshold circuits corresponding to the interferometers produce a digital bit signal from the analog bit representation signal.

Synthetic Analogs of Phospholipid Metabolites as Antimalarials.

DTIC Science & Technology

1979-07-01

phosphatidic acid analogs containing ether and phosphonate groups; completely non-hydrolyzable lecithin analogs containing phosphinate and ether groups...The phosphatidic acid and lecithin target compounds were successfully synthesized and submitted, together with a number of intermediates. A model of a... Phosphatidic acid analogs ......................... 5 Z.Z Lecithin Analogs .................................. 6 2.3 Analogs of Cytidine Diphosphate

Playing with a double-edged sword: Analogies in biochemistry

NASA Astrophysics Data System (ADS)

Orgill, Marykay

Analogy pervades our everyday reasoning. No situation we encounter is exactly like a situation we have encountered previously, and our ability to learn and survive in the world is based on our ability to find similarities between past and present situations and use the knowledge we have gained from past situations to manage current situations. Analogies can be powerful teaching tools because they can make new material intelligible to students by comparing it to material that is already familiar. It is clear, though, that not all analogies are good and that not all good analogies are useful to all students. In this study, I have used textbook analysis, classroom observations, student interviews and instructor interviews to determine the role that analogies play in biochemistry learning. Analogies are an important teaching technique in biochemistry classes, being used more often in both biochemistry classes and textbooks than they are in high school chemistry classes and textbooks. Most biochemistry students like, pay particular attention to, and remember the analogies their instructors provide; and they use these analogies to understand, visualize, and recall information from class. Even though students like and use analogies, they do not understand what analogies are or the mechanism by which they improve learning. For the students, analogies are simply any teaching technique that eases understanding, visualization, or recall. Instructors, on the other hand, have a good understanding of what analogies are and of how they should be presented in class; but they do not use analogies as effectively as they should. They do not plan, explain or identify the limitations of the analogies they use in class. However, regardless of how effectively instructors present analogies in class, this study indicates that, in general, analogies are useful in promoting understanding, visualization, recall, and motivation in biochemistry students at all levels. They would be even more useful if students understood what analogies are and how they can be used to improve understanding of biochemical concepts.

Promoting interdomain analogical transfer: When creating a problem helps to solve a problem.

PubMed

Minervino, Ricardo A; Olguín, Valeria; Trench, Máximo

2017-02-01

Research on analogical thinking has devised several ways of promoting an abstract encoding of base analogs, thus rendering them more retrievable during later encounters with similar situations lacking surface similarities. Recent studies have begun to explore ways of facilitating transfer at retrieval time, which could facilitate the retrieval of distant analogs learned within contexts that were not specially directed to emphasize their abstract structure. Such studies demonstrate that comparing a target problem to an analogous problem helps students retrieve base analogs that lack surface similarities. To devise more portable ways of enhancing analogical transfer, Experiment 1 replicated Kurtz and Loewenstein's (Memory & Cognition, 35, 334-341, 2007) target-comparison procedure with an additional condition in which participants compared the target to a nonanalogous problem before attempting to reach its solution. Although comparing two analogous targets outperformed the standard transfer condition in promoting analogical transfer, comparing nonanalogous problems did not yield a transfer advantage. Based on prior studies that showed that the activity of creating analogous problems during their initial encoding elicits a more abstract representation of base analogs, in Experiment 2 we assessed whether constructing a second analogous target problem at retrieval time helps participants retrieve superficially dissimilar base analogs. As predicted, target invention increased the retrieval of distant sources. In both experiments we found an association between the quality of the generated schemas and the probability of retrieving a distant base analog from memory.

Universal first-order reliability concept applied to semistatic structures

NASA Technical Reports Server (NTRS)

Verderaime, V.

1994-01-01

A reliability design concept was developed for semistatic structures which combines the prevailing deterministic method with the first-order reliability method. The proposed method surmounts deterministic deficiencies in providing uniformly reliable structures and improved safety audits. It supports risk analyses and reliability selection criterion. The method provides a reliability design factor derived from the reliability criterion which is analogous to the current safety factor for sizing structures and verifying reliability response. The universal first-order reliability method should also be applicable for air and surface vehicles semistatic structures.

Universal first-order reliability concept applied to semistatic structures

NASA Astrophysics Data System (ADS)

Verderaime, V.

1994-07-01

A reliability design concept was developed for semistatic structures which combines the prevailing deterministic method with the first-order reliability method. The proposed method surmounts deterministic deficiencies in providing uniformly reliable structures and improved safety audits. It supports risk analyses and reliability selection criterion. The method provides a reliability design factor derived from the reliability criterion which is analogous to the current safety factor for sizing structures and verifying reliability response. The universal first-order reliability method should also be applicable for air and surface vehicles semistatic structures.

The incidence of thromboembolism formation following the use of recombinant factor VIIa in patients suffering from blunt force trauma compared with penetrating trauma: a systematic review.

PubMed

Devlin, Raymond; Bonanno, Laura; Badeaux, Jennifer

2016-03-01

Rapid replacement of blood loss is critical in patients suffering from traumatic hemorrhage. When the availability of blood products is limited, certain interventions have shown promise in conserving blood supplies. Recombinant factor (rF) VIIa has been administered, as an off-label use, to assist in controlling hemorrhage in trauma patients. Although rFVIIa has a tendency to remain localized to areas of vascular insult, there may be an increase in thromboembolism formation when patients suffer multiple sites of injury as seen in blunt force trauma. This review aimed to synthesize the best available evidence regarding the incidence of thromboembolism formation after receiving rFVIIa as an adjunct to hemorrhage control measures (standard resuscitation efforts consisting of varying amounts of packed red blood cells [PRBCs], fresh frozen plasma [FFP], platelets and crystalloid solutions) in patients suffering from traumatic injuries (blunt force and penetrating trauma). Civilian and combat trauma patients who were 15 years and older suffering from blunt force and penetrating traumatic injuries. Use of rFVIIa as an adjunct to hemorrhage control measures (standard resuscitation efforts consisting of varying amounts of PRBCs, FFP, platelets and crystalloid solutions). This review considered both experimental and epidemiological study designs. Confirmed formation of thromboembolism (confirmation based on specific diagnostic tests such as ultrasound, ventilation-perfusion scan or angiography). The databases searched included CINAHL, Ovid MEDLINE, Web of Science, EMBASE and the Cochrane Control Register of Clinical Trials. Studies published after June 1986 were considered for inclusion in this review. Search for unpublished studies was performed. Studies selected for inclusion were critically appraised by two independent reviewers using standardized critical appraisal instruments from the Joanna Briggs Institute (JBI). Data was extracted from articles using standardized data extraction instruments from the JBI. Quantitative results were pooled in statistical meta-analysis using the Joanna Briggs software for meta-analysis. Two studies with a total of 831 participants were included. Both the studies were randomized, placebo-controlled, double-blind trials. No studies of combat trauma patients met the inclusion criteria for this review. A meta-analysis was performed. In blunt force trauma patients, the incidence of thromboembolism formation on administering rFVIIa revealed an overall relative risk of 1.17 with a 95% confidence interval (CI) from 0.77 to 1.79; results not statistically significant (P = 0.4594); large CI and imprecise estimate. In penetrating trauma patients, the incidence of thromboembolism formation on administering rFVIIa revealed an overall relative risk of 0.77 with a 95% CI from 0.27 to 2.20; results not statistically significant (P = 0.6242); very large CI and imprecise estimate. The estimates of the effects are imprecise, results are compatible with effects in opposite directions, increase or decrease of thromboembolism formation, and an increase of thromboembolism formation cannot be excluded. When rFVIIa is administered to trauma patients, there does not appear to be an increased risk of thromboembolism formation favoring one type of injury over the other (blunt force versus penetrating trauma). Owing to large CIs and imprecise estimates, the overall risk of thromboembolism cannot be excluded. The use of rFVIIa does appear to decrease the overall need for blood products in trauma patients with no statistically significant improvement in survival rates. With the high cost of rFVIIa, its use is limited to those facilities that can afford it. In situations wherein blood supply is limited, rFVIIa could conserve limited supplies of blood products with no difference in thromboembolism risk between blunt force versus penetrating trauma, but the high cost will ultimately limit its use to facilities that can afford it. The use of rFVIIa in blunt force and penetrating trauma patients has a JBI Grade B Recommendation (Appendix I). This review excluded patients receiving pharmacologic anticoagulation such as warfarin sodium or heparin. The actions of these drugs will most likely counteract the desired coagulation effect of rFVIIa. Many studies do not account for the effects of rFVIIa in trauma patients receiving pharmacologic anticoagulation and this could be a future area of research.

Models for randomly distributed nanoscopic domains on spherical vesicles

NASA Astrophysics Data System (ADS)

Anghel, Vinicius N. P.; Bolmatov, Dima; Katsaras, John

2018-06-01

The existence of lipid domains in the plasma membrane of biological systems has proven controversial, primarily due to their nanoscopic size—a length scale difficult to interrogate with most commonly used experimental techniques. Scattering techniques have recently proven capable of studying nanoscopic lipid domains populating spherical vesicles. However, the development of analytical methods able of predicting and analyzing domain pair correlations from such experiments has not kept pace. Here, we developed models for the random distribution of monodisperse, circular nanoscopic domains averaged on the surface of a spherical vesicle. Specifically, the models take into account (i) intradomain correlations corresponding to form factors and interdomain correlations corresponding to pair distribution functions, and (ii) the analytical computation of interdomain correlations for cases of two and three domains on a spherical vesicle. In the case of more than three domains, these correlations are treated either by Monte Carlo simulations or by spherical analogs of the Ornstein-Zernike and Percus-Yevick (PY) equations. Importantly, the spherical analog of the PY equation works best in the case of nanoscopic size domains, a length scale that is mostly inaccessible by experimental approaches such as, for example, fluorescent techniques and optical microscopies. The analytical form factors and structure factors of nanoscopic domains populating a spherical vesicle provide a new and important framework for the quantitative analysis of experimental data from commonly studied phase-separated vesicles used in a wide range of biophysical studies.

