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Sample records for doku kueltuerue ve

  1. Su Doku and Problem Solving

    ERIC Educational Resources Information Center

    Macintyre, Tom

    2006-01-01

    A lot has been made of the topical puzzle Su Doku, with various claims that it can support development of mathematical abilities. The latest, in March this year, came from the Training and Development Agency when a giant puzzle was used to attract graduates into a career of maths teaching. A giant Su Doku puzzle toured busy city centres with the…

  2. Oki-Doku: Number Puzzles

    ERIC Educational Resources Information Center

    Gomez, Cristina; Novak, Dani

    2014-01-01

    The Common Core State Standards for Mathematics (CCSSM) (CCSSI 2010) emphasize the Standards for Mathematical Practice (SMP) that describe processes and proficiencies included in the NCTM Process Standards (NCTM 2000) and in the Strands for Mathematical Proficiency (NRC 2001). The development of these mathematical practices should happen in…

  3. Vought VE-7

    NASA Technical Reports Server (NTRS)

    1923-01-01

    Vought VE-7: The Vought VE-7 was a two-seat trainer built primarily for the Navy. This NACA example, NACA 4, was Navy aircraft A-5669. NACA 4 was used for an investigation of slipstream velocities and for a comparison of propellers in flight compared to wind tunnel data.

  4. The VE/CAD synergism

    SciTech Connect

    Sperling, R.B.

    1993-03-19

    Value Engineering (VE) and Computer-Aided Design (CAD) can be used synergistically to reduce costs and improve facilities designs. The cost and schedule impacts of implementing alternative design ideas developed by VE teams can be greatly reduced when the drawings have been produced with interactive CAD systems. To better understand the interrelationship between VE and CAD, the fundamentals of the VE process are explained; and example of a VE proposal is described and the way CAD drawings facilitated its implementation is illustrated.

  5. 23 CFR 627.7 - VE programs.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... required to be conducted (as specified in 23 CFR 627.5(b)). (b) STAs shall ensure the required VE analysis... 23 Highways 1 2013-04-01 2013-04-01 false VE programs. 627.7 Section 627.7 Highways FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION ENGINEERING AND TRAFFIC OPERATIONS VALUE...

  6. 23 CFR 627.7 - VE programs.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... required to be conducted (as specified in 23 CFR 627.5(b)). (b) STAs shall ensure the required VE analysis... 23 Highways 1 2014-04-01 2014-04-01 false VE programs. 627.7 Section 627.7 Highways FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION ENGINEERING AND TRAFFIC OPERATIONS VALUE...

  7. 40 CFR 35.926 - Value engineering (VE).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Value engineering (VE). 35.926 Section... engineering (VE). (a) Value engineering proposal. All step 2 grant applications for projects having a... completion of VE analysis and submittal of VE summary reports). (b) Value engineering analysis. For...

  8. 40 CFR 35.926 - Value engineering (VE).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 1 2013-07-01 2013-07-01 false Value engineering (VE). 35.926 Section... engineering (VE). (a) Value engineering proposal. All step 2 grant applications for projects having a... completion of VE analysis and submittal of VE summary reports). (b) Value engineering analysis. For...

  9. 40 CFR 35.926 - Value engineering (VE).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 1 2014-07-01 2014-07-01 false Value engineering (VE). 35.926 Section... engineering (VE). (a) Value engineering proposal. All step 2 grant applications for projects having a... completion of VE analysis and submittal of VE summary reports). (b) Value engineering analysis. For...

  10. 40 CFR 35.926 - Value engineering (VE).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 1 2012-07-01 2012-07-01 false Value engineering (VE). 35.926 Section... engineering (VE). (a) Value engineering proposal. All step 2 grant applications for projects having a... completion of VE analysis and submittal of VE summary reports). (b) Value engineering analysis. For...

  11. 40 CFR 35.926 - Value engineering (VE).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 1 2011-07-01 2011-07-01 false Value engineering (VE). 35.926 Section... engineering (VE). (a) Value engineering proposal. All step 2 grant applications for projects having a... completion of VE analysis and submittal of VE summary reports). (b) Value engineering analysis. For...

  12. Interfering with VE-PTP stabilizes endothelial junctions in vivo via Tie-2 in the absence of VE-cadherin

    PubMed Central

    Frye, Maike; Dierkes, Martina; Küppers, Verena; Vockel, Matthias; Tomm, Janina; Zeuschner, Dagmar; Rossaint, Jan; Zarbock, Alexander; Koh, Gou Young; Peters, Kevin; Nottebaum, Astrid Fee

    2015-01-01

    Vascular endothelial (VE)–protein tyrosine phosphatase (PTP) associates with VE-cadherin, thereby supporting its adhesive activity and endothelial junction integrity. VE-PTP also associates with Tie-2, dampening the tyrosine kinase activity of this receptor that can support stabilization of endothelial junctions. Here, we have analyzed how interference with VE-PTP affects the stability of endothelial junctions in vivo. Blocking VE-PTP by antibodies, a specific pharmacological inhibitor (AKB-9778), and gene ablation counteracted vascular leak induction by inflammatory mediators. In addition, leukocyte transmigration through the endothelial barrier was attenuated. Interference with Tie-2 expression in vivo reversed junction-stabilizing effects of AKB-9778 into junction-destabilizing effects. Furthermore, lack of Tie-2 was sufficient to weaken the vessel barrier. Mechanistically, inhibition of VE-PTP stabilized endothelial junctions via Tie-2, which triggered activation of Rap1, which then caused the dissolution of radial stress fibers via Rac1 and suppression of nonmuscle myosin II. Remarkably, VE-cadherin gene ablation did not abolish the junction-stabilizing effect of the VE-PTP inhibitor. Collectively, we conclude that inhibition of VE-PTP stabilizes challenged endothelial junctions in vivo via Tie-2 by a VE-cadherin–independent mechanism. In the absence of Tie-2, however, VE-PTP inhibition destabilizes endothelial barrier integrity in agreement with the VE-cadherin–supportive effect of VE-PTP. PMID:26642851

  13. Interfering with VE-PTP stabilizes endothelial junctions in vivo via Tie-2 in the absence of VE-cadherin.

    PubMed

    Frye, Maike; Dierkes, Martina; Küppers, Verena; Vockel, Matthias; Tomm, Janina; Zeuschner, Dagmar; Rossaint, Jan; Zarbock, Alexander; Koh, Gou Young; Peters, Kevin; Nottebaum, Astrid Fee; Vestweber, Dietmar

    2015-12-14

    Vascular endothelial (VE)-protein tyrosine phosphatase (PTP) associates with VE-cadherin, thereby supporting its adhesive activity and endothelial junction integrity. VE-PTP also associates with Tie-2, dampening the tyrosine kinase activity of this receptor that can support stabilization of endothelial junctions. Here, we have analyzed how interference with VE-PTP affects the stability of endothelial junctions in vivo. Blocking VE-PTP by antibodies, a specific pharmacological inhibitor (AKB-9778), and gene ablation counteracted vascular leak induction by inflammatory mediators. In addition, leukocyte transmigration through the endothelial barrier was attenuated. Interference with Tie-2 expression in vivo reversed junction-stabilizing effects of AKB-9778 into junction-destabilizing effects. Furthermore, lack of Tie-2 was sufficient to weaken the vessel barrier. Mechanistically, inhibition of VE-PTP stabilized endothelial junctions via Tie-2, which triggered activation of Rap1, which then caused the dissolution of radial stress fibers via Rac1 and suppression of nonmuscle myosin II. Remarkably, VE-cadherin gene ablation did not abolish the junction-stabilizing effect of the VE-PTP inhibitor. Collectively, we conclude that inhibition of VE-PTP stabilizes challenged endothelial junctions in vivo via Tie-2 by a VE-cadherin-independent mechanism. In the absence of Tie-2, however, VE-PTP inhibition destabilizes endothelial barrier integrity in agreement with the VE-cadherin-supportive effect of VE-PTP. PMID:26642851

  14. Using VE to Strategically Plan Our Future

    SciTech Connect

    Margie Jeffs; Lori Braase; Alison Conner; Darcie Martinson; Jodi Grgich

    2009-06-01

    The Value Engineering (VE) Methodology is an effective tool for business or project strategic planning. In conjunction with the “Balanced Scorecard Approach” (Drs. Robert Kaplan, PhD, and David Norton, PhD, from the Balanced Scorecard Collaborative/Palladium Group), function analysis can be used to develop strategy maps and scorecards. The FAST diagram provides an integrated approach to strategy map development by formulating a cause and effect relationship and establishing the “how” and “why” behind the strategy map. By utilizing the VE Job Plan, one is able to move from strategic thinking all the way through to execution of the strategy.

  15. We've All Done This Before

    ERIC Educational Resources Information Center

    Stringer, John

    2003-01-01

    When the Association for Science Education published "I've done this before" in 1994, the ASE working party focused on continuity and progression. Now, nearly 10 years later, how far have schools progressed in their understanding and practice of transition? In this article, the author takes a look at the state of transition in primary science…

  16. Propeller Research Tunnel - Vought VE-7

    NASA Technical Reports Server (NTRS)

    1922-01-01

    This picture shows a Vought VE-7 airplane mounted on the test fuselage with an E-2 engine on the plate. The radiator is mounted independently of the engine and is not used for cooling. Cooling water is supplied and returned through rubber hose running back through the fuselage and down the rear post to the floor.

  17. 47 CFR 97.513 - VE session manager requirements.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 5 2013-10-01 2013-10-01 false VE session manager requirements. 97.513 Section 97.513 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.513 VE session manager requirements....

  18. 47 CFR 97.513 - VE session manager requirements.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 5 2014-10-01 2014-10-01 false VE session manager requirements. 97.513 Section 97.513 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.513 VE session manager requirements....

  19. 47 CFR 97.513 - VE session manager requirements.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 5 2011-10-01 2011-10-01 false VE session manager requirements. 97.513 Section 97.513 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.513 VE session manager requirements....

  20. 47 CFR 97.513 - VE session manager requirements.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 5 2010-10-01 2010-10-01 false VE session manager requirements. 97.513 Section 97.513 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.513 VE session manager requirements....

  1. 47 CFR 97.513 - VE session manager requirements.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 5 2012-10-01 2012-10-01 false VE session manager requirements. 97.513 Section 97.513 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.513 VE session manager requirements....

  2. 23 CFR 627.9 - Conducting a VE analysis.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... specified in 49 CFR 18.42). (e) For bridge projects, in addition to the requirements in paragraph (d) of... qualified consultants (as defined in 23 CFR 172) to conduct a VE analysis. The consultant shall possess the... to conduct or support a VE analysis if they have a conflict of interest (as specified in 23 CFR...

  3. 23 CFR 627.9 - Conducting a VE analysis.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... specified in 49 CFR 18.42). (e) For bridge projects, in addition to the requirements in paragraph (d) of... qualified consultants (as defined in 23 CFR 172) to conduct a VE analysis. The consultant shall possess the... to conduct or support a VE analysis if they have a conflict of interest (as specified in 23 CFR...

  4. Postoperative infant septicemia caused by Pseudomonas luteola (CDC group Ve-1) and Pseudomonas oryzihabitans (CDC group Ve-2).

    PubMed

    Freney, J; Hansen, W; Etienne, J; Vandenesch, F; Fleurette, J

    1988-06-01

    Pseudomonas luteola (CDC group Ve-1) and Pseudomonas oryzihabitans (CDC group Ve-2) were both isolated from the same blood culture of a 5-month-old infant, 8 days after open-heart surgery. He quickly responded to appropriate antibiotics. Carbon substrate assimilation tests and fatty acid analysis clearly differentiated these two rarely pathogenic organisms. PMID:3384937

  5. Propeller Research Tunnel - Vought VE-7

    NASA Technical Reports Server (NTRS)

    1922-01-01

    This picture shows the dial of the torque dynamometer in the rear cockpit of the Vought VE-7 setup. An electric starter was used to start the engine. The starter which can be seen just in front of the fuselage (the large gear with the chain) was 'secured to the entrance cone.... A hollow shaft with a pin meshing with a dog on the propeller shaft is driven by means of a chain from an electric motor. The whole unit is arranged to swing down clear of the air stream during a test.' (NACA TR No. 300, p. 438) Initially, the propellers had to be cranked by hand; an engineer precariously perched on a ladder would do the honors.

  6. Genetics Home Reference: Stüve-Wiedemann syndrome

    MedlinePlus

    ... formation, leading to osteopenia, bowed legs, and other skeletal problems common in Stüve-Wiedemann syndrome . In addition, development of nerve cells, particularly those involved in the autonomic nervous system, is abnormal, leading to the problems with breathing, ...

  7. Propeller Research Tunnel - Vought VE-7

    NASA Technical Reports Server (NTRS)

    1922-01-01

    Propeller Research Tunnel balance. Vought VE-7 airplane - set-up and balance details. Fred Weick and Donald Wood wrote in NACA TR No. 300: 'The fixed knife edges on the bell cranks are seated on blocks bolted to a rectangular steel frame rigidly fastened to the floor. In addition, this frame is provided with knife edges, links, and counterweights which hold the triangular frame in a fixed lateral position. Screws are also provide for raising the triangular frame from the knife edges while working on the attached apparatus. A stairway at the rear and a grating floor facilitate work on the supports and apparatus mounted on the balance. At each corner of the triangular frame are ball ended steel tubes, adjustable in length and angle, which support the body under test. The forward tubes, in the case of a fuselage with landing gear, have a fitting at the upper end which clamps the axle of the landing gear. The rear post has a ball-and-socket attachment to the fuselage.'

  8. Do the Naïve Know Best? The Predictive Power of Naïve Ratings of Couple Interactions

    PubMed Central

    Baucom, Katherine J.W.; Baucom, Brian R.; Christensen, Andrew

    2013-01-01

    We examined the utility of naïve ratings of communication patterns and relationship quality in a large sample of distressed couples. Untrained raters assessed 10-minute videotaped interactions from 134 distressed couples who participated in both problem solving and social support discussions at each of three time points (pre-therapy, post-therapy, and 2-year follow-up) during a randomized clinical trial of behavioral couple therapy. Teams of naïve raters observed a particular type of discussion from the three time points at one sitting in a random order and rated dyadic interaction patterns (negative reciprocity, positive reciprocity, wife demand/husband withdraw, husband demand/wife withdraw, and mutual avoidance) and the overall relationship quality of couples. These naïve ratings were strongly and consistently associated with both levels of, and changes in, trained observational codes and self-reported relationship satisfaction. Naïve ratings of couples accounted for similar – and at times superior – amounts of variance in both concurrent relationship satisfaction and divorce at 5-year follow-up when compared with trained ratings. These findings offer compelling support for the use of naïve raters in research with couples, and also suggest important future directions that are applicable to both research and practice with distressed couples. PMID:22708571

  9. Women Who've Battled Postpartum Depression Often Limit Family Size

    MedlinePlus

    ... fullstory_157855.html Women Who've Battled Postpartum Depression Often Limit Family Size They're unlikely to ... 2016 (HealthDay News) -- Women who've had postpartum depression may not have more than two children, a ...

  10. 47 CFR 97.509 - Administering VE requirements.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.509 Administering VE requirements. (a) Each examination for an amateur operator license must be administered by a team of at least 3 VEs at an... person who holds an amateur operator license of the class specified below: (i) Amateur Extra, Advanced...

  11. 47 CFR 97.509 - Administering VE requirements.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.509 Administering VE requirements. (a) Each examination for an amateur operator license must be administered by a team of at least 3 VEs at an... person who holds an amateur operator license of the class specified below: (i) Amateur Extra, Advanced...

  12. 47 CFR 97.509 - Administering VE requirements.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.509 Administering VE requirements. (a) Each examination for an amateur operator license must be administered by a team of at least 3 VEs at an... person who holds an amateur operator license of the class specified below: (i) Amateur Extra, Advanced...

  13. 47 CFR 97.509 - Administering VE requirements.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.509 Administering VE requirements. (a) Each examination for an amateur operator license must be administered by a team of at least 3 VEs at an... person who holds an amateur operator license of the class specified below: (i) Amateur Extra, Advanced...

  14. 47 CFR 97.509 - Administering VE requirements.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.509 Administering VE requirements. (a) Each examination for an amateur operator license must be administered by a team of at least 3 VEs at an... person who holds an amateur operator license of the class specified below: (i) Amateur Extra, Advanced...

  15. The Current State of Naïve Human Pluripotency

    PubMed Central

    Dodsworth, Benjamin T.; Flynn, Rowan

    2015-01-01

    Abstract Naïve or ground state pluripotency is a cellular state in vitro which resembles cells of the preimplantation epiblast in vivo. This state was first observed in mouse embryonic stem cells and is characterized by high rates of proliferation, the ability to differentiate widely, and global hypomethylation. Human pluripotent stem cells (hPSCs) correspond to a later or “primed” stage of embryonic development. The conversion of hPSCs to a naïve state is desirable as their features should facilitate techniques such as gene editing and more efficient differentiation. Here we review protocols which now allow derivation of naïve human pluripotent stem cells by transgene expression or the use of media formulations containing inhibitors and growth factors and correlate this with pathways involved. Maintenance of these ground state cells is possible using a combination of basic fibroblast growth factor and human leukemia inhibitory factor together with dual inhibition of glycogen synthase kinase 3 beta, and mitogen‐activated protein kinase kinase (MEK). Close similarity between the ground state hPSC and the in vivo preimplantation epiblast have been shown both by demonstrating similar upregulation of endogenous retroviruses and correlation of global RNA‐seq data. This suggests that the human naïve state is not an in vitro artifact. Stem Cells 2015;33:3181–3186 PMID:26119873

  16. GloVe C++ v. 1.0

    Energy Science and Technology Software Center (ESTSC)

    2015-12-02

    This code implements the GloVe algorithm for learning word vectors from a text corpus. It uses a modern C++ approach. This algorithm is described in the open literature in the referenced paper by Pennington, Jeffrey, Richard Socher, and Christopher D. Manning.

  17. Langley VEDIT for NOS/VE usage manual

    NASA Technical Reports Server (NTRS)

    Heaney, Margaret A.

    1987-01-01

    The use of the VEDIT editor on the CDC Network Operating System/Virtual Environment (NOS/VE) is discussed. The VEDIT, a utility, allows a user to edit files line by line (line mode). How to access and the use of VEDIT are explained. The parameters and the format of the individual commands are defined. Examples are included.

  18. VINYL-ESTER (VE) CURE CHARACTERIZATION VIA DIRECT CURRENT SENSORS

    EPA Science Inventory

    High-performance thermosetting composites typically consist of a high-modulus fibrous material embedded in a thermosetting polymer matrix. The behavior of the resulting composite depends on the properties of the reinforcement, the interphase, and the matrix. Vinyl-ester (VE) resi...

  19. TeVeS gets caught on caustics

    SciTech Connect

    Contaldi, Carlo R.; Wiseman, Toby; Withers, Benjamin

    2008-08-15

    TeVeS uses a dynamical vector field with timelike unit-norm constraint to specify a preferred local frame. When matter moves slowly in this frame--the so-called quasistatic regime--modified Newtonian dynamics results. Theories with such vectors (such as Einstein-Aether) are prone to the vector dynamics forming singularities that render their classical evolution problematic. Here, we analyze the dynamics of the vector in TeVeS in various situations. We begin by analytically showing that the vacuum solution of TeVeS forms caustic singularities under a large class of physically reasonably initial perturbations. This shows the classical evolution of TeVeS appears problematic in the absence of matter. We then consider matter by investigating black hole solutions. We find large classes of new black hole solutions with static geometries, where the curves generated by the vector field are attracted to the black hole and may form caustics. We go on to consider the full dynamics with matter by numerically simulating, assuming spherical symmetry, the gravitational collapse of a scalar, and the evolution of an initially nearly static boson star. We find that in both cases our initial data evolves so that the vector field develops caustic singularities on a time scale of order the gravitational in-fall time. Having shown singularity formation is generic with or without matter, Bekenstein's original formulation of TeVeS appears dynamically problematic. We argue that by modifying the vector field kinetic terms to the more general form used by Einstein-Aether, this problem may be avoided.

  20. Ectopic expression of a Ve homolog VvVe gene from Vitis vinifera enhances defense response to Verticillium dahliae infection in tobacco.

    PubMed

    Tang, Juan; Lin, Jing; Yang, Yuwen; Chen, Tianzi; Ling, Xitie; Zhang, Baolong; Chang, Youhong

    2016-01-15

    Verticillium wilt is a soil borne disease that can cause devastating losses to the production of many economically important crops. A Ve1 homologous gene responding to Verticillium dahliae infection was identified in Vitis vinifera cv. "HeiFeng" by semi-quantitative reverse transcription polymerase chain reaction and was designated as VvVe. The overexpression of VvVe in transgenic Nicotiana benthamiana plants significantly enhanced the resistance to isolate V991 of V. dahliae when compared with the wild type plants. The expressions of defense-related genes including the salicylic acid regulated gene pathogen-related 1 (PR1) but not PR2, the ethylene- and jasmonic acid-regulated genes ethylene response factor 1 (ERF1) and lipoxygenase (LOX) were significantly increased due to over expression of VvVe. And greater accumulation of active oxygen, callose and phenylalanine-ammonia lyase were observed in the leaves of transgenic VvVe tobacco plants than the wild type when under infection by V. dahliae. Moreover, the hypersensitive response mimicking cell death was exclusively occurred in the transgenic VvVe tobacco plants but not in the wild type. Taken together, the VvVe gene is a Ve1 like gene which involves in the signal cascade of salicylic acid, jasmonate, and ethylene defense pathways and enhances defense response to V. dahliae infection in the transgenic tobacco. PMID:26524501

  1. Integration of APECS and VE-Suite for Data Overlay

    SciTech Connect

    McCorkel, Doug; Bivins, Gerrick; Jordan, Terry; Bryden, Mark; Zitney, S.E.; Widmann, John; Osawe, Maxwell

    2008-06-01

    In the design of advanced power generation facilities, process simulation tools are being utilized to model plant behavior and quickly analyze results. While such tools enable investigation of crucial aspects of plant design, typical commercial process simulators still do not explore some plant design information, including high-fidelity data from computational fluid dynamics (CFD) models of complex thermal and fluid flow phenomena, economics data used for policy decisions, operational data after the plant is constructed, and as-built information for use in as-designed models. Software tools must be created that allow disparate sources of information to be integrated for facilitating accurate and effective plant design. At the Department of Energy’s (DOE) National Energy Technology Laboratory (NETL), the Advanced Process Engineering Co-Simulator (APECS) has been developed as an integrated software suite that combines process simulation (e.g., Aspen Plus®) and high-fidelity equipment simulation (e.g., FLUENT®). In this paper, the integration of the high-fidelity CFD data with overall process data in a virtual power simulation environment will be described. More specifically, we will highlight VE-Suite, an open-source virtual engineering (VE) software toolkit, and its support of Aspen Plus® Hierarchy blocks via the VE-AspenUnit.

  2. Relation between VE/VCO2 slope and maximum phonation time in chronic heart failure patients.

    PubMed

    Izawa, Kazuhiro P; Watanabe, Satoshi; Brubaker, Peter H; Tochimoto, Shinobu; Hirano, Yasuyuki; Matsushima, Shinya; Suzuki, Tomohiro; Oka, Koichiro; Saito, Takashi; Omori, Yutaka; Suzuki, Kengo; Osada, Naohiko; Omiya, Kazuto; Shimizu, Hiroyuki; Akashi, Yoshihiro J

    2014-12-01

    This study aimed to determine the relation between the regression slope relating minute ventilation to carbon dioxide output (VE/VCO2 slope) and maximum phonation time (MPT), and the MPT required to attain a threshold value for VE/VCO2 slope of ≤ 34 in chronic heart failure (CHF) patients. This cross-sectional study enrolled 115 CHF patients (mean age, 54.5 years; men, 84.9%). VE/VCO2 slope was assessed during cardiopulmonary exercise testing (CPX). Thereafter, patients were divided into 2 groups according to exercise capacity: VE/VCO2 slope ≤ 34 (VE/VCO2 ≤ 34 group, n = 81) and VE/VCO2 slope > 34 (VE/VCO2 > 34 group, n = 34). For MPT measurements, all patients produced a sustained vowel/a:/ for as long as possible during respiratory effort from the seated position. All subjects showed significant negative correlation between VE/VCO2 slope and MPT (r = -0.51, P < 0.001). After adjustment for clinical characteristics, MPT was significantly higher in the VE/VCO2 ≤ 34 group vs VE/VCO2 > 34 group (21.4 ± 6.4 vs 17.4 ± 4.3 s, F = 7.4, P = 0.007). The appropriate MPT cut-off value for identifying a VE/VCO2 slope ≤ 34 was 18.12 seconds. An MPT value of 18.12 seconds may be a useful target value for identifying CHF patients with a VE/VCO2 slope ≤ 34 and for risk management in these patients. PMID:25546676

  3. FvVE1 Regulates Biosynthesis of Fumonisins and Fusarins in Fusarium verticillioides

    PubMed Central

    MYUNG, KYUNG; LI, SHAOJIE; BUTCHKO, ROBERT A.E.; BUSMAN, MARK; PROCTOR, ROBERT H; ABBAS, HAMED K.; CALVO, ANA M.

    2009-01-01

    The veA gene positively regulates sterigmatocystin production in Aspergillus nidulans and aflatoxin production in A. parasiticus and A. flavus. Whether veA homologs have a role in regulating secondary metabolism in other fungal genera is unknown. In this study, we examined the role of the veA homolog, FvVE1, on production of two mycotoxin families, fumonisins and fusarins, in the important corn pathogen F. verticillioides. We found that FvVE1 deletion completely suppressed fumonisin production on two natural substrates, corn and rice. Furthermore, our results revealed that FvVE1 is necessary for the expression of the pathway-specific regulatory gene FUM21 and structural genes in the fumonisin biosynthetic gene (FUM) cluster. FvVE1 deletion also blocked production of fusarins. The effects of FvVE1 deletion on the production of these toxins were found to be the same in two separate mating types. Our results strongly suggest that FvVE1 play an important role in regulating mycotoxin production in F. verticillioides. PMID:19382792

  4. VE1 immunohistochemistry predicts BRAF V600E mutation status and clinical outcome in colorectal cancer

    PubMed Central

    Schafroth, Christian; Galván, José A.; Centeno, Irene; Koelzer, Viktor H.; Dawson, Heather E.; Sokol, Lena; Rieger, Gregor; Berger, Martin D.; Hädrich, Marion; Rosenberg, Robert; Nitsche, Ulrich; Schnüriger, Beat; Langer, Rupert; Inderbitzin, Daniel; Lugli, Alessandro; Zlobec, Inti

    2015-01-01

    Aim VE1 is a monoclonal antibody detecting mutant BRAFV600E protein by immunohistochemistry. Here we aim to determine the inter-observer agreement and concordance of VE1 with mutational status, investigate heterogeneity in colorectal cancers and metastases and determine the prognostic effect of VE1 in colorectal cancer patients. Methods Concordance of VE1 with mutational status and inter-observer agreement were tested on a pilot cohort of colorectal cancers (n = 34), melanomas (n = 23) and thyroid cancers (n = 8). Two prognostic cohorts were evaluated (n = 259, Cohort 1 and n = 226, Cohort 2) by multiple-punch tissue microarrays. VE1 staining on preoperative biopsies (n = 118 patients) was compared to expression in resections. Primary tumors and metastases from 13 patients were tested for VE1 heterogeneity using a tissue microarray generated from all available blocks (n = 100 blocks). Results Inter-observer agreement was 100% (kappa = 1.0). Concordance between VE1 and V600E mutation was 98.5%. Cohort 1: VE1 positivity (seen in 13.5%) was associated with older age (p = 0.0175) and MLH1 deficiency (p < 0.0001). Cohort 2: VE1 positivity (seen in 12.8%) was associated with female gender (p = 0.0016), right-sided tumor location (p < 0.0001), higher tumor grade (p < 0.0001) and mismatch repair (MMR)-deficiency (p < 0.0001). In survival analysis, MMR status and postoperative therapy were identified as possible confounding factors. Adjusting for these features, VE1 was an unfavorable prognostic factor. Preoperative biopsy staining matched resections in all cases except one. No heterogeneity was found across any primary/metastatic tumor blocks. Conclusion VE1 is highly concordant for V600E and homogeneously expressed suggesting staining can be analysed on resection specimens, preoperative biopsies, metastatic lesions and tissue microarrays. PMID:26496026

  5. Evaluation of the VE1 Antibody in Thyroid Cytology Using Ex Vivo Papillary Thyroid Carcinoma Specimens

    PubMed Central

    Kim, Yon Hee; Yim, Hyunee; Lee, Yong-Hee; Han, Jae Ho; Lee, Kyi Beom; Lee, Jeonghun; Soh, Euy Young; Jeong, Seon-Yong; Kim, Jang-Hee

    2016-01-01

    Background: Recently, VE1, a monoclonal antibody against the BRAFV600E mutant protein, has been investigated in terms of its detection of the BRAFV600E mutation. Although VE1 immunostaining and molecular methods used to assess papillary thyroid carcinoma in surgical specimens are in good agreement, evaluation of VE1 in thyroid cytology samples is rarely performed, and its diagnostic value in cytology has not been well established. In present study, we explored VE1 immunoexpression in cytology samples from ex vivo papillary thyroid carcinoma specimens in order to minimize limitations of low cellularity and sampling/targeting errors originated from thyroid fineneedle aspiration and compared our results with those obtained using the corresponding papillary thyroid carcinoma tissues. Methods: The VE1 antibody was evaluated in 21 cases of thyroid cytology obtained directly from ex vivo thyroid specimens. VE1 immunostaining was performed using liquid-based cytology, and the results were compared with those obtained using the corresponding tissues. Results: Of 21 cases, 19 classic papillary thyroid carcinomas had BRAFV600E mutations, whereas two follicular variants expressed wild-type BRAF. VE1 immunoexpression varied according to specimen type. In detection of the BRAFV600E mutation, VE1 immunostaining of the surgical specimen exhibited 100% sensitivity and 100% specificity, whereas VE1 immunostaining of the cytology specimen exhibited only 94.7% sensitivity and 0% specificity. Conclusions: Our data suggest that VE1 immunostaining of a cytology specimen is less specific than that of a surgical specimen for detection of the BRAFV600E mutation, and that VE1 immunostaining of a cytology specimen should be further evaluated and optimized for clinical use. PMID:26657312

  6. Arctic Boreal Vulnerability Experiment (ABoVE) Science Cloud

    NASA Astrophysics Data System (ADS)

    Duffy, D.; Schnase, J. L.; McInerney, M.; Webster, W. P.; Sinno, S.; Thompson, J. H.; Griffith, P. C.; Hoy, E.; Carroll, M.

    2014-12-01

    The effects of climate change are being revealed at alarming rates in the Arctic and Boreal regions of the planet. NASA's Terrestrial Ecology Program has launched a major field campaign to study these effects over the next 5 to 8 years. The Arctic Boreal Vulnerability Experiment (ABoVE) will challenge scientists to take measurements in the field, study remote observations, and even run models to better understand the impacts of a rapidly changing climate for areas of Alaska and western Canada. The NASA Center for Climate Simulation (NCCS) at the Goddard Space Flight Center (GSFC) has partnered with the Terrestrial Ecology Program to create a science cloud designed for this field campaign - the ABoVE Science Cloud. The cloud combines traditional high performance computing with emerging technologies to create an environment specifically designed for large-scale climate analytics. The ABoVE Science Cloud utilizes (1) virtualized high-speed InfiniBand networks, (2) a combination of high-performance file systems and object storage, and (3) virtual system environments tailored for data intensive, science applications. At the center of the architecture is a large object storage environment, much like a traditional high-performance file system, that supports data proximal processing using technologies like MapReduce on a Hadoop Distributed File System (HDFS). Surrounding the storage is a cloud of high performance compute resources with many processing cores and large memory coupled to the storage through an InfiniBand network. Virtual systems can be tailored to a specific scientist and provisioned on the compute resources with extremely high-speed network connectivity to the storage and to other virtual systems. In this talk, we will present the architectural components of the science cloud and examples of how it is being used to meet the needs of the ABoVE campaign. In our experience, the science cloud approach significantly lowers the barriers and risks to organizations

  7. Rac1 functions as a reversible tension modulator to stabilize VE-cadherin trans-interaction.

    PubMed

    Daneshjou, Nazila; Sieracki, Nathan; van Nieuw Amerongen, Geerten P; Schwartz, Martin A; Komarova, Yulia A; Malik, Asrar B; Conway, Daniel E

    2015-01-01

    The role of the RhoGTPase Rac1 in stabilizing mature endothelial adherens junctions (AJs) is not well understood. In this paper, using a photoactivatable probe to control Rac1 activity at AJs, we addressed the relationship between Rac1 and the dynamics of vascular endothelial cadherin (VE-cadherin). We demonstrated that Rac1 activation reduced the rate of VE-cadherin dissociation, leading to increased density of VE-cadherin at AJs. This response was coupled to a reduction in actomyosin-dependent tension across VE-cadherin adhesion sites. We observed that inhibiting myosin II directly or through photo-release of the caged Rho kinase inhibitor also reduced the rate of VE-cadherin dissociation. Thus, Rac1 functions by stabilizing VE-cadherin trans-dimers in mature AJs by counteracting the actomyosin tension. The results suggest a new model of VE-cadherin adhesive interaction mediated by Rac1-induced reduction of mechanical tension at AJs, resulting in the stabilization of VE-cadherin adhesions. PMID:25559184

  8. Tomato Ve disease resistance genes encode cell surface-like receptors

    PubMed Central

    Kawchuk, Lawrence M.; Hachey, John; Lynch, Dermot R.; Kulcsar, Frank; van Rooijen, Gijs; Waterer, Doug R.; Robertson, Albert; Kokko, Eric; Byers, Robert; Howard, Ronald J.; Fischer, Rainer; Prüfer, Dirk

    2001-01-01

    In tomato, Ve is implicated in race-specific resistance to infection by Verticillium species causing crop disease. Characterization of the Ve locus involved positional cloning and isolation of two closely linked inverted genes. Expression of individual Ve genes in susceptible potato plants conferred resistance to an aggressive race 1 isolate of Verticillium albo-atrum. The deduced primary structure of Ve1 and Ve2 included a hydrophobic N-terminal signal peptide, leucine-rich repeats containing 28 or 35 potential glycosylation sites, a hydrophobic membrane-spanning domain, and a C-terminal domain with the mammalian E/DXXXLφ or YXXφ endocytosis signals (φ is an amino acid with a hydrophobic side chain). A leucine zipper-like sequence occurs in the hydrophobic N-terminal signal peptide of Ve1 and a Pro-Glu-Ser-Thr (PEST)-like sequence resides in the C-terminal domain of Ve2. These structures suggest that the Ve genes encode a class of cell-surface glycoproteins with receptor-mediated endocytosis-like signals and leucine zipper or PEST sequences. PMID:11331751

  9. Genetic Dissection of Verticillium Wilt Resistance Mediated by Tomato Ve11[C][W][OA

    PubMed Central

    Fradin, Emilie F.; Zhang, Zhao; Juarez Ayala, Juan C.; Castroverde, Christian D.M.; Nazar, Ross N.; Robb, Jane; Liu, Chun-Ming; Thomma, Bart P.H.J.