Analogy Just Looks Like High Level Perception: Why a Domain-General Approach to Analogical Mapping is Right

DTIC Science & Technology

1998-01-01

rerepresentation processes) will be able to use analogy better than those who have not. There is some psychological evidence for this gentrification of knowledge... useful as a technical proposal. We focus on five issues: (1) how perception relates to analogy, (2) how flexibility arises in analogical processing, (3...whether analogy is a domain-general process, (4) how should micro-worlds be used in the study of analogy, and (5) how best to assess the psychological

DNA-inorganic hybrid nanovaccine for cancer immunotherapy.

PubMed

Zhu, Guizhi; Liu, Yijing; Yang, Xiangyu; Kim, Young-Hwa; Zhang, Huimin; Jia, Rui; Liao, Hsien-Shun; Jin, Albert; Lin, Jing; Aronova, Maria; Leapman, Richard; Nie, Zhihong; Niu, Gang; Chen, Xiaoyuan

2016-03-28

Cancer evolves to evade or compromise the surveillance of the immune system, and cancer immunotherapy aims to harness the immune system in order to inhibit cancer development. Unmethylated CpG dinucleotide-containing oligonucleotides (CpG), a class of potent adjuvants that activate the toll-like receptor 9 (TLR9) located in the endolysosome of many antigen-presenting cells (APCs), are promising for cancer immunotherapy. However, clinical application of synthetic CpG confronts many challenges such as suboptimal delivery into APCs, unfavorable pharmacokinetics caused by limited biostability and short in vivo half-life, and side effects associated with leaking of CpG into the systemic circulation. Here we present DNA-inorganic hybrid nanovaccines (hNVs) for efficient uptake into APCs, prolonged tumor retention, and potent immunostimulation and cancer immunotherapy. hNVs were self-assembled from concatemer CpG analogs and magnesium pyrophosphate (Mg2PPi). Mg2PPi renders hNVs resistant to nuclease degradation and thermal denaturation, both of which are demanding characteristics for effective vaccination and the storage and transportation of vaccines. Fluorophore-labeled hNVs were tracked to be efficiently internalized into the endolysosomes of APCs, where Mg2PPi was dissolved in an acidic environment and thus CpG analogs were exposed to hNVs. Internalized hNVs in APCs led to (1) elevated secretion of proinflammatory factors, and (2) elevated expression of co-stimulatory factors. Compared with molecular CpG, hNVs dramatically prolonged the tissue retention of CpG analogs and reduced splenomegaly, a common side effect of CpG. In a melanoma mouse model, two injections of hNVs significantly inhibited the tumor growth and outperformed the molecular CpG. These results suggest hNVs are promising for cancer immunotherapy.

Tissue factor pathway inhibitor prevents airway obstruction, respiratory failure and death due to sulfur mustard analog inhalation.

PubMed

Rancourt, Raymond C; Veress, Livia A; Ahmad, Aftab; Hendry-Hofer, Tara B; Rioux, Jacqueline S; Garlick, Rhonda B; White, Carl W

2013-10-01

Sulfur mustard (SM) inhalation causes airway injury, with enhanced vascular permeability, coagulation, and airway obstruction. The objective of this study was to determine whether recombinant tissue factor pathway inhibitor (TFPI) could inhibit this pathogenic sequence. Rats were exposed to the SM analog 2-chloroethyl ethyl sulfide (CEES) via nose-only aerosol inhalation. One hour later, TFPI (1.5mg/kg) in vehicle, or vehicle alone, was instilled into the trachea. Arterial O2 saturation was monitored using pulse oximetry. Twelve hours after exposure, animals were euthanized and bronchoalveolar lavage fluid (BALF) and plasma were analyzed for prothrombin, thrombin-antithrombin complex (TAT), active plasminogen activator inhibitor-1 (PAI-1) levels, and fluid fibrinolytic capacity. Lung steady-state PAI-1 mRNA was measured by RT-PCR analysis. Airway-capillary leak was estimated by BALF protein and IgM, and by pleural fluid measurement. In additional animals, airway cast formation was assessed by microdissection and immunohistochemical detection of airway fibrin. Airway obstruction in the form of fibrin-containing casts was evident in central conducting airways of rats receiving CEES. TFPI decreased cast formation, and limited severe hypoxemia. Findings of reduced prothrombin consumption, and lower TAT complexes in BALF, demonstrated that TFPI acted to limit thrombin activation in airways. TFPI, however, did not appreciably affect CEES-induced airway protein leak, PAI-1 mRNA induction, or inhibition of the fibrinolytic activity present in airway surface liquid. Intratracheal administration of TFPI limits airway obstruction, improves gas exchange, and prevents mortality in rats with sulfur mustard-analog-induced acute lung injury. Copyright © 2013 Elsevier Inc. All rights reserved.

Novel properties of the q-analogue quantized radiation field

NASA Technical Reports Server (NTRS)

Nelson, Charles A.

1993-01-01

The 'classical limit' of the q-analog quantized radiation field is studied paralleling conventional quantum optics analyses. The q-generalizations of the phase operator of Susskind and Glogower and that of Pegg and Barnett are constructed. Both generalizations and their associated number-phase uncertainty relations are manifestly q-independent in the n greater than g number basis. However, in the q-coherent state z greater than q basis, the variance of the generic electric field, (delta(E))(sup 2) is found to be increased by a factor lambda(z) where lambda(z) greater than 1 if q not equal to 1. At large amplitudes, the amplitude itself would be quantized if the available resolution of unity for the q-analog coherent states is accepted in the formulation. These consequences are remarkable versus the conventional q = 1 limit.

Optically-synchronized encoder and multiplexer scheme for interleaved photonics analog-to-digital conversion

NASA Astrophysics Data System (ADS)

Villa, Carlos; Kumavor, Patrick; Donkor, Eric

2008-04-01

Photonics Analog-to-Digital Converters (ADCs) utilize a train of optical pulses to sample an electrical input waveform applied to an electrooptic modulator or a reverse biased photodiode. In the former, the resulting train of amplitude-modulated optical pulses is detected (converter to electrical) and quantized using a conversional electronics ADC- as at present there are no practical, cost-effective optical quantizers available with performance that rival electronic quantizers. In the latter, the electrical samples are directly quantized by the electronics ADC. In both cases however, the sampling rate is limited by the speed with which the electronics ADC can quantize the electrical samples. One way to increase the sampling rate by a factor N is by using the time-interleaved technique which consists of a parallel array of N electrical ADC converters, which have the same sampling rate but different sampling phase. Each operating at a quantization rate of fs/N where fs is the aggregated sampling rate. In a system with no real-time operation, the N channels digital outputs are stored in memory, and then aggregated (multiplexed) to obtain the digital representation of the analog input waveform. Alternatively, for real-time operation systems the reduction of storing time in the multiplexing process is desired to improve the time response of the ADC. The complete elimination of memories come expenses of concurrent timing and synchronization in the aggregation of the digital signal that became critical for a good digital representation of the analog signal waveform. In this paper we propose and demonstrate a novel optically synchronized encoder and multiplexer scheme for interleaved photonics ADCs that utilize the N optical signals used to sample different phases of an analog input signal to synchronize the multiplexing of the resulting N digital output channels in a single digital output port. As a proof of concept, four 320 Megasamples/sec 12-bit of resolution digital signals were multiplexed to form an aggregated 1.28 Gigasamples/sec single digital output signal.

Microbial diversity and iron oxidation at Okuoku-hachikurou Onsen, a Japanese hot spring analog of Precambrian iron formations.

PubMed

Ward, L M; Idei, A; Terajima, S; Kakegawa, T; Fischer, W W; McGlynn, S E

2017-11-01

Banded iron formations (BIFs) are rock deposits common in the Archean and Paleoproterozoic (and regionally Neoproterozoic) sedimentary successions. Multiple hypotheses for their deposition exist, principally invoking the precipitation of iron via the metabolic activities of oxygenic, photoferrotrophic, and/or aerobic iron-oxidizing bacteria. Some isolated environments support chemistry and mineralogy analogous to processes involved in BIF deposition, and their study can aid in untangling the factors that lead to iron precipitation. One such process analog system occurs at Okuoku-hachikurou (OHK) Onsen in Akita Prefecture, Japan. OHK is an iron- and CO 2 -rich, circumneutral hot spring that produces a range of precipitated mineral textures containing fine laminae of aragonite and iron oxides that resemble BIF fabrics. Here, we have performed 16S rRNA gene amplicon sequencing of microbial communities across the range of microenvironments in OHK to describe the microbial diversity present and to gain insight into the cycling of iron, oxygen, and carbon in this ecosystem. These analyses suggest that productivity at OHK is based on aerobic iron-oxidizing Gallionellaceae. In contrast to other BIF analog sites, Cyanobacteria, anoxygenic phototrophs, and iron-reducing micro-organisms are present at only low abundances. These observations support a hypothesis where low growth yields and the high stoichiometry of iron oxidized per carbon fixed by aerobic iron-oxidizing chemoautotrophs like Gallionellaceae result in accumulation of iron oxide phases without stoichiometric buildup of organic matter. This system supports little dissimilatory iron reduction, further setting OHK apart from other process analog sites where iron oxidation is primarily driven by phototrophic organisms. This positions OHK as a study area where the controls on primary productivity in iron-rich environments can be further elucidated. When compared with geological data, the metabolisms and mineralogy at OHK are most similar to specific BIF occurrences deposited after the Great Oxygenation Event, and generally discordant with those that accumulated before it. © 2017 John Wiley & Sons Ltd.

Delayed release formulation of the somatostatin analog RC-160 inhibits the growth hormone (GH) response to GH-releasing factor-(1-29)NH2 and decreases elevated prolactin levels in rats.

PubMed

Bokser, L; Schally, A V

1988-10-01

Recently, we have developed a long-acting delivery system for our somatostatin (SS) analog RC-160 based on injectable microcapsules in poly-(D,L-lactide-coglycolide). We studied the capacity of this formulation to repeatedly block the GH secretion induced by administration of GRF-(1-29)NH2 (GRF) on different days. Male rats anesthetized with pentobarbital were injected iv with 2.5 micrograms/kg BW GRF-(1-29)NH2 or saline. Five minutes later, blood samples were taken for GH measurement, and the animals were injected im with RC-160 microcapsules at a dose calculated to release 25 micrograms/day of the analog for 7 days or with the vehicle. The GRF stimuli were repeated 48 h, 96 h, and 8 days after administration of SS analog in microcapsules. GRF administration increased GH levels at the four times tested (P less than 0.01) in the control group injected with vehicle, while RC-160 microcapsules inhibited the GH response for more than 96 h (P less than 0.01). The GH levels augmented by pentobarbital were also decreased by the RC-160 microcapsules (P less than 0.01). Animals treated with microcapsules showed smaller increases in their body weight than untreated rats (P less than 0.05). We also investigated the effect of RC-160 microcapsules on hyperprolactinemic female rats implanted with pituitary glands under the kidney capsules. High PRL levels in rats bearing pituitary grafts showed a significant decrease when measured 4 days after the administration of RC-160 microcapsules. These results demonstrate the efficacy of the long-acting delivery system of the SS analog RC-160 and suggest the possible clinical usefulness of this formulation for lowering GH and PRL levels.

The ESA-NASA CHOICE Study: Winterover at Concordia Station, Interior Antarctica, A Potential Analog for Spaceflight-Associated Immune Dysregulation

NASA Technical Reports Server (NTRS)

Crucian, B. E.; Stowe, R. P.; Mehta, S. K.; Quiriarte, H.; Pierson, D L.; Sams, C. F.

2010-01-01

For ground-based space physiological research, the choice of terrestrial analog must carefully match the system of interest. Antarctica winter-over at the European Concordia Station is potentially a superior ground-analog for spaceflight-associated immune dysregulation (SAID). Concordia missions consist of prolonged durations in an extreme/dangerous environment, station-based habitation, isolation, disrupted circadian rhythms and international crews. The ESA-NASA CHOICE study assesses innate and adaptive immunity, viral reactivation and stress factors during Concordia winterover deployment. Initial data obtained from the first study deployment (2009 mission; 'n' of 6) will be presented, and logistical challenges regarding analog usage for biological studies will also be discussed. The total WBC increased, and alterations in some peripheral leukocyte populations were observed during winterover at Concordia Station. Percentages of lymphocytes and monocytes increased, and levels of senescent CD8+ T cells were increased during deployment. Transient increases in constitutively activated T cell subsets were observed, at mission time points associated with endemic disease outbreaks. T cell function (early blastogenesis response) was increased near the entry/exit deployment phases, and production of most measured cytokines increased during deployment. Salivary cortisol demonstrated high variability during winterover, but was generally increased. A 2-point circadian rhythm of cortisol measurement (morning/evening) was unaltered during winterover. Perceived stress was mildly elevated during winterover. Other measures, including in-vitro DTH assessment, viral specific T cell number/function and latent herpesvirus reactivation have not yet been completed for the 2009 winterover subjects. Based on the preliminary data, alterations in immune cell distribution and function appear to persist during Antarctic winterover at Concordia Station. Some of these changes are similar to those observed in Astronauts, either during or immediately following spaceflight. Based on the initial immune data and environmental conditions, Concordia winterover may be an appropriate analog for some flight-associated immune changes.

How the creative use of analogies can shape medical practice.

PubMed

Prasad, G V Ramesh

2015-06-01

Analogical reasoning is central to medical progress, and is either creative or conservative. According to Hofmann et al., conservative analogy relates concepts from old technology to new technologies with emphasis on preservation of comprehension and conduct. Creative analogy however brings new understanding to new technology, brings similarities existing in the source domain to a target domain where they previously had no bearing, and imports something entirely different from the content of the analogy itself. I defend the claim that while conservative analogies are useful by virtue of being comfortable to use from familiarity and experience, and are more easily accepted by society, they only lead to incremental advances in medicine. However, creative analogies are more exciting and productive because they generate previously unexpected associations across widely separated domains, emphasize relations over physical similarities, and structure over superficiality. I use kidney transplantation and anti-rejection medication development as an exemplar of analogical reasoning used to improve medical practice. Anti-rejection medication has not helped highly sensitized patients because of their propensity to rejecting most organs. I outline how conservative analogical reasoning led to anti-rejection medication development, but creative analogical reasoning helped highly sensitized and blood type incompatible patients through domino transplants, by which they obtain a kidney to which they are not sensitized. Creative analogical reasoning is more likely than conservative analogical reasoning to lead to revolutionary progress. While these analogies overlap and creative analogies eventually become conservative, progress is best facilitated by combining conservative and creative analogical reasoning. © 2015 John Wiley & Sons, Ltd.

An analog of camptothecin inactive against Topoisomerase I is broadly neutralizing of HIV-1 through inhibition of Vif-dependent APOBEC3G degradation.

PubMed

Bennett, Ryan P; Stewart, Ryan A; Hogan, Priscilla A; Ptak, Roger G; Mankowski, Marie K; Hartman, Tracy L; Buckheit, Robert W; Snyder, Beth A; Salter, Jason D; Morales, Guillermo A; Smith, Harold C

2016-12-01

Camptothecin (CPT) is a natural product discovered to be active against various cancers through its ability to inhibit Topoisomerase I (TOP1). CPT analogs also have anti-HIV-1 (HIV) activity that was previously shown to be independent of TOP1 inhibition. We show that a cancer inactive CPT analog (O2-16) inhibits HIV infection by disrupting multimerization of the HIV protein Vif. Antiviral activity depended on the expression of the cellular viral restriction factor APOBEC3G (A3G) that, in the absence of functional Vif, has the ability to hypermutate HIV proviral DNA during reverse transcription. Our studies demonstrate that O2-16 has low cytotoxicity and inhibits Vif-dependent A3G degradation, enabling A3G packaging into HIV viral particles that results in A3G signature hypermutations in viral genomes. This antiviral activity was A3G-dependent and broadly neutralizing against sixteen HIV clinical isolates from groups M (subtypes A-G), N, and O as well as seven single and multi-drug resistant strains of HIV. Molecular modeling predicted binding near the PPLP motif crucial for Vif multimerization and activity. O2-16 also was active in blocking Vif degradation of APOBEC3F (A3F). We propose that CPT analogs not active against TOP1 have novel therapeutic potential as Vif antagonists that enable A3G-dependent hypermutation of HIV. Copyright © 2016 Elsevier B.V. All rights reserved.

Inhibition of mitogen activated protein kinases increases the sensitivity of A549 lung cancer cells to the cytotoxicity induced by a kava chalcone analog

PubMed Central

Warmka, Janel K.; Solberg, Eric L.; Zeliadt, Nicholette A.; Srinivasan, Balasubramanian; Charlson, Aaron T.; Xing, Chengguo; Wattenberg, Elizabeth V.

2012-01-01

We are interested in investigating the biological activity of chalcones, a major class of compounds found in the beverage kava, in order to develop potent and selective chemopreventive candidates. Consumption of kava in the South Pacific Islands is inversely correlated with cancer incidence, even among smokers. Accordingly, chalcones have anti-cancer activities in animal and cell culture models. To investigate signaling pathways that affect chalcone action we studied a potent analog, (E)-3-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (chalcone-24). Chalcone-24 was selected from a series of chalcone analogs that were synthesized based on the structures derived from flavokawain compounds found in kava, and screened in A549 lung cancer cells for induction of cytotoxicity and inhibition of NF-κB, a transcription factor associated with cell survival. Incubation of A549 cells with chalcone-24 resulted in a dose-dependent inhibition of cell viability, inhibition of NF-κB, activation of caspases, and activation of extracellular signal regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK); ERK1/2 and JNK are mitogen activated protein kinases that play central roles in regulating cell fate. Pharmacological inhibitors of ERK1/2 or JNK increased the sensitivity of A549 cells to chalcone-24-induced cytotoxicity, without affecting NF-κB or caspase activity. These results will help refine the synthesis of chalcone analogs to maximize the combination of actions required to prevent and treat cancer. PMID:22771807

Mechanisms of Cytotoxicity of the AIDS Virus.

DTIC Science & Technology

1991-10-10

lentiviruses causes immunosuppression in cats ( feline immunodeficiency virus) (Pederson et al., 1987; Luciw et al., 1989), sheep (visna virus) (Haas et...determinant within the human immunodeficiency virus 1 surface envelope glycoprotein critical for productive infection of primary monocytes. 4. Simian... Immunodeficiency Virus Negative Factor Suppresses the Level of Viral mRNA in COS cells 5. Protein N-myristoylation/AIDS/fatty acid analogs 6. Functional

Impact of Cognitive, Psychosocial, and Career Factors on Educational and Workplace Success. Issues in College Success

ERIC Educational Resources Information Center

ACT, Inc., 2007

2007-01-01

Postsecondary and work success is central to the economic and social wellbeing of a country. Fundamentally, college success is measured by persistence to degree attainment. Analogously, work success refers to effective performance of a job's required tasks. To succeed in college, one must be ready for college. A student who is ready for college is…

Approaching a Conceptual Understanding of Enzyme Kinetics and Inhibition: Development of an Active Learning Inquiry Activity for Prehealth and Nonscience Majors

ERIC Educational Resources Information Center

House, Chloe; Meades, Glen; Linenberger, Kimberly J.