    2009-01-01

    Vascular wilt diseases caused by soil-borne pathogens are among the most devastating plant diseases worldwide. The Verticillium genus includes vascular wilt pathogens with a wide host range. Although V. longisporum infects various hosts belonging to the Cruciferaceae, V. dahliae and V. albo-atrum cause vascular wilt diseases in over 200 dicotyledonous species, including economically important crops. A locus responsible for resistance against race 1 strains of V. dahliae and V. albo-atrum has been cloned from tomato (Solanum lycopersicum) only. This locus, known as Ve, comprises two closely linked inversely oriented genes, Ve1 and Ve2, that encode cell surface receptor proteins of the extracellular leucine-rich repeat receptor-like protein class of disease resistance proteins. Here, we show that Ve1, but not Ve2, provides resistance in tomato against race 1 strains of V. dahliae and V. albo-atrum and not against race 2 strains. Using virus-induced gene silencing in tomato, the signaling cascade downstream of Ve1 is shown to require both EDS1 and NDR1. In addition, NRC1, ACIF, MEK2, and SERK3/BAK1 also act as positive regulators of Ve1 in tomato. In conclusion, Ve1-mediated resistance signaling only partially overlaps with signaling mediated by Cf proteins, type members of the receptor-like protein class of resistance proteins. PMID:19321708

  10. Building Students' Understanding of Quadratic Equation Concept Using Naïve Geometry

    ERIC Educational Resources Information Center

    Fachrudin, Achmad Dhany; Putri, Ratu Ilma Indra; Darmawijoyo

    2014-01-01

    The purpose of this research is to know how Naïve Geometry method can support students' understanding about the concept of solving quadratic equations. In this article we will discuss one activities of the four activities we developed. This activity focused on how students linking the Naïve Geometry method with the solving of the quadratic…

  11. Decreased expression of VE-cadherin and claudin-5 and increased phosphorylation of VE-cadherin in vascular endothelium in nasal polyps.

    PubMed

    Yukitatsu, Yoriko; Hata, Masaki; Yamanegi, Koji; Yamada, Naoko; Ohyama, Hideki; Nakasho, Keiji; Kojima, Yusuke; Oka, Hideki; Tsuzuki, Kenzo; Sakagami, Masafumi; Terada, Nobuyuki

    2013-06-01

    VE-cadherin and claudin-5 are major components of adherens and tight junctions of vascular endothelial cells and a decrease in their expression and an increase in the tyrosine-phosphorylation of VE-cadherin are associated with an increase in endothelial paracellular permeability. To clarify the mechanism underlying the development of edema in nasal polyps, we studied these molecules in polyp microvessels. Normal inferior turbinate mucosal tissues and nasal polyps from patients treated with or without glucocorticoid were stained for VE-cadherin or claudin-5 and CD31 by a double-immunofluorescence method and the immunofluorescence intensities were graded 1-3 with increasing intensity. To correct for differences in fluorescence intensity attributable to a different endothelial area being exposed in a section or to the thickness of a section, the relative immunofluorescence intensity was estimated by dividing the grade of VE-cadherin or claudin-5 by that of CD31 in each microvessel. Tyrosine-phosphorylation of VE-cadherin was examined by Western blot analysis. The relative intensities of VE-cadherin and claudin-5 in the CD31-positive microvessels significantly decreased in the following order; inferior turbinate mucosa, treated polyps and untreated polyps. The ratio of tyrosine-phosphorylated VE-cadherin to VE-cadherin was significantly higher in untreated polyps than in the inferior turbinate mucosa and treated polyps, between which no significant difference in the ratio was seen. Thus, in nasal polyps, the barrier function of endothelial adherens and tight junctions is weakened, although glucocorticoid treatment improves this weakened barrier function. PMID:23474739

  12. Naïve T Cell Homeostasis Regulated by Stress Responses and TCR Signaling

    PubMed Central

    Kamimura, Daisuke; Atsumi, Toru; Stofkova, Andrea; Nishikawa, Naoki; Ohki, Takuto; Suzuki, Hironao; Katsunuma, Kokichi; Jiang, Jing-jing; Bando, Hidenori; Meng, Jie; Sabharwal, Lavannya; Ogura, Hideki; Hirano, Toshio; Arima, Yasunobu; Murakami, Masaaki

    2015-01-01

    The survival of naïve T cells is believed to require signals from TCR–pMHC interactions and cytokines such as IL-7. In contrast, signals that negatively impact naïve T cell survival are less understood. We conducted a forward genetic screening of mice and found a mutant mouse line with reduced number of naïve T cells (T-Red mice). T-Red mice have a point mutation in the Kdelr1 gene, and their naïve T cells show enhanced integrated stress response (ISR), which eventually induces their apoptosis. Therefore, naïve T cells require a KDEL receptor-mediated mechanism that efficiently relieves cellular stress for their survival in vivo. Interestingly, naïve T cells expressing TCR with higher affinity/avidity to self-antigens survive in T-Red mice, suggesting the possible link between TCR-mediated survival and ISR-induced apoptosis. In this article, we discuss the regulation of naïve T cell homeostasis, keeping special attention on the ISR and TCR signal. PMID:26734005

  13. Karhunen-Loéve expansion for random earthquake excitations

    NASA Astrophysics Data System (ADS)

    He, Jun

    2015-03-01

    This paper develops a trigonometric-basis-function based Karhunen-Loéve (KL) expansion for simulating random earthquake excitations with known covariance functions. The methods for determining the number of the KL terms and defining the involved random variables are described in detail. The simplified form of the KL expansion is given, whereby the relationship between the KL expansion and the spectral representation method is investigated and revealed. The KL expansion is of high efficiency for simulating long-term earthquake excitations in the sense that it needs a minimum number of random variables, as compared with the spectral representation method. Numerical examples demonstrate the convergence and accuracy of the KL expansion for simulating two commonly-used random earthquake excitation models and estimating linear and nonlinear random responses to the random excitations.

  14. In vitro anti-myeloma activity of the Aurora kinase inhibitor VE-465.

    PubMed

    Negri, Joseph M; McMillin, Douglas W; Delmore, Jake; Mitsiades, Nicholas; Hayden, Patrick; Klippel, Steffen; Hideshima, Teru; Chauhan, Dharminder; Munshi, Nikhil C; Buser, Carolyn A; Pollard, John; Richardson, Paul G; Anderson, Kenneth C; Mitsiades, Constantine S

    2009-12-01

    This study characterized the preclinical anti-myeloma activity of VE465, a low molecular weight pan-Aurora kinase inhibitor. After 96-h drug exposure, several multiple myeloma (MM) cell lines were more sensitive to VE465 compared to non-malignant cells. The anti-MM activity of VE465 was maintained in the presence of interleukin-6 and, interestingly, enhanced by co-culture with stromal cells. However, primary MM cells were less responsive than cell lines. Combinations with dexamethasone (Dex), doxorubicin (Doxo) and bortezomib showed no antagonism. Our study highlights the potential role of the tumour microenvironment in modulating the activity of this drug class. PMID:19751238

  15. What to Do After You've Gotten the Smallpox Vaccine

    MedlinePlus

    ... to Do After You’ve Gotten the Smallpox Vaccine The smallpox vaccine contains a live virus called vaccinia. After vaccination, this live virus is present at the vaccine site and can be spread to other parts ...

  16. Scientists Say They've Created New Type of Stem Cells

    MedlinePlus

    ... Scientists Say They've Created New Type of Stem Cells Carrying just one copy of human DNA ... HealthDay News) -- Scientists say they have created embryonic stem cells with just one copy of human DNA ...

  17. S-nitrosylation regulates VE-cadherin phosphorylation and internalization in microvascular permeability.

    PubMed

    Guequén, Anita; Carrasco, Rodrigo; Zamorano, Patricia; Rebolledo, Lorena; Burboa, Pia; Sarmiento, José; Boric, Mauricio P; Korayem, Adam; Durán, Walter N; Sánchez, Fabiola A

    2016-04-15

    The adherens junction complex, composed mainly of vascular endothelial (VE)-cadherin, β-catenin, p120, and γ-catenin, is the main element of the endothelial barrier in postcapillary venules.S-nitrosylation of β-catenin and p120 is an important step in proinflammatory agents-induced hyperpermeability. We investigated in vitro and in vivo whether or not VE-cadherin isS-nitrosylated using platelet-activating factor (PAF) as agonist. We report that PAF-stimulatesS-nitrosylation of VE-cadherin, which disrupts its association with β-catenin. In addition, based on inhibition of nitric oxide production, our results strongly suggest thatS-nitrosylation is required for VE-cadherin phosphorylation on tyrosine and for its internalization. Our results unveil an important mechanism to regulate phosphorylation of junctional proteins in association withS-nitrosylation. PMID:26921435

  18. Evidence for Post-Translational Processing of Vascular Endothelial (VE)-Cadherin in Brain Tumors: Towards a Candidate Biomarker

    PubMed Central

    Vilgrain, Isabelle; Sidibé, Adama; Polena, Helena; Cand, Francine; Mannic, Tiphaine; Arboleas, Mélanie; Boccard, Sandra; Baudet, Antoine; Gulino-Debrac, Danielle; Bouillet, Laurence; Quesada, Jean-Louis; Mendoza, Christophe; Lebas, Jean-François; Pelletier, Laurent; Berger, François

    2013-01-01

    Vessel abnormalities are among the most important features in malignant glioma. Vascular endothelial (VE)-cadherin is of major importance for vascular integrity. Upon cytokine challenge, VE-cadherin structural modifications have been described including tyrosine phosphorylation and cleavage. The goal of this study was to examine whether these events occurred in human glioma vessels. We demonstrated that VE-cadherin is highly expressed in human glioma tissue and tyrosine phosphorylated at site Y685, a site previously found phosphorylated upon VEGF challenge, via Src activation. In vitro experiments showed that VEGF-induced VE-cadherin phosphorylation, preceded the cleavage of its extracellular adhesive domain (sVE, 90 kDa). Interestingly, metalloproteases (MMPs) secreted by glioma cell lines were responsible for sVE release. Because VEGF and MMPs are important components of tumor microenvironment, we hypothesized that VE-cadherin proteolysis might occur in human brain tumors. Analysis of glioma patient sera prior treatment confirmed the presence of sVE in bloodstream. Furthermore, sVE levels studied in a cohort of 53 glioma patients were significantly predictive of the overall survival at three years (HR 0.13 [0.04; 0.40] p≤0.001), irrespective to histopathological grade of tumors. Altogether, these results suggest that VE-cadherin structural modifications should be examined as candidate biomarkers of tumor vessel abnormalities, with promising applications in oncology. PMID:24358106

  19. Secondary Metabolism and Development Is Mediated by LlmF Control of VeA Subcellular Localization in Aspergillus nidulans

    PubMed Central

    Palmer, Jonathan M.; Theisen, Jeffrey M.; Duran, Rocio M.; Grayburn, W. Scott; Calvo, Ana M.; Keller, Nancy P.

    2013-01-01

    Secondary metabolism and development are linked in Aspergillus through the conserved regulatory velvet complex composed of VeA, VelB, and LaeA. The founding member of the velvet complex, VeA, shuttles between the cytoplasm and nucleus in response to alterations in light. Here we describe a new interaction partner of VeA identified through a reverse genetics screen looking for LaeA-like methyltransferases in Aspergillus nidulans. One of the putative LaeA-like methyltransferases identified, LlmF, is a negative regulator of sterigmatocystin production and sexual development. LlmF interacts directly with VeA and the repressive function of LlmF is mediated by influencing the localization of VeA, as over-expression of llmF decreases the nuclear to cytoplasmic ratio of VeA while deletion of llmF results in an increased nuclear accumulation of VeA. We show that the methyltransferase domain of LlmF is required for function; however, LlmF does not directly methylate VeA in vitro. This study identifies a new interaction partner for VeA and highlights the importance of cellular compartmentalization of VeA for regulation of development and secondary metabolism. PMID:23341778

  20. The aged lymphoid tissue environment fails to support naïve T cell homeostasis

    PubMed Central

    Becklund, Bryan R.; Purton, Jared F.; Ramsey, Chris; Favre, Stéphanie; Vogt, Tobias K.; Martin, Christopher E.; Spasova, Darina S.; Sarkisyan, Gor; LeRoy, Eric; Tan, Joyce T.; Wahlus, Heidi; Bondi-Boyd, Brea; Luther, Sanjiv A.; Surh, Charles D.

    2016-01-01

    Aging is associated with a gradual loss of naïve T cells and a reciprocal increase in the proportion of memory T cells. While reduced thymic output is important, age-dependent changes in factors supporting naïve T cells homeostasis may also be involved. Indeed, we noted a dramatic decrease in the ability of aged mice to support survival and homeostatic proliferation of naïve T cells. The defect was not due to a reduction in IL-7 expression, but from a combination of changes in the secondary lymphoid environment that impaired naïve T cell entry and access to key survival factors. We observed an age-related shift in the expression of homing chemokines and structural deterioration of the stromal network in T cell zones. Treatment with IL-7/mAb complexes can restore naïve T cell homeostatic proliferation in aged mice. Our data suggests that homeostatic mechanisms that support the naïve T cell pool deteriorate with age. PMID:27480406

  1. Validation of the VE1 Immunostain for the BRAF V600E Mutation in Melanoma

    PubMed Central

    Pearlstein, Michelle V.; Zedek, Daniel C.; Ollila, David W.; Treece, Amanda; Gulley, Margaret L.; Groben, Pamela A.; Thomas, Nancy E.

    2014-01-01

    BACKGROUND BRAF mutation status, and therefore eligibility for BRAF inhibitors, is currently determined by sequencing methods. We assessed the validity of VE1, a monoclonal antibody against the BRAF V600E mutant protein, in the detection of mutant BRAF V600E melanomas as classified by DNA pyrosequencing. METHODS The cases were 76 metastatic melanoma patients with only one known primary melanoma who had had BRAF codon 600 pyrosequencing of either their primary (n=19), metastatic (n=57) melanoma, or both (n=17). All melanomas (n=93) were immunostained with the BRAF VE1 antibody using a red detection system. The staining intensity of these specimens was scored from 0 – 3+ by a dermatopathologist. Scores of 0 and 1+ were considered as negative staining while scores of 2+ and 3+ were considered positive. RESULTS The VE1 antibody demonstrated a sensitivity of 85% and a specificity of 100% as compared to DNA pyrosequencing results. There was 100% concordance between VE1 immunostaining of primary and metastatic melanomas from the same patient. V600K, V600Q, and V600R BRAF melanomas did not positively stain with VE1. CONCLUSIONS This hospital-based study finds high sensitivity and specificity for the BRAF VE1 immunostain in comparison to pyrosequencing in detection of BRAF V600E in melanomas. PMID:24917033

  2. The aged lymphoid tissue environment fails to support naïve T cell homeostasis.

    PubMed

    Becklund, Bryan R; Purton, Jared F; Ramsey, Chris; Favre, Stéphanie; Vogt, Tobias K; Martin, Christopher E; Spasova, Darina S; Sarkisyan, Gor; LeRoy, Eric; Tan, Joyce T; Wahlus, Heidi; Bondi-Boyd, Brea; Luther, Sanjiv A; Surh, Charles D

    2016-01-01

    Aging is associated with a gradual loss of naïve T cells and a reciprocal increase in the proportion of memory T cells. While reduced thymic output is important, age-dependent changes in factors supporting naïve T cells homeostasis may also be involved. Indeed, we noted a dramatic decrease in the ability of aged mice to support survival and homeostatic proliferation of naïve T cells. The defect was not due to a reduction in IL-7 expression, but from a combination of changes in the secondary lymphoid environment that impaired naïve T cell entry and access to key survival factors. We observed an age-related shift in the expression of homing chemokines and structural deterioration of the stromal network in T cell zones. Treatment with IL-7/mAb complexes can restore naïve T cell homeostatic proliferation in aged mice. Our data suggests that homeostatic mechanisms that support the naïve T cell pool deteriorate with age. PMID:27480406

  3. Stem cells. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation.

    PubMed

    Geula, Shay; Moshitch-Moshkovitz, Sharon; Dominissini, Dan; Mansour, Abed AlFatah; Kol, Nitzan; Salmon-Divon, Mali; Hershkovitz, Vera; Peer, Eyal; Mor, Nofar; Manor, Yair S; Ben-Haim, Moshe Shay; Eyal, Eran; Yunger, Sharon; Pinto, Yishay; Jaitin, Diego Adhemar; Viukov, Sergey; Rais, Yoach; Krupalnik, Vladislav; Chomsky, Elad; Zerbib, Mirie; Maza, Itay; Rechavi, Yoav; Massarwa, Rada; Hanna, Suhair; Amit, Ido; Levanon, Erez Y; Amariglio, Ninette; Stern-Ginossar, Noam; Novershtern, Noa; Rechavi, Gideon; Hanna, Jacob H

    2015-02-27

    Naïve and primed pluripotent states retain distinct molecular properties, yet limited knowledge exists on how their state transitions are regulated. Here, we identify Mettl3, an N(6)-methyladenosine (m(6)A) transferase, as a regulator for terminating murine naïve pluripotency. Mettl3 knockout preimplantation epiblasts and naïve embryonic stem cells are depleted for m(6)A in mRNAs, yet are viable. However, they fail to adequately terminate their naïve state and, subsequently, undergo aberrant and restricted lineage priming at the postimplantation stage, which leads to early embryonic lethality. m(6)A predominantly and directly reduces mRNA stability, including that of key naïve pluripotency-promoting transcripts. This study highlights a critical role for an mRNA epigenetic modification in vivo and identifies regulatory modules that functionally influence naïve and primed pluripotency in an opposing manner. PMID:25569111

  4. The interplays among technology and content, immersant and VE

    NASA Astrophysics Data System (ADS)

    Song, Meehae; Gromala, Diane; Shaw, Chris; Barnes, Steven J.

    2010-01-01

    The research program aims to explore and examine the fine balance necessary for maintaining the interplays between technology and the immersant, including identifying qualities that contribute to creating and maintaining a sense of "presence" and "immersion" in an immersive virtual reality (IVR) experience. Building upon and extending previous work, we compare sitting meditation with walking meditation in a virtual environment (VE). The Virtual Meditative Walk, a new work-in-progress, integrates VR and biofeedback technologies with a self-directed, uni-directional treadmill. As immersants learn how to meditate while walking, robust, real-time biofeedback technology continuously measures breathing, skin conductance and heart rate. The physiological states of the immersant will in turn affect the audio and stereoscopic visual media through shutter glasses. We plan to test the potential benefits and limitations of this physically active form of meditation with data from a sitting form of meditation. A mixed-methods approach to testing user outcomes parallels the knowledge bases of the collaborative team: a physician, computer scientists and artists.

  5. Interfamily Transfer of Tomato Ve1 Mediates Verticillium Resistance in Arabidopsis1[C][W][OA

    PubMed Central

    Fradin, Emilie F.; Abd-El-Haliem, Ahmed; Masini, Laura; van den Berg, Grardy C.M.; Joosten, Matthieu H.A.J.; Thomma, Bart P.H.J.

    2011-01-01

    Vascular wilts caused by soil-borne fungal species of the Verticillium genus are devastating plant diseases. The most common species, Verticillium dahliae and Verticillium albo-atrum, have broad host ranges and are notoriously difficult to control. Therefore, genetic resistance is the preferred method for disease control. Only from tomato (Solanum lycopersicum) has a Verticillium resistance locus been cloned, comprising the Ve1 gene that encodes a receptor-like protein-type cell surface receptor. Due to lack of a suitable model for receptor-like protein (RLP)-mediated resistance signaling in Arabidopsis (Arabidopsis thaliana), so far relatively little is known about RLP signaling in pathogen resistance. Here, we show that Ve1 remains fully functional after interfamily transfer to Arabidopsis and that Ve1-transgenic Arabidopsis is resistant to race 1 but not to race 2 strains of V. dahliae and V. albo-atrum, nor to the Brassicaceae-specific pathogen Verticillium longisporum. Furthermore, we show that signaling components utilized by Ve1 in Arabidopsis to establish Verticillium resistance overlap with those required in tomato and include SERK3/BAK1, EDS1, and NDR1, which strongly suggests that critical components for resistance signaling are conserved. We subsequently investigated the requirement of SERK family members for Ve1 resistance in Arabidopsis, revealing that SERK1 is required in addition to SERK3/BAK1. Using virus-induced gene silencing, the requirement of SERK1 for Ve1-mediated resistance was confirmed in tomato. Moreover, we show the requirement of SERK1 for resistance against the foliar fungal pathogen Cladosporium fulvum mediated by the RLP Cf-4. Our results demonstrate that Arabidopsis can be used as model to unravel the genetics of Ve1-mediated resistance. PMID:21617027

  6. Plasmodium vivax Sporozoite Challenge in Malaria-Naïve and Semi-Immune Colombian Volunteers

    PubMed Central

    Arévalo-Herrera, Myriam; Forero-Peña, David A.; Rubiano, Kelly; Gómez-Hincapie, José; Martínez, Nora L.; Lopez-Perez, Mary; Castellanos, Angélica; Céspedes, Nora; Palacios, Ricardo; Oñate, José Millán; Herrera, Sócrates

    2014-01-01

    Background Significant progress has been recently achieved in the development of Plasmodium vivax challenge infections in humans, which are essential for vaccine and drug testing. With the goal of accelerating clinical development of malaria vaccines, the outcome of infections experimentally induced in naïve and semi-immune volunteers by infected mosquito bites was compared. Methods Seven malaria-naïve and nine semi-immune Colombian adults (n = 16) were subjected to the bites of 2–4 P. vivax sporozoite-infected Anopheles mosquitoes. Parasitemia levels, malaria clinical manifestations, and immune responses were assessed and compared. Results All volunteers developed infections as confirmed by microscopy and RT-qPCR. No significant difference in the pre-patent period (mean 12.5 and 12.8 days for malaria-naïve and malaria-exposed, respectively) was observed but naïve volunteers developed classical malaria signs and symptoms, while semi-immune volunteers displayed minor or no symptoms at the day of diagnosis. A malaria-naïve volunteer developed a transient low submicroscopic parasitemia that cured spontaneously. Infection induced an increase in specific antibody levels in both groups. Conclusion Sporozoite infectious challenge was safe and reproducible in semi-immune and naïve volunteers. This model will provide information for simultaneous comparison of the protective efficacy of P. vivax vaccines in naïve and semi-immune volunteers under controlled conditions and would accelerate P. vivax vaccine development. Trial Registration clinicaltrials.gov NCT01585077 PMID:24963662

  7. Interfacing with in-Situ Data Networks during the Arctic Boreal Vulnerability Experiment (ABoVE)

    NASA Astrophysics Data System (ADS)

    McInerney, M.; Griffith, P. C.; Duffy, D.; Hoy, E.; Schnase, J. L.; Sinno, S.; Thompson, J. H.

    2014-12-01

    The Arctic Boreal Vulnerability Experiment (ABoVE) is designed to improve understanding of the causes and impacts of ecological changes in Arctic/boreal regions, and will integrate field-based studies, modeling, and data from airborne and satellite remote sensing. ABoVE will result in a fuller understanding of ecosystem vulnerability and resilience to environmental change in the Arctic and boreal regions of western North America, and provide scientific information required to develop options for societal responses to the impacts of these changes. The studies sponsored by NASA during ABoVE will be coordinated with research and in-situ monitoring activities being sponsored by a number of national and international partners. The NASA Center for Climate Simulation at the Goddard Space Flight Center has partnered with the NASA Carbon Cycle & Ecosystems Office to create a science cloud designed for this field campaign - the ABoVE Science Cloud (ASC). The ASC combines high performance computing with emerging technologies to create an environment specifically designed for large-scale modeling, analysis of remote sensing data, copious disk storage with integrated data management, and integration of core variables from in-situ networks identified by the ABoVE Science Definition Team. In this talk, we will present the scientific requirements driving the development of the ABoVE Science Cloud, discuss the necessary interfaces, both computational and human, with in-situ monitoring networks, and show examples of how the ASC is being used to meet the needs of the ABoVE campaign.

  8. Human VE-Cadherin Fusion Protein as an Artificial Extracellular Matrix Enhancing the Proliferation and Differentiation Functions of Endothelial Cell.

    PubMed

    Xu, Ke; Shuai, Qizhi; Li, Xiaoning; Zhang, Yan; Gao, Chao; Cao, Lei; Hu, Feifei; Akaike, Toshihiro; Wang, Jian-xi; Gu, Zhongwei; Yang, Jun

    2016-03-14

    In an attempt to enhance endothelial cell capture and promote the vascularization of engineered tissue, we biosynthesized and characterized the recombinant fusion protein consisting of human vascular endothelial-cadherin extracellular domain and immunoglobulin IgG Fc region (hVE-cad-Fc) to serve as a bioartificial extracellular matrix. The hVE-cad-Fc protein naturally formed homodimers and was used to construct hVE-cad-Fc matrix by stably adsorbing on polystyrene plates. Atomic force microscop assay showed uniform hVE-cad-Fc distribution with nanorod topography. The hVE-cad-Fc matrix markedly promoted human umbilical vein endothelial cells (HUVECs) adhesion and proliferation with fibroblastoid morphology. Additionally, the hVE-cad-Fc matrix improved HUVECs migration, vWF expression, and NO release, which are closely related to vascularization. Furthermore, the hVE-cad-Fc matrix activated endogenous VE-cadherin/β-catenin proteins and effectively triggered the intracellular signals such as F-actin stress fiber, p-FAK, AKT, and Bcl-2. Taken together, hVE-cad-Fc could be a promising bioartificial matrix to promote vascularization in tissue engineering. PMID:26859785

  9. Nitric Oxide Increases Arterial Endotheial Permeability through Mediating VE-Cadherin Expression during Arteriogenesis

    PubMed Central

    Wu, Xiaoqiong; Guan, Yinglu; Zhang, Bin; Cai, Weijun; Schaper, Jutta; Schaper, Wolfgang

    2015-01-01

    Macrophage invasion is an important event during arteriogenesis, but the underlying mechanism is still only partially understood. The present study tested the hypothesis that nitric oxide (NO) and VE-cadherin, two key mediators for vascular permeability, contribute to this event in a rat ischemic hindlimb model. In addition, the effect of NO on expression of VE-caherin and endothelial permeability was also studied in cultured HUVECs. We found that: 1) in normal arteriolar vessels (NAV), eNOS was moderately expressed in endothelial cells (EC) and iNOS was rarely detected. In contrast, in collateral vessels (CVs) induced by simple femoral artery ligation, both eNOS and iNOS were significantly upregulated (P<0.05). Induced iNOS was found mainly in smooth muscle cells, but also in other vascular cells and macrophages; 2) in NAV VE-cadherin was strongly expressed in EC. In CVs, VE-cadherin was significantly downregulated, with a discontinuous and punctate pattern. Administration of nitric oxide donor DETA NONOate (NONOate) further reduced the amounts of Ve-cadherin in CVs, whereas NO synthase inhibitor L-NAME inhibited downregulation of VE-cadherin in CVs; 3) in normal rats Evans blue extravasation (EBE) was low in the musculus gracilis, FITC-dextron leakage was not detected in the vascular wall and few macrophages were observed in perivascular space. In contrast, EBE was significantly increased in femoral artery ligation rats, FITC-dextron leakage and increased amounts of macrophages were detected in CVs, which were further enhanced by administration of NONOate, but inhibited by L-NAME supplement; 4) in vitro experiments confirmed that an increase in NO production reduced VE-cadherin expression, correlated with increases in the permeability of HUVECs. In conclusion, our data for the first time reveal the expression profile of VE-cadherin and alterations of vascular permeability in CVs, suggesting that NO-mediated VE-cadherin pathway may be one important mechanism

  10. [Monotherapy in treatment-naïve patients].

    PubMed

    Arranz Caso, José Alberto

    2008-12-01

    The development of antiretroviral therapy (ART) with current triple drug combinations has dramatically reduced morbidity and mortality in HIV-infected patients. However, there is a need for less toxic treatments without sacrificing efficacy, as well as for less expensive drugs to facilitate universal access to this therapy. The protease inhibitors (PI) administered with ritonavir have a favorable pharmacokinetic profile and high genetic barrier and consequently are ideal candidates for use in monotherapy, thus avoiding the toxicity and cost associated with nucleoside analogs, as well as preserving drugs for future options. The promising results of studies performed with lopinavir/ritonavir (LPV/r) in induction-maintenance regimens in patients without prior failure to PIs encourage research into the cost-effectiveness of LPV/r in monotherapy from the beginning of ART. The few studies performed in this context seem to indicate the following: a) LPV/r monotherapy achieves undetectable viral loads in a large proportion of treatment-naïve patients, b) future treatment options are not compromised in patients not achieving undetectable viral loads since the likelihood of resistance mutations is low and treatment intensification achieves suppression of viral replication, and c) strategies for early detection can probably be considered in patients who will not achieve complete suppression with LPV/r monotherapy. Nevertheless, before LPV/r monotherapy can be considered a first-line option, new studies with larger samples and longer follow-up are required. These studies should pay particular attention to viral replication in areas where PI show less penetration. PMID:19572437

  11. A Novel Feature Selection Technique for Text Classification Using Naïve Bayes

    PubMed Central

    Dey Sarkar, Subhajit; Goswami, Saptarsi; Agarwal, Aman; Aktar, Javed

    2014-01-01

    With the proliferation of unstructured data, text classification or text categorization has found many applications in topic classification, sentiment analysis, authorship identification, spam detection, and so on. There are many classification algorithms available. Naïve Bayes remains one of the oldest and most popular classifiers. On one hand, implementation of naïve Bayes is simple and, on the other hand, this also requires fewer amounts of training data. From the literature review, it is found that naïve Bayes performs poorly compared to other classifiers in text classification. As a result, this makes the naïve Bayes classifier unusable in spite of the simplicity and intuitiveness of the model. In this paper, we propose a two-step feature selection method based on firstly a univariate feature selection and then feature clustering, where we use the univariate feature selection method to reduce the search space and then apply clustering to select relatively independent feature sets. We demonstrate the effectiveness of our method by a thorough evaluation and comparison over 13 datasets. The performance improvement thus achieved makes naïve Bayes comparable or superior to other classifiers. The proposed algorithm is shown to outperform other traditional methods like greedy search based wrapper or CFS.

  12. Plasminogen Activator Inhibitor-1 Controls Vascular Integrity by Regulating VE-Cadherin Trafficking

    PubMed Central

    Daniel, Anna E.; Timmerman, Ilse; Kovacevic, Igor; Hordijk, Peter L.; Adriaanse, Luc; Paatero, Ilkka; Belting, Heinz-Georg; van Buul, Jaap D.

    2015-01-01

    Background Plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor, is expressed and secreted by endothelial cells. Patients with PAI-1 deficiency show a mild to moderate bleeding diathesis, which has been exclusively ascribed to the function of PAI-1 in down-regulating fibrinolysis. We tested the hypothesis that PAI-1 function plays a direct role in controlling vascular integrity and permeability by keeping endothelial cell-cell junctions intact. Methodology/Principal Findings We utilized PAI-039, a specific small molecule inhibitor of PAI-1, to investigate the role of PAI-1 in protecting endothelial integrity. In vivo inhibition of PAI-1 resulted in vascular leakage from intersegmental vessels and in the hindbrain of zebrafish embryos. In addition PAI-1 inhibition in human umbilical vein endothelial cell (HUVEC) monolayers leads to a marked decrease of transendothelial resistance and disrupted endothelial junctions. The total level of the endothelial junction regulator VE-cadherin was reduced, whereas surface VE-cadherin expression was unaltered. Moreover, PAI-1 inhibition reduced the shedding of VE-cadherin. Finally, we detected an accumulation of VE-cadherin at the Golgi apparatus. Conclusions/Significance Our findings indicate that PAI-1 function is important for the maintenance of endothelial monolayer and vascular integrity by controlling VE-cadherin trafficking to and from the plasma membrane. Our data further suggest that therapies using PAI-1 antagonists like PAI-039 ought to be used with caution to avoid disruption of the vessel wall. PMID:26714278

  13. First-year medical students' naïve beliefs about respiratory physiology.

    PubMed

    Badenhorst, Elmi; Mamede, Silvia; Abrahams, Amaal; Bugarith, Kishor; Friedling, Jacqui; Gunston, Geney; Kelly-Laubscher, Roisin; Schmidt, Henk G

    2016-09-01

    The present study explored the nature and frequency of physiology naïve beliefs by investigating novices' understanding of the respiratory system. Previous studies have shown considerable misconceptions related to physiology but focused mostly on specific physiological processes of normal respiration. Little is known about novices' broader understanding of breathing in a clinical context. Our study hypothesized that naïve beliefs could hamper participants' ability to understand the interrelatedness of respiratory structures and functions related to breathing during a clinical complication. The study entailed both quantitative and qualitative foci. A two-tier test was designed and administered to 211 first-year medical students. Participants were asked to choose the correct answer out of a set of four options and to substantiate their choices. Questions were purposefully left open to elicit a wide range of responses. Statistical analysis (SPSS) was done to evaluate the frequency of naïve beliefs. Thematic analysis was used to determine themes within the raw data. The majority of participants selected incorrect answers in the multiple-choice question part of the questionnaire. Results from the thematic analysis yielded a considerable range of naïve beliefs about gas exchange, foundational physics, airflow, anatomic structures, and breathing pathways. An awareness of the existence of such naive beliefs in respiratory physiology will allow educators to address them in their teaching and thereby prevent naïve beliefs transforming into misconceptions. PMID:27445283

  14. Optimum Vehicle Component Integration with InVeST (Integrated Vehicle Simulation Testbed)

    SciTech Connect

    Ng, W; Paddack, E; Aceves, S

    2001-12-27

    We have developed an Integrated Vehicle Simulation Testbed (InVeST). InVeST is based on the concept of Co-simulation, and it allows the development of virtual vehicles that can be analyzed and optimized as an overall integrated system. The virtual vehicle is defined by selecting different vehicle components from a component library. Vehicle component models can be written in multiple programming languages running on different computer platforms. At the same time, InVeST provides full protection for proprietary models. Co-simulation is a cost-effective alternative to competing methodologies, such as developing a translator or selecting a single programming language for all vehicle components. InVeST has been recently demonstrated using a transmission model and a transmission controller model. The transmission model was written in SABER and ran on a Sun/Solaris workstation, while the transmission controller was written in MATRIXx and ran on a PC running Windows NT. The demonstration was successfully performed. Future plans include the applicability of Co-simulation and InVeST to analysis and optimization of multiple complex systems, including those of Intelligent Transportation Systems.

  15. VeA and LaeA transcriptional factors regulate ochratoxin A biosynthesis in Aspergillus carbonarius.

    PubMed

    Crespo-Sempere, A; Marín, S; Sanchis, V; Ramos, A J

    2013-09-16

    Ochratoxin A (OTA) is a mycotoxin with nephrotoxic, teratogenic and immunotoxic properties which represents a serious risk for human and animal health. Aspergillus carbonarius is considered the main OTA-producing species in grapes and products such as raisins, wine or juices, although it has also been isolated from coffee, cocoa and cereals. Till now not much information is available about regulatory mechanisms of OTA production by A. carbonarius. A better understanding of how environmental factors influence OTA production and which genes are involved in its regulation could help us design new control strategies. In this study, we have evaluated the role of VeA and LaeA transcriptional factors, which have been shown to regulate secondary metabolism in response to light in A. carbonarius. To this aim, veA and laeA genes were deleted in an ochratoxigenic A. carbonarius strain by targeted gene replacement using Agrobacterium tumefaciens-mediated transformation. Loss of veA and laeA in A. carbonarius yields to an organism with slight differences in vegetative growth but a strong reduction in conidial production. A drastic decrease of OTA production that ranged from 68.5 to 99.4% in ΔveA and ΔlaeA null mutants was also observed, which was correlated with a downregulation of a nonribosomal peptide synthetase involved in OTA biosynthesis. These findings suggest that VeA and LaeA have an important role regulating conidiation and OTA biosynthesis in response to light in A. carbonarius in a similar way to other fungi where functions of VeA and LaeA have been previously described. This is the first report of a transcriptional factor governing the production of OTA by A. carbonarius. PMID:24041999

  16. Evidence of a common mechanism of disassembly of adherens junctions through Gα13 targeting of VE-cadherin

    PubMed Central

    Gong, Haixia; Gao, Xiaopei; Feng, Shaoting; Siddiqui, M. Rizwan; Garcia, Alexander; Bonini, Marcelo G.; Komarova, Yulia; Vogel, Stephen M.; Mehta, Dolly

    2014-01-01

    The heterotrimeric G protein Gα13 transduces signals from G protein–coupled receptors (GPCRs) to induce cell spreading, differentiation, migration, and cell polarity. Here, we describe a novel GPCR-independent function of Gα13 in regulating the stability of endothelial cell adherens junctions (AJs). We observed that the oxidant H2O2, which is released in response to multiple proinflammatory mediators, induced the interaction of Gα13 with VE-cadherin. Gα13 binding to VE-cadherin in turn induced Src activation and VE-cadherin phosphorylation at Tyr 658, the p120-catenin binding site thought to be responsible for VE-cadherin internalization. Inhibition of Gα13–VE-cadherin interaction using an interfering peptide derived from the Gα13 binding motif on VE-cadherin abrogated the disruption of AJs in response to inflammatory mediators. These studies identify a unique role of Gα13 binding to VE-cadherin in mediating VE-cadherin internalization and endothelial barrier disruption and inflammation. PMID:24590762

  17. 76 FR 24883 - DNB Exports LLC, and AFI Elektromekanikanik Ve Elektronik San. Tic. Ltd. Sti. v. Barsan Global...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-03

    ... From the Federal Register Online via the Government Publishing Office FEDERAL MARITIME COMMISSION DNB Exports LLC, and AFI Elektromekanikanik Ve Elektronik San. Tic. Ltd. Sti. v. Barsan Global... Commission (``Commission'') by DNB Exports LLC (``DNB''), and AFI Elektromekanikanik Ve Elektronik San....

  18. Effect of pantoprazole on insulin secretion in drug-naïve patients with type 2 diabetes.

    PubMed

    González-Ortiz, Manuel; Martínez-Abundis, Esperanza; Mercado-Sesma, Arieh R; Álvarez-Carrillo, Rebeca

    2015-04-01

    To evaluate the effect of pantoprazole during 45 days on insulin secretion in drug-naïve patients with type 2 diabetes, a randomized, double blind, placebo control clinical trial was performed in 14 drug-naïve volunteers. Significant increases in late insulin phase and total insulin secretion, and decreases in HbA1c levels were found. PMID:25704601

  19. Stüve-Wiedemann Syndrome: Update on Clinical and Genetic Aspects.

    PubMed

    Romeo Bertola, Débora; Honjo, Rachel S; Baratela, Wagner A R

    2016-04-01

    Stüve-Wiedemann syndrome is a rare autosomal recessive disorder characterized by bowed long bones, joint restrictions, dysautonomia, and respiratory and feeding difficulties, leading to death in the neonatal period and infancy in several occasions. Since the first cases in 1971, much has been learned about this condition, including its molecular basis - mutations in the leukemia inhibitory factor receptor gene (LIFR) -, natural history and management possibilities. This review aims to highlight the clinical aspects, radiological features, molecular findings, and management strategies in Stüve-Wiedemann syndrome. PMID:27194968

  20. Lessons about Virtual-Environment Software Systems from 20 years of VE building

    PubMed Central

    Taylor, Russell M.; Jerald, Jason; VanderKnyff, Chris; Wendt, Jeremy; Borland, David; Marshburn, David; Sherman, William R.; Whitton, Mary C.

    2010-01-01

    What are desirable and undesirable features of virtual-environment (VE) software architectures? What should be present (and absent) from such systems if they are to be optimally useful? How should they be structured? To help answer these questions we present experience from application designers, toolkit designers, and VE system architects along with examples of useful features from existing systems. Topics are organized under the major headings of: 3D space management, supporting display hardware, interaction, event management, time management, computation, portability, and the observation that less can be better. Lessons learned are presented as discussion of the issues, field experiences, nuggets of knowledge, and case studies. PMID:20567602

  1. Application Of Small Molecules Favoring Naïve Pluripotency during Human Embryonic Stem Cell Derivation

    PubMed Central

    Van der Jeught, Margot; Taelman, Jasin; Duggal, Galbha; Ghimire, Sabitri; Lierman, Sylvie; Chuva de Sousa Lopes, Susana M.; Deforce, Dieter; Deroo, Tom; De Sutter, Petra

    2015-01-01

    Abstract In mice, inhibition of both the fibroblast growth factor (FGF) mitogen-activated protein kinase kinase/extracellular-signal regulated kinase (MEK/Erk) and the Wnt signaling inhibitor glycogen synthase-3β (GSK3β) enables the derivation of mouse embryonic stem cells (mESCs) from nonpermissive strains in the presence of leukemia inhibitory factor (LIF). Whereas mESCs are in an uncommitted naïve state, human embryonic stem cells (hESCs) represent a more advanced state, denoted as primed pluripotency. This burdens hESCs with a series of characteristics, which, in contrast to naïve ESCs, makes them not ideal for key applications such as cell-based clinical therapies and human disease modeling. In this study, different small molecule combinations were applied during human ESC derivation. Hereby, we aimed to sustain the naïve pluripotent state, by interfering with various key signaling pathways. First, we tested several combinations on existing, 2i (PD0325901 and CHIR99021)-derived mESCs. All combinations were shown to be equally adequate to sustain the expression of naïve pluripotency markers. Second, these conditions were tested during hESC derivation. Overall, the best results were observed in the presence of medium supplemented with 2i, LIF, and the noncanonical Wnt signaling agonist Wnt5A, alone and combined with epinephrine. In these conditions, outgrowths repeatedly showed an ESC progenitor-like morphology, starting from day 3. Culturing these “progenitor cells” did not result in stable, naïve hESC lines in the current conditions. Although Wnt5A could not promote naïve hESC derivation, we found that it was sustaining the conversion of established hESCs toward a more naïve state. Future work should aim to distinct the effects of the various culture formulations, including our Wnt5A-supplemented medium, reported to promote stable naïve pluripotency in hESCs. PMID:26053517

  2. Application Of Small Molecules Favoring Naïve Pluripotency during Human Embryonic Stem Cell Derivation.

    PubMed

    Van der Jeught, Margot; Taelman, Jasin; Duggal, Galbha; Ghimire, Sabitri; Lierman, Sylvie; Chuva de Sousa Lopes, Susana M; Deforce, Dieter; Deroo, Tom; De Sutter, Petra; Heindryckx, Björn

    2015-06-01

    In mice, inhibition of both the fibroblast growth factor (FGF) mitogen-activated protein kinase kinase/extracellular-signal regulated kinase (MEK/Erk) and the Wnt signaling inhibitor glycogen synthase-3β (GSK3β) enables the derivation of mouse embryonic stem cells (mESCs) from nonpermissive strains in the presence of leukemia inhibitory factor (LIF). Whereas mESCs are in an uncommitted naïve state, human embryonic stem cells (hESCs) represent a more advanced state, denoted as primed pluripotency. This burdens hESCs with a series of characteristics, which, in contrast to naïve ESCs, makes them not ideal for key applications such as cell-based clinical therapies and human disease modeling. In this study, different small molecule combinations were applied during human ESC derivation. Hereby, we aimed to sustain the naïve pluripotent state, by interfering with various key signaling pathways. First, we tested several combinations on existing, 2i (PD0325901 and CHIR99021)-derived mESCs. All combinations were shown to be equally adequate to sustain the expression of naïve pluripotency markers. Second, these conditions were tested during hESC derivation. Overall, the best results were observed in the presence of medium supplemented with 2i, LIF, and the noncanonical Wnt signaling agonist Wnt5A, alone and combined with epinephrine. In these conditions, outgrowths repeatedly showed an ESC progenitor-like morphology, starting from day 3. Culturing these "progenitor cells" did not result in stable, naïve hESC lines in the current conditions. Although Wnt5A could not promote naïve hESC derivation, we found that it was sustaining the conversion of established hESCs toward a more naïve state. Future work should aim to distinct the effects of the various culture formulations, including our Wnt5A-supplemented medium, reported to promote stable naïve pluripotency in hESCs. PMID:26053517

  3. Intramembrane binding of VE-cadherin to VEGFR2 and VEGFR3 assembles the endothelial mechanosensory complex

    PubMed Central

    Coon, Brian G.; Baeyens, Nicolas; Han, Jinah; Budatha, Madhusudhan; Ross, Tyler D.; Fang, Jennifer S.; Yun, Sanguk; Thomas, Jeon-Leon

    2015-01-01

    Endothelial responses to fluid shear stress are essential for vascular development and physiology, and determine the formation of atherosclerotic plaques at regions of disturbed flow. Previous work identified VE-cadherin as an essential component, along with PECAM-1 and VEGFR2, of a complex that mediates flow signaling. However, VE-cadherin’s precise role is poorly understood. We now show that the transmembrane domain of VE-cadherin mediates an essential adapter function by binding directly to the transmembrane domain of VEGFR2, as well as VEGFR3, which we now identify as another component of the junctional mechanosensory complex. VEGFR2 and VEGFR3 signal redundantly downstream of VE-cadherin. Furthermore, VEGFR3 expression is observed in the aortic endothelium, where it contributes to flow responses in vivo. In summary, this study identifies a novel adapter function for VE-cadherin mediated by transmembrane domain association with VEGFRs. PMID:25800053

  4. The conserved global regulator veA is necessary for symptom production and mycotoxin synthesis in maize seedlings by Fusarium verticillioides

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The veA or velvet gene is necessary for biosynthesis of mycotoxins and other secondary metabolites in Aspergillus species. In addition, veA has also been demonstrated to be necessary for normal seed colonization in Aspergillus flavus and Aspergillus parasiticus. The present study shows that veA hom...

  5. Cortisol awakening response in drug-naïve panic disorder

    PubMed Central

    Jakuszkowiak-Wojten, Katarzyna; Landowski, Jerzy; Wiglusz, Mariusz S; Cubała, Wiesław Jerzy

    2016-01-01

    Background It is unclear whether hypothalamic–pituitary–adrenal axis is involved in the pathophysiology of panic disorder (PD). The findings remain inconsistent. Cortisol awakening response (CAR) is a noninvasive biomarker of stress system activity. We designed the study to assess CAR in drug-naïve PD patients. Materials and methods We assessed CAR in 14 psychotropic drug-naïve outpatients with PD and 14 healthy controls. The severity of PD was assessed with Panic and Agoraphobia Scale. The severity of anxiety and depression was screened with Hospital Anxiety and Depression Scale. Results No significant difference in CAR between PD patients and control group was found. No correlations were observed between CAR and anxiety severity measures in PD patients and controls. Limitations The number of participating subjects was relatively small, and the study results apply to nonsuicidal drug-naïve PD patients without agoraphobia and with short-illness duration. There was a lack of control on subjects’ compliance with the sampling instructions. Conclusion The study provides no support for elevated CAR levels in drug-naïve PD patients without agoraphobia. PMID:27390521

  6. Naïve prey exhibit reduced antipredator behavior and survivorship

    PubMed Central

    2014-01-01

    Prey naiveté has been hypothesized to be one of the major driving forces behind population declines following the introduction of novel predators or release of inexperienced prey into predator rich environments. In these cases, naïve prey may lack sufficient antipredator behavior and, as a result, suffer increased mortality. Despite this, some evidence suggests that many prey utilize a generalized response to predators. Here, the naiveté hypothesis is tested using a predator–prey pair sharing an evolutionary history: the red swamp crayfish (Procambarus clarkii Girard, 1852) and largemouth bass (Micropterus salmoides Lacépède, 1802). Using farm-reared, naïve crayfish and wild-caught, experienced individuals, laboratory experiments demonstrated that naïve, farmed crayfish lack behavioral responses to chemical cues from bass, both in terms of movement and use of structural refuge. In contrast, experienced crayfish responded strongly to the same cues. In a subsequent field tethering experiment, these naïve individuals suffered a three-fold increase in predation rate. Based on these results, recognition of predators may not be innate in all prey, and previous experience and learning likely play a key role in the development of antipredator behavior. PMID:25392763

  7. "You've Got the Power": Documentary Film as a Tool of Environmental Adult Education

    ERIC Educational Resources Information Center

    Clover, Darlene E.

    2011-01-01

    Educators call for more creative means to combat the moribund narratives of contemporary environmentalism. Using visual methodology and environmental adult education theory, this article discusses how a documentary film titled "You've Got the Power" works to pose questions about complex environmental issues and develop critical thinking and…

  8. Small-Molecule Induction of Canine Embryonic Stem Cells Toward Naïve Pluripotency.

    PubMed

    Tobias, Ian C; Brooks, Courtney R; Teichroeb, Jonathan H; Villagómez, Daniel A; Hess, David A; Séguin, Cheryle A; Betts, Dean H

    2016-08-15

    Naïve and primed pluripotent stem cells (PSCs) reflect discrete pluripotent states that approximate the inner cell mass or the progressively lineage-restricted perigastrulation epiblast, respectively. Cells that occupy primed pluripotency have distinct epigenetic landscapes, transcriptional circuitry, and trophic requirements compared with their naïve counterparts. The existence of multiple pluripotent states has not been explored in dogs, which show promise as outbred biomedical models with more than 300 inherited diseases that also afflict humans. However, our understanding of canine embryogenesis and embryo-derived stem cells is limited. Herein, we converted leukemia inhibitory factor (LIF)-dependent and fibroblast growth factor 2 (FGF2)-dependent canine embryonic stem cells (cESCs) resembling primed PSCs toward a naïve pluripotent state using LIF and inhibitors of glycogen synthase kinase 3β and mitogen-activated protein kinase kinase 1/2 [called 2i and LIF (2iL)]. cESCs propagated in 2iL exhibited significant induction of genes associated with the naïve pluripotent state (eg, REX1, TBX3) and downregulation of primed pluripotency markers (eg, OTX2, FGF5) (P < 0.05). Differential phosphorylation of signal transducer and activator of transcription 3 (STAT3) and cell fate decisions on exposure to bone morphogenetic protein 4 (BMP4) suggested that a novel pluripotent identity has been established with 2iL. Accordingly, cESCs cultured with 2iL formed colonies at a greater efficiency than LIF-FGF2 cESCs following single-cell dissociation. Total genomic DNA methylation and histone H3 lysine 27 trimethylation signals were reduced in 2iL-treated cESCs. Our data suggest that 2iL culture conditions promote the conversion of cESCs toward an epigenetically distinct pluripotent state resembling naïve PSCs. PMID:27392793

  9. VeA Is Associated with the Response to Oxidative Stress in the Aflatoxin Producer Aspergillus flavus

    PubMed Central

    Baidya, Sachin; Duran, Rocio M.; Lohmar, Jessica M.; Harris-Coward, Pamela Y.; Cary, Jeffrey W.; Hong, Sung-Yong; Roze, Ludmila V.; Linz, John E.

    2014-01-01

    Survival of fungal species depends on the ability of these organisms to respond to environmental stresses. Osmotic stress or high levels of reactive oxygen species (ROS) can cause stress in fungi resulting in growth inhibition. Both eukaryotic and prokaryotic cells have developed numerous mechanisms to counteract and survive the stress in the presence of ROS. In many fungi, the HOG signaling pathway is crucial for the oxidative stress response as well as for osmotic stress response. This study revealed that while the osmotic stress response is only slightly affected by the master regulator veA, this gene, also known to control morphological development and secondary metabolism in numerous fungal species, has a profound effect on the oxidative stress response in the aflatoxin-producing fungus Aspergillus flavus. We found that the expression of A. flavus homolog genes involved in the HOG signaling pathway is regulated by veA. Deletion of veA resulted in a reduction in transcription levels of oxidative stress response genes after exposure to hydrogen peroxide. Furthermore, analyses of the effect of VeA on the promoters of cat1 and trxB indicate that the presence of VeA alters DNA-protein complex formation. This is particularly notable in the cat1 promoter, where the absence of VeA results in abnormally stronger complex formation with reduced cat1 expression and more sensitivity to ROS in a veA deletion mutant, suggesting that VeA might prevent binding of negative transcription regulators to the cat1 promoter. Our study also revealed that veA positively influences the expression of the transcription factor gene atfB and that normal formation of DNA-protein complexes in the cat1 promoter is dependent on AtfB. PMID:24951443

  10. Modelling pathogen log10 reduction values achieved by activated sludge treatment using naïve and semi naïve Bayes network models.

    PubMed

    Carvajal, Guido; Roser, David J; Sisson, Scott A; Keegan, Alexandra; Khan, Stuart J

    2015-11-15

    Risk management for wastewater treatment and reuse have led to growing interest in understanding and optimising pathogen reduction during biological treatment processes. However, modelling pathogen reduction is often limited by poor characterization of the relationships between variables and incomplete knowledge of removal mechanisms. The aim of this paper was to assess the applicability of Bayesian belief network models to represent associations between pathogen reduction, and operating conditions and monitoring parameters and predict AS performance. Naïve Bayes and semi-naïve Bayes networks were constructed from an activated sludge dataset including operating and monitoring parameters, and removal efficiencies for two pathogens (native Giardia lamblia and seeded Cryptosporidium parvum) and five native microbial indicators (F-RNA bacteriophage, Clostridium perfringens, Escherichia coli, coliforms and enterococci). First we defined the Bayesian network structures for the two pathogen log10 reduction values (LRVs) class nodes discretized into two states (< and ≥ 1 LRV) using two different learning algorithms. Eight metrics, such as Prediction Accuracy (PA) and Area Under the receiver operating Curve (AUC), provided a comparison of model prediction performance, certainty and goodness of fit. This comparison was used to select the optimum models. The optimum Tree Augmented naïve models predicted removal efficiency with high AUC when all system parameters were used simultaneously (AUCs for C. parvum and G. lamblia LRVs of 0.95 and 0.87 respectively). However, metrics for individual system parameters showed only the C. parvum model was reliable. By contrast individual parameters for G. lamblia LRV prediction typically obtained low AUC scores (AUC < 0.81). Useful predictors for C. parvum LRV included solids retention time, turbidity and total coliform LRV. The methodology developed appears applicable for predicting pathogen removal efficiency in water treatment

  11. Most microbe-specific naïve CD4⁺ T cells produce memory cells during infection.

    PubMed

    Tubo, Noah J; Fife, Brian T; Pagan, Antonio J; Kotov, Dmitri I; Goldberg, Michael F; Jenkins, Marc K

    2016-01-29

    Infection elicits CD4(+) memory T lymphocytes that participate in protective immunity. Although memory cells are the progeny of naïve T cells, it is unclear that all naïve cells from a polyclonal repertoire have memory cell potential. Using a single-cell adoptive transfer and spleen biopsy method, we found that in mice, essentially all microbe-specific naïve cells produced memory cells during infection. Different clonal memory cell populations had different B cell or macrophage helper compositions that matched effector cell populations generated much earlier in the response. Thus, each microbe-specific naïve CD4(+) T cell produces a distinctive ratio of effector cell types early in the immune response that is maintained as some cells in the clonal population become memory cells. PMID:26823430

  12. 75 FR 35872 - In the Matter of the Designation of Doku Umarov and Other Aliases as a Specially Designated...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-23

    ... determined to be subject to the Order who might have a constitutional presence in the United States would... subject to this determination who might have a constitutional presence in the United States, because to...

  13. Karhunen-Loève transform for compressive sampling hyperspectral images

    NASA Astrophysics Data System (ADS)

    Liu, Lei; Yan, Jingwen; Zheng, Xianwei; Peng, Hong; Guo, Di; Qu, Xiaobo

    2015-01-01

    Compressed sensing (CS) is a new jointly sampling and compression technology for remote sensing. In hyperspectral imaging, a typical CS method encodes the two-dimensional (2-D) spatial information of each spectral band or encodes the third spectral information simultaneously. However, encoding the spatial information is much easier than encoding the spectral information. Therefore, it is crucial to make use of the spectral information to improve the compression rate on 2-D CS data. We propose to encode the third spectral information with an adaptive Karhunen-Loève transform. With a mathematical proof, we show that interspectral correlations are preserved among 2-D randomly encoded spatial information. This property means that one can compress 2-D CS data effectively with a Karhunen-Loève transform. Experiments demonstrate that the proposed method can better reconstruct both spectral curves and spatial images than traditional compression methods at the bit rates 0 to 1.

  14. The Naïve Utility Calculus: Computational Principles Underlying Commonsense Psychology.

    PubMed

    Jara-Ettinger, Julian; Gweon, Hyowon; Schulz, Laura E; Tenenbaum, Joshua B

    2016-08-01

    We propose that human social cognition is structured around a basic understanding of ourselves and others as intuitive utility maximizers: from a young age, humans implicitly assume that agents choose goals and actions to maximize the rewards they expect to obtain relative to the costs they expect to incur. This 'naïve utility calculus' allows both children and adults observe the behavior of others and infer their beliefs and desires, their longer-term knowledge and preferences, and even their character: who is knowledgeable or competent, who is praiseworthy or blameworthy, who is friendly, indifferent, or an enemy. We review studies providing support for the naïve utility calculus, and we show how it captures much of the rich social reasoning humans engage in from infancy. PMID:27388875

  15. Naïve pluripotency is associated with global DNA hypomethylation

    PubMed Central

    Leitch, Harry G.; McEwen, Kirsten R.; Turp, Aleksandra; Encheva, Vesela; Carroll, Tom; Grabole, Nils; Mansfield, William; Nashun, Buhe; Knezovich, Jaysen G.; Smith, Austin; Surani, M. Azim; Hajkova, Petra

    2013-01-01

    Naïve pluripotent embryonic stem (ESCs) cells and embryonic germ (EGCs) cells are derived from the preimplantation epiblast and primordial germ cells (PGCs), respectively. We investigated whether differences exist between ESCs and EGCs in view of their distinct developmental origins. PGCs are programmed to undergo global DNA demethylation; however we find that EGCs exhibit equivalent levels of global DNA methylation to ESCs. Importantly, inhibition of MEK and Gsk3b by 2i conditions leads to a pronounced reduction in DNA methylation in both cell types. This is driven by Prdm14 and is associated with downregulation of Dnmt3a and Dnmt3b. However, genomic imprints are maintained in 2i and we report derivation of EGCs with intact genomic imprints. Collectively, our findings establish that culture in 2i instils a naïve pluripotent state with a distinctive epigenetic configuration that parallels molecular features observed in both the preimplantation epiblast and nascent PGCs. PMID:23416945

  16. Caffeine Toxicity Due to Supplement Use in Caffeine--Naïve Individual: A Cautionary Tale.

    PubMed

    Lystrup, Robert M; Leggit, Jeffery C

    2015-08-01

    Thousands of military members self-medicate with dietary supplements containing unknown quantities of pharmacologically active compounds. These poorly regulated substances can cause real harm to the military population, especially when they contain stimulants such as caffeine. When taken regularly, caffeine has several performance-enhancing benefits. However, when used excessively or in vulnerable populations, caffeine can cause several unwanted side effects such as nervousness, sensory disturbances, insomnia, arrhythmia, excitability, inattentiveness, restlessness, mood changes, gastrointestinal disturbances, and even psychosis. Vulnerable patients include the caffeine-naïve, physiologically stressed, young, and mentally ill patients. One such case describes a caffeine-naïve service member who suffered an adverse reaction after taking an allegedly moderate dose of caffeine from a pill he obtained from a teammate. This case highlights the importance of supplement awareness among service members, increased provider vigilance, third party verification, and enhanced regulation on the approval and marketing of dietary supplements. PMID:26226540

  17. Distinct TLR-mediated cytokine production and immunoglobulin secretion in human newborn naïve B cells.

    PubMed

    Pettengill, Matthew A; van Haren, Simon D; Li, Ning; Dowling, David J; Bergelson, Ilana; Jans, Jop; Ferwerda, Gerben; Levy, Ofer

    2016-08-01

    Neonatal innate immunity is distinct from that of adults, which may contribute to increased susceptibility to infection and limit vaccine responses. B cells play critical roles in protection from infection and detect PAMPs via TLRs, that, when co-activated with CD40, can drive B-cell proliferation and Ab production. We characterized the expression of TLRs in circulating B cells from newborns and adults, and evaluated TLR- and CD40-mediated naïve B-cell class-switch recombination (CSR) and cytokine production. Gene expression levels of most TLRs was similar between newborn and adult B cells, except that newborn naïve B cells expressed more TLR9 than adult naïve B cells. Neonatal naïve B cells demonstrated impaired TLR2- and TLR7- but enhanced TLR9-mediated cytokine production. Significantly fewer newborn naïve B cells underwent CSR to produce IgG, an impairment also noted with IL-21 stimulation. Additionally, co-stimulation via CD40 and TLRs induced greater cytokine production in adult B cells. Thus, while newborn naïve B cells demonstrate adult-level expression of TLRs and CD40, the responses to stimulation of these receptors are distinct. Relatively high expression of TLR9 and impaired CD40-mediated Ig secretion contributes to distinct innate and adaptive immunity of human newborns and may inform novel approaches to early-life immunization. PMID:27252169

  18. Blockade of cholinergic transmission elicits somatic signs in nicotine-naïve adolescent rats

    PubMed Central

    Schmidt, Clare E.; Manbeck, Katherine E.; Shelley, David; Harris, Andrew C.

    2015-01-01

    High doses of the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine can elicit somatic signs resembling those associated with nicotine withdrawal in nicotine-naïve adult rats. Understanding this phenomenon, and its possible modulation by acute nicotine and age, could inform the use of mecamylamine as both an experimental tool and potential pharmacotherapy for tobacco dependence and other disorders. This study evaluated the ability of high-dose mecamylamine to elicit somatic signs in adolescent rats, and the potential for acute nicotine pretreatment to potentiate this effect as previously reported in adults. Single or repeated injections of mecamylamine (1.5 or 3.0 mg/kg, s.c.) elicited somatic signs in nicotine-naïve adolescents, but this effect was not influenced by 2 h pretreatment with acute nicotine (0.5 mg/kg, s.c.). In an initial evaluation of the effects of age in this model, mecamylamine (2.25 mg/kg, s.c.) elicited somatic signs in nicotine-naïve adolescents and adults. This effect was modestly enhanced following acute nicotine injections in adults but not in adolescents, even when a higher nicotine dose (1.0 rather than 0.5 mg/kg, s.c.) was used in adolescents to account for age differences in nicotine pharmacokinetics. These studies are the first to show that mecamylamine elicits somatic signs in nicotine-naïve adolescent rats, an effect that should be considered when designing and interpreting studies examining effects of high doses of mecamylamine in adolescents. Our findings also provide preliminary evidence that these signs may be differentially modulated by acute nicotine pretreatment in adolescents versus adults. PMID:26539119

  19. Abacavir-Reactive Memory T Cells Are Present in Drug Naïve Individuals

    PubMed Central

    Lucas, Andrew; Lucas, Michaela; Strhyn, Anette; Keane, Niamh M.; McKinnon, Elizabeth; Pavlos, Rebecca; Moran, Ellen M.; Meyer-Pannwitt, Viola; Gaudieri, Silvana; D’Orsogna, Lloyd; Kalams, Spyros; Ostrov, David A.; Buus, Søren; Peters, Bjoern; Mallal, Simon; Phillips, Elizabeth

    2015-01-01

    Background Fifty-five percent of individuals with HLA-B*57:01 exposed to the antiretroviral drug abacavir develop a hypersensitivity reaction (HSR) that has been attributed to naïve T-cell responses to neo-antigen generated by the drug. Immunologically confirmed abacavir HSR can manifest clinically in less than 48 hours following first exposure suggesting that, at least in some cases, abacavir HSR is due to re-stimulation of a pre-existing memory T-cell population rather than priming of a high frequency naïve T-cell population. Methods To determine whether a pre-existing abacavir reactive memory T-cell population contributes to early abacavir HSR symptoms, we studied the abacavir specific naïve or memory T-cell response using HLA-B*57:01 positive HSR patients or healthy controls using ELISpot assay, intra-cellular cytokine staining and tetramer labelling. Results Abacavir reactive CD8+ T-cell responses were detected in vitro in one hundred percent of abacavir unexposed HLA-B*57:01 positive healthy donors. Abacavir-specific CD8+ T cells from such donors can be expanded from sorted memory, and sorted naïve, CD8+ T cells without need for autologous CD4+ T cells. Conclusions We propose that these pre-existing abacavir-reactive memory CD8+ T-cell responses must have been primed by earlier exposure to another foreign antigen and that these T cells cross-react with an abacavir-HLA-B*57:01-endogenous peptide ligand complex, in keeping with the model of heterologous immunity proposed in transplant rejection. PMID:25674793

  20. Gender differences in non-motor symptoms in early, drug naïve Parkinson's disease.

    PubMed

    Picillo, Marina; Amboni, Marianna; Erro, Roberto; Longo, Katia; Vitale, Carmine; Moccia, Marcello; Pierro, Angela; Santangelo, Gabriella; De Rosa, Anna; De Michele, Giuseppe; Santoro, Lucio; Orefice, Giuseppe; Barone, Paolo; Pellecchia, Maria Teresa

    2013-11-01

    Gender differences in brain structure and function may lead to differences in the clinical expression of neurological diseases, including Parkinson's disease (PD). Few studies reported gender-related differences in the burden of non-motor symptoms (NMS) in treated PD patients, but this matter has not been previously explored in drug-naïve PD patients. This study is to assess gender differences in the prevalence of NMS in a large sample of early, drug-naïve PD patients compared with age and sex-matched healthy controls. Two hundred early, drug-naïve PD patients and ninety-three age and sex-matched healthy controls were included in the study. Frequency of NMS was evaluated by means of the Non-Motor Symptoms Questionnaire. The difference in gender distribution of NMS was evaluated with the χ (2) exact test; multiple comparisons were corrected with the Benjamini-Hochberg method. Male PD patients complained of problems having sex and taste/smelling difficulties significantly more frequently than female PD patients. Furthermore, men with PD complained more frequently of dribbling, sadness/blues, loss of interest, anxiety, acting during dreams, and taste/smelling difficulties as compared to healthy control men, while female PD patients reported more frequently loss of interest and anxiety as compared with healthy control women. This study shows specific sex-related patterns of NMS in drug-naïve PD. In contrast with previous data, female PD patients did not present higher prevalence of mood symptoms as compared to male PD patients. Comparison with healthy controls showed that some NMS classically present in premotor and early stage of disease (i.e., acting out during dreams, taste/smelling difficulties) are more frequent in male than in female patients. PMID:23989344

  1. VE-cadherin facilitates BMP-induced endothelial cell permeability and signaling.

    PubMed

    Benn, Andreas; Bredow, Clara; Casanova, Isabel; Vukičević, Slobodan; Knaus, Petra

    2016-01-01

    Several vascular disorders, such as aberrant angiogenesis, atherosclerosis and pulmonary hypertension, have been linked to dysfunctional BMP signaling. Vascular hyperpermeability via distortion of endothelial cell adherens junctions is a common feature of these diseases, but the role of BMPs in this process has not been investigated. BMP signaling is initiated by binding of ligand to, and activation of, BMP type I (BMPRI) and type II (BMPRII) receptors. Internalization of VE-cadherin as well as c-Src kinase-dependent phosphorylation have been implicated in the loosening of cell-cell contacts, thereby modulating vascular permeability. Here we demonstrate that BMP6 induces hyperpermeabilization of human endothelial cells by inducing internalization and c-Src-dependent phosphorylation of VE-cadherin. Furthermore, we show BMP-dependent physical interaction of VE-cadherin with the BMP receptor ALK2 (BMPRI) and BMPRII, resulting in stabilization of the BMP receptor complex and, thereby, the support of BMP6-Smad signaling. Our results provide first insights into the molecular mechanism of BMP-induced vascular permeability, a hallmark of various vascular diseases, and provide the basis for further investigations of BMPs as regulators of vascular integrity, both under physiological and pathophysiological conditions. PMID:26598555

  2. Dopamine transporter availability in motor subtypes of de novo drug-naïve Parkinson's disease.

    PubMed

    Moccia, Marcello; Pappatà, Sabina; Picillo, Marina; Erro, Roberto; Coda, Anna Rita Daniela; Longo, Katia; Vitale, Carmine; Amboni, Marianna; Brunetti, Arturo; Capo, Giuseppe; Salvatore, Marco; Barone, Paolo; Pellecchia, Maria Teresa

    2014-11-01

    Tremor dominant (TD) and akinetic-rigid type (ART) are two motor subtypes of Parkinson's disease associated with different disease progression and neurochemical/neuropathological features. The role of presynaptic nigrostriatal dopaminergic damage is still controversial, poorly explored, and only assessed in medicated patients. In this study, we investigated with FP-CIT SPECT the striatal dopamine transporter (DAT) availability in drug-naïve PD patients with ART and TD phenotypes. Fifty-one de novo, drug-naïve patients with PD underwent FP-CIT SPECT studies. Patients were evaluated with Unified Parkinson's Disease Rating Scale (UPDRS) part III and Hoehn and Yahr scale (H&Y) and divided into ART (24/51) and TD (27/51) according to UPDRS part III. ART and TD patients were not different with regard to age, gender, and disease duration. However, compared to TD, ART patients presented higher UPDRS part III (p = 0.01) and H&Y (p = 0.02) and lower DAT availability in affected and unaffected putamen (p = 0.008 and p = 0.007, respectively), whereas no differences were found in caudate. Moreover, in the whole group of patients, rigidity and bradykinesia, but not tremor scores of UPDRS part III were significantly related to FP-CIT binding in the putamen. These results suggest that in newly diagnosed drug-naïve PD patients DAT availability might be different between ART and TD in relation to different disease severity. PMID:25119838

  3. Naïve Electronic Health Record Phenotype Identification for Rheumatoid Arthritis

    PubMed Central

    Carroll, Robert J.; Eyler, Anne E.; Denny, Joshua C.