2016-01-01

Presented is a guided inquiry activity designed to be conducted with prenursing students using an analogous system to help develop a conceptual understanding of factors impacting enzyme kinetics and the various types of enzyme inhibition. Pre- and postconceptual understanding evaluations and effectiveness of implementation surveys were given to…

Is Mathematics to Blame? An Investigation into High School Students' Difficulty in Performing Calculations in Chemistry

ERIC Educational Resources Information Center

Scott, Fraser J.

2012-01-01

Mathematical ability is a major contributory factor to the success of a student in any science course. This paper aims to determine the source of the difficulty that students often find when performing calculations in chemistry. Through the design and analysis of a set of chemistry questions and analogous mathematics questions, set in a Standard…

A Standard for RF Modulation Factor,

DTIC Science & Technology

1979-09-01

Mathematics of Physics and Chemistry, pp. 474-477 (D. Van Nostrand Co., Inc., New York, N.Y., 1943). [23] Graybill , F. A., An Introduction to Linear ...circuit model . The primary limitation on the quadratic technique is the linearity and bandwidth of the analog multiplier. A high speed (5 MHz...o ...... . ..... 39 7.2.1. Nonlinearity Model ............................................... 41 7.2.2. Model Parameters

77 FR 4227 - Implantation or Injectable Dosage Form New Animal Drugs; Gonadotropin Releasing Factor Analog...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-27

... for Injection, administered as two doses 4 weeks apart to intact male pigs for the reduction of boar... pigs and barrows. Do not use in intact male pigs intended for breeding because of the disruption of.... Pigs should be slaughtered no earlier than 3 weeks and no later than 10 weeks after the second dose...

Parent Report of Early Lexical Production in Bilingual Children: A Cross-Linguistic CDI Comparison

ERIC Educational Resources Information Center

O'Toole, Ciara; Gatt, Daniela; Hickey, Tina M.; Miekisz, Aneta; Haman, Ewa; Armon-Lotem, Sharon; Rinker, Tanja; Ohana, Odelya; dos Santos, Christophe; Kern, Sophie

2017-01-01

This paper compared the vocabulary size of a group of 250 bilinguals aged 24-36 months acquiring six different language pairs using an analogous tool, and attempted to identify factors that influence vocabulary sizes and ultimately place children at risk for language delay. Each research group used adaptations of the MacArthur-Bates Communicative…

Energy Blocks — A Physical Model for Teaching Energy Concepts

NASA Astrophysics Data System (ADS)

Hertting, Scott

2016-01-01

Most physics educators would agree that energy is a very useful, albeit abstract topic. It is therefore important to use various methods to help the student internalize the concept of energy itself and its related ideas. These methods include using representations such as energy bar graphs, energy pie charts, or energy tracking diagrams. Activities and analogies like Energy Theater and Richard Feynman's blocks, as well as the popular money (or wealth) analogy, can also be very effective. The goal of this paper is to describe a physical model of Feynman's blocks that can be employed by instructors to help students learn the following energy-related concepts: 1. The factors affecting each individual mechanical energy storage mode (this refers to what has been traditionally called a form of energy, and while the Modeling Method of instruction is not the focus of this paper, much of the energy related language used is specific to the Modeling Method). For example, how mass or height affects gravitational energy; 2. Energy conservation; and 3. The graphical relationships between the energy storage mode and a factor affecting it. For example, the graphical relationship between elastic energy and the change in length of a spring.

Influence of Germanium source on dopingless tunnel-FET for improved analog/RF performance

NASA Astrophysics Data System (ADS)

Cecil, Kanchan; Singh, Jawar

2017-01-01

Dopingless (DL) and junctionless devices have attracted attention due to their simplified fabrication process and low thermal budget requirements. Therefore, in this work, we investigated the influence of low band gap Germanium (Ge) instead of Silicon (Si) as a "Source region" material in dopingless (DL) tunnel field-effect transistor (DLTFET). We observed that the Ge source DLTFET delivers much better performance in comparison to Si DLTFET under various analog/RF figure of merits (FOMs), such as transconductance (gm), transconductance generation factor (TGF) (gm /Id), output conductance (gd), output resistance (RO), intrinsic gain (gmRO), intrinsic gate delay (τ) and RF FOMs, like unity gain frequency (fT), gain bandwidth product (GBW) along with various gate capacitances. These parameters were extracted using 2D TCAD device simulations through small signal ac analysis. Higher ION /IOFF ratio (1014) of Ge source DLTFET can reduce the dynamic as well as static power in digital circuits, while higher transconductance generation factor (gm /Id) ∼ 2287 V-1 can lower the bias power of an amplifier. Similarly, enhanced RF FOMs i.e unity gain frequency (fT) and gain bandwidth product (GBW) in Gigahertz range projects the proposed device preference for RF circuits.

Method of pedestal and common-mode noise correction for switched-capacitor analog memories

DOEpatents

Britton, Charles L.

1997-01-01

A method and apparatus for correcting common-mode noise and pedestal noise in a multichannel array of switched-capacitor analog memories wherein each analog memory is connected to an associated analog-to-digital converter. The apparatus comprises a single differential element in two different embodiments. In a first embodiment, the differential element is a reference analog memory connected to a buffer. In the second embodiment, the differential dement is a reference analog memory connected to a reference analog-to-digital connected to an array of digital summing circuits.

Method of pedestal and common-mode noise correction for switched-capacitor analog memories

DOEpatents

Britton, Charles L.

1996-01-01

A method and apparatus for correcting common-mode noise and pedestal noise in a multichannel array of switched-capacitor analog memories wherein each analog memory is connected to an associated analog-to-digital converter. The apparatus comprises a single differential element in two different embodiments. In a first embodiment, the differential element is a reference analog memory connected to a buffer. In the second embodiment, the differential element is a reference analog memory connected to a reference analog-to-digital connected to an array of digital summing circuits.

Analogical acts as conceptual strategies in science, engineering and the humanities

NASA Technical Reports Server (NTRS)

Winkler, V. M.

1981-01-01

The composing models which operate by means of analogy are identified. The importance of analogical acts in the prewriting stage of the composing process is discussed. The relations between analogical acts and concept formation are explored. A basic correspondence between the analogical thinking employed in successful learning and analogical thinking as a composing strategy is discussed. Teaching analogical acts as conceptual strategies for exploring problems and generating the form and content of discourse is presented in support of the contention that writing is a unique mode of learning.

The importance of explicitly mapping instructional analogies in science education

NASA Astrophysics Data System (ADS)

Asay, Loretta Johnson

Analogies are ubiquitous during instruction in science classrooms, yet research about the effectiveness of using analogies has produced mixed results. An aspect seldom studied is a model of instruction when using analogies. The few existing models for instruction with analogies have not often been examined quantitatively. The Teaching With Analogies (TWA) model (Glynn, 1991) is one of the models frequently cited in the variety of research about analogies. The TWA model outlines steps for instruction, including the step of explicitly mapping the features of the source to the target. An experimental study was conducted to examine the effects of explicitly mapping the features of the source and target in an analogy during computer-based instruction about electrical circuits. Explicit mapping was compared to no mapping and to a control with no analogy. Participants were ninth- and tenth-grade biology students who were each randomly assigned to one of three conditions (no analogy module, analogy module, or explicitly mapped analogy module) for computer-based instruction. Subjects took a pre-test before the instruction, which was used to assign them to a level of previous knowledge about electrical circuits for analysis of any differential effects. After the instruction modules, students took a post-test about electrical circuits. Two weeks later, they took a delayed post-test. No advantage was found for explicitly mapping the analogy. Learning patterns were the same, regardless of the type of instruction. Those who knew the least about electrical circuits, based on the pre-test, made the most gains. After the two-week delay, this group maintained the largest amount of their gain. Implications exist for science education classrooms, as analogy use should be based on research about effective practices. Further studies are suggested to foster the building of research-based models for classroom instruction with analogies.

Strategy for Restoring Drug Sensitivity to Triple-Negative Breast Cancer

DTIC Science & Technology

2011-09-01

tocopherol ether-linked acetic acid analog -TEA), a non-hydrolyzable ether analog of RRR- - tocopherol in p53 mutant TNBC cells, and to understand...cells with a unique analog of vitamin E (alpha- tocopherol ether-linked acetic acid analog; abbreviated α-TEA) in combination with chemotherapeutic...p53-mutant, triple-negative breast cancer (TNBC) cells with a unique analog of vitamin E (alpha- tocopherol ether-linked acetic acid analog

A CCD Monolithic LMS Adaptive Analog Signal Processor Integrated Circuit.

DTIC Science & Technology

1980-03-01

adaptive filter with electrically- reprogrammable MOS analog conductance weights. I The analog and digital peripheral MOS on-chip circuits are provided with...electrically reprogrammable analog weights at tap positions along a CCD analog delay line in order to form a basic linear combiner for adaptive filtering...electrically reprogrammable analog conductance weights was introduced with the use of non-volatile MNOS memory 6-7 transistors biased in their triode

Copper Filtration and kVp: Effect on Entrance Skin Exposure.