    2011-01-01

    Electronic Health Records (EHRs) provide a real-world patient cohort for clinical and genomic research. Phenotype identification using informatics algorithms has been shown to replicate known genetic associations found in clinical trials and observational cohorts. However, development of accurate phenotype identification methods can be challenging, requiring significant time and effort. We applied Support Vector Machines (SVMs) to both naïve (i.e., non-curated) and expert-defined collections of EHR features to identify Rheumatoid Arthritis cases using billing codes, medication exposures, and natural language processing-derived concepts. SVMs trained on naïve and expert-defined data outperformed an existing deterministic algorithm; the best performing naïve system had precision of 0.94 and recall of 0.87, compared to precision of 0.75 and recall of 0.51 for the deterministic algorithm. We show that with an expert defined feature set as few as 50–100 training samples are required. This study demonstrates that SVMs operating on non-curated sets of attributes can accurately identify cases from an EHR. PMID:22195070

  4. Diesel Exhaust Particle Exposure Causes Redistribution of Endothelial Tube VE-Cadherin

    PubMed Central

    Chao, Ming-Wei; Kozlosky, John; Po, Iris P.; Strickland, Pamela Ohman; Svoboda, Kathy K. H.; Cooper, Keith; Laumbach, Robert; Gordon, Marion K.

    2010-01-01

    Whether diesel exhaust particles (DEPs) potentially have a direct effect on capillary endothelia was examined by following the adherens junction component, vascular endothelial cell cadherin (VE-cadherin). This molecule is incorporated into endothelial adherens junctions at the cell surface, where it forms homodimeric associations with adjacent cells and contributes to the barrier function of the vasculature (Dejana et al., 2008; Venkiteswaran et al., 2002; Villasante et al., 2007). Human umbilical vein endothelial cells (HUVECs) that were pre-formed into capillary-like tube networks in vitro were exposed to DEPs for 24 hr. After exposure, the integrity of VE-cadherin in adherens junctions was assessed by immunofluorescence analysis, and demonstrated that increasing concentrations of DEPs caused increasing redistribution of VE-cadherin away from the cell-cell junctions toward intracellular locations. Since HUVEC tube networks are three-dimensional structures, whether particles entered the endothelial cells or tubular lumens was also examined. The data indicate that translocation of the particles does occur. The results, obtained in a setting that removes the confounding effects of inflammatory cells or blood components, suggest that if DEPs encounter alveolar capillaries in vivo, they may be able to directly affect the endothelial cell-cell junctions. PMID:20887764

  5. Feature weighted naïve Bayes algorithm for information retrieval of enterprise systems

    NASA Astrophysics Data System (ADS)

    Wang, Li; Ji, Ping; Qi, Jing; Shan, Siqing; Bi, Zhuming; Deng, Weiguo; Zhang, Naijing

    2014-01-01

    Automated information retrieval is critical for enterprise information systems to acquire knowledge from the vast amount of data sets. One challenge in information retrieval is text classification. Current practices rely heavily on the classical naïve Bayes algorithm due to its simplicity and robustness. However, results from this algorithm are not always satisfactory. In this article, the limitations of the naïve Bayes algorithm are discussed, and it is found that the assumption on the independence of terms is the main reason for an unsatisfactory classification in many real-world applications. To overcome the limitations, the dependent factors are considered by integrating a term frequency-inverse document frequency (TF-IDF) weighting algorithm in the naïve Bayes classification. Moreover, the TF-IDF algorithm itself is improved so that both frequencies and distribution information are taken into consideration. To illustrate the effectiveness of the proposed method, two simulation experiments were conducted, and the comparisons with other classification methods have shown that the proposed method has outperformed other existing algorithms in terms of precision and index recall rate.

  6. A Ve homologous gene from Gossypium barbadense, Gbvdr3, enhances the defense response against Verticillium dahliae.

    PubMed

    Chen, Tianzi; Kan, Jialiang; Yang, Yuwen; Ling, Xitie; Chang, Youhong; Zhang, Baolong

    2016-01-01

    The tomato Ve1 gene and several Ve1 homologues are involved in the resistance to Verticillium dahliae. Here, we report on another Ve homologous gene, Gbvdr3, from a Verticillium wilt-resistant cotton cultivar, Gossypium barbadense Hai7124, which has a 3207-bp region that encodes a predicted receptor-like protein. Transient expression analyses indicated that Gbvdr3 is localized in the plasma membrane, and virus-induced gene silencing of Gbvdr3 compromised the resistance of Hai7124 cotton to a defoliating strain of V. dahliae, V991, but not to a non-defoliating strain, BP2. This resistance pattern was further confirmed by over-expression of Gbvdr3 in transgenic Arabidopsis, which significantly elevated the expression of the ethylene-regulated gene GST2, the ethylene- and jasmonic acid-regulated defense-related genes PR3 and PDF1.2, and the salicylic acid-regulated genes PR1 and PR5, but not the PR2 gene. It also triggered the accumulation of hydrogen peroxide and callose at early time points during infection by the V991 defoliating strain. In contrast, elevated accumulation of hydrogen peroxide or callose in Gbvdr3-expressed Arabidopsis leaves was not apparent under infection by the non-defoliating strain, BP2. These results suggested that Gbvdr3 is involved in the resistance to a unique spectrum of defoliating V. dahliae strains. PMID:26686282

  7. A distinct plasmablast and naïve B-cell phenotype in primary immune thrombocytopenia

    PubMed Central

    Flint, Shaun M.; Gibson, Adele; Lucas, Geoff; Nandigam, Raghava; Taylor, Louise; Provan, Drew; Newland, Adrian C.; Savage, Caroline O.; Henderson, Robert B.

    2016-01-01

    Primary immune thrombocytopenia is an autoimmune disorder in which platelet destruction is a consequence of both B- and T-cell dysregulation. Flow cytometry was used to further characterize the B- and T-cell compartments in a cross-sectional cohort of 26 immune thrombocytopenia patients including antiplatelet antibody positive (n=14) and negative (n=12) patients exposed to a range of therapies, and a cohort of matched healthy volunteers. Markers for B-cell activating factor and its receptors, relevant B-cell activation markers (CD95 and CD21) and markers for CD4+ T-cell subsets, including circulating T-follicular helper-like cells, were included. Our results indicate that an expanded population of CD95+ naïve B cells correlated with disease activity in immune thrombocytopenia patients regardless of treatment status. A population of CD21-naïve B cells was specifically expanded in autoantibody-positive immune thrombocytopenia patients. Furthermore, the B-cell maturation antigen, a receptor for B-cell activating factor, was consistently and strongly up-regulated on plasmablasts from immune thrombocytopenia patients. These observations have parallels in other autoantibody-mediated diseases and suggest that loss of peripheral tolerance in naïve B cells may be an important component of immune thrombocytopenia pathogenesis. Moreover, the B-cell maturation antigen represents a potential target for plasma cell directed therapies in immune thrombocytopenia. PMID:26969086

  8. A Multilayer Naïve Bayes Model for Analyzing User's Retweeting Sentiment Tendency.

    PubMed

    Wang, Mengmeng; Zuo, Wanli; Wang, Ying

    2015-01-01

    Today microblogging has increasingly become a means of information diffusion via user's retweeting behavior. Since retweeting content, as context information of microblogging, is an understanding of microblogging, hence, user's retweeting sentiment tendency analysis has gradually become a hot research topic. Targeted at online microblogging, a dynamic social network, we investigate how to exploit dynamic retweeting sentiment features in retweeting sentiment tendency analysis. On the basis of time series of user's network structure information and published text information, we first model dynamic retweeting sentiment features. Then we build Naïve Bayes models from profile-, relationship-, and emotion-based dimensions, respectively. Finally, we build a multilayer Naïve Bayes model based on multidimensional Naïve Bayes models to analyze user's retweeting sentiment tendency towards a microblog. Experiments on real-world dataset demonstrate the effectiveness of the proposed framework. Further experiments are conducted to understand the importance of dynamic retweeting sentiment features and temporal information in retweeting sentiment tendency analysis. What is more, we provide a new train of thought for retweeting sentiment tendency analysis in dynamic social networks. PMID:26417367

  9. A Multilayer Naïve Bayes Model for Analyzing User's Retweeting Sentiment Tendency

    PubMed Central

    Wang, Mengmeng; Zuo, Wanli; Wang, Ying

    2015-01-01

    Today microblogging has increasingly become a means of information diffusion via user's retweeting behavior. Since retweeting content, as context information of microblogging, is an understanding of microblogging, hence, user's retweeting sentiment tendency analysis has gradually become a hot research topic. Targeted at online microblogging, a dynamic social network, we investigate how to exploit dynamic retweeting sentiment features in retweeting sentiment tendency analysis. On the basis of time series of user's network structure information and published text information, we first model dynamic retweeting sentiment features. Then we build Naïve Bayes models from profile-, relationship-, and emotion-based dimensions, respectively. Finally, we build a multilayer Naïve Bayes model based on multidimensional Naïve Bayes models to analyze user's retweeting sentiment tendency towards a microblog. Experiments on real-world dataset demonstrate the effectiveness of the proposed framework. Further experiments are conducted to understand the importance of dynamic retweeting sentiment features and temporal information in retweeting sentiment tendency analysis. What is more, we provide a new train of thought for retweeting sentiment tendency analysis in dynamic social networks. PMID:26417367

  10. VE-cadherin facilitates BMP-induced endothelial cell permeability and signaling

    PubMed Central

    Benn, Andreas; Bredow, Clara; Casanova, Isabel; Vukičević, Slobodan; Knaus, Petra

    2016-01-01

    ABSTRACT Several vascular disorders, such as aberrant angiogenesis, atherosclerosis and pulmonary hypertension, have been linked to dysfunctional BMP signaling. Vascular hyperpermeability via distortion of endothelial cell adherens junctions is a common feature of these diseases, but the role of BMPs in this process has not been investigated. BMP signaling is initiated by binding of ligand to, and activation of, BMP type I (BMPRI) and type II (BMPRII) receptors. Internalization of VE-cadherin as well as c-Src kinase-dependent phosphorylation have been implicated in the loosening of cell–cell contacts, thereby modulating vascular permeability. Here we demonstrate that BMP6 induces hyperpermeabilization of human endothelial cells by inducing internalization and c-Src-dependent phosphorylation of VE-cadherin. Furthermore, we show BMP-dependent physical interaction of VE-cadherin with the BMP receptor ALK2 (BMPRI) and BMPRII, resulting in stabilization of the BMP receptor complex and, thereby, the support of BMP6-Smad signaling. Our results provide first insights into the molecular mechanism of BMP-induced vascular permeability, a hallmark of various vascular diseases, and provide the basis for further investigations of BMPs as regulators of vascular integrity, both under physiological and pathophysiological conditions. PMID:26598555

  11. The Fumagillin Gene Cluster, an Example of Hundreds of Genes under veA Control in Aspergillus fumigatus

    PubMed Central

    Dhingra, Sourabh; Lind, Abigail L.; Lin, Hsiao-Ching; Tang, Yi; Rokas, Antonis; Calvo, Ana M.

    2013-01-01

    Aspergillus fumigatus is the causative agent of invasive aspergillosis, leading to infection-related mortality in immunocompromised patients. We previously showed that the conserved and unique-to-fungi veA gene affects different cell processes such as morphological development, gliotoxin biosynthesis and protease activity, suggesting a global regulatory effect on the genome of this medically relevant fungus. In this study, RNA sequencing analysis revealed that veA controls the expression of hundreds of genes in A. fumigatus, including those comprising more than a dozen known secondary metabolite gene clusters. Chemical analysis confirmed that veA controls the synthesis of other secondary metabolites in this organism in addition to gliotoxin. Among the secondary metabolite gene clusters regulated by veA is the elusive but recently identified gene cluster responsible for the biosynthesis of fumagillin, a meroterpenoid known for its anti-angiogenic activity by binding to human methionine aminopeptidase 2. The fumagillin gene cluster contains a veA-dependent regulatory gene, fumR (Afu8g00420), encoding a putative C6 type transcription factor. Deletion of fumR results in silencing of the gene cluster and elimination of fumagillin biosynthesis. We found expression of fumR to also be dependent on laeA, a gene encoding another component of the fungal velvet complex. The results in this study argue that veA is a global regulator of secondary metabolism in A. fumigatus, and that veA may be a conduit via which chemical development is coupled to morphological development and other cellular processes. PMID:24116213

  12. Psychotropic effects of Lactobacillus plantarum PS128 in early life-stressed and naïve adult mice.

    PubMed

    Liu, Yen-Wenn; Liu, Wei-Hsien; Wu, Chien-Chen; Juan, Yi-Chen; Wu, Yu-Chen; Tsai, Huei-Ping; Wang, Sabrina; Tsai, Ying-Chieh

    2016-01-15

    Ingestion of specific probiotics, namely "psychobiotics", produces psychotropic effects on behavior and affects the hypothalamic-pituitary-adrenal axis and neurochemicals in the brain. We examined the psychotropic effects of a potential psychobiotic bacterium, Lactobacillus plantarum strain PS128 (PS128), on mice subjected to early life stress (ELS) and on naïve adult mice. Behavioral tests revealed that chronic ingestion of PS128 increased the locomotor activities in both ELS and naïve adult mice in the open field test. In the elevated plus maze, PS128 significantly reduced the anxiety-like behaviors in naïve adult mice but not in the ELS mice; whereas the depression-like behaviors were reduced in ELS mice but not in naïve mice in forced swimming test and sucrose preference test. PS128 administration also reduced ELS-induced elevation of serum corticosterone under both basal and stressed states but had no effect on naïve mice. In addition, PS128 reduced inflammatory cytokine levels and increased anti-inflammatory cytokine level in the serum of ELS mice. Furthermore, the dopamine level in the prefrontal cortex (PFC) was significantly increased in PS128 treated ELS and naïve adult mice whereas serotonin (5-HT) level was increased only in the naïve adult mice. These results suggest that chronic ingestion of PS128 could ameliorate anxiety- and depression-like behaviors and modulate neurochemicals related to affective disorders. Thus PS128 shows psychotropic properties and has great potential for improving stress-related symptoms. PMID:26620542

  13. Fixed bimonthly aflibercept in naïve and switched neovascular age-related macular degeneration patients: one year outcomes

    PubMed Central

    Warwick, Alasdair N; Leaver, Hannah H; Lotery, Andrew J; Goverdhan, Srini V

    2016-01-01

    AIM To determine real life clinical outcomes in poorly responsive and treatment-naïve neovascular age related macular degeneration (nvAMD) patients using bimonthly fixed dosing aflibercept regimen. METHODS This was a retrospective study of 165 eyes with nvAMD started on aflibercept at Southampton Eye Unit between June 2013 and June 2014. Patients were either switched from pro re nata (PRN) ranibizumab/bevacizumab due to poor response (107 eyes), or treatment-naïve (58 eyes). Patients initially received 3-monthly intravitreal aflibercept injections followed by 2-monthly fixed doses. Clinic visits were scheduled at month 0, 4, 10 and 12. Mean change in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) from baseline were assessed using the Wilcoxon signed-rank test. The proportion of patients maintaining BCVA (<15 letters loss) at 12mo was also evaluated. RESULTS Mean BCVA change at month 12 was +3.29 and +4.67 letters in the switched and naïve aflibercept groups respectively (P<0.01). BCVA was maintained in 95.3% of switched and 96.6% of naïve patients. CRT at month 12 showed a decrease of -6.16 µm in the switched group and -35.36 µm in the naïve group (P<0.01). Patients previously treated with ranibizumab/bevacizumab had on average received 7.4 ranibizumab/bevacizumab injections over 12.6mo, attending 10 clinic visits. The fixed dosing aflibercept regimen required an average of 7.1 injections (naïve group), 7.5 injections (switched group) and 4 clinic visits per year. CONCLUSION Fixed bimonthly aflibercept is effective in both treatment-naïve and poorly responsive nvAMD patients. Adopting a fixed dosing regimen can reduce patient burden without compromising on outcomes. PMID:27588271

  14. Human naïve regulatory T-cells feature high steady-state turnover and are maintained by IL-7

    PubMed Central

    Serra-Caetano, Ana; Foxall, Russell B.; Pires, Ana R.; Matoso, Paula; Fernandes, Susana M.; Ferreira, João; Cheynier, Rémi; Victorino, Rui M. M.; Caramalho, Iris; Barata, João T.; Sousa, Ana E.

    2016-01-01

    Naïve FoxP3-expressing regulatory T-cells (Tregs) are essential to control immune responses via continuous replenishment of the activated-Treg pool with thymus-committed suppressor cells. The mechanisms underlying naïve-Treg maintenance throughout life in face of the age-associated thymic involution remain unclear. We found that in adults thymectomized early in infancy the naïve-Treg pool is remarkably well preserved, in contrast to conventional naïve CD4 T-cells. Naïve-Tregs featured high levels of cycling and pro-survival markers, even in healthy individuals, and contrasted with other circulating naïve/memory CD4 T-cell subsets in terms of their strong γc-cytokine-dependent signaling, particularly in response to IL-7. Accordingly, ex-vivo stimulation of naïve-Tregs with IL-7 induced robust cytokine-dependent signaling, Bcl-2 expression, and phosphatidylinositol 3-kinase (PI3K)-dependent proliferation, whilst preserving naïve phenotype and suppressive capacity. Altogether, our data strongly implicate IL-7 in the thymus-independent long-term survival of functional naïve-Tregs, and highlight the potential of targeting the IL-7 pathway to modulate Tregs in different clinical settings. PMID:26910841

  15. Human naïve regulatory T-cells feature high steady-state turnover and are maintained by IL-7.

    PubMed

    Silva, Susana L; Albuquerque, Adriana S; Serra-Caetano, Ana; Foxall, Russell B; Pires, Ana R; Matoso, Paula; Fernandes, Susana M; Ferreira, João; Cheynier, Rémi; Victorino, Rui M M; Caramalho, Iris; Barata, João T; Sousa, Ana E

    2016-03-15

    Naïve FoxP3-expressing regulatory T-cells (Tregs) are essential to control immune responses via continuous replenishment of the activated-Treg pool with thymus-committed suppressor cells. The mechanisms underlying naïve-Treg maintenance throughout life in face of the age-associated thymic involution remain unclear. We found that in adults thymectomized early in infancy the naïve-Treg pool is remarkably well preserved, in contrast to conventional naïve CD4 T-cells. Naïve-Tregs featured high levels of cycling and pro-survival markers, even in healthy individuals, and contrasted with other circulating naïve/memory CD4 T-cell subsets in terms of their strong γc-cytokine-dependent signaling, particularly in response to IL-7. Accordingly, ex-vivo stimulation of naïve-Tregs with IL-7 induced robust cytokine-dependent signaling, Bcl-2 expression, and phosphatidylinositol 3-kinase (PI3K)-dependent proliferation, whilst preserving naïve phenotype and suppressive capacity. Altogether, our data strongly implicate IL-7 in the thymus-independent long-term survival of functional naïve-Tregs, and highlight the potential of targeting the IL-7 pathway to modulate Tregs in different clinical settings. PMID:26910841

  16. The conserved global regulator VeA is necessary for symptom production and mycotoxin synthesis in maize seedlings by Fusarium verticillioides

    PubMed Central

    Myung, K.; Zitomer, N. C.; Duvall, M.; Glenn, A. E.; Riley, R. T.; Calvo, A. M.

    2011-01-01

    The veA or velvet gene is necessary for biosynthesis of mycotoxins and other secondary metabolites in Aspergillus species. In addition, veA has also been demonstrated to be necessary for normal seed colonization in Aspergillus flavus and Aspergillus parasiticus. The present study shows that veA homologues are broadly distributed in fungi, particularly in Ascomycetes. The Fusarium verticillioides veA orthologue, FvVE1, is also required for the synthesis of several secondary metabolites, including fumonisin and fusarins. This study also shows that maize plants grown from seeds inoculated with FvVE1 deletion mutants did not show disease symptoms, while plants grown from seeds inoculated with the F. verticillioides wildtype and complementation strains clearly showed disease symptoms under the same experimental conditions. In this latter case, the presence of lesions coincided with accumulation of fumonisins in the plant tissues, and only these plant tissues had elevated levels of sphingoid bases and their 1-phosphate derivatives, indicating inhibition of ceramide synthase and disruption of sphingolipid metabolism. The results strongly suggest that FvVE1 is necessary for pathogenicity by F. verticillioides against maize seedlings. The conservation of veA homologues among ascomycetes suggests that veA could play a pivotal role in regulating secondary metabolism and associated pathogenicity in other fungi. PMID:22247572

  17. The actin-binding protein EPS8 binds VE-cadherin and modulates YAP localization and signaling

    PubMed Central

    Disanza, Andrea; Bravi, Luca; Barrios-Rodiles, Miriam; Corada, Monica; Frittoli, Emanuela; Savorani, Cecilia; Lampugnani, Maria Grazia; Boggetti, Barbara; Niessen, Carien; Wrana, Jeff L.

    2015-01-01

    Vascular endothelial (VE)–cadherin transfers intracellular signals contributing to vascular hemostasis. Signaling through VE-cadherin requires association and activity of different intracellular partners. Yes-associated protein (YAP)/TAZ transcriptional cofactors are important regulators of cell growth and organ size. We show that EPS8, a signaling adapter regulating actin dynamics, is a novel partner of VE-cadherin and is able to modulate YAP activity. By biochemical and imaging approaches, we demonstrate that EPS8 associates with the VE-cadherin complex of remodeling junctions promoting YAP translocation to the nucleus and transcriptional activation. Conversely, in stabilized junctions, 14–3-3–YAP associates with the VE–cadherin complex, whereas Eps8 is excluded. Junctional association of YAP inhibits nuclear translocation and inactivates its transcriptional activity both in vitro and in vivo in Eps8-null mice. The absence of Eps8 also increases vascular permeability in vivo, but did not induce other major vascular defects. Collectively, we identified novel components of the adherens junction complex, and we introduce a novel molecular mechanism through which the VE-cadherin complex controls YAP transcriptional activity. PMID:26668327

  18. Ph+/VE-cadherin+ identifies a stem cell like population of acute lymphoblastic leukemia sustained by bone marrow niche cells.

    PubMed

    Wang, Lin; O'Leary, Heather; Fortney, James; Gibson, Laura F

    2007-11-01

    Although leukemic stem cells (LSCs) show a symbiotic relationship with bone marrow microenvironmental niches, the mechanism by which the marrow microenvironment contributes to self-renewal and proliferation of LSCs remains elusive. In the present study, we identified a unique subpopulation of Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL) cells coexpressing markers of endothelial cells (including VE-cadherin, PECAM-1, and Flk-1) and committed B-lineage progenitors. After long-term coculture with bone marrow stromal cells, tumor cells formed hematopoietic colonies and cords, expressed early stem- cell markers, and showed endothelial sprouting. Gene expression profiles of LSCs were altered in the presence of stromal cell contact. Stromal cell contact promoted leukemic cell VE-cadherin expression, stabilized beta-catenin, and up-regulated Bcr-abl fusion gene expression. Our study indicates that these specific tumor cells are uniquely positioned to respond to microenvironment-derived self-renewing and proliferative cues. Ph(+)/VE-cadherin(+) tumor subpopulation circumvents the requirement of exogenous Wnt signaling for self-renewal through stromal cell support of leukemic cell VE-cadherin expression and up-regulated Bcr-abl tyrosine kinase activity. These data suggest that strategies targeting signals in the marrow microenvironment that amplify the Bcr-abl/VE-cadherin/beta-catenin axis may have utility in sensitizing drug-resistant leukemic stem cells. PMID:17638851

  19. Single tracking location acoustic radiation force impulse viscoelasticity estimation (STL-VE): A method for measuring tissue viscoelastic parameters.

    PubMed

    Langdon, Jonathan H; Elegbe, Etana; McAleavey, Stephen A

    2015-07-01

    Single tracking location (STL) shear wave elasticity imaging (SWEI) is a method for detecting elastic differences between tissues. It has the advantage of intrinsic speckle bias suppression compared with multiple tracking location variants of SWEI. However, the assumption of a linear model leads to an overestimation of the shear modulus in viscoelastic media. A new reconstruction technique denoted single tracking location viscosity estimation (STL-VE) is introduced to correct for this overestimation. This technique utilizes the same raw data generated in STL-SWEI imaging. Here, the STL-VE technique is developed by way of a maximum likelihood estimation for general viscoelastic materials. The method is then implemented for the particular case of the Kelvin-Voigt Model. Using simulation data, the STL-VE technique is demonstrated and the performance of the estimator is characterized. Finally, the STL-VE method is used to estimate the viscoelastic parameters of ex vivo bovine liver. We find good agreement between the STL-VE results and the simulation parameters as well as between the liver shear wave data and the modeled data fit. PMID:26168170

  20. Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation

    PubMed Central

    Fokas, E; Prevo, R; Pollard, J R; Reaper, P M; Charlton, P A; Cornelissen, B; Vallis, K A; Hammond, E M; Olcina, M M; Gillies McKenna, W; Muschel, R J; Brunner, T B

    2012-01-01

    Combined radiochemotherapy is the currently used therapy for locally advanced pancreatic ductal adenocarcinoma (PDAC), but normal tissue toxicity limits its application. Here we test the hypothesis that inhibition of ATR (ATM-Rad3-related) could increase the sensitivity of the cancer cells to radiation or chemotherapy without affecting normal cells. We tested VE-822, an ATR inhibitor, for in vitro and in vivo radiosensitization. Chk1 phosphorylation was used to indicate ATR activity, γH2AX and 53BP1 foci as evidence of DNA damage and Rad51 foci for homologous recombination activity. Sensitivity to radiation (XRT) and gemcitabine was measured with clonogenic assays in vitro and tumor growth delay in vivo. Murine intestinal damage was evaluated after abdominal XRT. VE-822 inhibited ATR in vitro and in vivo. VE-822 decreased maintenance of cell-cycle checkpoints, increased persistent DNA damage and decreased homologous recombination in irradiated cancer cells. VE-822 decreased survival of pancreatic cancer cells but not normal cells in response to XRT or gemcitabine. VE-822 markedly prolonged growth delay of pancreatic cancer xenografts after XRT and gemcitabine-based chemoradiation without augmenting normal cell or tissue toxicity. These findings support ATR inhibition as a promising new approach to improve the therapeutic ration of radiochemotherapy for patients with PDAC. PMID:23222511

  1. Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation.

    PubMed

    Fokas, E; Prevo, R; Pollard, J R; Reaper, P M; Charlton, P A; Cornelissen, B; Vallis, K A; Hammond, E M; Olcina, M M; Gillies McKenna, W; Muschel, R J; Brunner, T B

    2012-01-01

    Combined radiochemotherapy is the currently used therapy for locally advanced pancreatic ductal adenocarcinoma (PDAC), but normal tissue toxicity limits its application. Here we test the hypothesis that inhibition of ATR (ATM-Rad3-related) could increase the sensitivity of the cancer cells to radiation or chemotherapy without affecting normal cells. We tested VE-822, an ATR inhibitor, for in vitro and in vivo radiosensitization. Chk1 phosphorylation was used to indicate ATR activity, γH2AX and 53BP1 foci as evidence of DNA damage and Rad51 foci for homologous recombination activity. Sensitivity to radiation (XRT) and gemcitabine was measured with clonogenic assays in vitro and tumor growth delay in vivo. Murine intestinal damage was evaluated after abdominal XRT. VE-822 inhibited ATR in vitro and in vivo. VE-822 decreased maintenance of cell-cycle checkpoints, increased persistent DNA damage and decreased homologous recombination in irradiated cancer cells. VE-822 decreased survival of pancreatic cancer cells but not normal cells in response to XRT or gemcitabine. VE-822 markedly prolonged growth delay of pancreatic cancer xenografts after XRT and gemcitabine-based chemoradiation without augmenting normal cell or tissue toxicity. These findings support ATR inhibition as a promising new approach to improve the therapeutic ration of radiochemotherapy for patients with PDAC. PMID:23222511

  2. VE-cadherin is a critical molecule for trophoblast-endothelial cell interaction in decidual spiral arteries

    SciTech Connect

    Bulla, Roberta; Villa, Antonello; Bossi, Fleur; Cassetti, Arianna; Radillo, Oriano; Spessotto, Paola; De Seta, Francesco; Guaschino, Secondo; Tedesco, Francesco . E-mail: tedesco@univ.trieste.it

    2005-02-01

    Fetal cytotrophoblasts colonize the decidual spiral arteries during pregnancy and partially replace the endothelium by an as yet unknown mechanism. To clarify this issue, we cocultured trophoblast cells (TCs) and decidual endothelial cells (DECs) isolated from first trimester placentae and found by electron microscopic analysis that TCs adhered to DECs and migrated through the interendothelial junctions within 24 h. Since extravillous TCs were shown by FACS analysis to express vascular-endothelial (VE)-cadherin and platelet endothelial cell adhesion molecule-1 (PECAM)-1, we investigated the role of these junctional molecules in TC adhesion to DECs and transendothelial migration of cytotrophoblasts. Both VE-cadherin and PECAM-1 were present at the contact sites between TCs and DECs in decidual sections. TC adhesion and migration were markedly inhibited by mAbs to VE-cadherin and marginally by mAb to PECAM-1. Increased expression of VE-cadherin was observed at the contact areas between TCs and DECs, whereas PECAM-1 was found to be redistributed from intercellular junctions. The induction of apoptosis of DECs by TCs, as the mechanism responsible for their replacement, was ruled out by the negative staining with TUNEL of DECs cocultured with TCs and the absence of DNA fragmentation. In conclusion, VE-cadherin is involved in transendothelial migration of TCs, and replacement of DECs by TCs is not the result of apoptosis.

  3. Hormone naïve prostate cancer: predicting and maximizing response intervals

    PubMed Central

    Moul, Judd W

    2015-01-01

    Hormone naïve advanced prostate cancer is subdivided into two disease states: biochemical recurrence and traditional M1 (metastatic) prostate cancer and characterized by no prior hormonal therapy or androgen deprivation therapy (ADT). In biochemical recurrence/prostate-specific antigen (PSA) recurrence, men should be risk-stratified based on their PSA doubling time, the Gleason score and the timing of the recurrence. In general, only men who are at high risk should be considered for early/immediate ADT although this is best done using shared decision with the patient. The type of ADT to be used in biochemical recurrence ranging from oral-only peripheral blockade (peripheral androgen deprivation) to complete hormonal therapy (combined androgen blockade [CAB]) remains in debate owing to lack of randomized controlled trials (RCT). However, there is good RCT support for use of intermittent hormonal therapy (IHT). There is also limited research on biomarker response (PSA and testosterone decline) to predict prognosis. On the other hand, in the setting of M1 hormone naïve prostate cancer, there are many more RCT's to inform our decisions. CAB and gonadotrophin-releasing hormone antagonists perhaps provide a slight efficacy advantage while IHT may be slightly inferior with minimal M1 disease. The PSA nadir at 7 months after starting ADT is a powerful prognostic tool for M1 patients. There is growing recognition that serum testosterone (T) control while on ADT is linked to the development of castrate-resistant prostate cancer. Especially for a M1 patient, maintaining a serum T below 20–30 ng dl−1 prolongs the response to ADT. Novel oral agents (abiraterone and enzalutamide) may soon find use in hormone naïve disease and may alter the treatment landscape. Despite over 75 years of experience with ADT, many questions remain, and the field continues to evolve. PMID:26112479

  4. Radiosensitization of Human Leukemic HL-60 Cells by ATR Kinase Inhibitor (VE-821): Phosphoproteomic Analysis

    PubMed Central

    Šalovská, Barbora; Fabrik, Ivo; Ďurišová, Kamila; Link, Marek; Vávrová, Jiřina; Řezáčová, Martina; Tichý, Aleš

    2014-01-01

    DNA damaging agents such as ionizing radiation or chemotherapy are frequently used in oncology. DNA damage response (DDR)—triggered by radiation-induced double strand breaks—is orchestrated mainly by three Phosphatidylinositol 3-kinase-related kinases (PIKKs): Ataxia teleangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK) and ATM and Rad3-related kinase (ATR). Their activation promotes cell-cycle arrest and facilitates DNA damage repair, resulting in radioresistance. Recently developed specific ATR inhibitor, VE-821 (3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide), has been reported to have a significant radio- and chemo-sensitizing effect delimited to cancer cells (largely p53-deficient) without affecting normal cells. In this study, we employed SILAC-based quantitative phosphoproteomics to describe the mechanism of the radiosensitizing effect of VE-821 in human promyelocytic leukemic cells HL-60 (p53-negative). Hydrophilic interaction liquid chromatography (HILIC)-prefractionation with TiO2-enrichment and nano-liquid chromatography—tandem mass spectrometry (LC-MS/MS) analysis revealed 9834 phosphorylation sites. Proteins with differentially up-/down-regulated phosphorylation were mostly localized in the nucleus and were involved in cellular processes such as DDR, all phases of the cell cycle, and cell division. Moreover, sequence motif analysis revealed significant changes in the activities of kinases involved in these processes. Taken together, our data indicates that ATR kinase has multiple roles in response to DNA damage throughout the cell cycle and that its inhibitor VE-821 is a potent radiosensitizing agent for p53-negative HL-60 cells. PMID:25003641

  5. Dipeptidyl Peptidase-4 Inhibitor Increases Vascular Leakage in Retina through VE-cadherin Phosphorylation

    PubMed Central

    Lee, Choon-Soo; Kim, Yun Gi; Cho, Hyun-Jai; Park, Jonghanne; Jeong, Heewon; Lee, Sang-Eun; Lee, Seung-Pyo; Kang, Hyun-Jae; Kim, Hyo-Soo

    2016-01-01

    The inhibitors of CD26 (dipeptidyl peptidase-4; DPP4) have been widely prescribed to control glucose level in diabetic patients. DPP4-inhibitors, however, accumulate stromal cell-derived factor-1α (SDF-1α), a well-known inducer of vascular leakage and angiogenesis both of which are fundamental pathophysiology of diabetic retinopathy. The aim of this study was to investigate the effects of DPP4-inhibitors on vascular permeability and diabetic retinopathy. DPP4-inhibitor (diprotin A or sitagliptin) increased the phosphorylation of Src and vascular endothelial-cadherin (VE-cadherin) in human endothelial cells and disrupted endothelial cell-to-cell junctions, which were attenuated by CXCR4 (receptor of SDF-1α)-blocker or Src-inhibitor. Disruption of endothelial cell-to-cell junctions in the immuno-fluorescence images correlated with the actual leakage of the endothelial monolayer in the transwell endothelial permeability assay. In the Miles assay, vascular leakage was observed in the ears into which SDF-1α was injected, and this effect was aggravated by DPP4-inhibitor. In the model of retinopathy of prematurity, DPP4-inhibitor increased not only retinal vascularity but also leakage. Additionally, in the murine diabetic retinopathy model, DPP4-inhibitor increased the phosphorylation of Src and VE-cadherin and aggravated vascular leakage in the retinas. Collectively, DPP4-inhibitor induced vascular leakage by augmenting the SDF-1α/CXCR4/Src/VE-cadherin signaling pathway. These data highlight safety issues associated with the use of DPP4-inhibitors. PMID:27381080

  6. Dipeptidyl Peptidase-4 Inhibitor Increases Vascular Leakage in Retina through VE-cadherin Phosphorylation.

    PubMed

    Lee, Choon-Soo; Kim, Yun Gi; Cho, Hyun-Jai; Park, Jonghanne; Jeong, Heewon; Lee, Sang-Eun; Lee, Seung-Pyo; Kang, Hyun-Jae; Kim, Hyo-Soo

    2016-01-01

    The inhibitors of CD26 (dipeptidyl peptidase-4; DPP4) have been widely prescribed to control glucose level in diabetic patients. DPP4-inhibitors, however, accumulate stromal cell-derived factor-1α (SDF-1α), a well-known inducer of vascular leakage and angiogenesis both of which are fundamental pathophysiology of diabetic retinopathy. The aim of this study was to investigate the effects of DPP4-inhibitors on vascular permeability and diabetic retinopathy. DPP4-inhibitor (diprotin A or sitagliptin) increased the phosphorylation of Src and vascular endothelial-cadherin (VE-cadherin) in human endothelial cells and disrupted endothelial cell-to-cell junctions, which were attenuated by CXCR4 (receptor of SDF-1α)-blocker or Src-inhibitor. Disruption of endothelial cell-to-cell junctions in the immuno-fluorescence images correlated with the actual leakage of the endothelial monolayer in the transwell endothelial permeability assay. In the Miles assay, vascular leakage was observed in the ears into which SDF-1α was injected, and this effect was aggravated by DPP4-inhibitor. In the model of retinopathy of prematurity, DPP4-inhibitor increased not only retinal vascularity but also leakage. Additionally, in the murine diabetic retinopathy model, DPP4-inhibitor increased the phosphorylation of Src and VE-cadherin and aggravated vascular leakage in the retinas. Collectively, DPP4-inhibitor induced vascular leakage by augmenting the SDF-1α/CXCR4/Src/VE-cadherin signaling pathway. These data highlight safety issues associated with the use of DPP4-inhibitors. PMID:27381080

  7. Effects of Risperidone on Cytokine Profile in Drug-Naïve First-Episode Psychosis

    PubMed Central

    Noto, Cristiano; Ota, Vanessa Kiyomi; Gouvea, Eduardo S.; Rizzo, Lucas B.; Spindola, Leticia M. N.; Honda, Pedro H. S.; Cordeiro, Quirino; Belangero, Sintia Iole; Bressan, Rodrigo Affonseca; Gadelha, Ary; Maes, Michael

    2015-01-01

    Background: There is robust evidence that schizophrenia is characterized by immune-inflammatory abnormalities, including variations on cytokine levels. The results of previous studies, however, are heterogeneous due to several confounding factors, such as the effects of antipsychotic drugs. Therefore, research on drug-naïve first-episode psychosis (FEP) patients is essential to elucidate the role of immune processes in that disorder. Methods: The aim of this study is to compare cytokine levels (IL-2, IL-10, IL-4, IL-6, IFN-γ, TNF-α, and IL-17) in drug-naïve FEP patients both before and after treatment with risperidone for 10 weeks, and to investigate possible associations between cytokine levels and clinical responses to treatment and presence of depressive symptoms. It this study, we included 55 drug-naïve FEP patients who had repeated measurements of cytokine levels and 57 healthy controls. Results: We found that FEP patients had significantly higher IL-6, IL-10 and TNF-α levels than healthy controls. After risperidone treatment, these three cytokines and additionally IL-4 decreased significantly. No significant difference was found between the post-treatment cytokine levels in FEP patients and in healthy controls, suggesting that these alterations in cytokine profiles are a state marker of FEP. No significant association was found between risperidone-induced changes in cytokines and the clinical response to treatment or the presence of depression. There was a significant inverse association between the risperidone-induced changes in IL-10 and the negative symptoms. Conclusions: In conclusion, our results show a specific cytokine profile in FEP patients (monocytic and regulatory T-cell activation) and suggest immunoregulatory effects of risperidone treatment, characterized by suppressant effects on monocytic, Th2, and T-regulatory functions. PMID:25522386

  8. Research on micro-blog character analysis based on Naïve Bayes

    NASA Astrophysics Data System (ADS)

    Liu, Yun; Liu, Tong; Wang, Yanbo J.

    2015-07-01

    With the development of Information Technology, people have entered the era of Big Data, and the demand for intelligent information is more intense. How to make computer provide more personalized and efficient service for all walks of life, is something worth exploring. In this paper, we aim to predict user's character by analyzing the textual content of his/her micro-blog, which is the foundation of Personalized Service. Our study describes the method of creating a prediction model about user's character by using Bayesian algorithms. Experimental results show that the Naïve Bayes approach is a valid and promoted analytic method in micro-blog character analysis.

  9. Aluminum-Oxide Temperatures on the Mark VB, VE, VR, 15, and Mark 25 Assemblies

    SciTech Connect

    Aleman, S.E.

    2001-07-17

    The task was to compute the maximum aluminum-oxide and oxide-coolant temperatures of assemblies cladded in 99+ percent aluminum. The assemblies considered were the Mark VB, VE, V5, 15 and 25. These assemblies consist of nested slug columns with individual uranium slugs cladded in aluminum cans. The CREDIT code was modified to calculate the oxide film thickness and the aluminum-oxide temperature at each axial increment. This information in this report will be used to evaluate the potential for cladding corrosion of the Mark 25 assembly.

  10. Aluminum-Oxide Temperatures on the Mark VB, VE, VR, 15, and Mark 25 Assemblies

    SciTech Connect

    Aleman, S.E.

    2001-07-17

    The task was to compute the maximum aluminum-oxide and oxide-coolant temperatures of assemblies cladded in 99 plus percent aluminum. The assemblies considered were the Mark VB, VE, V5, 15 and 25. These assemblies consist of nested slug columns with individual uranium slugs cladded in aluminum cans. The CREDIT code was modified to calculate the oxide film thickness and the aluminum-oxide temperature at each axial increment. The information in this report will be used to evaluate the potential for cladding corrosion of the Mark 25 assembly.

  11. Endocrine therapy for hormone treatment-naïve advanced breast cancer.

    PubMed

    Martin, Miguel; Lopez-Tarruella, Sara; Gilarranz, Yolanda Jerez

    2016-08-01

    A proportion of patients with hormone receptor-positive locally advanced or metastatic breast cancer will not have received prior endocrine therapy. However, there are limited clinical data specifically in these patients. We conducted a review of randomized phase II and III clinical studies of anastrozole, letrozole, exemestane, palbociclib, and fulvestrant to determine the evidence base supporting use of specific endocrine therapies in this patient population. From our findings, there is a paucity of clinical studies in patients with endocrine therapy-naïve disease; however, it appears that first-line treatment effects are consistent between patients who have and have not received prior endocrine treatment. PMID:27326977

  12. Hilbert-space Karhunen-Loève transform with application to image analysis.

    PubMed

    Levy, A; Rubinstein, J

    1999-01-01

    A generalization of the Karhunen-Loève (KL) transform to Hilbert spaces is developed. It allows one to find the best low-dimensional approximation of an ensemble of images with respect to a variety of distance functions other than the traditional mean square error (L2 norm). A simple and intuitive characterization of the family of Hilbert norms in finite-dimensional spaces leads to an algorithm for calculating the Hilbert-KL expansion. KL approximations of ensembles of objects and faces optimized with respect to a norm based on the modulation transfer function of the human visual system are compared with the standard L2 approximations. PMID:9919692

  13. A naïve Gaussian Bayes classifier for detection of mental activity in gait signature.

    PubMed

    Joshi, Deepak; Mishra, A; Anand, Sneh

    2012-01-01

    A probabilistic modelling is presented to detect mental activity from gait signature recorded from healthy subjects. The proposed scheme is based on principal component analysis with reduced feature dimension followed by a naïve Gaussian Bayes classifier. The leave-one-out cross-validation shows the detection accuracy of 94% with specificity and sensitivity of 96% and 98.3%, respectively. The research has a potential application in the prevention of elderly risk falls, lie detection and rehabilitation among Parkinson's patients. PMID:21978095

  14. Thermoresponsive hydrogel maintains the mouse embryonic stem cell "naïve" pluripotency phenotype.

    PubMed

    Mangani, Christian; Lilienkampf, Annamaria; Roy, Marcia; de Sousa, Paul A; Bradley, Mark

    2015-10-15

    A chemically defined thermoresponsive hydrogel, poly(AEtMA-Cl-co-DEAEA) cross-linked with N,N'-methylenebisacrylamide, which allows enzyme-free passaging, was used as a substrate to culture murine embryonic stem cells (mESCs) under defined and undefined conditions. Analysis of 14 stem cell markers showed that the mESCs remained in a "naïve" state of pluripotency with differentiation potential to form endoderm, mesoderm, and ectoderm derived lineages. These results validate the use of a chemically defined hydrogel for standardised and inexpensive mESC culture. PMID:26372076

  15. [Efficacy of dolutegravir in treatment-naïve patients. The SPRING-1, SPRING-2, SINGLE and FLAMINGO trials].

    PubMed

    Bernardino, José I; Antela, Antonio

    2015-03-01

    The efficacy of dolutegravir (DTG) in treatment-naïve patients has been analyzed in the SPRING 1 and 2, SINGLE and FLAMINGO trials, which compared dolutegravir with the agents currently recommended as the drugs of choice in clinical practice guidelines in treatment-naïve patients: efavirenz, raltegravir and darunavir/ritonavir. These trials confirmed the superiority (SINGLE and FLAMINGO) or the non-inferiority (SPRING-2) of dolutegravir. More than 2,000 patients were included in these 4 studies, lending value to their results and reinforcing the view of dolutegravir as the drug of choice in treatment-naïve patients, accompanied either by abacavir/lamivudine (Kivexa(®)) or tenofovir/emtricitabine (Truvada®). PMID:25858607

  16. The metabolome regulates the epigenetic landscape during naïve to primed human embryonic stem cell transition

    PubMed Central

    Sperber, Henrik; Mathieu, Julie; Wang, Yuliang; Ferreccio, Amy; Hesson, Jennifer; Xu, Zhuojin; Fischer, Karin A.; Devi, Arikketh; Detraux, Damien; Gu, Haiwei; Battle, Stephanie L.; Showalter, Megan; Valensisi, Cristina; Bielas, Jason H.; Ericson, Nolan G.; Margaretha, Lilyana; Robitaille, Aaron M.; Margineantu, Daciana; Fiehn, Oliver; Hockenbery, David; Blau, C. Anthony; Raftery, Daniel; Margolin, Adam; Hawkins, R. David; Moon, Randall T.; Ware, Carol B.; Ruohola-Baker, Hannele

    2015-01-01

    For nearly a century developmental biologists have recognized that cells from embryos can differ in their potential to differentiate into distinct cell types. Recently, it has been recognized that embryonic stem cells derived from both mice and humans display two stable yet epigenetically distinct states of pluripotency, naïve and primed. We now show that nicotinamide-N-methyl transferase (NNMT) and metabolic state regulate pluripotency in hESCs. Specifically, in naïve hESCs NNMT and its enzymatic product 1-methylnicotinamide (1-MNA) are highly upregulated, and NNMT is required for low SAM levels and H3K27me3 repressive state. NNMT consumes SAM in naïve cells, making it unavailable for histone methylation that represses Wnt and activates HIF pathway in primed hESCs. These data support the hypothesis that the metabolome regulates the epigenetic landscape of the earliest steps in human development. PMID:26571212

  17. Karhunen-Loève expansion revisited for vector-valued random fields: Scaling, errors and optimal basis.

    NASA Astrophysics Data System (ADS)

    Perrin, G.; Soize, C.; Duhamel, D.; Funfschilling, C.

    2013-06-01

    Due to scaling effects, when dealing with vector-valued random fields, the classical Karhunen-Loève expansion, which is optimal with respect to the total mean square error, tends to favorize the components of the random field that have the highest signal energy. When these random fields are to be used in mechanical systems, this phenomenon can introduce undesired biases for the results. This paper presents therefore an adaptation of the Karhunen-Loève expansion that allows us to control these biases and to minimize them. This original decomposition is first analyzed from a theoretical point of view, and is then illustrated on a numerical example.

  18. Regulation of leukocyte tricarboxylic acid cycle in drug-naïve Bipolar Disorder.

    PubMed

    de Sousa, Rafael T; Streck, Emilio L; Forlenza, Orestes V; Brunoni, Andre R; Zanetti, Marcus V; Ferreira, Gabriela K; Diniz, Breno S; Portela, Luis V; Carvalho, André F; Zarate, Carlos A; Gattaz, Wagner F; Machado-Vieira, Rodrigo

    2015-09-25

    Several lines of evidence suggest a role for mitochondrial dysfunction in the pathophysiology of bipolar disorder (BD). The tricarboxylic acid cycle (TCA cycle) is fundamental for mitochondrial energy production and produces substrates used in oxidative phosphorylation by the mitochondrial electron transport chain. The activity of the key TCA cycle enzymes citrate synthase, malate dehydrogenase, and succinate dehydrogenase has never been evaluated in BD. In the present study, these enzymes were assayed from leukocytes of drug-naïve BD patients in a major depressive episode (n=18) and compared to 24 age-matched healthy controls. Drug-naïve BD patients did not show differences in activities of citrate synthase (p=0.79), malate dehydrogenase (p=0.17), and succinate dehydrogenase (p=0.35) compared with healthy controls. No correlation between any TCA cycle enzyme activity and severity of depressive symptoms was observed. Overall, these data suggest that the activities of the TCA cycle enzymes are not altered in major depressive episodes of recent-onset BD, which may support the concept of illness staging and neuroprogression in BD. PMID:26297865

  19. Towards the Integration of APECS and VE-Suite for Virtual Power Plant Co-Simulation

    SciTech Connect

    Zitney, S.E.; McCorkle, D.; Yang, C.; Jordan, T.; Swensen, D.; Bryden, M.

    2007-05-01

    Process modeling and simulation tools are widely used for the design and operation of advanced power generation systems. These tools enable engineers to solve the critical process systems engineering problems that arise throughout the lifecycle of a power plant, such as designing a new process, troubleshooting a process unit or optimizing operations of the full process. To analyze the impact of complex thermal and fluid flow phenomena on overall power plant performance, the Department of Energy’s (DOE) National Energy Technology Laboratory (NETL) has developed the Advanced Process Engineering Co-Simulator (APECS). The APECS system is an integrated software suite that combines process simulation (e.g., Aspen Plus) and high-fidelity equipment simulations such as those based on computational fluid dynamics (CFD), together with advanced analysis capabilities including case studies, sensitivity analysis, stochastic simulation for risk/uncertainty analysis, and multi-objective optimization. In this paper we discuss the initial phases of the integration of the APECS system with the immersive and interactive virtual engineering software, VE-Suite, developed at Iowa State University and Ames Laboratory. VE-Suite uses the ActiveX (OLE Automation) controls in the Aspen Plus process simulator wrapped by the CASI library developed by Reaction Engineering International to run process/CFD co-simulations and query for results. This integration represents a necessary step in the development of virtual power plant co-simulations that will ultimately reduce the time, cost, and technical risk of developing advanced power generation systems.

  20. HyVE: hybrid vibro-electrotactile stimulation for sensory feedback and substitution in rehabilitation.

    PubMed

    D'Alonzo, Marco; Dosen, Strahinja; Cipriani, Christian; Farina, Dario

    2014-03-01

    Electro- or vibro-tactile stimulations were used in the past to provide sensory information in many different applications ranging from human manual control to prosthetics. The two modalities were used separately in the past, and we hypothesized that a hybrid vibro-electrotactile (HyVE) stimulation could provide two afferent streams that are independently perceived by a subject, although delivered in parallel and through the same skin location. We conducted psychophysical experiments where healthy subjects were asked to recognize the intensities of electroand vibro-tactile stimuli during hybrid and single modality stimulations. The results demonstrated that the subjects were able to discriminate the features of the two modalities within the hybrid stimulus, and that the cross-modality interaction was limited enough to allow better transmission of discrete information (messages) using hybrid versus singlemodality coding. The percentages of successful recognitions (mean ± standard deviation) for nine messages were 56 ± 11 % and 72 ± 8 % for two hybrid coding schemes, compared to 29 ±7 % for vibrotactile and 44 ± 4 % for electrotactile coding. The HyVE can be therefore an attractivesolution in numerous application for providing sensory feedbackin prostheses and rehabilitation, and it could be used to increase the resolution of a single variable or to simultaneously feedback two different variables. PMID:23782817

  1. Cerebellar volume deficits in medication-naïve obsessive compulsive disorder.

    PubMed

    Narayanaswamy, Janardhanan C; Jose, Dania; Kalmady, Sunil V; Agarwal, Sri Mahavir; Venkatasubramanian, Ganesan; Janardhan Reddy, Y C

    2016-08-30

    Even though conventional neurobiological models of obsessive compulsive disorder (OCD) commonly demonstrate abnormalities involving fronto-striatal circuits, there is emerging evidence regarding the role of posterior brain structures such as cerebellum. In this study, we examined the cerebellar regional volume in a large sample of medication-naïve OCD patients compared to matched healthy controls (HC). In 49 medication naïve right handed OCD patients and 39 age and sex matched HC, sub-region wise volume of cerebellum was extracted from the T1 weighted images using Spatially Unbiased Infra tentorial Template (SUIT) toolbox and compared using hypothesis driven, region of interest approach after clinical assessment with standard scales. After controlling for age, sex and ICV, the subjects with OCD had significantly smaller cerebellum compared to HC, especially in the posterior lobe sub-regions - lobule VI and left crus 1. This study gives preliminary evidence for region specific cerebellar volumetric deficits in the pathophysiological of OCD. Regional cerebellar volume deficits conform to the abnormal connectivity of cerebellum to specific cortical regions and it is indicative of involvement of regions outside the conventional fronto-striatal circuitry. This might be important in the context of cognitive deficits seen in OCD. PMID:27454206

  2. Single and paired pulse transcranial magnetic stimulation in drug naïve epilepsy.

    PubMed

    de Goede, Annika A; Ter Braack, Esther M; van Putten, Michel J A M

    2016-09-01

    Transcranial magnetic stimulation (TMS) measures cortical excitability and is therefore potentially suitable as an additional tool for epilepsy diagnostics and therapy evaluation. In this review we discuss the application of TMS in epilepsy research and systematically analyze single and paired pulse TMS outcomes from 31 drug naïve patient studies. Despite a large variety in used TMS protocols, there was no relation between specific protocol aspects and the occurrence of significant results. Protocols were often not in accordance with latest guidelines and recommendations. Cortical excitability, as measured by TMS, was increased in drug naïve epilepsy patients, being most prominent for generalized epilepsy. Single pulse TMS indicated a trend towards a lower resting motor threshold (rMT) and a prolonged cortical silent period (CSP) for generalized epilepsy, while inconclusive results were found for focal epilepsy. The paired pulse TMS outcomes, short intracortical inhibition (SICI) and long intracortical inhibition (LICI), showed the most consistent significant increase in cortical excitability in generalized and focal epilepsy patients. Future epilepsy research should especially focus on the interstimulus intervals 2 and 5ms for SICI, and 250 and 300ms for LICI. Furthermore, combining TMS with electroencephalography (EEG) may contribute to analysis on an individual patient level. PMID:27472551

  3. Karhunen-Loève basis of Kolmogorov phase screens covering a rectangular stripe

    NASA Astrophysics Data System (ADS)

    Mathar, Richard J.

    2010-01-01

    Karhunen-Loève functions are statistically independent base functions to be multiplied with randomized coefficients to generate instances of the underlying statistics with specific covariances. In the context of numerical simulation of atmospheric turbulence, they are tools to generate phase distributions in the input pupil of telescope optics. Within the Taylor frozen screen approximation, the favorable geometry of phase screens is a stripe as wide as the telescope diameter, but much longer. A phase screen movie is generated by dragging the stripe across the telescope pupil. The aim is to avoid the wasteful alternative of cutting through a virtual circular phase screen with a diameter equal to the stripe's length. We calculate Karhunen-Loève functions over rectangular stripes by solving the well-known integral equation for isotropic variance of the phase distribution. They are expanded in products of Legendre functions along the two Cartesian coordinates, represented by spherical Bessel functions in Fourier space. The rectangular shape of the integral's domain breaks the symmetry of the structure function. Yet, the matrix elements of the eigenvalue equation can be calculated by separating the primitive Cartesian basis via a Neumann series of radial and azimuthal terms.

  4. The ontogeny of naïve and regulatory CD4+ T-cell subsets during the first postnatal year: a cohort study

    PubMed Central

    Collier, Fiona M; Tang, Mimi L K; Martino, David; Saffery, Richard; Carlin, John; Jachno, Kim; Ranganathan, Sarath; Burgner, David; Allen, Katrina J; Vuillermin, Peter; Ponsonby, Anne-Louise

    2015-01-01

    As there is limited knowledge regarding the longitudinal development and early ontogeny of naïve and regulatory CD4+ T-cell subsets during the first postnatal year, we sought to evaluate the changes in proportion of naïve (thymic and central) and regulatory (resting and activated) CD4+ T-cell populations during the first postnatal year. Blood samples were collected and analyzed at birth, 6 and 12 months of age from a population-derived sample of 130 infants. The proportion of naïve and regulatory CD4+ T-cell populations was determined by flow cytometry, and the thymic and central naïve populations were sorted and their phenotype confirmed by relative expression of T cell-receptor excision circle DNA (TREC). At birth, the majority (94%) of CD4+ T cells were naïve (CD45RA+), and of these, ~80% had a thymic naïve phenotype (CD31+ and high TREC), with the remainder already central naïve cells (CD31− and low TREC). During the first year of life, the naïve CD4+ T cells retained an overall thymic phenotype but decreased steadily. From birth to 6 months of age, the proportion of both resting naïve T regulatory cells (rTreg; CD4+CD45RA+FoxP3+) and activated Treg (aTreg, CD4+CD45RA−FoxP3high) increased markedly. The ratio of thymic to central naïve CD4+ T cells was lower in males throughout the first postnatal year indicating early sexual dimorphism in immune development. This longitudinal study defines proportions of CD4+ T-cell populations during the first year of postnatal life that provide a better understanding of normal immune development. PMID:25859389

  5. Type 1 interferon licenses naïve CD8 T cells to mediate anti-viral cytotoxicity.

    PubMed

    Urban, Stina L; Berg, Leslie J; Welsh, Raymond M

    2016-06-01

    Naïve T cells, unlike memory T cells, exhibit very limited effector function in response to cognate antigen, but exposure to type 1 interferon (IFN) prior to cognate antigen allows for rapid manifestation of effector functions. A full assessment of the functions of these IFN-sensitized otherwise naïve T cells has not been made, nor has their capacity to be effector cells in vivo. We describe here that IFN-sensitized naïve T cells in the absence of cognate antigen adopt a partial activated phenotype distinguished by the upregulation of the surface activation marker CD69, effector-associated transcription factors Eomes and IRF4, and cytotoxicity effector molecule granzyme B. IFN-sensitized naive T cells lysed target cells in vivo and responded to low concentrations and affinities of cognate ligands. We suggest that this rapid and sensitive effector function of IFN-conditioned naïve CD8 T cells may play a role in pathogen control and help ward off superinfections. PMID:26999026

  6. The Naïve and the Distrustful: state dependency of hippocampal computations in manipulative memory distortion.

    PubMed

    Ludmer, Rachel; Edelson, Micah G; Dudai, Yadin

    2015-02-01

    Flexible mnemonic mechanisms that adjust to different internal mental states can provide a major adaptive advantage. However, little is known regarding how this flexibility is achieved in the human brain. We examined brain activity during retrieval of false memories of a movie, generated by exposing participants to misleading information. Half of the participants suspected the memory manipulation (Distrustful), whereas the other half did not (Naïve). Distrustful displayed more accurate memory performance and a brain signature different than that of Naïve. In Distrustful, the ability to differentiate true from false information was driven by a qualitatively distinct hippocampal activity for endorsed items, consistent with the view that hippocampal encoding allows recollection of a specific source. Conversely, in Naïve, BOLD differences between true and false memories were linearly correlated with accuracy across participants, suggesting that Naïve subjects needed to reinstate and evaluate stored information to discern true from false. We propose that our results lend support to models suggesting that hippocampal activity can exhibit different computational schemes, depending on memorandum attributes. Furthermore, we show that trust, considered as a subjective state of mind, may alter basic hippocampal strategies, influencing the ability to separate real from false memory. PMID:25242726

  7. Isolation of Flavimonas oryzihabitans (CDC group Ve-2) from catheter-induced bacteremia in an immunocompromised patient.

    PubMed

    Mutters, R; Köppler, H; Krause, T

    1990-12-01

    Bacteria of the newly proposed genus and combination Flavimonas oryzihabitans, previously known as CDC group Ve-2 or Pseudomonas oryzihabitans, are uncommon pathogens. We report here the first isolation of the organism in Germany from a case of bacteremia and describe the phenotypic characteristics of the strain. PMID:2091948

  8. Elucidation of veA Dependent Genes Associated with Aflatoxin and Sclerotial Production in Aspergillus flavus by Functional Genomics

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The aflatoxin-producing fungi, Aspergillus flavus and A. parasiticus, form structures called sclerotia that allow for survival under adverse conditions. Deletion of the veA gene in A. flavus and A. parasiticus blocks production of aflatoxin, as well as sclerotial formation. We used microarray tech...

  9. The Communication of Naïve Theories of the Social World in Parent-Child Conversation

    ERIC Educational Resources Information Center

    Chalik, Lisa; Rhodes, Marjorie

    2015-01-01

    Three studies examined the communication of naïve theories of social groups in conversations between parents and their 4-year-old children (N = 48). Parent-child dyads read and discussed a storybook in which they either explained why past social interactions had occurred (Study 1) or evaluated whether future social interactions should occur…

  10. Tomato immune receptor Ve1 recognizes effector of multiple fungal pathogens uncovered by genome and RNA sequencing

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fungal plant pathogens secrete effector molecules to establish disease on their hosts, while plants in turn utilize immune receptors to intercept these effectors. The tomato immune receptor Ve1 governs resistance to race 1 strains of the soil-borne vascular wilt fungi Verticillium dahliae and V. alb...

  11. The Public's View of Agricultural Education: We've Come a Long Way--Or Have We?

    ERIC Educational Resources Information Center

    Krueger, David E.; And Others

    1995-01-01

    Includes "We've Come a Long Way--Or Have We?" (Krueger); "If Agricultural Education Were a Coca-Cola" (Doerfert); "Agriculture Is Taught? In High School?" (Elliot); "Let's Tell Our Story" (Davis); "Perception, Reality or Idealism" (Powers, Bull); "Agricultural Education under the Bright Lights" (Foster); and "The Changing Face of Agricultural…

  12. The veA gene of the pine needle pathogen Dothistroma septosporum regulates sporulation and secondary metabolism

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fungi possess genetic systems to regulate the expression of genes involved in complex processes such as development and secondary metabolite biosynthesis. The product of the velvet gene veA, first identified and characterized in Aspergillus nidulans, is a key player in the regulation of both of thes...

  13. Antibody Profiling in Naïve and Semi-immune Individuals Experimentally Challenged with Plasmodium vivax Sporozoites

    PubMed Central

    Arévalo-Herrera, Myriam; Lopez-Perez, Mary; Dotsey, Emmanuel; Jain, Aarti; Rubiano, Kelly; Felgner, Philip L.; Davies, D. Huw; Herrera, Sócrates

    2016-01-01

    Background Acquisition of malaria immunity in low transmission areas usually occurs after relatively few exposures to the parasite. A recent Plasmodium vivax experimental challenge trial in malaria naïve and semi-immune volunteers from Colombia showed that all naïve individuals developed malaria symptoms, whereas semi-immune subjects were asymptomatic or displayed attenuated symptoms. Sera from these individuals were analyzed by protein microarray to identify antibodies associated with clinical protection. Methodology/Principal Findings Serum samples from naïve (n = 7) and semi-immune (n = 9) volunteers exposed to P. vivax sporozoite-infected mosquito bites were probed against a custom protein microarray displaying 515 P. vivax antigens. The array revealed higher serological responses in semi-immune individuals before the challenge, although malaria naïve individuals also had pre-existing antibodies, which were higher in Colombians than US adults (control group). In both experimental groups the response to the P. vivax challenge peaked at day 45 and returned to near baseline at day 145. Additional analysis indicated that semi-immune volunteers without fever displayed a lower response to the challenge, but recognized new antigens afterwards. Conclusion Clinical protection against experimental challenge in volunteers with previous P. vivax exposure was associated with elevated pre-existing antibodies, an attenuated serological response to the challenge and reactivity to new antigens. PMID:27014875

  14. Feeding preferences of experienced and naïve goats and sheep for the toxic plant Ipomoea carnea subsp. fistulosa

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ipomoea carnea is a toxic plant that grazing goats and cattle may learn to ingest with repeated exposure. The objective of this study was to evaluate the feeding preferences of experienced and non-experienced (naïve) goats and sheep for I. carnea. The study used 3 groups of 5 goats (Group 1, experi...