PubMed

Barba, James; Culp, Melissa

2015-01-01

The selection of technical factors to produce an image is driven primarily by the patient, body part, and factors regarding the status of that patient or part. Analog receptor systems are restricted by the ranges of data they are able to record, as well as the quantity and quality of data required to record an image. Using digital receptors allows for a wider range of exposure factors because of the nature of the receptor systems and the data processing methods employed. Thus, factor selection can be more patient centered when using digital receptors to produce a radiograph. To explore the relationship between milliampere seconds (mAs), kilovoltage peak (kVp), and additional copper filtration with exposure indicators and entrance skin exposure (ESE) using both analog and digital receptors. Researchers conducted 2-tailed t-tests using Stata/IC version 11.2 software (StataCorp LP) to compare ESE from several trials using hip and knee phantoms. The analysis indicated that increasing kVp, adding 0.1 mm copper filtration, and correspondingly reducing mAs reduced ESE on a hip phantom by 64%, from 151 mR to 54.4 mR and reduced ESE on a knee phantom by 51%, from 27.2 mR to 13.4 mR. Radiology departments and radiologic technologists can consider these data when creating dose reduction protocols. The wider latitude range of digital radiography can be used to minimize patient exposure while still producing images of diagnostic quality within the acceptable exposure indicator range stated by the manufacturer.

Analogical Reasoning in the Engineering Design Process and Technology Education Applications

ERIC Educational Resources Information Center

Daugherty, Jenny; Mentzer, Nathan

2008-01-01

This synthesis paper discusses the research exploring analogical reasoning, the role of analogies in the engineering design process, and educational applications for analogical reasoning. Researchers have discovered that analogical reasoning is often a fundamental cognitive tool in design problem solving. Regarding the possible role of analogical…

Perceptions of Rebuttal Analogy: Politeness and Implications for Persuasion.

ERIC Educational Resources Information Center

Whaley, Bryan B.

1997-01-01

States that recent theorizing about the role of analogy in persuasion suggests that "rebuttal" analogy addresses two communicative functions by serving as argument and a method of social attack. Examines message receivers' perceptions of rebuttal analogy and rebuttal analogy users. Finds that participants perceived the communicator using…

Analogy-Enhanced Instruction: Effects on Reasoning Skills in Science

ERIC Educational Resources Information Center

Remigio, Krisette B.; Yangco, Rosanelia T.; Espinosa, Allen A.

2014-01-01

The study examined the reasoning skills of first year high school students after learning general science concepts through analogies. Two intact heterogeneous sections were randomly assigned to Analogy-Enhanced Instruction (AEI) group and Non Analogy-Enhanced (NAEI) group. Various analogies were incorporated in the lessons of the AEI group for…

Analogical Reasoning in Geometry Education

ERIC Educational Resources Information Center

Magdas, Ioana

2015-01-01

The analogical reasoning isn't used only in mathematics but also in everyday life. In this article we approach the analogical reasoning in Geometry Education. The novelty of this article is a classification of geometrical analogies by reasoning type and their exemplification. Our classification includes: analogies for understanding and setting a…

Method of pedestal and common-mode noise correction for switched-capacitor analog memories

DOEpatents

Britton, C.L.

1997-09-23

A method and apparatus are disclosed for correcting common-mode noise and pedestal noise in a multichannel array of switched-capacitor analog memories wherein each analog memory is connected to an associated analog-to-digital converter. The apparatus comprises a single differential element in two different embodiments. In a first embodiment, the differential element is a reference analog memory connected to a buffer. In the second embodiment, the differential dement is a reference analog memory connected to a reference analog-to-digital connected to an array of digital summing circuits. 4 figs.

Method of pedestal and common-mode noise correction for switched-capacitor analog memories

DOEpatents

Britton, C.L.

1996-12-31

A method and apparatus are disclosed for correcting common-mode noise and pedestal noise in a multichannel array of switched-capacitor analog memories wherein each analog memory is connected to an associated analog-to-digital converter. The apparatus comprises a single differential element in two different embodiments. In a first embodiment, the differential element is a reference analog memory connected to a buffer. In the second embodiment, the differential element is a reference analog memory connected to a reference analog-to-digital connected to an array of digital summing circuits. 4 figs.

Analog current mode analog/digital converter

NASA Technical Reports Server (NTRS)

Hadidi, Khayrollah (Inventor)

1996-01-01

An improved subranging or comparator circuit is provided for an analog-to-digital converter. As a subranging circuit, the circuit produces a residual signal representing the difference between an analog input signal and an analog of a digital representation. This is achieved by subdividing the digital representation into two or more parts and subtracting from the analog input signal analogs of each of the individual digital portions. In another aspect of the present invention, the subranging circuit comprises two sets of differential input pairs in which the transconductance of one differential input pair is scaled relative to the transconductance of the other differential input pair. As a consequence, the same resistor string may be used for two different digital-to-analog converters of the subranging circuit.

Placental Growth Factor Levels in Populations with High Versus Low Risk for Cardiovascular Disease and Stressful Physiological Environments such as Microgravity: A Pilot Study

NASA Astrophysics Data System (ADS)

Sundaresan, Alamelu; Mehta, Satish K.; Schlegel, Todd. T.; Russomano, Thais; Pierson, Duane L.; Mann, Vivek; Mansoor, Elvedina; Olamigoke, Loretta; Okoro, Elvis

2017-02-01

This pilot study compared placental growth factor (PIGF) levels in populations with high versus low risk for cardiovascular disease. Previous experiments from our laboratory (Sundaresan et al. 2005, 2009) revealed that the angiogenic factor PIGF was up regulated in modeled microgravity conditions in human lymphocytes leading to possible atherogenesis and pathogenesis in microgravity. Since the findings came from microgravity analog experiments, there is a strong link to its usefulness in the microgravity field as a biomarker. It is important to understand, that these findings came from both studies on expression levels of this cardiovascular marker in human lymphocytes in microgravity ( in vitro microgravity analog), and a follow up gene expression study in hind limb suspended mice ( in vivo microgravity analog). The relevance is enhanced because in life on earth, PIGF is an inflammatory biomarker for cardiovascular disease. Studies on the levels of PIGF would help to reduce the risk and prevention of heart failures in astronauts. If we can use this marker to predict and reduce the risk of cardiac events in astronauts and pilots, it would significantly help aerospace medicine operations. The investigations here confirmed that in a cardiovascular stressed population such as coronary artery disease (CAD) and acute coronary syndrome (ACS) patients, PIGF could be overexpressed. We desired to re-evaluate this marker in patients with cardiovascular disease in our own study. PIGF is a marker of inflammation and a predictor of short-term and long-term adverse outcome in ACS. In addition, elevated PIGF levels may be associated with increased risk for CAD.PIGF levels were determined in thirty-one patients undergoing cardiovascular catheterization for reasons other than ACS and in thirty-three low-risk asymptomatic subjects. Additional data on traditional cardiovascular risk factors for both populations were also compiled and compared. We found that PIGF levels were significantly higher in the high-risk population as compared to low-risk population. Also we were able to ascertain that PIGF levels were inversely correlated with HDL-cholesterol but directly correlated with the triglyceride levels. With further validation, PIGF may prove a useful addition to the armamentarium of noninvasive biomarkers for cardiovascular disease including a new area of stressful physiological conditions such as microgravity.

Abstract analogical reasoning in high-functioning children with autism spectrum disorders.

PubMed

Green, Adam E; Kenworthy, Lauren; Mosner, Maya G; Gallagher, Natalie M; Fearon, Edward W; Balhana, Carlos D; Yerys, Benjamin E

2014-12-01

Children with autism spectrum disorders (ASD) exhibit a deficit in spontaneously recognizing abstract similarities that are crucial for generalizing learning to new situations. This may contribute to deficits in the development of appropriate schemas for navigating novel situations, including social interactions. Analogical reasoning is the central cognitive mechanism that enables typically developing children to understand abstract similarities between different situations. Intriguingly, studies of high-functioning children with ASD point to a relative cognitive strength in basic, nonabstract forms of analogical reasoning. If this analogical reasoning ability extends to abstract analogical reasoning (i.e., between superficially dissimilar situations), it may provide a bridge between a cognitive capability and core ASD deficits in areas such as generalization and categorization. This study tested whether preserved analogical reasoning abilities in ASD can be extended to abstract analogical reasoning, using photographs of real-world items and situations. Abstractness of the analogies was determined via a quantitative measure of semantic distance derived from latent semantic analysis. Children with ASD performed as well as typically developing children at identifying abstract analogical similarities when explicitly instructed to apply analogical reasoning. Individual differences in abstract analogical reasoning ability predicted individual differences in a measure of social function in the ASD group. Preliminary analyses indicated that children with ASD, but not typically developing children, showed an effect of age on abstract analogical reasoning. These results provide new evidence that children with ASD are capable of identifying abstract similarities through analogical reasoning, pointing to abstract analogical reasoning as a potential lever for improving generalization skills and social function in ASD. © 2014 International Society for Autism Research, Wiley Periodicals, Inc.

Improved performance of analog and digital acousto-optic modulation with feedback under profiled beam propagation for secure communication using chaos

NASA Astrophysics Data System (ADS)

Almehmadi, Fares S.; Chatterjee, Monish R.

2014-12-01

Using intensity feedback, the closed-loop behavior of an acousto-optic hybrid device under profiled beam propagation has been recently shown to exhibit wider chaotic bands potentially leading to an increase in both the dynamic range and sensitivity to key parameters that characterize the encryption. In this work, a detailed examination is carried out vis-à-vis the robustness of the encryption/decryption process relative to parameter mismatch for both analog and pulse code modulation signals, and bit error rate (BER) curves are used to examine the impact of additive white noise. The simulations with profiled input beams are shown to produce a stronger encryption key (i.e., much lower parametric tolerance thresholds) relative to simulations with uniform plane wave input beams. In each case, it is shown that the tolerance for key parameters drops by factors ranging from 10 to 20 times below those for uniform plane wave propagation. Results are shown to be at consistently lower tolerances for secure transmission of analog and digital signals using parameter tolerance measures, as well as BER performance measures for digital signals. These results hold out the promise for considerably greater information transmission security for such a system.

Realization of rapid debugging for detection circuit of optical fiber gas sensor: Using an analog signal source

NASA Astrophysics Data System (ADS)

Tian, Changbin; Chang, Jun; Wang, Qiang; Wei, Wei; Zhu, Cunguang

2015-03-01

An optical fiber gas sensor mainly consists of two parts: optical part and detection circuit. In the debugging for the detection circuit, the optical part usually serves as a signal source. However, in the debugging condition, the optical part can be easily influenced by many factors, such as the fluctuation of ambient temperature or driving current resulting in instability of the wavelength and intensity for the laser; for dual-beam sensor, the different bends and stresses of the optical fiber will lead to the fluctuation of the intensity and phase; the intensity noise from the collimator, coupler, and other optical devices in the system will also result in the impurity of the optical part based signal source. In order to dramatically improve the debugging efficiency of the detection circuit and shorten the period of research and development, this paper describes an analog signal source, consisting of a single chip microcomputer (SCM), an amplifier circuit, and a voltage-to-current conversion circuit. It can be used to realize the rapid debugging detection circuit of the optical fiber gas sensor instead of optical part based signal source. This analog signal source performs well with many other advantages, such as the simple operation, small size, and light weight.

Quantitative analysis of Ostracoda and water masses around Japan: Application to Pliocene and Pleistocene paleoceanography

USGS Publications Warehouse

Ikeya, Noriyuki; Cronin, Thomas M.

1993-01-01

An ostracode data base consisting of 273 samples from coretops and comprising 226 species was developed for the seas around the Japanese Islands to determine zoogeographic patterns and for application to Pliocene and Pleistocene paleoceanography in the area. Quantitative analyses of the 59 most common taxa between 0 and 300m water depth indicate that ostracode associations are controlled by the main oceanic water masses around Japan and that bottom water temperature is a key factor influencing species distributions. Ostracodes from the following water masses were studied: warm Kuroshio Current, Tsushima Current (Tsugaru Current and Soya Current), Japan Sea intermediate water, Japan Sea proper water and cold Oyashio Current. In order to apply the modem coretop data base to fossil ostracode assemblages, the modem analog technique (MAT) using a squared chord distance (SCD) measure of dissimilarity was tested as a means of comparing fossil and modem assemblages. SCD values of 0.25 or less adequately identify modem analogs from the coretop data set at the local ecological level (i.e. within the same modern bay), while values of 0.25-0.5 identify modem analogs at the level of the zoogeographic province. The MAT method was tested against 3 Pliocene and 11 Pleistocene formations in Japan to examine the use of the MAT in paleoceanographic reconstruction.

NF-κB dynamics show digital activation and analog information processing in cells

NASA Astrophysics Data System (ADS)

Tay, Savas; Hughey, Jake; Lee, Timothy; Lipniacki, Tomasz; Covert, Markus; Quake, Stephen

2010-03-01

Cells operate in ever changing environments using extraordinary communication capabilities. Cell-to-cell communication is mediated by signaling molecules that form spatiotemporal concentration gradients, which requires cells to respond to a wide range of signal intensities. We used high-throughput microfluidic cell culture, quantitative gene expression analysis and mathematical modeling to investigate how single mammalian cells respond to different concentrations of the signaling molecule TNF-α via the transcription factor NF-κB. We measured NF-κB activity in thousands of live cells under TNF-α doses covering four orders of magnitude. In contrast to population studies, the activation is a stochastic, switch-like process at the single cell level with fewer cells responding at lower doses. The activated cells respond fully and express early genes independent of the TNF-α concentration, while only high dose stimulation results in the expression of late genes. Cells also encode a set of analog parameters such as the NF-κB peak intensity, response time and number of oscillations to modulate the outcome. We developed a stochastic model that reproduces both the digital and analog dynamics as well as the gene expression profiles at all measured conditions, constituting a broadly applicable model for TNF-α induced NF-κB signaling in various types of cells.

Binding affinity toward human prion protein of some anti-prion compounds - Assessment based on QSAR modeling, molecular docking and non-parametric ranking.

PubMed

Kovačević, Strahinja; Karadžić, Milica; Podunavac-Kuzmanović, Sanja; Jevrić, Lidija

2018-01-01

The present study is based on the quantitative structure-activity relationship (QSAR) analysis of binding affinity toward human prion protein (huPrP C ) of quinacrine, pyridine dicarbonitrile, diphenylthiazole and diphenyloxazole analogs applying different linear and non-linear chemometric regression techniques, including univariate linear regression, multiple linear regression, partial least squares regression and artificial neural networks. The QSAR analysis distinguished molecular lipophilicity as an important factor that contributes to the binding affinity. Principal component analysis was used in order to reveal similarities or dissimilarities among the studied compounds. The analysis of in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) parameters was conducted. The ranking of the studied analogs on the basis of their ADMET parameters was done applying the sum of ranking differences, as a relatively new chemometric method. The main aim of the study was to reveal the most important molecular features whose changes lead to the changes in the binding affinities of the studied compounds. Another point of view on the binding affinity of the most promising analogs was established by application of molecular docking analysis. The results of the molecular docking were proven to be in agreement with the experimental outcome. Copyright © 2017 Elsevier B.V. All rights reserved.

Analogical Reasoning: What Develops? A Review of Research and Theory.

ERIC Educational Resources Information Center

Goswami, Usha

1991-01-01

Children's analogical reasoning has traditionally been measured by classical four-term analogy tasks or problem-solving tasks. Current theories of analogical development and the evidence on which they are based are reviewed. It is concluded that structural views of analogical development are wrong, and knowledge-based accounts of what develops are…

A Study on Analogies Used in New Ninth Grade Biology Textbook

ERIC Educational Resources Information Center

Dikmenli, Musa

2015-01-01

Analogies have many advantages for students such as concretizing abstract concepts and enabling motivation. Analogies are frequently used in textbooks. Research shows that the analogies in textbooks are not used based on certain directives and sometimes lead to misconceptions for students. Therefore, analysing the analogies in textbooks on several…

Lunar Analog

NASA Technical Reports Server (NTRS)

Cromwell, Ronita L.

2009-01-01

In this viewgraph presentation, a ground-based lunar analog is developed for the return of manned space flight to the Moon. The contents include: 1) Digital Astronaut; 2) Bed Design; 3) Lunar Analog Feasibility Study; 4) Preliminary Data; 5) Pre-pilot Study; 6) Selection of Stockings; 7) Lunar Analog Pilot Study; 8) Bed Design for Lunar Analog Pilot.

Using Analogies in Teaching Physics: A Study on Latvian Teachers' Views and Experience

ERIC Educational Resources Information Center

Jonane, Lolita

2015-01-01

The role of analogies as tools for teaching difficult science concepts has been widely discussed in science education. The application of analogies in the context of sustainable education involves richer potential. The purposeful use of appropriate analogies can facilitate analogical thinking and transfer skills, as well as develop abilities which…

Cross-Domain Analogies as Relating Derived Relations among Two Separate Relational Networks

PubMed Central

Ruiz, Francisco J; Luciano, Carmen

2011-01-01

Contemporary behavior analytic research is making headway in analyzing analogy as the establishment of a relation of coordination among common types of trained or derived relations. Previous studies have been focused on within-domain analogy. The current study expands previous research by analyzing cross-domain analogy as relating relations among separate relational networks and by correlating participants' performance with a standard measure of analogical reasoning. In two experiments, adult participants first completed general intelligence and analogical reasoning tests. Subsequently, they were exposed to a computerized conditional discrimination training procedure designed to create two relational networks, each consisting of two 3-member equivalence classes. The critical test was a two-part analogical test in which participants had to relate combinatorial relations of coordination and distinction between the two relational networks. In Experiment 1, combinatorial relations for each network were individually tested prior to analogical testing, but in Experiment 2 they were not. Across both experiments, 65% of participants passed the analogical test on the first attempt. Moreover, results from the training procedure were strongly correlated with the standard measure of analogical reasoning. PMID:21547072

Established Stem Cell Model of Spinal Muscular Atrophy Is Applicable in the Evaluation of the Efficacy of Thyrotropin-Releasing Hormone Analog

PubMed Central

Ohuchi, Kazuki; Kato, Zenichiro; Seki, Junko; Kawase, Chizuru; Tamai, Yuya; Ono, Yoko; Nagahara, Yuki; Noda, Yasuhiro; Kameyama, Tsubasa; Ando, Shiori; Tsuruma, Kazuhiro; Shimazawa, Masamitsu; Hara, Hideaki; Kaneko, Hideo

2016-01-01

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by the degeneration of spinal motor neurons. This disease is mainly caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene. Currently, no effective treatment is available, and only symptomatic treatment can be provided. Our purpose in the present study was to establish a human SMA-derived induced pluripotent stem cell (SMA-iPSC) disease model and assay a therapeutic drug in preparation for the development of a novel treatment of SMA. We generated iPSCs from the skin fibroblasts of a patient with SMA and confirmed that they were pluripotent and undifferentiated. The neural differentiation of SMA-iPSCs shortened the dendrite and axon length and increased the apoptosis of the spinal motor neurons. In addition, we found activated astrocytes in differentiated SMA-iPSCs. Using this model, we confirmed that treatment with the thyrotropin-releasing hormone (TRH) analog, 5-oxo-l-prolyl-l-histidyl-l-prolinamide, which had marginal effects in clinical trials, increases the SMN protein level. This increase was mediated through the transcriptional activation of the SMN2 gene and inhibition of glycogen synthase kinase-3β activity. Finally, the TRH analog treatment resulted in dendrite and axon development of spinal motor neurons in differentiated SMA-iPSCs. These results suggest that this human in vitro disease model stimulates SMA pathology and reveal the potential efficacy of TRH analog treatment for SMA. Therefore, we can screen novel therapeutic drugs such as TRH for SMA easily and effectively using the human SMA-iPSC model. Significance Platelet-derived growth factor (PDGF) has recently been reported to produce the greatest increase in survival motor neuron protein levels by inhibiting glycogen synthase kinase (GSK)-3β; however, motor neurons lack PDGF receptors. A human in vitro spinal muscular atrophy-derived induced pluripotent stem cell model was established, which showed that the thyrotropin releasing hormone (TRH) analog promoted transcriptional activation of the SMN2 gene and inhibition of GSK-3β activity, resulting in the increase and stabilization of the SMN protein and axon elongation of spinal motor neurons. These results reveal the potential efficacy of TRH analog treatment for SMA. PMID:26683872

Established Stem Cell Model of Spinal Muscular Atrophy Is Applicable in the Evaluation of the Efficacy of Thyrotropin-Releasing Hormone Analog.