  15. In Vitro Priming of Naı̈ve T-cells with p-Phenylenediamine and Bandrowski's Base.

    PubMed

    Gibson, Andrew; Kim, Seung-Hyun; Faulkner, Lee; Evely, Jane; Pirmohamed, Munir; Park, Kevin B; Naisbitt, Dean J

    2015-10-19

    p-Phenylenediamine (PPD) is a component of hair dye formulations that is associated with T-cell mediated allergic contact dermatitis. Antigen-specific T-cells from allergic contact dermatitis patients are activated with either PPD or the oxidation product, Bandrowski's base. In nonallergic individuals, T-cells that are activated by Bandrowski's base, but not by PPD, are readily detectable. The aim of the current study was to use an in vitro T-cell priming assay to assess the activation of memory and naı̈ve T-cells from healthy donors with PPD and Bandrowski's base, and to compare these responses to those observed from allergic patients. Both PPD and Bandrowski's base-responsive clones were generated from allergic patients. The majority of Bandrowski's base-responsive clones were CD4+ and displayed a lack of PPD reactivity. In contrast, CD4+ and CD8+ clones displaying PPD reactivity were detected. Approximately 25% of these displayed low levels of reactivity to Bandrowski's base. Clones from the allergic patients secreted a range of cytokines including IFN-γ, Il-13, and Il-22. In healthy donors, Bandrowski's base-specific T-cell proliferative responses and cytokine secretion were detected with both naı̈ve and memory T-cells. T-cell clones generated from the Bandrowski's base-responsive cultures responded to Bandrowski's base but not PPD. PPD-specific naı̈ve and memory T-cell responses were not detected from healthy donors. These data show that Bandrowski's base stimulates pre-existing memory T-cells isolated from healthy donors and primes naı̈ve T-cells when the chemical is bound to autologous dendritic cells. Priming naı̈ve T-cells against PPD failed, suggesting an important individual susceptibility factor is missing from the in vitro T-cell priming assay. PMID:26355666

  16. Tomato immune receptor Ve1 recognizes effector of multiple fungal pathogens uncovered by genome and RNA sequencing

    PubMed Central

    de Jonge, Ronnie; Peter van Esse, H.; Maruthachalam, Karunakaran; Bolton, Melvin D.; Santhanam, Parthasarathy; Saber, Mojtaba Keykha; Zhang, Zhao; Usami, Toshiyuki; Lievens, Bart; Subbarao, Krishna V.; Thomma, Bart P. H. J.

    2012-01-01

    Fungal plant pathogens secrete effector molecules to establish disease on their hosts, and plants in turn use immune receptors to try to intercept these effectors. The tomato immune receptor Ve1 governs resistance to race 1 strains of the soil-borne vascular wilt fungi Verticillium dahliae and Verticillium albo-atrum, but the corresponding Verticillium effector remained unknown thus far. By high-throughput population genome sequencing, a single 50-Kb sequence stretch was identified that only occurs in race 1 strains, and subsequent transcriptome sequencing of Verticillium-infected Nicotiana benthamiana plants revealed only a single highly expressed ORF in this region, designated Ave1 (for Avirulence on Ve1 tomato). Functional analyses confirmed that Ave1 activates Ve1-mediated resistance and demonstrated that Ave1 markedly contributes to fungal virulence, not only on tomato but also on Arabidopsis. Interestingly, Ave1 is homologous to a widespread family of plant natriuretic peptides. Besides plants, homologous proteins were only found in the bacterial plant pathogen Xanthomonas axonopodis and the plant pathogenic fungi Colletotrichum higginsianum, Cercospora beticola, and Fusarium oxysporum f. sp. lycopersici. The distribution of Ave1 homologs, coincident with the presence of Ave1 within a flexible genomic region, strongly suggests that Verticillium acquired Ave1 from plants through horizontal gene transfer. Remarkably, by transient expression we show that also the Ave1 homologs from F. oxysporum and C. beticola can activate Ve1-mediated resistance. In line with this observation, Ve1 was found to mediate resistance toward F. oxysporum in tomato, showing that this immune receptor is involved in resistance against multiple fungal pathogens. PMID:22416119

  17. CRSBP-1/LYVE-1 ligands disrupt lymphatic intercellular adhesion by inducing tyrosine phosphorylation and internalization of VE-cadherin

    PubMed Central

    Hou, Wei-Hsien; Liu, I-Hua; Tsai, Cheng C.; Johnson, Frank E.; Huang, Shuan Shian; Huang, Jung San

    2011-01-01

    Cell-surface retention sequence (CRS) binding protein (CRSBP-1) is a membrane glycoprotein identified by its ability to bind PDGF-BB and VEGF-A via their CRS motifs (clusters of basic amino acid residues). CRSBP-1 is identical to LYVE-1 and exhibits dual ligand (CRS-containing proteins and hyaluronic acid) binding activity, suggesting the importance of CRSBP-1 ligands in lymphatic function. Here, we show that CRSBP-1 ligands induce disruption of VE-cadherin-mediated intercellular adhesion and opening of intercellular junctions in lymphatic endothelial cell (LEC) monolayers as determined by immunofluorescence microscopy and Transwell permeability assay. This occurs by interaction with CRSBP-1 in the CRSBP-1–PDGFβR–β-catenin complex, resulting in tyrosine phosphorylation of the complex, dissociation of β-catenin and p120-catenin from VE-cadherin, and internalization of VE-cadherin. Pretreatment of LECs with a PDGFβR kinase inhibitor abolishes ligand-stimulated tyrosine phosphorylation of VE-cadherin, halts the ligand-induced disruption of VE-cadherin intercellular adhesion and blocks the ligand-induced opening of intercellular junctions. These CRSBP-1 ligands also induce opening of lymphatic intercellular junctions that respond to PDGFβR kinase inhibitor in wild-type mice (but not in Crsbp1-null mice) as evidenced by increased transit of injected FITC–dextran and induced edema fluid from the interstitial space into lymphatic vessels. These results disclose a novel mechanism involved in the opening of lymphatic intercellular junctions. PMID:21444752

  18. Tomato immune receptor Ve1 recognizes effector of multiple fungal pathogens uncovered by genome and RNA sequencing.

    PubMed

    de Jonge, Ronnie; van Esse, H Peter; Maruthachalam, Karunakaran; Bolton, Melvin D; Santhanam, Parthasarathy; Saber, Mojtaba Keykha; Zhang, Zhao; Usami, Toshiyuki; Lievens, Bart; Subbarao, Krishna V; Thomma, Bart P H J

    2012-03-27

    Fungal plant pathogens secrete effector molecules to establish disease on their hosts, and plants in turn use immune receptors to try to intercept these effectors. The tomato immune receptor Ve1 governs resistance to race 1 strains of the soil-borne vascular wilt fungi Verticillium dahliae and Verticillium albo-atrum, but the corresponding Verticillium effector remained unknown thus far. By high-throughput population genome sequencing, a single 50-Kb sequence stretch was identified that only occurs in race 1 strains, and subsequent transcriptome sequencing of Verticillium-infected Nicotiana benthamiana plants revealed only a single highly expressed ORF in this region, designated Ave1 (for Avirulence on Ve1 tomato). Functional analyses confirmed that Ave1 activates Ve1-mediated resistance and demonstrated that Ave1 markedly contributes to fungal virulence, not only on tomato but also on Arabidopsis. Interestingly, Ave1 is homologous to a widespread family of plant natriuretic peptides. Besides plants, homologous proteins were only found in the bacterial plant pathogen Xanthomonas axonopodis and the plant pathogenic fungi Colletotrichum higginsianum, Cercospora beticola, and Fusarium oxysporum f. sp. lycopersici. The distribution of Ave1 homologs, coincident with the presence of Ave1 within a flexible genomic region, strongly suggests that Verticillium acquired Ave1 from plants through horizontal gene transfer. Remarkably, by transient expression we show that also the Ave1 homologs from F. oxysporum and C. beticola can activate Ve1-mediated resistance. In line with this observation, Ve1 was found to mediate resistance toward F. oxysporum in tomato, showing that this immune receptor is involved in resistance against multiple fungal pathogens. PMID:22416119

  19. Aberrant Development of Functional Connectivity among Resting State-Related Functional Networks in Medication-Naïve ADHD Children

    PubMed Central

    Choi, Jeewook; Jeong, Bumseok; Lee, Sang Won; Go, Hyo-Jin

    2013-01-01

    Objective The aim of this study was to investigate the compromised developmental trajectory of the functional connectivity among resting-state-related functional networks (RSFNs) in medication-naïve children with attention-deficit/hyperactivity disorder (ADHD). Subjects and Methods Using both independent component analysis and dual regression, subject-specific time courses of 12 RSFNs were extracted from both 20 medication-naïve children with ADHD, and 20 age and gender-matched control children showing typical development (TDC). Both partial correlation coefficients among the 12 RSFNs and a resting-state resource allocation index (rsRAI) of the salience network (SN) were entered into multiple linear regression analysis to investigate the compromised, age-related change in medication-naïve ADHD children. Finally, correlation analyses were performed between the compromised RSFN connections showing significant group-by-age interaction and rsRAI of SN or clinical variables. Results Medication-naïve ADHD subjects failed to show age-related increment of functional connectivity in both rsRAI of SN and two RSFN connections, SN-Sensory/motor and posterior default mode/precuneus network (pDMN/prec) – anterior DMN. Lower SN-Sensory/motor connectivity was related with higher scores on the ADHD Rating Scale, and with poor scores on the continuous performance test. The pDMN/prec-aDMN connectivity was positively related with rsRAI of SN. Conclusions Our results suggest that medication-naïve ADHD subjects may have delayed maturation of the two functional connections, SN-Sensory/Motor and aDMN-pDMN/prec. Interventions that enhance the functional connectivity of these two connections may merit attention as potential therapeutic or preventive options in both ADHD and TDC. PMID:24386219

  20. The P2Y2 Receptor Interacts with VE-Cadherin and VEGF Receptor-2 to Regulate Rac1 Activity in Endothelial Cells

    PubMed Central

    Liao, Zhongji; Cao, Chen; Wang, Jianjie; Huxley, Virginia H.; Baker, Olga; Weisman, Gary A.

    2015-01-01

    Vascular endothelial cadherin (VE-cadherin) mediates homophylic adhesion between endothelial cells and is an important regulator of angiogenesis, blood vessel permeability and leukocyte trafficking. Rac1, a member of the Rho family of GTPases, controls VE-cadherin adhesion by acting downstream of several growth factors, including angiopoietin-1 and vascular endothelial growth factor (VEGF). Here we show that UTP-induced activation of the Gq protein-coupled P2Y2 nucleotide receptor (P2Y2R) in human coronary artery endothelial cells (HCAECs) activated Rac1 and caused a transient complex to form between P2Y2R, VE-cadherin and VEGF receptor-2 (VEGFR-2). Knockdown of VE-cadherin expression with siRNA did not affect UTP-induced activation of extracellular signal-regulated kinases 1/2 (ERK1/2) but led to a loss of UTP-induced Rac1 activation and tyrosine phosphorylation of p120 catenin, a cytoplasmic protein known to interact with VE-cadherin. Activation of the P2Y2R by UTP also caused a prolonged interaction between p120 catenin and vav2 (a guanine nucleotide exchange factor for Rac) that correlated with the kinetics of UTP-induced tyrosine phosphorylation of p120 catenin and VE-cadherin. Inhibitors of VEGFR-2 (SU1498) or Src (PP2) significantly diminished UTP-induced Rac1 activation, tyrosine phosphorylation of p120 catenin and VE-cadherin, and association of the P2Y2R with VE-cadherin and p120 catenin with vav2. These findings suggest that the P2Y2R uses Src and VEGFR-2 to mediate association of the P2Y2R with VE-cadherin complexes in endothelial adherens junctions to activate Rac1. PMID:25657827

  1. Influenza-like illness surveillance on Twitter through automated learning of naïve language.

    PubMed

    Gesualdo, Francesco; Stilo, Giovanni; Agricola, Eleonora; Gonfiantini, Michaela V; Pandolfi, Elisabetta; Velardi, Paola; Tozzi, Alberto E

    2013-01-01

    Twitter has the potential to be a timely and cost-effective source of data for syndromic surveillance. When speaking of an illness, Twitter users often report a combination of symptoms, rather than a suspected or final diagnosis, using naïve, everyday language. We developed a minimally trained algorithm that exploits the abundance of health-related web pages to identify all jargon expressions related to a specific technical term. We then translated an influenza case definition into a Boolean query, each symptom being described by a technical term and all related jargon expressions, as identified by the algorithm. Subsequently, we monitored all tweets that reported a combination of symptoms satisfying the case definition query. In order to geolocalize messages, we defined 3 localization strategies based on codes associated with each tweet. We found a high correlation coefficient between the trend of our influenza-positive tweets and ILI trends identified by US traditional surveillance systems. PMID:24324799

  2. Synergistic potentiation of (-)-lomaiviticin A cytotoxicity by the ATR inhibitor VE-821.

    PubMed

    Colis, Laureen C; Herzon, Seth B

    2016-07-01

    (-)-Lomaiviticin A (1) is a cytotoxic bacterial metabolite that induces double-strand breaks in DNA. Here we show that the cytotoxicity of (-)-lomaiviticin A (1) is synergistically potentiated in the presence of VE-821 (7), an inhibitor of ataxia telangiectasia and Rad3-related protein (ATR). While 0.5nM 1 or 10μM 7 alone are non-lethal to K562 cells, co-incubation of the two leads to high levels of cell kill (81% and 94% after 24 and 48h, respectively). Mechanistic data indicate that cells treated with 1 and 7 suffer extensive DNA double-strand breaks and apoptosis. These data suggest combinations of 1 and 7 may be a valuable chemotherapeutic strategy. PMID:27177826

  3. Flavimonas oryzihabitans (Pseudomonas oryzihabitans; CDC group Ve-2) bacteremia in the immunocompromised host.

    PubMed

    Decker, C F; Simon, G L; Keiser, J F

    1991-03-01

    Flavimonas oryzihabitans, known previously as Pseudomonas oryzihabitans, and a member of the Centers for Disease Control group Ve-2, is a gram-negative organism that has rarely been implicated as a human pathogen. Flavimonas oryzihabitans appears to be a soil and saprophytic organism that survives in moist environments and is indigenous to rice paddles. To our knowledge, only seven cases of human infection caused by this organism have been reported; they involved four patients with bacteremia and three patients with peritonitis who were receiving continuous ambulatory peritoneal dialysis. In this report, we describe three immunocompromised patients with catheter-associated bacteremia: a patient with cancer, a patient with acquired immunodeficiency syndrome, and a patient with sickle cell disease. There is emerging clinical evidence that F oryzihabitans should be recognized as an organism that is capable of causing human disease, particularly in immunocompromised patients and with the increased usage of permanent catheters. PMID:2001143

  4. Influenza-Like Illness Surveillance on Twitter through Automated Learning of Naïve Language

    PubMed Central

    Gesualdo, Francesco; Stilo, Giovanni; Agricola, Eleonora; Gonfiantini, Michaela V.; Pandolfi, Elisabetta; Velardi, Paola; Tozzi, Alberto E.

    2013-01-01

    Twitter has the potential to be a timely and cost-effective source of data for syndromic surveillance. When speaking of an illness, Twitter users often report a combination of symptoms, rather than a suspected or final diagnosis, using naïve, everyday language. We developed a minimally trained algorithm that exploits the abundance of health-related web pages to identify all jargon expressions related to a specific technical term. We then translated an influenza case definition into a Boolean query, each symptom being described by a technical term and all related jargon expressions, as identified by the algorithm. Subsequently, we monitored all tweets that reported a combination of symptoms satisfying the case definition query. In order to geolocalize messages, we defined 3 localization strategies based on codes associated with each tweet. We found a high correlation coefficient between the trend of our influenza-positive tweets and ILI trends identified by US traditional surveillance systems. PMID:24324799

  5. Naïve impetus and Michotte's "tool effect": evidence from representational momentum.

    PubMed

    Hubbard, Timothy L; Favretto, Alessia

    2003-05-01

    Displacement in the remembered position of targets in displays based on Michotte's (1951/1991) tool effect paradigm was examined. Targets in tool effect displays exhibited less forward displacement than did otherwise identical targets presented in isolation; the decrease in forward displacement was not dependent upon the motion of a visible intermediary, but was dependent upon a visible intermediary contacting both the launcher and the target. The data were consistent with naïve impetus theory and the hypothesis that decreases in forward displacement of targets in tool effect displays resulted from the intermediary transferring perceived impetus of the launcher to the target and a dissipation of that impetus with subsequent target motion. Possible connections between displacement, impetus, and the perception of causality are discussed. PMID:12739148

  6. Stüve-Wiedemann syndrome: LIFR and associated cytokines in clinical course and etiology

    PubMed Central

    2014-01-01

    Stüve-Wiedemann syndrome (STWS; OMIM #610559) is a rare bent-bone dysplasia that includes radiologic bone anomalies, respiratory distress, feeding difficulties, and hyperthermic episodes. STWS usually results in infant mortality, yet some STWS patients survive into and, in some cases, beyond adolescence. STWS is caused by a mutation in the leukemia inhibitory factor receptor (LIFR) gene, which is inherited in an autosomally recessive pattern. Most LIFR mutations resulting in STWS are null mutations which cause instability of the mRNA and prevent the formation of LIFR, impairing the signaling pathway. LIFR signaling usually follows the JAK/STAT3 pathway, and is initiated by several interleukin-6-type cytokines. STWS is managed on a symptomatic basis since there is no treatment currently available. PMID:24618404

  7. Learning accurate and concise naïve Bayes classifiers from attribute value taxonomies and data

    PubMed Central

    Kang, D.-K.; Silvescu, A.; Honavar, V.

    2009-01-01

    In many application domains, there is a need for learning algorithms that can effectively exploit attribute value taxonomies (AVT)—hierarchical groupings of attribute values—to learn compact, comprehensible and accurate classifiers from data—including data that are partially specified. This paper describes AVT-NBL, a natural generalization of the naïve Bayes learner (NBL), for learning classifiers from AVT and data. Our experimental results show that AVT-NBL is able to generate classifiers that are substantially more compact and more accurate than those produced by NBL on a broad range of data sets with different percentages of partially specified values. We also show that AVT-NBL is more efficient in its use of training data: AVT-NBL produces classifiers that outperform those produced by NBL using substantially fewer training examples. PMID:20351793

  8. Study of the η‧→Ve+e- decay with hidden local symmetry model

    NASA Astrophysics Data System (ADS)

    Yang, Yue-Ling; Huang, Jin-Shu; Lu, Gong-Ru

    2015-02-01

    Within the hidden local symmetry framework, the Dalitz decay η‧→Ve+e- is studied with the vector meson dominance model. It is found that the partial width Γ(η‧→ωe+e-) ≈ 40 eV and branching ratio β(η‧→ωe+e-) ≈ 2×10-4, and Γ(η‧→ρe+e-) ≈ 10Γ(η‧→ωe+e-) and β(η‧→ρe+e-) ≈ 10β(η‧→ωe+e-). The maximum position of the dilepton distribution is me+e- ≈1.33 MeV. These decays are measurable with the advent of high statistic η‧ experiments. Supported by National Natural Science Foundation of China (11147008, 11275057, U1332103, U1232101) and Program for Science and Technology Innovation Talents in Universities of Henan Province (2012HASTIT030)

  9. Naïve conceptions about multimedia learning: a study on primary school textbooks

    PubMed Central

    Colombo, Barbara; Antonietti, Alessandro

    2013-01-01

    HIGHLIGHTS This interview study explores beliefs about the instructional role of illustrationsWe compared illustrators', teachers', students' and common people's ideasParticipants' responses were internally coherent and close to multimedia learning theoryWe propose and discuss an integrated multimedia learning model An interview study, based on specific pictures taken from textbooks used in primary schools, was carried out to investigate illustrators', teachers', students', and common people's beliefs about the role that illustrations play in facilitating learning. Participants' responses were internally coherent, indicating a systematic nature of the underlying naïve conceptions. Findings disprove Mayer's pessimistic claim that laypersons' conceptions of multimedia learning fail to match experimentally supported principles and theories. On the contrary, interviewees spontaneously came very close to the multimedia learning theory, which states that students learn better from pictures, which fit specific cognitive principles. Implications for school instruction are highlighted. PMID:23908636

  10. Investigation of Blue Bedding in Cages Housing Treatment-Naïve Hamsters

    PubMed Central

    Shah, Vishal D; Walton, Betsy J; Culp, Amanda G; Castellino, Stephen

    2015-01-01

    During the acclimation phase of a preclinical safety study involving Syrian golden hamsters, some of the cages of treatment-naïve animals were noted to contain blue-tinged bedding; the urine of these hamsters was not discolored. We sought to understand the underlying cause of this unusual finding to ensure that the study animals were healthy and free from factors that might confound the interpretation of the study. Analysis of extracts from the blue bedding by using HPLC with inline UV detection and high-resolution mass spectrometry indicated that the color was due to the presence of indigo blue. Furthermore, the indigo blue likely was formed through a series of biochemical events initiated by the intestinal metabolism of tryptophan to an indoxyl metabolite. We offer 2 hypotheses regarding the fate of the indoxyl metabolite: indigo blue formation through oxidative coupling in the liver or through urinary bacterial metabolism. PMID:26632791

  11. Investigation of Blue Bedding in Cages Housing Treatment-Naïve Hamsters.

    PubMed

    Shah, Vishal D; Walton, Betsy J; Culp, Amanda G; Castellino, Stephen

    2015-11-01

    During the acclimation phase of a preclinical safety study involving Syrian golden hamsters, some of the cages of treatment-naïve animals were noted to contain blue-tinged bedding; the urine of these hamsters was not discolored. We sought to understand the underlying cause of this unusual finding to ensure that the study animals were healthy and free from factors that might confound the interpretation of the study. Analysis of extracts from the blue bedding by using HPLC with inline UV detection and high-resolution mass spectrometry indicated that the color was due to the presence of indigo blue. Furthermore, the indigo blue likely was formed through a series of biochemical events initiated by the intestinal metabolism of tryptophan to an indoxyl metabolite. We offer 2 hypotheses regarding the fate of the indoxyl metabolite: indigo blue formation through oxidative coupling in the liver or through urinary bacterial metabolism. PMID:26632791

  12. Abnormalities of cingulate cortex in antipsychotic-naïve chronic schizophrenia.

    PubMed

    Liu, Xiaoyi; Wang, Xijin; Lai, Yunyao; Hao, Chuanxi; Chen, Lei; Zhou, Zhenyu; Yu, Xin; Hong, Nan

    2016-05-01

    While several morphometric studies have postulated a critical contribution of the cingulate cortex (CC) to the pathophysiology of schizophrenia based on abnormalities in CC volume, other studies have been inconclusive. Most such studies have focused only on changes in cortical volume, whereas other morphometric parameters such as surface area and cortical thickness could be more relevant and possibly account for these discrepancies. Furthermore, factors such as antipsychotic drug use and treatment duration may also influence cortical morphology. To clarify the association between schizophrenia and CC deficits, we investigated morphometric abnormalities of the CC in antipsychotic drug (AD)-naïve chronic schizophrenia patients by comparing T1-weighted magnetic resonance images (T1WI-MRI) from patients (n=17) to healthy controls (n=17) using the surface-based morphometry program FreeSurfer. Partial correlations were examined between abnormal morphometric measures and both clinical variables and cognitive performance scores. Compared to healthy controls, drug-naïve schizophrenia patients exhibited significantly lower volumes in both left rostral anterior CC (rACC) and left posterior CC (PCC). These reductions in CC volume resulted from reduced surface area rather than reduced cortical thickness. There was also a significant relationship between left PCC volume and working memory in patients. No significant correlations were observed between CC volume and clinical variables. The results suggest that abnormalities in the CC as manifested by reduced surface area may contribute to cognitive dysfunction in schizophrenia. This article is part of a Special Issue entitled SI: PSC and the brain. PMID:26459991

  13. Heterodimeric protein complex identification by naïve Bayes classifiers

    PubMed Central

    2013-01-01

    Background Protein complexes are basic cellular entities that carry out the functions of their components. It can be found that in databases of protein complexes of yeast like CYC2008, the major type of known protein complexes is heterodimeric complexes. Although a number of methods for trying to predict sets of proteins that form arbitrary types of protein complexes simultaneously have been proposed, it can be found that they often fail to predict heterodimeric complexes. Results In this paper, we have designed several features characterizing heterodimeric protein complexes based on genomic data sets, and proposed a supervised-learning method for the prediction of heterodimeric protein complexes. This method learns the parameters of the features, which are embedded in the naïve Bayes classifier. The log-likelihood ratio derived from the naïve Bayes classifier with the parameter values obtained by maximum likelihood estimation gives the score of a given pair of proteins to predict whether the pair is a heterodimeric complex or not. A five-fold cross-validation shows good performance on yeast. The trained classifiers also show higher predictability than various existing algorithms on yeast data sets with approximate and exact matching criteria. Conclusions Heterodimeric protein complex prediction is a rather harder problem than heteromeric protein complex prediction because heterodimeric protein complex is topologically simpler. However, it turns out that by designing features specialized for heterodimeric protein complexes, predictability of them can be improved. Thus, the design of more sophisticate features for heterodimeric protein complexes as well as the accumulation of more accurate and useful genome-wide data sets will lead to higher predictability of heterodimeric protein complexes. Our tool can be downloaded from http://imi.kyushu-u.ac.jp/~om/. PMID:24299017

  14. Antiretroviral drug resistance mutations in naïve and experienced patients in Shiraz, Iran, 2014.

    PubMed

    Naziri, Hamed; Baesi, Kazem; Moradi, Abdolvahab; Aghasadeghi, Mohammad R; Tabarraei, Alijan; McFarland, Willi; Davarpanah, Mohamad Ali

    2016-09-01

    Resistance to antiretroviral agents is a significant concern in the clinical management of HIV-infected individuals, particularly in areas of the world where treatment options are limited. In this study, we aimed to identify HIV drug-resistance-associated mutations in 40 drug-naïve patients and 62 patients under antiretroviral therapy (ART) referred to the Shiraz HIV/AIDS Research Center - the first such data available for the south of Iran. HIV reverse transcriptase and protease genes were amplified and sequenced to determine subtypes and antiretroviral- resistance-associated mutations (RAMs). Subtype CRF35-AD recombinant was the most prevalent in all patients (98 of 102, 96 %), followed by subtype A1, and subtype B (one each, 2 %). Among the 40 ART-naïve patients, two mutations associated with nucleoside reverse transcriptase inhibitor (NRTI) resistance (two with Y115F and T215I) and three associated with non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance (two with G190S and Y181C, four with V179T) were found. Among ART-experienced patients, four mutations associated with resistance to NRTI, four with NNRTI, and five with protease inhibitors (PI) were found. Twenty patients with high levels of resistance were already on second-line therapy. We document for the first time in this region of Iran high levels of ART resistance to multiple drugs. Our findings call for more vigilant systematic ART resistance surveillance, increased resistance testing, careful management of patients with existing regimens, and strong advocacy for expansion of available drugs in Iran. PMID:27368990

  15. Quinolinic acid-immunoreactivity in the naïve mouse brain.

    PubMed

    Lopez, Yara Pujol; Kenis, Gunter; Rutten, Bart P F; Myint, Aye M; Steinbusch, Harry W M; van den Hove, Daniel L A

    2016-01-01

    Quinolinic acid (QUIN) has been suggested to be involved in infections, inflammatory neurological disorders and in the development of psychiatric disorders. In this view, several studies have been performed to investigate QUIN localization in the brain and its neurotoxic effects. However, evidence is lacking regarding QUIN in healthy, control conditions. The aim of this study was to investigate the region-specific distribution and pattern of QUIN expression in the naïve mouse brain. In addition, possible sex differences in QUIN-immunoreactivity and its link with affect-related behavioural observations were assessed. For this purpose, naïve mice were subjected to the forced swim test (FST) and 20 min open field (OF) testing to measure affect-related behaviour. Afterwards, brains were assessed for QUIN-immunoreactivity. QUIN-immunoreactivity was particularly observed in the cingulate cortex (CC), highlighting clearly delineated cells, and the thalamic reticular nucleus (TRN), showing a more diffuse staining pattern. Subsequently, QUIN-positive cells in the CC were counted, while QUIN-immunoreactivity in the TRN was examined using gray value measurements. No significant differences between sexes were observed for the number of QUIN-positive cells in the CC, neither in levels of QUIN-immunoreactivity in the TRN. A direct correlation was found between QUIN-positive cells in the CC and QUIN-immunoreactivity in the TRN. Moreover, in male mice, a very strong correlation (rsp=.943; p<.01) between QUIN-immunoreactivity at the level of the TRN and motor activity in the OF was observed. Thus, our results suggest that QUIN - detected in the CC and the TRN - may play a role in regulating motor activity in normal conditions. PMID:26686288

  16. Antipsychotics reverse abnormal EEG complexity in drug-naïve schizophrenia: A multiscale entropy analysis

    PubMed Central

    Takahashi, Tetsuya; Cho, Raymond Y.; Mizuno, Tomoyuki; Kikuchi, Mitsuru; Murata, Tetsuhito; Takahashi, Koichi; Wada, Yuji

    2010-01-01

    Multiscale entropy (MSE) analysis is a novel entropy-based approach for measuring dynamical complexity in physiological systems over a range of temporal scales. To evaluate this analytic approach as an aid to elucidating the pathophysiologic mechanisms in schizophrenia, we examined MSE in EEG activity in drug-naïve schizophrenia subjects pre- and post-treatment with antipsychotics in comparison with traditional EEG analysis. We recorded eyes-closed resting state EEG from frontal, temporal, parietal and occipital regions in drug-naïve 22 schizophrenia and 24 age-matched healthy control subjects. Fifteen patients were re-evaluated within 2–8 weeks after the initiation of antipsychotic treatment. For each participant, MSE was calculated on one continuous 60 second epoch for each experimental session. Schizophrenia subjects showed significantly higher complexity at higher time scales (lower frequencies), than that of healthy controls in fronto-centro-temporal, but not in parieto-occipital regions. Post-treatment, this higher complexity decreased to healthy control subject levels selectively in fronto-central regions, while the increased complexity in temporal sites remained higher. Comparative power analysis identified spectral slowing in frontal regions in pre-treatment schizophrenia subjects, consistent with previous findings, whereas no antipsychotic treatment effect was observed. In summary, multiscale entropy measures identified abnormal dynamical EEG signal complexity in anterior brain areas in schizophrenia that normalized selectively in fronto-central areas with antipsychotic treatment. These findings show that entropy-based analytic methods may serve as a novel approach for characterizing and understanding abnormal cortical dynamics in schizophrenia, and elucidating the therapeutic mechanisms of antipsychotics. PMID:20149880

  17. sLORETA intracortical lagged coherence during breath counting in meditation-naïve participants

    PubMed Central

    Milz, Patricia; Faber, Pascal L.; Lehmann, Dietrich; Kochi, Kieko; Pascual-Marqui, Roberto D.

    2013-01-01

    We investigated brain functional connectivity comparing no-task resting to breath counting (a meditation exercise but given as task without referring to meditation). Functional connectivity computed as EEG coherence between head-surface data suffers from localization ambiguity, reference dependence, and overestimation due to volume conduction. Lagged coherence between intracortical model sources addresses these criticisms. With this analysis approach, experienced meditators reportedly showed reduced coherence during meditation, meditation-naïve participants have not yet been investigated. 58-channel EEG from 23 healthy, right-handed, meditation-naïve males during resting [3 runs] and breath counting [2 runs] was computed into sLORETA time series of intracortical electrical activity in 19 regions of interest (ROI) corresponding to the cortex underlying 19 scalp electrode sites, for each of the eight independent EEG frequency bands covering 1.5–44 Hz. Intracortical lagged coherences and head-surface conventional coherences were computed between the 19 regions/sites. During breath counting compared to resting, paired t-tests corrected for multiple testing revealed four significantly lower intracortical lagged coherences, but four significantly higher head-surface conventional coherences. Lowered intracortical lagged coherences involved left BA 10 and right BAs 3, 10, 17, 40. In conclusion, intracortical lagged coherence can yield results that are inverted to those of head-surface conventional coherence. The lowered functional connectivity between cognitive control areas and sensory perception areas during meditation-type breath counting compared to resting conceivably reflects the attention to a bodily percept without cognitive reasoning. The reductions in functional connectivity were similar but not as widespread as the reductions reported during meditation in experienced meditators. PMID:24860483

  18. Bayesian estimation of Karhunen-Loève expansions; A random subspace approach

    NASA Astrophysics Data System (ADS)

    Chowdhary, Kenny; Najm, Habib N.

    2016-08-01

    One of the most widely-used procedures for dimensionality reduction of high dimensional data is Principal Component Analysis (PCA). More broadly, low-dimensional stochastic representation of random fields with finite variance is provided via the well known Karhunen-Loève expansion (KLE). The KLE is analogous to a Fourier series expansion for a random process, where the goal is to find an orthogonal transformation for the data such that the projection of the data onto this orthogonal subspace is optimal in the L2 sense, i.e., which minimizes the mean square error. In practice, this orthogonal transformation is determined by performing an SVD (Singular Value Decomposition) on the sample covariance matrix or on the data matrix itself. Sampling error is typically ignored when quantifying the principal components, or, equivalently, basis functions of the KLE. Furthermore, it is exacerbated when the sample size is much smaller than the dimension of the random field. In this paper, we introduce a Bayesian KLE procedure, allowing one to obtain a probabilistic model on the principal components, which can account for inaccuracies due to limited sample size. The probabilistic model is built via Bayesian inference, from which the posterior becomes the matrix Bingham density over the space of orthonormal matrices. We use a modified Gibbs sampling procedure to sample on this space and then build probabilistic Karhunen-Loève expansions over random subspaces to obtain a set of low-dimensional surrogates of the stochastic process. We illustrate this probabilistic procedure with a finite dimensional stochastic process inspired by Brownian motion.