PubMed

Ohuchi, Kazuki; Funato, Michinori; Kato, Zenichiro; Seki, Junko; Kawase, Chizuru; Tamai, Yuya; Ono, Yoko; Nagahara, Yuki; Noda, Yasuhiro; Kameyama, Tsubasa; Ando, Shiori; Tsuruma, Kazuhiro; Shimazawa, Masamitsu; Hara, Hideaki; Kaneko, Hideo

2016-02-01

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by the degeneration of spinal motor neurons. This disease is mainly caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene. Currently, no effective treatment is available, and only symptomatic treatment can be provided. Our purpose in the present study was to establish a human SMA-derived induced pluripotent stem cell (SMA-iPSC) disease model and assay a therapeutic drug in preparation for the development of a novel treatment of SMA. We generated iPSCs from the skin fibroblasts of a patient with SMA and confirmed that they were pluripotent and undifferentiated. The neural differentiation of SMA-iPSCs shortened the dendrite and axon length and increased the apoptosis of the spinal motor neurons. In addition, we found activated astrocytes in differentiated SMA-iPSCs. Using this model, we confirmed that treatment with the thyrotropin-releasing hormone (TRH) analog, 5-oxo-l-prolyl-l-histidyl-l-prolinamide, which had marginal effects in clinical trials, increases the SMN protein level. This increase was mediated through the transcriptional activation of the SMN2 gene and inhibition of glycogen synthase kinase-3β activity. Finally, the TRH analog treatment resulted in dendrite and axon development of spinal motor neurons in differentiated SMA-iPSCs. These results suggest that this human in vitro disease model stimulates SMA pathology and reveal the potential efficacy of TRH analog treatment for SMA. Therefore, we can screen novel therapeutic drugs such as TRH for SMA easily and effectively using the human SMA-iPSC model. Significance: Platelet-derived growth factor (PDGF) has recently been reported to produce the greatest increase in survival motor neuron protein levels by inhibiting glycogen synthase kinase (GSK)-3β; however, motor neurons lack PDGF receptors. A human in vitro spinal muscular atrophy-derived induced pluripotent stem cell model was established, which showed that the thyrotropin releasing hormone (TRH) analog promoted transcriptional activation of the SMN2 gene and inhibition of GSK-3β activity, resulting in the increase and stabilization of the SMN protein and axon elongation of spinal motor neurons. These results reveal the potential efficacy of TRH analog treatment for SMA. ©AlphaMed Press.

Analog-to-digital conversion techniques for precision photometry

NASA Technical Reports Server (NTRS)

Opal, Chet B.

1988-01-01

Three types of analog-to-digital converters are described: parallel, successive-approximation, and integrating. The functioning of comparators and sample-and-hold amplifiers is explained. Differential and integral linearity are defined, and good and bad examples are illustrated. The applicability and relative advantages of the three types of converters for precision astronomical photometric measurements are discussed. For most measurements, integral linearity is more important than differential linearity. Successive-approximation converters should be used with multielement solid state detectors because of their high speed, but dual slope integrating converters may be superior for use with single element solid state detectors where speed of digitization is not a factor. In all cases, the input signal should be tailored so that they occupy the upper part of the converter's dynamic range; this can be achieved by providing adjustable gain, or better by varying the integration time of the observation if possible.

Synthesis, X-ray crystallography, spectroscopic characterization and spectroscopic/electrochemical evidence of formation of phenoxy free radical in active center analogs of galactose oxidase - [Cu(Salgly)H₂O] and [Cu(Salphenylalanine)H₂O].

PubMed

Das, Biva; Medhi, Okhil K

2013-03-01

The formation of phenolate free radical is the factor of high turnover for catalytic activity of galactose oxidase (GO) compared to that by inorganic complexes. A new active center analog of GO, [Cu(II)(Salphenylalanine)H(2)O] have been synthesized and its single crystal X-ray analysis was done. In aqueous surfactant micellar solution chemical oxidation as well as electrochemical oxidation of structural models of galactose oxidase - [Cu(II)Salgly·H(2)O] and [Cu(II)(Salphenylalanine)·H(2)O], have been found to generate free radical originating at the phenolate group. Formation of the free radical have been proved by electron paramagnetic resonance spectroscopy, electronic spectroscopy and electrochemistry. Copyright © 2012 Elsevier B.V. All rights reserved.

Interhemispheric compensation: a hypothesis of TMS-induced effects on language-related areas.

PubMed

Andoh, Jamila; Martinot, Jean-Luc

2008-06-01

Repetitive transcranial magnetic stimulation (rTMS) applied over brain regions responsible for language processing is used to curtail potentially auditory hallucinations in schizophrenia patients and to investigate the functional organisation of language-related areas. Variability of effects is, however, marked across studies and between subjects. Furthermore, the mechanisms of action of rTMS are poorly understood. Here, we reviewed different factors related to the structural and functional organisation of the brain that might influence rTMS-induced effects. Then, by analogy with aphasia studies, and the plastic-adaptive changes in both the left and right hemispheres following aphasia recovery, a hypothesis is proposed about rTMS mechanisms over language-related areas (e.g. Wernicke, Broca). We proposed that the local interference induced by rTMS in language-related areas might be analogous to aphasic stroke and might lead to a functional reorganisation in areas connected to the virtual lesion for language recovery.

Six networks on a universal neuromorphic computing substrate.

PubMed

Pfeil, Thomas; Grübl, Andreas; Jeltsch, Sebastian; Müller, Eric; Müller, Paul; Petrovici, Mihai A; Schmuker, Michael; Brüderle, Daniel; Schemmel, Johannes; Meier, Karlheinz

2013-01-01

In this study, we present a highly configurable neuromorphic computing substrate and use it for emulating several types of neural networks. At the heart of this system lies a mixed-signal chip, with analog implementations of neurons and synapses and digital transmission of action potentials. Major advantages of this emulation device, which has been explicitly designed as a universal neural network emulator, are its inherent parallelism and high acceleration factor compared to conventional computers. Its configurability allows the realization of almost arbitrary network topologies and the use of widely varied neuronal and synaptic parameters. Fixed-pattern noise inherent to analog circuitry is reduced by calibration routines. An integrated development environment allows neuroscientists to operate the device without any prior knowledge of neuromorphic circuit design. As a showcase for the capabilities of the system, we describe the successful emulation of six different neural networks which cover a broad spectrum of both structure and functionality.

Concurrent validity of caregiver/parent report measures of language for children who are learning both English and Spanish.

PubMed

Marchman, Virginia A; Martine-Sussmann, Carmen

2002-10-01

The validity of two analogous caregiver/parent report measures of early language development in young children who are learning both English and Spanish is examined. Caregiver/parent report indices of vocabulary production and grammar were obtained for 26 children using the MacArthur Communicative Development Inventory: Words & Sentences (CDI; Fenson et al., 1994) and the Inventario del Desarrollo de Habilidades Comunicativas: Palabras y Enunciados (IDHC; Jackson-Maldonado, Bates, & Thal, 1992). Scores were significantly correlated with analogous laboratory measures in both English and Spanish, including a real-object naming task and spontaneous language use during free-play. The findings offer evidence that the CDI and IDHC provide valid assessments of early language milestones in young English- and Spanish-speaking children. Factors that may influence the validity of these tools for use with this population are also discussed.

Do anorectic men share personality traits with opiate dependent men? A case-control study.

PubMed

Abbate-Daga, Giovanni; Amianto, Federico; Rogna, Lorenzo; Fassino, Secondo

2007-01-01

Eating disorders (ED) and substance use disorders (SUD) display clinical and psychodynamic analogies. The co-diagnosis of a substance use disorder in male ED patients is frequent. Nevertheless, knowledge about the mutual predisposing factors or personality analogies is currently scarce and hypotheses are controversial. The Temperament and Character Inventory (TCI) was used to assess 21 anorectic men, 79 heroin-dependent men, and 75 control men matched for age and education. Anorectic and opiate-addicted patients displayed higher Harm Avoidance and lower Self-directedness and Cooperativeness. Anorectic men displayed lower Reward Dependence and higher Persistence. Opiate addicts had higher Novelty Seeking and Self-transcendence. Anorectic and heroine-dependent subjects share personality traits related to anxiety, fearfulness and antisocial features. Nevertheless, the personality profile does not completely overlap and this could influence the choice of the "substance" of abuse and the related clinical differences between anorexia and heroin dependence.