  19. A Longitudinal Functional Neuroimaging Study in Medication-Naïve Depression after Antidepressant Treatment

    PubMed Central

    Kawasaki, Shingo; Pu, Shenghong; Iwanami, Akira; Hirano, Jinichi; Nakagome, Kazuyuki; Mimura, Masaru

    2015-01-01

    Recent studies have indicated the potential clinical use of near infrared spectroscopy (NIRS) as a tool in assisting the diagnosis of major depressive disorder (MDD); however, it is still unclear whether NIRS signal changes during cognitive task are state- or trait-dependent, and whether NIRS could be a neural predictor of treatment response. Therefore, we conducted a longitudinal study to explore frontal haemodynamic changes following antidepressant treatment in medication-naïve MDD using 52-channel NIRS. This study included 25 medication-naïve individuals with MDD and 62 healthy controls (HC). We performed NIRS scans before and after antidepressant treatment and measured changes of [oxy-Hb] activation during a verbal fluency task (VFT) following treatment. Individuals with MDD showed significantly decreased [oxy-Hb] values during a VFT compared with HC in the bilateral frontal and temporal cortices at baseline. There were no [oxy-Hb] changes between pre- and post-antidepressant treatment time points in the MDD cohort despite significant improvement in depressive symptoms. There was a significant association between mean [oxy-Hb] values during a VFT at baseline and improvement in depressive symptoms following treatment in the bilateral inferior frontal and middle temporal gyri in MDD. These findings suggest that hypofrontality response to a VFT may represent a potential trait marker for depression rather than a state marker. Moreover, the correlation analysis indicates that the NIRS signals before the initiation of treatment may be a biological marker to predict patient’s clinical response to antidepressant treatment. The present study provides further evidence to support a potential application of NIRS for the diagnosis and treatment of depression. PMID:25786240

  20. Lung Microbiome Analysis in Steroid-Naїve Asthma Patients by Using Whole Sputum

    PubMed Central

    Jung, Jae-Woo; Choi, Jae-Chol; Shin, Jong-Wook; Kim, Jae-Yeol; Park, In-Won; Choi, Byoung Whui; Park, Heung-Woo; Cho, Sang-Heon

    2016-01-01

    Background Although recent metagenomic approaches have characterized the distinguished microbial compositions in airways of asthmatics, these results did not reach a consensus due to the small sample size, non-standardization of specimens and medication status. We conducted a metagenomics approach by using terminal restriction fragment length polymorphism (T-RFLP) analysis of the induced whole sputum representing both the cellular and fluid phases in a relative large number of steroid naïve asthmatics. Methods Induced whole sputum samples obtained from 36 healthy subjects and 89 steroid-naїve asthma patients were analyzed through T-RFLP analysis. Results In contrast to previous reports about microbiota in the asthmatic airways, the diversity of microbial composition was not significantly different between the controls and asthma patients (p=0.937). In an analysis of similarities, the global R-value showed a statistically significant difference but a very low separation (0.148, p=0.002). The dissimilarity in the bacterial communities between groups was 28.74%, and operational taxonomic units (OTUs) contributing to this difference were as follows: OTU 789 (Lachnospiraceae), 517 (Comamonadaceae, Acetobacteraceae , and Chloroplast), 633 (Prevotella), 645 (Actinobacteria and Propionibacterium acnes), 607 (Lactobacillus buchneri, Lactobacillus otakiensis, Lactobacillus sunkii, and Rhodobacteraceae), and 661 (Acinetobacter, Pseudomonas, and Leptotrichiaceae), and they were significantly more prevalent in the sputum of asthma patients than in the sputum of the controls. Conclusion Before starting anti-asthmatic treatment, the microbiota in the whole sputum of patients with asthma showed a marginal difference from the microbiota in the whole sputum of the controls. PMID:27433177

  1. HIV DNA Reservoir Increases Risk for Cognitive Disorders in cART-Naïve Patients

    PubMed Central

    Valcour, Victor G.; Ananworanich, Jintanat; Agsalda, Melissa; Sailasuta, Napapon; Chalermchai, Thep; Schuetz, Alexandra; Shikuma, Cecilia; Liang, Chin-Yuan; Jirajariyavej, Supunee; Sithinamsuwan, Pasiri; Tipsuk, Somporn; Clifford, David B.; Paul, Robert; Fletcher, James L. K.; Marovich, Mary A.; Slike, Bonnie M.; DeGruttola, Victor; Shiramizu, Bruce

    2013-01-01

    Objectives Cognitive impairment remains frequent in HIV, despite combination antiretroviral therapy (cART). Leading theories implicate peripheral monocyte HIV DNA reservoirs as a mechanism for spread of the virus to the brain. These reservoirs remain present despite cART. The objective of this study was to determine if the level of HIV DNA in CD14+ enriched monocytes predicted cognitive impairment and brain injury. Methods We enrolled 61 cART-naïve HIV-infected Thais in a prospective study and measured HIV DNA in CD14+ enriched monocyte samples in a blinded fashion. We determined HAND diagnoses by consensus panel and all participants underwent magnetic resonance spectroscopy (MRS) to measure markers of brain injury. Immune activation was measured via cytokines in cerebrospinal fluid (CSF). Results The mean (SD) age was 35 (6.9) years, CD4 T-lymphocyte count was 236 (139) and log10 plasma HIV RNA was 4.8 (0.73). Twenty-eight of 61 met HAND criteria. The log10 CD14+ HIV DNA was associated with HAND in unadjusted and adjusted models (p = 0.001). There was a 14.5 increased odds ratio for HAND per 1 log-value of HIV DNA (10-fold increase in copy number). Plasma CD14+ HIV DNA was associated with plasma and CSF neopterin (p = 0.023) and with MRS markers of neuronal injury (lower N-acetyl aspartate) and glial dysfunction (higher myoinositol) in multiple brain regions. Interpretation Reservoir burden of HIV DNA in monocyte-enriched (CD14+) peripheral blood cells increases risk for HAND in treatment-naïve HIV+ subjects and is directly associated with CSF immune activation and both brain injury and glial dysfunction by MRS. PMID:23936155

  2. Symmetry is in the eye of the `beeholder': innate preference for bilateral symmetry in flower-naïve bumblebees

    NASA Astrophysics Data System (ADS)

    Rodríguez, Ivana; Gumbert, Andreas; Hempel de Ibarra, Natalie; Kunze, Jan; Giurfa, Martin

    Bilateral symmetry has been considered as an indicator of phenotypic and genotypic quality supporting innate preferences for highly symmetric partners. Insect pollinators preferentially visit flowers of a particular symmetry type, thus leading to the suggestion that they have innate preferences for symmetrical flowers or flower models. Here we show that flower-naïve bumblebees (Bombus terrestris), with no experience of symmetric or asymmetric patterns and whose visual experience was accurately controlled, have innate preferences for bilateral symmetry. The presence of color cues did not influence the bees' original preference. Our results thus show that bilateral symmetry is innately preferred in the context of food search, a fact that supports the selection of symmetry in flower displays. Furthermore, such innate preferences indicate that the nervous system of naïve animals may be primed to respond to relevant sensory cues in the environment.

  3. Neuron-specific enolase levels in drug-naïve young adults with major depressive disorder.

    PubMed

    Wiener, Carolina David; Molina, Mariane Lopez; Passos, Miguel; Moreira, Fernanda Pedrotti; Bittencourt, Guilherme; de Mattos Souza, Luciano Dias; da Silva, Ricardo Azevedo; Jansen, Karen; Oses, Jean Pierre

    2016-05-01

    The aim of this study is to assess neuron-specific enolase (NSE) levels and clinical features in subjects with major depressive disorder (MDD). This is a cross-sectional study with drug-naïve young adults with MDD (aged 18-29 years). Serum levels of NSE were assessed using the electrochemiluminescence method. MDD diagnosis, suicidal ideation, and time of disease were assessed using the Structured Clinical Interview for DSM-IV (SCID). The Hamilton Depression Rating Scale (HDRS) and Hamilton Anxiety Rating Scale (HARS) were used to assess depressive and anxiety symptoms. No relationship was observed between NSE levels and severity of depressive and anxiety symptoms, time of disease, and suicidal ideation. These results suggest that NSE serum levels were not associated with clinical features of MDD among drug-naïve young adults. PMID:27026487

  4. Selection of Neospora caninum antigens stimulating bovine CD4+ve T cell responses through immuno-potency screening and proteomic approaches.

    PubMed

    Rocchi, Mara S; Bartley, Paul M; Inglis, Neil F; Collantes-Fernandez, Esther; Entrican, Gary; Katzer, Frank; Innes, Elisabeth A

    2011-01-01

    Neospora caninum is recognised worldwide as a major cause of bovine infectious abortion. There is a real need to develop effective strategies to control infection during pregnancy which may lead to either abortion or congenital transmission. Due to the intracellular nature of the parasite, cell-mediated immune (CMI) responses involving CD4(+ve), CD8(+ve), γ/δ TCR(+ve) T cells and NK cells, as well as production of IFN-γ, are thought to be important for protective immunity. In this study we applied a combination of proteomic and immunological approaches to identify antigens of N. caninum that are recognized by CD4(+ve) T cell lines derived from infected cattle. Initially, N. caninum tachyzoite Water Soluble Antigens (NcWSA) were fractionated by size-exclusion HPLC and then screened for immune-potency using CD4(+ve) T cell lines. LC-ESI-MS/MS (liquid chromatography electrospray ionisation tandem mass spectrometry) was employed to catalogue and identify the proteins comprising three immunologically selected fractions and led to the identification of six N. caninum target proteins as well as sixteen functional orthologues of Toxoplasma gondii. This approach allows the screening of biologically reactive antigenic fractions by the immune cells responsible for protection (such as bovine CD4(+ve) cells) and the subsequent identification of the stimulating components using tandem mass spectrometry. PMID:21813001

  5. In vivo Expansion of Naïve CD4+CD25high FOXP3+ Regulatory T Cells in Patients with Colorectal Carcinoma after IL-2 Administration

    PubMed Central

    Beyer, Marc; Schumak, Beatrix; Weihrauch, Martin R.; Andres, Bettina; Giese, Thomas; Endl, Elmar; Knolle, Percy A.; Classen, Sabine; Limmer, Andreas; Schultze, Joachim L.

    2012-01-01

    Regulatory T cells (Treg cells) are increased in context of malignancies and their expansion can be correlated with higher disease burden and decreased survival. Initially, interleukin 2 (IL-2) has been used as T-cell growth factor in clinical vaccination trials. In murine models, however, a role of IL-2 in development, differentiation, homeostasis, and function of Treg cells was established. In IL-2 treated cancer patients a further Treg-cell expansion was described, yet, the mechanism of expansion is still elusive. Here we report that functional Treg cells of a naïve phenotype - as determined by CCR7 and CD45RA expression - are significantly expanded in colorectal cancer patients. Treatment of 15 UICC stage IV colorectal cancer patients with IL-2 in a phase I/II peptide vaccination trial further enlarges the already increased naïve Treg-cell pool. Higher frequencies of T-cell receptor excision circles in naïve Treg cells indicate IL-2 dependent thymic generation of naïve Treg cells as a mechanism leading to increased frequencies of Treg cells post IL-2 treatment in cancer patients. This finding could be confirmed in naïve murine Treg cells after IL-2 administration. These results point to a more complex regulation of Treg cells in context of IL-2 administration. Future strategies therefore might aim at combining IL-2 therapy with novel strategies to circumvent expansion and differentiation of naïve Treg cells. PMID:22276195

  6. Naïve-like conversion enhances the difference in innate in vitro differentiation capacity between rabbit ES cells and iPS cells

    PubMed Central

    HONSHO, Kimiko; HIROSE, Michiko; HATORI, Masanori; YASMIN, Lubna; IZU, Haruna; MATOBA, Shogo; TOGAYACHI, Sumie; MIYOSHI, Hiroyuki; SANKAI, Tadashi; OGURA, Atsuo; HONDA, Arata

    2014-01-01

    Quality evaluation of pluripotent stem cells using appropriate animal models needs to be improved for human regenerative medicine. Previously, we demonstrated that although the in vitro neural differentiating capacity of rabbit induced pluripotent stem cells (iPSCs) can be mitigated by improving their baseline level of pluripotency, i.e., by converting them into the so-called “naïve-like” state, the effect after such conversion of rabbit embryonic stem cells (ESCs) remains to be elucidated. Here we found that naïve-like conversion enhanced the differences in innate in vitro differentiation capacity between ESCs and iPSCs. Naïve-like rabbit ESCs exhibited several features indicating pluripotency, including the capacity for teratoma formation. They differentiated into mature oligodendrocytes much more effectively (3.3–7.2 times) than naïve-like iPSCs. This suggests an inherent variation in differentiation potential in vitro among PSC lines. When naïve-like ESCs were injected into preimplantation rabbit embryos, although they contributed efficiently to forming the inner cell mass of blastocysts, no chimeric pups were obtained. Thus, in vitro neural differentiation following naïve-like conversion is a promising option for determining the quality of PSCs without the need to demonstrate chimeric contribution. These results provide an opportunity to evaluate which pluripotent stem cells or treatments are best suited for therapeutic use. PMID:25345855

  7. Transcriptome Analysis of Aspergillus flavus Reveals veA-Dependent Regulation of Secondary Metabolite Gene Clusters, Including the Novel Aflavarin Cluster

    PubMed Central

    Cary, J. W.; Han, Z.; Yin, Y.; Lohmar, J. M.; Shantappa, S.; Harris-Coward, P. Y.; Mack, B.; Ehrlich, K. C.; Wei, Q.; Arroyo-Manzanares, N.; Uka, V.; Vanhaecke, L.; Bhatnagar, D.; Yu, J.; Nierman, W. C.; Johns, M. A.; Sorensen, D.; Shen, H.; De Saeger, S.; Diana Di Mavungu, J.

    2015-01-01

    The global regulatory veA gene governs development and secondary metabolism in numerous fungal species, including Aspergillus flavus. This is especially relevant since A. flavus infects crops of agricultural importance worldwide, contaminating them with potent mycotoxins. The most well-known are aflatoxins, which are cytotoxic and carcinogenic polyketide compounds. The production of aflatoxins and the expression of genes implicated in the production of these mycotoxins are veA dependent. The genes responsible for the synthesis of aflatoxins are clustered, a signature common for genes involved in fungal secondary metabolism. Studies of the A. flavus genome revealed many gene clusters possibly connected to the synthesis of secondary metabolites. Many of these metabolites are still unknown, or the association between a known metabolite and a particular gene cluster has not yet been established. In the present transcriptome study, we show that veA is necessary for the expression of a large number of genes. Twenty-eight out of the predicted 56 secondary metabolite gene clusters include at least one gene that is differentially expressed depending on presence or absence of veA. One of the clusters under the influence of veA is cluster 39. The absence of veA results in a downregulation of the five genes found within this cluster. Interestingly, our results indicate that the cluster is expressed mainly in sclerotia. Chemical analysis of sclerotial extracts revealed that cluster 39 is responsible for the production of aflavarin. PMID:26209694

  8. Selection of Neospora caninum antigens stimulating bovine CD4+ve T cell responses through immuno-potency screening and proteomic approaches

    PubMed Central

    2011-01-01

    Neospora caninum is recognised worldwide as a major cause of bovine infectious abortion. There is a real need to develop effective strategies to control infection during pregnancy which may lead to either abortion or congenital transmission. Due to the intracellular nature of the parasite, cell-mediated immune (CMI) responses involving CD4+ve, CD8+ve, γ/δ TCR+ve T cells and NK cells, as well as production of IFN-γ, are thought to be important for protective immunity. In this study we applied a combination of proteomic and immunological approaches to identify antigens of N. caninum that are recognized by CD4+ve T cell lines derived from infected cattle. Initially, N. caninum tachyzoite Water Soluble Antigens (NcWSA) were fractionated by size-exclusion HPLC and then screened for immune-potency using CD4+ve T cell lines. LC-ESI-MS/MS (liquid chromatography electrospray ionisation tandem mass spectrometry) was employed to catalogue and identify the proteins comprising three immunologically selected fractions and led to the identification of six N. caninum target proteins as well as sixteen functional orthologues of Toxoplasma gondii. This approach allows the screening of biologically reactive antigenic fractions by the immune cells responsible for protection (such as bovine CD4+ve cells) and the subsequent identification of the stimulating components using tandem mass spectrometry. PMID:21813001

  9. Involvement of a Velvet Protein FgVeA in the Regulation of Asexual Development, Lipid and Secondary Metabolisms and Virulence in Fusarium graminearum

    PubMed Central

    Jiang, Jinhua; Liu, Xin; Yin, Yanni; Ma, Zhonghua

    2011-01-01

    The velvet protein, VeA, is involved in the regulation of diverse cellular processes. In this study, we explored functions of FgVeA in the wheat head blight pathogen, Fusarium graminearum,using a gene replacement strategy. The FgVEA deletion mutant exhibited a reduction in aerial hyphae formation, hydrophobicity, and deoxynivalenol (DON) biosynthesis. Deletion of FgVEA gene led to an increase in conidial production, but a delay in conidial germination. Pathogencity assays showed that the mutant was impaired in virulence on flowering wheat head. Sensitivity tests to various stresses exhibited that the FgVEA deletion mutant showed increased resistance to osmotic stress and cell wall-damaging agents, but increased sensitivity to iprodione and fludioxonil fungicides. Ultrastructural and histochemical analyses revealed that conidia of FgVeA deletion mutant contained an unusually high number of large lipid droplets, which is in agreement with the observation that the mutant accumulated a higher basal level of glycerol than the wild-type progenitor. Serial analysis of gene expression (SAGE) in the FgVEA mutant confirmed that FgVeA was involved in various cellular processes. Additionally, six proteins interacting with FgVeA were identified by yeast two hybrid assays in current study. These results indicate that FgVeA plays a critical role in a variety of cellular processes in F. graminearum. PMID:22140571

  10. Flavimonas oryzihabitans (Pseudomonas oryzihabitans; CDC group Ve-2): an emerging pathogen in peritonitis related to continuous ambulatory peritoneal dialysis?

    PubMed

    Bendig, J W; Mayes, P J; Eyers, D E; Holmes, B; Chin, T T

    1989-01-01

    A case of peritonitis caused by Flavimonas oryzihabitans (Pseudomonas oryzihabitans; CDC group VE-2) in a patient on continuous ambulatory peritoneal dialysis is reported. This is the seventh case of infection caused by this organism reported in the English literature and the third reported case of continuous ambulatory peritoneal dialysis-related peritonitis caused by this organism; it is the first case of infection of any kind caused by this organism in England. PMID:2913032

  11. Pressure distribution on wing ribs of the VE-7 and TS airplanes in flight Part II : pull-ups

    NASA Technical Reports Server (NTRS)

    Rhode, R V

    1928-01-01

    This paper is the second of a series of notes, each of which presents the complete results of pressure distribution tests made at Langley Field by the National Advisory Committee for Aeronautics, on wing and tail ribs of the VE-7 and TS airplanes for a particular maneuver of flight. The results for pull-ups are presented in the form of curves which show the variation of pressure distribution, total loads, normal acceleration and center of pressure with respect to time.

  12. Cardiac Effects of Antiretroviral-Naïve versus Antiretroviral-Exposed HIV Infection in Children

    PubMed Central

    Grobbee, Diederick E.; Burgner, David; Kurniati, Nia

    2016-01-01

    Background Cardiac involvement in HIV infected children has been frequently reported, but whether this is due to HIV infection itself or to antiretroviral treatment (ART) is unknown. Methods This cross sectional study involved 114 vertically-acquired HIV-infected (56 ART-naive, 58 ART-exposed) and 51 healthy children in Jakarta, Indonesia. Echocardiography was performed to measure dimensions of the left ventricle (LV) and systolic functions. We applied general linear modeling to evaluate the associations between HIV infection/treatment status and cardiac parameters with further adjustment for potential confounders or explanatory variables. Findings are presented as (adjusted) mean differences between each of the two HIV groups and healthy children, with 95% confidence intervals and p values. Results Compared to healthy children, ART-naïve HIV-infected children did not show significant differences in age-and-height adjusted cardiac dimensions apart from larger LV internal diameter (difference 2.0 mm, 95%CI 0.2 to 3.7), whereas ART exposed HIV infection showed thicker LV posterior walls (difference = 1.1 mm, 95%CI 0.5 to 1.6), larger LV internal diameter (difference = 1.7 mm, 95%CI 0.2 to 3.2) and higher LV mass (difference = 14.0 g, 7.4 to 20.5). With respect to systolic function, reduced LV ejection fraction was seen in both ART-naïve HIV infected (adjusted difference = -6.7%, -11.4 to -2.0) and, to a lesser extent, in ART-exposed HIV infected children (difference = -4.5%, -8.5 to -0.4). Inflammation level seemed to be involved in most associations in ART-exposed HIV-infected, but few, if any, for decreased function in the ART-naive ones, whereas lower hemoglobin appeared to partially mediate chamber dilation in both groups and reduced function, mainly in ART-exposed children. Conclusions ART-naive HIV infected children have a substantial decrease in cardiac systolic function, whereas the ART-exposed have thicker ventricular walls with larger internal diameter

  13. Probabilistic evaluation of decadal CMIP5 hindcasts with the VeCAP verification package

    NASA Astrophysics Data System (ADS)

    Stolzenberger, S.; Hense, A.; Glowienka-Hense, R.; Spangehl, T.; Mazurkiewicz, A.; Schroeder, M.

    2013-12-01

    The project VeCAP (Verification, Calibration and Assessment of Predictability of medium-range climate predictions using satellite data) is part of the German research programme MiKlip (Mittelfristige Klimaprognosen - Decadal climate predictions) developing a system for decadal climate predictions. This contribution introduces the VeCAP verification package focusing on the probabilistic evaluation of decadal CMIP5 hindcast experiments. The verification tool contains necessary and sufficient tests for probabilistic evaluation of ensemble predictions. A necessary test for reliability of ensemble predictions is assessed by analysis rank histograms (ARH). These histograms are parametrized by Beta-distributions and the so called Beta-scores summarizing the graphical character of ARHs are derived. Potential sharpness is evaluated by implementing one-way and two-way anova (analysis of variance) of the ensemble predictions with fixed effects and without interactions. Additionally there is a basic suite of sufficient verification statistics for continuous variables and sea level pressure based circulation indices. This includes the mean square error statistics, scores and skill scores which relate to climate or other reference forecasts. Discrete variables and their predictive probabilities are evaluated by e.g. Brier scores and Brier skill scores. Besides these calculations based on standard univariate methods, a set of multivariate scores is available. Moreover the application of spatial and temporal filtering is possible. The ERA-Interim reanalyses from ECMWF and selected essential variables e.g. cloud cover from CM SAF (Satellite Application Facility on Climate Monitoring) form the basic atmospheric observations because the first intention of the verification is to provide the modelling community with relevant information about the performance of the forecasting system. The simulations to be compared are based on the MPI-ESM model output of the baseline 0 and the updated

  14. The Motion Verified Red Stars (MoVeRS) Catalog and Low-Mass Field Stars with Warm Dust

    NASA Astrophysics Data System (ADS)

    Theissen, Christopher; West, Andrew A.; Dhital, Saurav

    2016-01-01

    We present the Motion Verified Red Stars (MoVeRS) catalog of proper motion selected low-mass stars from SDSS, 2MASS, and WISE. These surveys provide a time baseline of ~12 years for sources found in all three surveys, and a precision better than 10 mas/year.The MoVeRS catalog is augmented with proper motions from SDSS+USNO-B and the full sample contains 8,735,004 photometric point-sources selected based on colors and their significant (2σ) proper motions. This catalog will be useful for finding new low-mass common proper motion systems, along with providing a large input catalog for numerous studies of low-mass stars. In addition, we use the MoVeRS catalog to present a preliminary sample of low-mass field stars exhibiting signatures of warm dust (mid-infrared excesses). Such systems are thought to originate from collisions of terrestrial planets, raising even more questions about the habitability of planetary systems around low-mass stars.

  15. The F-BAR protein pacsin2 inhibits asymmetric VE-cadherin internalization from tensile adherens junctions

    PubMed Central

    Dorland, Yvonne L.; Malinova, Tsveta S.; van Stalborch, Anne-Marieke D.; Grieve, Adam G.; van Geemen, Daphne; Jansen, Nicolette S.; de Kreuk, Bart-Jan; Nawaz, Kalim; Kole, Jeroen; Geerts, Dirk; Musters, René J. P.; de Rooij, Johan; Hordijk, Peter L.; Huveneers, Stephan

    2016-01-01

    Vascular homoeostasis, development and disease critically depend on the regulation of endothelial cell–cell junctions. Here we uncover a new role for the F-BAR protein pacsin2 in the control of VE-cadherin-based endothelial adhesion. Pacsin2 concentrates at focal adherens junctions (FAJs) that are experiencing unbalanced actomyosin-based pulling. FAJs move in response to differences in local cytoskeletal geometry and pacsin2 is recruited consistently to the trailing end of fast-moving FAJs via a mechanism that requires an intact F-BAR domain. Photoconversion, photobleaching, immunofluorescence and super-resolution microscopy reveal polarized dynamics, and organization of junctional proteins between the front of FAJs and their trailing ends. Interestingly, pacsin2 recruitment inhibits internalization of the VE-cadherin complex from FAJ trailing ends and is important for endothelial monolayer integrity. Together, these findings reveal a novel junction protective mechanism during polarized trafficking of VE-cadherin, which supports barrier maintenance within dynamic endothelial tissue. PMID:27417273

  16. The F-BAR protein pacsin2 inhibits asymmetric VE-cadherin internalization from tensile adherens junctions.

    PubMed

    Dorland, Yvonne L; Malinova, Tsveta S; van Stalborch, Anne-Marieke D; Grieve, Adam G; van Geemen, Daphne; Jansen, Nicolette S; de Kreuk, Bart-Jan; Nawaz, Kalim; Kole, Jeroen; Geerts, Dirk; Musters, René J P; de Rooij, Johan; Hordijk, Peter L; Huveneers, Stephan

    2016-01-01

    Vascular homoeostasis, development and disease critically depend on the regulation of endothelial cell-cell junctions. Here we uncover a new role for the F-BAR protein pacsin2 in the control of VE-cadherin-based endothelial adhesion. Pacsin2 concentrates at focal adherens junctions (FAJs) that are experiencing unbalanced actomyosin-based pulling. FAJs move in response to differences in local cytoskeletal geometry and pacsin2 is recruited consistently to the trailing end of fast-moving FAJs via a mechanism that requires an intact F-BAR domain. Photoconversion, photobleaching, immunofluorescence and super-resolution microscopy reveal polarized dynamics, and organization of junctional proteins between the front of FAJs and their trailing ends. Interestingly, pacsin2 recruitment inhibits internalization of the VE-cadherin complex from FAJ trailing ends and is important for endothelial monolayer integrity. Together, these findings reveal a novel junction protective mechanism during polarized trafficking of VE-cadherin, which supports barrier maintenance within dynamic endothelial tissue. PMID:27417273

  17. A DTI study on the corpus callosum of treatment-naïve boys with 'pure' Tourette syndrome.

    PubMed

    Wolff, Nicole; Luehr, Ina; Sender, Jennifer; Ehrlich, Stefan; Schmidt-Samoa, Carsten; Dechent, Peter; Roessner, Veit

    2016-01-30

    Disturbances in the corpus callosum (CC) indicating altered interhemispheric connectivity have been associated with Tourette syndrome (TS). The objective of the present study was to refine knowledge about interhemispheric connectivity in TS by analyzing four different diffusion tensor imaging (DTI) parameters in a very homogeneous group of treatment-naïve boys with pure TS in comparison to male healthy controls (HC). Fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD) and mean diffusivity (MD) of five CC-segments were assessed from DTI of 26 treatment-naïve boys with pure TS and 24 HC. We observed no group differences in both FA and RD. However, we found a significant effect for AD and a trend for MD, being both reduced in boys with TS in comparison to HC. Moreover, a negative correlation between AD and the Yale Global Tic Severity Scale total score was observed. Reduced AD of the CC in treatment-naïve boys with pure TS in comparison to HC may indicate that significant alterations in white matter microstructure of the CC contribute to tic symptomatology per se and seem not to be related to confounders such as consequences of long-term medication, tic performance or tic suppression. PMID:26747579

  18. Sulfuric acid vapor in the atmosphere of Venus as observed by the Venus Express Radio Science experiment VeRa

    NASA Astrophysics Data System (ADS)

    Oschlisniok, Janusz; Pätzold, Martin; Häusler, Bernd; Tellmann, Silvia; Bird, Mike; Andert, Tom

    2016-04-01

    The cloud deck within Venus' atmosphere, which covers the entire planet between approx. 50 and 70 km altitude, consists mostly of liquid and gaseous sulfuric acid. The gaseous part increases strongly just below the main clouds and builds an approx. 15 km thick haze layer of H2SO4. This region is responsible for a strong absorption of radio waves as seen in VeRa radio science observations. The amount of the absorption, which is used to derive the abundance of gaseous sulfuric acid, depends on the signal frequency. VeRa probed the atmosphere of Venus between 2006 and 2015 with radio signals at 13 cm (S-band) and 3.6 cm (X-band) wavelengths. We present H2SO4 profiles derived from S-band and X-band absorption during the first occultation season in 2006. The comparison of the H2SO4 profiles derived from both frequency bands provides a reliable picture of the H2SO4 abundance. Distinct differences in the S- and X-band profiles may give a clue to increased SO2 abundances. The derived VeRa results shall be compared with results provided by other experiments onboard Venus Express as well as with previous missions.

  19. HIV co-receptor tropism prediction remains stable over time in treatment-naïve patients.

    PubMed

    Philip, Keir Ej; Macartney, Malcolm J; Conibear, Tim Cr; Smith, Colette J; Marshall, Neal; Johnson, Margaret A; Haque, Tanzina; Webster, Daniel P

    2016-06-01

    HIV co-receptor tropism determination is essential before prescribing the CCR5 antagonist maraviroc. British HIV Association guidelines suggest tropism testing may remain valid for only 90 days in antiretroviral-naïve patients. We aimed to determine the accuracy of this figure. Tropism was assessed in 26 antiretroviral-naïve patients with ongoing viral replication, sampled yearly from first clinic visit. The V3 region of HIV-1 was sequenced in triplicate, then tropism predicted using the Geno2Pheno system. Baseline tropism prediction remained valid for a median of 52 months (range 7-81). For 19/26 individuals baseline tropism remained unchanged throughout a median of 54 months follow-up; 18 R5 tropic and 1 X4 tropic. In seven patients (27%) baseline tropism switched at least once (range 1-4 switches) during follow-up; however, their baseline tropism prediction remained valid for a median of 45 months. Co-receptor tropism in treatment-naïve patients with ongoing viral replication appears highly stable over time, suggesting that baseline genotypic tropism prediction may be valid for a longer duration in patients delaying ART initiation. In this study, baseline tropism prediction remained valid for a median of 52 months, suggesting current guidelines recommending repeat testing after 90 days may be excessively conservative in their assessment of tropism stability. PMID:25999168

  20. Deadly intentions: naïve introduced foxes show rapid attraction to odour cues of an unfamiliar native prey

    PubMed Central

    Bytheway, Jenna P.; Price, Catherine J.; Banks, Peter B.

    2016-01-01

    Introduced predators have caused declines and extinctions of native species worldwide, seemingly able to find and hunt new, unfamiliar prey from the time of their introduction. Yet, just as native species are often naïve to introduced predators, in theory, introduced predators should initially be naïve in their response to novel native prey. Here we examine the response of free-living introduced red foxes (Vulpes vulpes) to their first encounter with the odour cues of a novel native prey, the long-nosed bandicoot (Perameles nasuta). Despite no experience with bandicoots at the study site, foxes were significantly more interested in bandicoot odour compared to untreated controls and to a co-evolved prey, the black rat (Rattus rattus). So what gives introduced predators a novelty advantage over native prey? Such neophilia towards novel potential food sources carries little costs, however naïve native prey often lack analogous neophobic responses towards novel predators, possibly because predator avoidance is so costly. We propose that this nexus between the costs and benefits of responding to novel information is different for alien predators and native prey, giving alien predators a novelty advantage over native prey. This may explain why some introduced predators have rapid and devastating impacts on native fauna. PMID:27416966

  1. Serum Micronutrient Status of Haart-Naïve, HIV Infected Children in South Western Nigeria: A Case Controlled Study

    PubMed Central

    Anyabolu, H. C.; Adejuyigbe, E. A.; Adeodu, O. O.

    2014-01-01

    Background. Though micronutrients are vital in the pathogenesis of human immunodeficiency virus infection, most studies have been conducted in adults. Knowledge of the status of key micronutrients in HIV infected African children will indicate if supplementation may be beneficial to these children living in this resource-poor region. Objectives. We sought to determine the micronutrient status and associated factors of HAART-naïve HIV infected children and compare them with those of the HIV negative controls. Methods. We enrolled 70 apparently stable HAART naïve HIV infected children. Seventy age and sex matched HIV negative children were equally enrolled as the controls. Their social class, anthropometry, clinical stage, CD4 counts, serum zinc, selenium, and vitamin C were determined. Results. The prevalence of zinc, selenium, and vitamin C deficiency in HIV infected subjects was 77.1%, 71.4%, and 70.0%, respectively, as compared to 44.3%, 18.6%, and 15.7% in HIV negative controls. Among the HIV infected subjects, 58.6% were deficient in the three micronutrients. Micronutrient status was related to the weight, clinical, and immunological stages but not BMI or social class. Conclusion. Deficiency of these key micronutrients is widely prevalent in HAART naïve HIV infected children irrespective of social class. This suggests that supplementation trial studies may be indicated in this population. PMID:25180086

  2. Taxane Chemotherapy for Hormone-Naïve Prostate Cancer with Its Expanding Role as Breakthrough Strategy

    PubMed Central

    Shiota, Masaki; Yokomizo, Akira; Eto, Masatoshi

    2016-01-01

    Historically, androgen-deprivation therapy (ADT) was the only primary treatment for metastatic prostate cancer. After prostate cancer develops into castration-resistant prostate cancer (CRPC), there are a few life-prolonging drugs, including taxanes, such as docetaxel and cabazitaxel, as well as novel androgen receptor-targeting agents, such as abiraterone acetate and enzalutamide, which have been proved in clinical trials. However, the prognosis of men with CRPC is still poor. The duration from initiation of ADT to CRPC has not improved in recent decades because no novel therapeutic options have emerged. However, recently, up-front docetaxel chemotherapy has been shown to prolong progression-free as well as overall survival in men with metastatic hormone-naïve prostate cancer. This offers a new way to expand the role of chemotherapy for hormone-naïve prostate cancer. In this review, we summarize the proof-of-concept as well as the current status of taxane chemotherapy for hormone-naïve prostate cancer, focusing on phase 3 clinical trials investigating oncological outcome, and discuss the future direction in this field. PMID:26793621

  3. Deadly intentions: naïve introduced foxes show rapid attraction to odour cues of an unfamiliar native prey.

    PubMed

    Bytheway, Jenna P; Price, Catherine J; Banks, Peter B

    2016-01-01

    Introduced predators have caused declines and extinctions of native species worldwide, seemingly able to find and hunt new, unfamiliar prey from the time of their introduction. Yet, just as native species are often naïve to introduced predators, in theory, introduced predators should initially be naïve in their response to novel native prey. Here we examine the response of free-living introduced red foxes (Vulpes vulpes) to their first encounter with the odour cues of a novel native prey, the long-nosed bandicoot (Perameles nasuta). Despite no experience with bandicoots at the study site, foxes were significantly more interested in bandicoot odour compared to untreated controls and to a co-evolved prey, the black rat (Rattus rattus). So what gives introduced predators a novelty advantage over native prey? Such neophilia towards novel potential food sources carries little costs, however naïve native prey often lack analogous neophobic responses towards novel predators, possibly because predator avoidance is so costly. We propose that this nexus between the costs and benefits of responding to novel information is different for alien predators and native prey, giving alien predators a novelty advantage over native prey. This may explain why some introduced predators have rapid and devastating impacts on native fauna. PMID:27416966

  4. Rat Cytomegalovirus Vaccine Prevents Accelerated Chronic Rejection in CMV-Naïve Recipients of Infected Donor Allograft Hearts.