Opioid Crisis: No Easy Fix to Its Social and Economic Determinants

PubMed Central

Beletsky, Leo; Ciccarone, Daniel

2018-01-01

The accepted wisdom about the US overdose crisis singles out prescribing as the causative vector. Although drug supply is a key factor, we posit that the crisis is fundamentally fueled by economic and social upheaval, its etiology closely linked to the role of opioids as a refuge from physical and psychological trauma, concentrated disadvantage, isolation, and hopelessness. Overreliance on opioid medications is emblematic of a health care system that incentivizes quick, simplistic answers to complex physical and mental health needs. In an analogous way, simplistic measures to cut access to opioids offer illusory solutions to this multidimensional societal challenge. We trace the crisis’ trajectory through the intertwined use of opioid analgesics, heroin, and fentanyl analogs, and we urge engaging the structural determinants lens to address this formidable public health emergency. A broad focus on suffering should guide both patient- and community-level interventions. PMID:29267060

Six Networks on a Universal Neuromorphic Computing Substrate

PubMed Central

Pfeil, Thomas; Grübl, Andreas; Jeltsch, Sebastian; Müller, Eric; Müller, Paul; Petrovici, Mihai A.; Schmuker, Michael; Brüderle, Daniel; Schemmel, Johannes; Meier, Karlheinz

2013-01-01

In this study, we present a highly configurable neuromorphic computing substrate and use it for emulating several types of neural networks. At the heart of this system lies a mixed-signal chip, with analog implementations of neurons and synapses and digital transmission of action potentials. Major advantages of this emulation device, which has been explicitly designed as a universal neural network emulator, are its inherent parallelism and high acceleration factor compared to conventional computers. Its configurability allows the realization of almost arbitrary network topologies and the use of widely varied neuronal and synaptic parameters. Fixed-pattern noise inherent to analog circuitry is reduced by calibration routines. An integrated development environment allows neuroscientists to operate the device without any prior knowledge of neuromorphic circuit design. As a showcase for the capabilities of the system, we describe the successful emulation of six different neural networks which cover a broad spectrum of both structure and functionality. PMID:23423583

Pancreatic Polypeptide Cell Proliferation in the Pancreas and Duodenum Coexisting in a Patient With Pancreatic Adenocarcinoma Treated With a GLP-1 Analog.

PubMed

Talmon, Geoffrey A; Wren, J David; Nguyen, Christophe L; Pour, Parviz M

2017-07-01

A partial pancreaticogastrodudenectomy was performed on a 66-year old man with type 2 diabetes mellitus because of an invasive, moderately differentiated adenocarcinoma in the head of the pancreas. In the adjacent grossly normal tissue of the uncinate process, there was a massive proliferation of pancreatic polypeptide (PP) cells confined to this region and showed invasive pattern. Strikingly, in the heaped area of his duodenum, there was a strikingly large number of PP, glucagon, a few insulin cells in a mini-islet-like patterns composed of glucagon and insulin cells. Among the etiological factors, the possible long-lasting effects of the GLP-1 analog, with which the patient was treated, are discussed. This is the first report in the literature of both the coexistence of a pancreatic adenocarcinoma and invasive PPoma and the occurrence of PP and insulin cells in human duodenal mucosa.

Dual-range linearized transimpedance amplifier system

DOEpatents

Wessendorf, Kurt O.

2010-11-02

A transimpedance amplifier system is disclosed which simultaneously generates a low-gain output signal and a high-gain output signal from an input current signal using a single transimpedance amplifier having two different feedback loops with different amplification factors to generate two different output voltage signals. One of the feedback loops includes a resistor, and the other feedback loop includes another resistor in series with one or more diodes. The transimpedance amplifier system includes a signal linearizer to linearize one or both of the low- and high-gain output signals by scaling and adding the two output voltage signals from the transimpedance amplifier. The signal linearizer can be formed either as an analog device using one or two summing amplifiers, or alternately can be formed as a digital device using two analog-to-digital converters and a digital signal processor (e.g. a microprocessor or a computer).

A low power low noise analog front end for portable healthcare system

NASA Astrophysics Data System (ADS)

Yanchao, Wang; Keren, Ke; Wenhui, Qin; Yajie, Qin; Ting, Yi; Zhiliang, Hong

2015-10-01

The presented analog front end (AFE) used to process human bio-signals consists of chopping instrument amplifier (IA), chopping spikes filter and programmable gain and bandwidth amplifier. The capacitor-coupling input of AFE can reject the DC electrode offset. The power consumption of current-feedback based IA is reduced by adopting capacitor divider in the input and feedback network. Besides, IA's input thermal noise is decreased by utilizing complementary CMOS input pairs which can offer higher transconductance. Fabricated in Global Foundry 0.35 μm CMOS technology, the chip consumes 3.96 μA from 3.3 V supply. The measured input noise is 0.85 μVrms (0.5-100 Hz) and the achieved noise efficient factor is 6.48. Project supported by the Science and Technology Commission of Shanghai Municipality (No. 13511501100), the State Key Laboratory Project of China (No. 11MS002), and the State Key Laboratory of ASIC & System, Fudan University.

Mars weathering analogs - Secondary mineralization in Antarctic basalts

NASA Technical Reports Server (NTRS)

Berkley, J. L.

1982-01-01

Alkalic basalt samples from Ross Island, Antarctica, are evaluated as terrestrial analogs to weathered surface materials on Mars. Secondary alteration in the rocks is limited to pneumatolytic oxidation of igneous minerals and glass, rare groundmass clay and zeolite mineralization, and hydrothermal minerals coating fractures and vesicle surfaces. Hydrothermal mineral assemblages consist mainly of K-feldspar, zeolites (phillipsite and chabazite), calcite, and anhydrite. Low alteration rates are attributed to cold and dry environmental factors common to both Antarctica and Mars. It is noted that mechanical weathering (aeolian abrasion) of Martian equivalents to present Antarctic basalts would yield minor hydrothermal minerals and local surface fines composed of primary igneous minerals and glass but would produce few hydrous products, such as palagonite, clay or micas. It is thought that leaching of hydrothermal vein minerals by migrating fluids and redeposition in duricrust deposits may represent an alternate process for incorporating secondary minerals of volcanic origin into Martian surface fines.

Parametrically coupled fermionic oscillators: Correlation functions and phase-space description

NASA Astrophysics Data System (ADS)

Ghosh, Arnab

2015-01-01

A fermionic analog of a parametric amplifier is used to describe the joint quantum state of the two interacting fermionic modes. Based on a two-mode generalization of the time-dependent density operator, time evolution of the fermionic density operator is determined in terms of its two-mode Wigner and P function. It is shown that the equation of motion of the Wigner function corresponds to a fermionic analog of Liouville's equation. The equilibrium density operator for fermionic fields developed by Cahill and Glauber is thus extended to a dynamical context to show that the mathematical structures of both the correlation functions and the weight factors closely resemble their bosonic counterpart. It has been shown that the fermionic correlation functions are marked by a characteristic upper bound due to Fermi statistics, which can be verified in the matter wave counterpart of photon down-conversion experiments.

Combining four Monte Carlo estimators for radiation momentum deposition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Urbatsch, Todd J; Hykes, Joshua M

2010-11-18

Using four distinct Monte Carlo estimators for momentum deposition - analog, absorption, collision, and track-length estimators - we compute a combined estimator. In the wide range of problems tested, the combined estimator always has a figure of merit (FOM) equal to or better than the other estimators. In some instances the gain in FOM is only a few percent higher than the FOM of the best solo estimator, the track-length estimator, while in one instance it is better by a factor of 2.5. Over the majority of configurations, the combined estimator's FOM is 10-20% greater than any of the solomore » estimators FOM. In addition, the numerical results show that the track-length estimator is the most important term in computing the combined estimator, followed far behind by the analog estimator. The absorption and collision estimators make negligible contributions.« less

Opioid Crisis: No Easy Fix to Its Social and Economic Determinants.

PubMed

Dasgupta, Nabarun; Beletsky, Leo; Ciccarone, Daniel

2018-02-01

The accepted wisdom about the US overdose crisis singles out prescribing as the causative vector. Although drug supply is a key factor, we posit that the crisis is fundamentally fueled by economic and social upheaval, its etiology closely linked to the role of opioids as a refuge from physical and psychological trauma, concentrated disadvantage, isolation, and hopelessness. Overreliance on opioid medications is emblematic of a health care system that incentivizes quick, simplistic answers to complex physical and mental health needs. In an analogous way, simplistic measures to cut access to opioids offer illusory solutions to this multidimensional societal challenge. We trace the crisis' trajectory through the intertwined use of opioid analgesics, heroin, and fentanyl analogs, and we urge engaging the structural determinants lens to address this formidable public health emergency. A broad focus on suffering should guide both patient- and community-level interventions.

Knowledge and Ability Factors Underlying Simple Learning by Accretion

DTIC Science & Technology

1989-10-01

processing framework of Craik and Lockhart (1972) suggested that a permanent memory trace could be established without conscious effort so long as the...correlation/regression analysis for the behavioral sciences Hillsdale, NJ: Lawrence Eribaum. Craik , F.I.M., & Lockhart , R.S. (1972). Levels of...elaborative processing in associative learning, verbal analogy solution should be a significant predictor of paired associate learning. The levels of

Synthetic Vision Systems

NASA Technical Reports Server (NTRS)

Prinzel, L.J.; Kramer, L.J.

2009-01-01

A synthetic vision system is an aircraft cockpit display technology that presents the visual environment external to the aircraft using computer-generated imagery in a manner analogous to how it would appear to the pilot if forward visibility were not restricted. The purpose of this chapter is to review the state of synthetic vision systems, and discuss selected human factors issues that should be considered when designing such displays.

Laughlin states on the Poincaré half-plane and their quantum group symmetry

NASA Astrophysics Data System (ADS)

Alimohammadi, M.; Mohseni Sadjadi, H.

1996-09-01

We find the Laughlin states of the electrons on the Poincaré half-plane in different representations. In each case we show that a quantum group 0305-4470/29/17/025/img5 symmetry exists such that the Laughlin states are a representation of it. We calculate the corresponding filling factor by using the plasma analogy of the fractional quantum Hall effect.