    PubMed

    Streblow, D N; Hwee, Y K; Kreklywich, C N; Andoh, T; Denton, M; Smith, P; Hart, E; Broekel, R; Pallett, C; Rogers, K; Streblow, A D; Chuop, M; Perry, A; Slifka, M; Messaoudi, I; Orloff, S L

    2015-07-01

    Cytomegalovirus accelerates transplant vascular sclerosis (TVS) and chronic rejection (CR) in solid organ transplants; however, the mechanisms involved are unclear. We determined the efficacy of a CMV vaccine in preventing CMV-accelerated rat cardiac allograft rejection in naïve recipients of CMV+ donor hearts. F344 donor rats were infected with RCMV 5 days prior to heterotopic cardiac transplantation into CMV-naïve or H2 O2 -inactivated RCMV-vaccinated Lewis recipients. Recipients of RCMV-infected donor hearts rejected at POD59, whereas vaccinated recipients exhibited a significantly prolonged time to rejection-POD97, similar to recipients of uninfected donor hearts (POD108). Although all of the donor hearts were preinfected, the vaccinated recipients had lower graft and PBMC viral loads at POD 7 compared to unvaccinated controls. Adoptive T cell and passive antibody transfers from vaccinated Lewis rats into naïve recipients demonstrate that both T-cell and B-cell arms of the adaptive immune response provide protection against CMV-accelerated rejection. Similar findings were obtained when testing three different adjuvants in passive transfer experiments. We have determined that the timing of the vaccine prior to transplantation and the specific adjuvant play critical roles in mediating anti-viral responses and promoting graft survival. CMV vaccination prior to transplantation may effectively increase graft survival. PMID:25766876

  5. Optimized suppression of coherent noise from seismic data using the Karhunen-Loève transform.

    PubMed

    Montagne, Raúl; Vasconcelos, Giovani L

    2006-07-01

    Signals obtained in land seismic surveys are usually contaminated with coherent noise, among which the ground roll (Rayleigh surface waves) is of major concern for it can severely degrade the quality of the information obtained from the seismic record. This paper presents an optimized filter based on the Karhunen-Loève transform for processing seismic images contaminated with ground roll. In this method, the contaminated region of the seismic record, to be processed by the filter, is selected in such way as to correspond to the maximum of a properly defined coherence index. The main advantages of the method are that the ground roll is suppressed with negligible distortion of the remnant reflection signals and that the filtering procedure can be automated. The image processing technique described in this study should also be relevant for other applications where coherent structures embedded in a complex spatiotemporal pattern need to be identified in a more refined way. In particular, it is argued that the method is appropriate for processing optical coherence tomography images whose quality is often degraded by coherent noise (speckle). PMID:16907183

  6. BIM expression in treatment naïve cancers predicts responsiveness to kinase inhibitors

    PubMed Central

    Faber, Anthony; Corcoran, Ryan B.; Ebi, Hiromichi; Sequist, Lecia V.; Waltman, Belinda A.; Chung, Euiheon; Incio, Joao; Digumarthy, Subba R.; Pollack, Sarah F.; Song, Youngchul; Muzikansky, Alona; Lifshits, Eugene; Roberge, Sylvie; Coffman, Erik J.; Benes, Cyril; Gómez, Henry; Baselga, Jose; Arteaga, Carlos L.; Rivera, Miguel N.; Dias-Santagata, Dora; Jain, Rakesh K.; Engelman, Jeffrey A.

    2011-01-01

    Cancers with specific genetic mutations are susceptible to selective kinase inhibitors. However, there is wide spectrum of benefit among cancers harboring the same sensitizing genetic mutations. Herein, we measured apoptotic rates among cell lines sharing the same driver oncogene following treatment with the corresponding kinase inhibitor. There was a wide range of kinase inhibitor-induced apoptosis despite comparable inhibition of the target and associated downstream signaling pathways. Surprisingly, pre-treatment RNA levels of the BH3-only pro-apoptotic BIM strongly predicted the capacity of EGFR, HER2, and PI3K inhibitors to induce apoptosis in EGFR mutant, HER2 amplified, and PIK3CA mutant cancers, respectively, but BIM levels did not predict responsiveness to standard chemotherapies. Furthermore, BIM RNA levels in EGFR mutant lung cancer specimens predicted response and duration of clinical benefit from EGFR inhibitors. These findings suggest assessment of BIM levels in treatment naïve tumor biopsies may indicate the degree of benefit from single-agent kinase inhibitors in multiple oncogene-addiction paradigms. PMID:22145099

  7. Children's conceptions of mental illness: a naïve theory approach.

    PubMed

    Fox, Claudine; Buchanan-Barrow, Eithne; Barrett, Martyn

    2010-09-01

    This paper reports two studies that investigated children's conceptions of mental illness using a naïve theory approach, drawing upon a conceptual framework for analysing illness representations which distinguishes between the identity, causes, consequences, curability, and timeline of an illness. The studies utilized semi-structured interviewing and card selection tasks to assess 6- to 11-year-old children's conceptions of the causes and consequences (Study 1) and the curability and timeline (Study 2) of different mental and physical illnesses/ailments. The studies revealed that, at all ages, the children held coherent causal-explanatory ideas about the causes, consequences, curability, and timeline of both mental and physical illnesses/ailments. However, while younger children tended to rely on their knowledge of common physical illnesses when thinking about mental illnesses, providing contagion and contamination explanations of cause, older children demonstrated differences in their thinking about mental and physical illnesses. No substantial gender differences were found in the children's thinking. It is argued that children hold coherent conceptions of mental illness at all ages, but that mental illness only emerges as an ontologically distinct conceptual domain by the end of middle childhood. PMID:20849036

  8. Meditation-based treatment yielding immediate relief for meditation-naïve migraineurs.

    PubMed

    Tonelli, Makenzie E; Wachholtz, Amy B

    2014-03-01

    Meditation is gaining popularity as an effective means of managing and attenuating pain and has been particularly effective for migraines. Meditation additionally addresses the negative emotional states known to exist with migraines. The purpose of this study was to evaluate the effectiveness of meditation as an immediate intervention for reducing migraine pain as well as alleviating emotional tension, examined herein as a negative affect hypothesized to be correlated with pain. Twenty-seven migraineurs, with two to ten migraines per month, reported migraine-related pain and emotional tension ratings on a Likert scale (ranging from 0 to 10) before and after exposure to a brief meditation-based treatment. All participants were meditation- naïve, and attended one 20-minute guided meditation session based on the Buddhist "loving kindness" approach. After the session, participants reported a 33% decrease in pain and a 43% decrease in emotional tension. The data suggest that a single exposure to a brief meditative technique can significantly reduce pain and tension, as well as offer several clinical implications. It can be concluded that single exposure to a meditative technique can significantly reduce pain and tension. The effectiveness and immediacy of this intervention offers several implications for nurses. PMID:24602422

  9. VE-cadherin cleavage by ovarian cancer microparticles induces β-catenin phosphorylation in endothelial cells.

    PubMed

    Al Thawadi, Hamda; Abu-Kaoud, Nadine; Al Farsi, Haleema; Hoarau-Véchot, Jessica; Rafii, Shahin; Rafii, Arash; Pasquier, Jennifer

    2016-02-01

    Microparticles (MPs) are increasingly recognized as important mediators of cell-cell communication in tumour growth and metastasis by facilitating angiogenesis-related processes. While the effects of the MPs on recipient cells are usually well described in the literature, the leading process remains unclear. Here we isolated MPs from ovarian cancer cells and investigated their effect on endothelial cells. First, we demonstrated that ovarian cancer MPs trigger β-catenin activation in endothelial cells, inducing the upregulation of Wnt/β-catenin target genes and an increase of angiogenic properties. We showed that this MPs mediated activation of β-catenin in ECs was Wnt/Frizzled independent; but dependent on VE-cadherin localization disruption, αVβ3 integrin activation and MMP activity. Finally, we revealed that Rac1 and AKT were responsible for β-catenin phosphorylation and translocation to the nucleus. Overall, our results indicate that MPs released from cancer cells could play a major role in neo-angiogenesis through activation of beta catenin pathway in endothelial cells. PMID:26700621

  10. The Ontogeny of Bumblebee Flight Trajectories: From Naïve Explorers to Experienced Foragers

    PubMed Central

    Osborne, Juliet L.; Smith, Alan; Clark, Suzanne J.; Reynolds, Don R.; Barron, Mandy C.; Lim, Ka S.; Reynolds, Andy M.

    2013-01-01

    Understanding strategies used by animals to explore their landscape is essential to predict how they exploit patchy resources, and consequently how they are likely to respond to changes in resource distribution. Social bees provide a good model for this and, whilst there are published descriptions of their behaviour on initial learning flights close to the colony, it is still unclear how bees find floral resources over hundreds of metres and how these flights become directed foraging trips. We investigated the spatial ecology of exploration by radar tracking bumblebees, and comparing the flight trajectories of bees with differing experience. The bees left the colony within a day or two of eclosion and flew in complex loops of ever-increasing size around the colony, exhibiting Lévy-flight characteristics constituting an optimal searching strategy. This mathematical pattern can be used to predict how animals exploring individually might exploit a patchy landscape. The bees’ groundspeed, maximum displacement from the nest and total distance travelled on a trip increased significantly with experience. More experienced bees flew direct paths, predominantly flying upwind on their outward trips although forage was available in all directions. The flights differed from those of naïve honeybees: they occurred at an earlier age, showed more complex looping, and resulted in earlier returns of pollen to the colony. In summary bumblebees learn to find home and food rapidly, though phases of orientation, learning and searching were not easily separable, suggesting some multi-tasking. PMID:24265707

  11. Follower ants in a tandem pair are not always naïve

    PubMed Central

    Schultheiss, Patrick; Raderschall, Chloé A; Narendra, Ajay

    2015-01-01

    In addition to foraging individually several species of ants guide nestmates to a goal by tandem running. We found that the Australian ant, Camponotus consobrinus, forages both individually and by tandem running to head to the same goal, nest-specific native Australian trees on which they forage. While paths of solitary foragers and initial paths of tandem followers showed no differences in heading directions or straightness, tandem followers moved at about half the speed of solitary runs. When leaders were experimentally removed, follower ants initially engaged in a systematic search around the point of interruption, following which they either (a) headed directly towards and successfully reached the foraging trees, or (b) continued searching or (c) returned to the nest. The high incidence of followers that successfully navigated towards the foraging trees on their own provides strong evidence that many tandem followers are in fact experienced foragers. Detailed analysis of the searching behaviour revealed that even seemingly lost followers displayed a directional bias towards the foraging trees in their search path. Our results show that in a foraging context follower ants in a tandem pair are not always naïve. PMID:26021611

  12. A naïve Bayesian classifier for identifying plant microRNAs.

    PubMed

    Douglass, Stephen; Hsu, Ssu-Wei; Cokus, Shawn; Goldberg, Robert B; Harada, John J; Pellegrini, Matteo

    2016-06-01

    MicroRNAs (miRNAs) are important regulatory molecules in eukaryotic organisms. Existing methods for the identification of mature miRNA sequences in plants rely extensively on the search for stem-loop structures, leading to high false negative rates. Here, we describe a probabilistic method for ranking putative plant miRNAs using a naïve Bayes classifier and its publicly available implementation. We use a number of properties to construct the classifier, including sequence length, number of observations, existence of detectable predicted miRNA* sequences, the distribution of nearby reads and mapping multiplicity. We apply the method to small RNA sequence data from soybean, peach, Arabidopsis and rice and provide experimental validation of several predictions in soybean. The approach performs well overall and strongly enriches for known miRNAs over other types of sequences. By utilizing a Bayesian approach to rank putative miRNAs, our method is able to score miRNAs that would be eliminated by other methods, such as those that have low counts or lack detectable miRNA* sequences. As a result, we are able to detect several soybean miRNA candidates, including some that are 24 nucleotides long, a class that is almost universally eliminated by other methods. PMID:27061965

  13. Strong lensing probability in TeVeS (tensor-vector-scalar) theory

    SciTech Connect

    Chen Daming

    2008-01-15

    We recalculate the strong lensing probability as a function of the image separation in TeVeS (tensor-vector-scalar) cosmology, which is a relativistic version of MOND (MOdified Newtonian Dynamics). The lens is modeled by the Hernquist profile. We assume an open cosmology with {Omega}{sub b} = 0.04 and {Omega}{sub {Lambda}} = 0.5 and three different kinds of interpolating functions. Two different galaxy stellar mass functions (GSMF) are adopted: PHJ (Panter, Heavens and Jimenez 2004 Mon. Not. R. Astron. Soc. 355 764) determined from SDSS data release 1 and Fontana (Fontana et al 2006 Astron. Astrophys. 459 745) from GOODS-MUSIC catalog. We compare our results with both the predicted probabilities for lenses from singular isothermal sphere galaxy halos in LCDM (Lambda cold dark matter) with a Schechter-fit velocity function, and the observational results for the well defined combined sample of the Cosmic Lens All-Sky Survey (CLASS) and Jodrell Bank/Very Large Array Astrometric Survey (JVAS). It turns out that the interpolating function {mu}(x) = x/(1+x) combined with Fontana GSMF matches the results from CLASS/JVAS quite well.

  14. Infectious diarrhoea in antiretroviral therapy-naïve HIV/AIDS patients in Kenya

    PubMed Central

    Wanyiri, Jane W.; Kanyi, Henry; Maina, Samuel; Wang, David E.; Ngugi, Paul; O'Connor, Roberta; Kamau, Timothy; Waithera, Tabitha; Kimani, Gachuhi; Wamae, Claire N.; Mwamburi, Mkaya; Ward, Honorine D.

    2013-01-01

    Background Diarrhoea is a significant cause of morbidity and mortality in immunocompromised patients. The objectives of this study were to investigate the aetiological agents, risk factors and clinical features associated with diarrhoea in HIV/AIDS patients in Kenya. Methods Sociodemographic, epidemiological and clinical data were obtained for 164 HIV/AIDS patients (70 with and 94 without diarrhoea) recruited from Kenyatta National Hospital, Kenya. Stool samples were examined for enteric pathogens by microscopy and bacteriology. Results Intestinal protozoa and fungi were identified in 70% of patients, more frequently in those with diarrhoea (p<0.001). Helminths were detected in 25.6% of patients overall, and bacterial pathogens were identified in 51% of patients with diarrhoea. Polyparasitism was more common in patients with diarrhoea than those without (p<0.0001). Higher CD4+ T-cell count (OR = 0.995, 95% CI 0.992–0.998) and water treatment (OR = 0.231, 95% CI 0.126–0.830) were associated with a lower risk of diarrhoea, while close contact with cows (OR = 3.200, 95% CI 1.26–8.13) or pigs (OR = 11.176, 95% CI 3.76–43.56) were associated with a higher risk of diarrhoea. Conclusions Multiple enteric pathogens that are causative agents of diarrhoea were isolated from stools of antiretroviral therapy-naïve HIV/AIDS patients, indicating a need for surveillance, treatment and promotion of hygienic practices. PMID:24026463

  15. The Effect of Orthopedic Advertising and Self-Promotion on a Naïve Population.

    PubMed

    Mohney, Stephen; Lee, Daniel J; Elfar, John C

    2016-01-01

    There has been a marked increase in the number of physicians marketing themselves directly to patients and consumers. However, it is unclear how different promotional styles affect patients' perceptions of their physicians. We hypothesized that self-promoting orthopedic surgeons enjoy a more positive impact on nonphysician patients as compared to non-self-promoting surgeons, as well as a corresponding negative impact on their peer-surgeons. Surgeon websites were selected from the 5 largest population centers in the United States. Subjects with varying degrees of familiarity with orthopedic surgery evaluated Internet profiles of surgeons on a forced choice Likert scale to measure the amount of self-promotion. The naïve subjects judged self-promoting surgeons more favorably than the orthopedic surgeons. In contrast, board-certified orthopedic surgeons viewed self-promoting surgeons more negatively than did their nonphysician counterparts. In summary, the present study revealed that the potential for self-promotion to unduly influence potential patients is real and should be a considerable concern to surgeons, patients, and the profession. PMID:27327932

  16. A Pairwise Naïve Bayes Approach to Bayesian Classification

    PubMed Central

    Betensky, Rebecca A.

    2016-01-01

    Despite the relatively high accuracy of the naïve Bayes (NB) classifier, there may be several instances where it is not optimal, i.e. does not have the same classification performance as the Bayes classifier utilizing the joint distribution of the examined attributes. However, the Bayes classifier can be computationally intractable due to its required knowledge of the joint distribution. Therefore, we introduce a “pairwise naïve” Bayes (PNB) classifier that incorporates all pairwise relationships among the examined attributes, but does not require specification of the joint distribution. In this paper, we first describe the necessary and sufficient conditions under which the PNB classifier is optimal. We then discuss sufficient conditions for which the PNB classifier, and not NB, is optimal for normal attributes. Through simulation and actual studies, we evaluate the performance of our proposed classifier relative to the Bayes and NB classifiers, along with the HNB, AODE, LBR and TAN classifiers, using normal density and empirical estimation methods. Our applications show that the PNB classifier using normal density estimation yields the highest accuracy for data sets containing continuous attributes. We conclude that it offers a useful compromise between the Bayes and NB classifiers. PMID:27087730

  17. On the application of Karhunen-Loève transform to transient dynamic systems

    NASA Astrophysics Data System (ADS)

    Glüsmann, Philipp; Kreuzer, Edwin

    2009-12-01

    The Karhunen-Loève transform (KLT) has become a popular method in various fields of engineering science. Due to its ability to identify the most prominent features in the underlying system dynamics the KLT is a favorable method for such tasks as process monitoring, model order reduction or optimum control. However, it is a well-known fact that the KLT is 'case sensitive'. That is that changes in the dynamic system behavior can decisively affect the KLT results. As much as this property is desired for monitoring problems, it limits the performance of KLT in model order reduction or optimum control problems, if systems are subject to structural changes. Recent research interest focuses on extending applications of KLT to systems with transient dynamic behavior or changing boundary conditions. Approaches have been published that circumvent the limitations of KLT by either assuming reasonable comparability of system dynamics or by measuring the representative performance of KLT-bases a posteriori. However, such methods require additional simulations of the full size system and thus jeopardize the idea of model order reduction. In this paper, we introduce a novel a priori measure to evaluate the performance of the current KLT-basis. This procedure can be of great help in either monitoring or adaptive control of systems that show intermittent transient and (quasi-)stationary dynamic behavior. This a priori measure prepares the path for adaptive model order reduction schemes. Moreover, it can be used to measure the stationarity of multidimensional dynamic processes.

  18. DNA damage and antioxidants in treatment naïve children with obsessive-compulsive disorder.

    PubMed

    Şimşek, Şeref; Gençoğlan, Salih; Yüksel, Tuğba

    2016-03-30

    The current study aimed to investigate whether serum antioxidant levels and DNA damage differ between the children and adolescents with Obsessive Compulsive Disorder (OCD) and healthy controls. The study included 31 children (Male/Female, 22/9; age range 7-17 years), with treatment naïve OCD diagnosed according to Diagnostic and Statistical Manual of Mental Disorders-V (DSM-V) and 28 age- and gender-matched healthy control subjects. Children's Yale Brown Obsession Compulsion Scale (CY-BOC) was applied to the children. Glutathione peroxidase (GPx), superoxide dismutase (SOD), coenzyme Q (CoQ), and 8-Hydroxy-2-Deoxyguanosine (8-OHdG) were all measured by the enzyme-linked immunosorbent assay method. GPx, CoQ and 8-OHdG levels were found to be significantly higher in the OCD group, compared to the control group (p=0.010, p=0.034, p=0.010, respectively); however, no significant difference was found in the SOD levels between two groups (p=0.10). There were no correlations between the CY-BOC scores, depression scores, duration of the disease and biochemical parameters (p>0.05, for all). Children with OCD were found to have higher antioxidant levels and oxidative DNA damage. The findings of this study support the role of oxidative stress in the pathogenesis of OCD. In this regard, any possible effect of adding antioxidants to conventional treatment can be investigated. PMID:26833278

  19. VizieR Online Data Catalog: Motion Verified Red Stars (MoVeRS) (Theissen+, 2016)

    NASA Astrophysics Data System (ADS)

    Theissen, C. A.; West, A. A.; Dhital, S.

    2015-09-01

    We present a photometric catalog of 8,735,004 proper motion selected low-mass stars (KML-spectral types) within the Sloan Digital Sky Survey (SDSS) footprint, from the combined SDSS-DR10, Two-Micron All-Sky Survey (2MASS) Point Source Catalog (PSC), and Wide-field Infrared Survey Explorer (WISE) AllWISE catalog. Stars were selected using r-i, i-z, r-z, z-J, and z-W1 colors, and SDSS, WISE, and 2MASS astrometry was combined to compute proper motions. The resulting 3,518,150 stars were augmented with proper motions for 5,216,854 earlier type stars from the combined SDSS and United States Naval Observatory B1.0 catalog (USNO-B). We used SDSS+USNO-B proper motions to determine the best criteria for selecting a clean sample of stars. Only stars whose proper motions were greater than their 2-sigma uncertainty were included. Our Motion Verified Red Stars (MoVeRS) catalog is available through SDSS CasJobs and VizieR. (2 data files).

  20. Metabolomics study of fatigue in patients with rheumatoid arthritis naïve to biological treatment.

    PubMed

    Surowiec, Izabella; Gjesdal, Clara Gram; Jonsson, Grete; Norheim, Katrine Brække; Lundstedt, Torbjörn; Trygg, Johan; Omdal, Roald

    2016-05-01

    Fatigue occurs in all chronic inflammatory diseases, in cancer, and in some neurological conditions. Patients often regard fatigue as one of their most debilitating problems, but currently there is no established treatment and the mechanisms that lead to and regulate fatigue are incompletely understood. Our objective was to more completely understand the physiology of this phenomenon. Twenty-four patients with rheumatoid arthritis (RA) naïve to treatment with biological drugs were enrolled for the study. Fatigue was measured with a fatigue visual analogue scale (fVAS). Ethylenediaminetetraacetic acid (EDTA) plasma samples were subjected to gas chromatography-time-of-flight mass spectrometry (GC/MS-TOF)-based metabolite profiling. Obtained metabolite data were evaluated by multivariate data analysis with orthogonal projections to latent structures (OPLS) method to pinpoint metabolic changes related to fatigue severity. A significant multivariate OPLS model was obtained between the fVAS scores and the measured metabolic levels. Increasing fatigue scores were associated with a metabolic pattern characterized by down-regulation of metabolites from the urea cycle, fatty acids, tocopherols, aromatic amino acids, and hypoxanthine. Uric acid levels were increased. Apart from fatigue, we found no other disease-related variables that might be responsible for these changes. Our MS-based metabolomic approach demonstrated strong associations between fatigue and several biochemical patterns related to oxidative stress. PMID:26803313

  1. Social isolation prompts maternal behavior in sexually naïve male ddN mice.

    PubMed

    Orikasa, Chitose; Nagaoka, Kentaro; Katsumata, Harumi; Sato, Manami; Kondo, Yasuhiko; Minami, Shiro; Sakuma, Yasuo

    2015-11-01

    Maternal behavior in mice is considered to be sexually dimorphic; that is, females show maternal care for their offspring, whereas this behavior is rarely shown in males. Here, we examined how social isolation affects the interaction of adult male mice with pups. Three weeks of isolation during puberty (5-8 weeks old) induced retrieving and crouching when exposed to pups, while males with 1 week isolation (7-8 weeks old) also showed such maternal care, but were less responsive to pups. We also examined the effect of isolation during young adulthood (8-11 weeks old), and found an induction of maternal behavior comparable to that in younger male mice. This effect was blocked by exposure to chemosensory and auditory social signals derived from males in an attached compartment separated by doubled opaque barriers. These results demonstrate that social isolation in both puberty and postpuberty facilitates male maternal behavior in sexually naïve mice. The results also indicate that air-borne chemicals and/or sounds of male conspecifics, including ultrasonic vocalization and noise by their movement may be sufficient to interfere with the isolation effect on induction of maternal behavior in male mice. PMID:26166155

  2. Volatile profiling reveals intracellular metabolic changes in Aspergillus parasiticus: veA regulates branched chain amino acid and ethanol metabolism

    PubMed Central

    2010-01-01

    Background Filamentous fungi in the genus Aspergillus produce a variety of natural products, including aflatoxin, the most potent naturally occurring carcinogen known. Aflatoxin biosynthesis, one of the most highly characterized secondary metabolic pathways, offers a model system to study secondary metabolism in eukaryotes. To control or customize biosynthesis of natural products we must understand how secondary metabolism integrates into the overall cellular metabolic network. By applying a metabolomics approach we analyzed volatile compounds synthesized by Aspergillus parasiticus in an attempt to define the association of secondary metabolism with other metabolic and cellular processes. Results Volatile compounds were examined using solid phase microextraction - gas chromatography/mass spectrometry. In the wild type strain Aspergillus parasiticus SU-1, the largest group of volatiles included compounds derived from catabolism of branched chain amino acids (leucine, isoleucine, and valine); we also identified alcohols, esters, aldehydes, and lipid-derived volatiles. The number and quantity of the volatiles produced depended on media composition, time of incubation, and light-dark status. A block in aflatoxin biosynthesis or disruption of the global regulator veA affected the volatile profile. In addition to its multiple functions in secondary metabolism and development, VeA negatively regulated catabolism of branched chain amino acids and synthesis of ethanol at the transcriptional level thus playing a role in controlling carbon flow within the cell. Finally, we demonstrated that volatiles generated by a veA disruption mutant are part of the complex regulatory machinery that mediates the effects of VeA on asexual conidiation and sclerotia formation. Conclusions 1) Volatile profiling provides a rapid, effective, and powerful approach to identify changes in intracellular metabolic networks in filamentous fungi. 2) VeA coordinates the biosynthesis of secondary

  3. Construction of naïve camelids VHH repertoire in phage display-based library.

    PubMed

    Sabir, Jamal S M; Atef, Ahmed; El-Domyati, Fotouh M; Edris, Sherif; Hajrah, Nahid; Alzohairy, Ahmed M; Bahieldin, Ahmed

    2014-04-01

    Camelids have unique antibodies, namely HCAbs (VHH) or commercially named Nanobodies(®) (Nb) that are composed only of a heavy-chain homodimer. As libraries based on immunized camelids are time-consuming, costly and likely redundant for certain antigens, we describe the construction of a naïve camelid VHHs library from blood serum of non-immunized camelids with affinity in the subnanomolar range and suitable for standard immune applications. This approach is rapid and recovers VHH repertoire with the advantages of being more diverse, non-specific and devoid of subpopulations of specific antibodies, which allows the identification of binders for any potential antigen (or pathogen). RNAs from a number of camelids from Saudi Arabia were isolated and cDNAs of the diverse vhh gene were amplified; the resulting amplicons were cloned in the phage display pSEX81 vector. The size of the library was found to be within the required range (10(7)) suitable for subsequent applications in disease diagnosis and treatment. Two hundred clones were randomly selected and the inserted gene library was either estimated for redundancy or sequenced and aligned to the reference camelid vhh gene (acc. No. ADE99145). Results indicated complete non-specificity of this small library in which no single event of redundancy was detected. These results indicate the efficacy of following this approach in order to yield a large and diverse enough gene library to secure the presence of the required version encoding the required antibodies for any target antigen. This work is a first step towards the construction of phage display-based biosensors useful in disease (e.g., TB or tuberculosis) diagnosis and treatment. PMID:24702893

  4. Glucose disturbances in first-episode drug-naïve schizophrenia: Relationship to psychopathology.

    PubMed

    Zhang, Xiang Yang; Chen, Da-Chun; Tan, Yun-Long; An, Hui-Mei; Zunta-Soares, Giovana B; Huang, Xu-Feng; Soares, Jair C

    2015-12-01

    Accumulating evidence shows abnormal glucose metabolism in schizophrenia, even at the onset of psychosis. This study aims to examine the glucose and lipid metabolism in first-episode and drug naïve (FEDN) patients with schizophrenia and to explore their relationships with psychopathology, which have been under-investigated. Fasting glucose and lipid profiles, as well as homeostasis model of assessment-insulin resistance (HOMA-IR) index were determined in 120 never-medicated first-episode and 31 healthy control subjects matched for gender and age. The schizophrenia symptomatology was assessed by the positive and negative syndrome scale (PANSS). Our results showed that schizophrenia patients had a significantly higher level of fasting plasma glucose (p<0.0001) and insulin (p=0.038). HOMA, an indicator of insulin resistance was higher in the patients than in the healthy controls (p=0.008). No differences were found between the patients and healthy subjects in the levels of plasma triglycerides, high-density lipoprotein, and low-density lipoprotein, except that the cholesterol level was higher in the patients than health subjects (p=0.016). A significant negative association between plasma glucose levels and the PANSS positive symptom subscores was observed (p=0.013). Stepwise multiple regression analysis identified insulin resistance, insulin and the PANSS positive symptom subscore as significant predictor factors for glucose level. These results suggest that abnormal glucose metabolism may be associated with the pathogenesis and psychopathology of schizophrenia in the early phases of the disease process. PMID:26385108

  5. Gene expression profiling of Naïve sheep genetically resistant and susceptible to gastrointestinal nematodes

    PubMed Central

    Keane, Orla M; Zadissa, Amonida; Wilson, Theresa; Hyndman, Dianne L; Greer, Gordon J; Baird, David B; McCulloch, Alan F; Crawford, Allan M; McEwan, John C

    2006-01-01

    Background Gastrointestinal nematodes constitute a major cause of morbidity and mortality in grazing ruminants. Individual animals or breeds, however, are known to differ in their resistance to infection. Gene expression profiling allows us to examine large numbers of transcripts simultaneously in order to identify those transcripts that contribute to an animal's susceptibility or resistance. Results With the goal of identifying genes with a differential pattern of expression between sheep genetically resistant and susceptible to gastrointestinal nematodes, a 20,000 spot ovine cDNA microarray was constructed. This array was used to interrogate the expression of 9,238 known genes in duodenum tissue of four resistant and four susceptible female lambs. Naïve animals were used in order to look at genes that were differentially expressed in the absence of infection with gastrointestinal nematodes. Forty one unique known genes were identified that were differentially expressed between the resistant and susceptible animals. Northern blotting of a selection of the genes confirmed differential expression. The differentially expressed genes had a variety of functions, although many genes relating to the stress response and response to stimulus were more highly expressed in the susceptible animals. Conclusion We have constructed the first reported ovine microarray and used this array to examine gene expression in lambs genetically resistant and susceptible to gastrointestinal nematode infection. This study indicates that susceptible animals appear to be generating a hyper-sensitive immune response to non-nematode challenges. The gastrointestinal tract of susceptible animals is therefore under stress and compromised even in the absence of gastrointestinal nematodes. These factors may contribute to the genetic susceptibility of these animals. PMID:16515715

  6. Cabozantinib resolves bone scans in tumor-naïve mice harboring skeletal injuries.

    PubMed

    Doran, Michael G; Spratt, Daniel E; Wongvipat, John; Ulmert, David; Carver, Brett S; Sawyers, Charles L; Evans, Michael J

    2014-01-01

    The receptor tyrosine kinase inhibitor cabozantinib (XL184, BMS-907351 Cometriq) has displayed impressive clinical activity against several indications, culminating in its recent approval for medullary thyroid cancer. Among malignancies with tropism for the bone (prostate, breast), one striking feature of early clinical reports about this drug has been the rapid and complete resolution of bone scans, a phenomenon almost never observed even among therapies already shown to confer survival benefit. In castration-resistant prostate cancer, not all conventional response indicators change as dramatically posttreatment, raising the possibility that cabozantinib may impair the ability of bone-seeking radionuclides to integrate within the remodeling bone. To test this hypothesis, we surgically induced bone remodeling via physical insult in non-tumor-bearing mice and performed 18F-sodium fluoride (18F-NaF) positron emission tomographic (PET) and technetium 99m-methylene diphosphonate (99mTc-MDP) single-photon emission computed tomographic (SPECT) scans pre- and posttreatment with cabozantinib and related inhibitors. A consistent reduction in the accumulation of either radiotracer at the site of bone remodeling was observed in animals treated with cabozantinib. Given that cabozantinib is known to inhibit several receptor tyrosine kinases, we drugged animals with various permutations of more selective inhibitors to attempt to refine the molecular basis of bone scan resolution. Neither the vascular endothelial growth factor receptor (VEGFR) inhibitor axitinib, the MET inhibitor crizotinib, nor the combination was capable of inhibiting 18F-NaF accumulation at known bioactive doses. In summary, although the mechanism by which cabozantinib suppresses radionuclide incorporation into foci undergoing bone remodeling remains unknown, that this phenomenon occurs in tumor-naïve models indicates that caution should be exercised in interpreting the clinical significance of this event

  7. Hamiltonian Map to Conformal Modification of Spacetime Metric: Kaluza-Klein and TeVeS

    NASA Astrophysics Data System (ADS)

    Horwitz, Lawrence; Gershon, Avi; Schiffer, Marcelo

    2011-01-01

    It has been shown that the orbits of motion for a wide class of non-relativistic Hamiltonian systems can be described as geodesic flows on a manifold and an associated dual by means of a conformal map. This method can be applied to a four dimensional manifold of orbits in spacetime associated with a relativistic system. We show that a relativistic Hamiltonian which generates Einstein geodesics, with the addition of a world scalar field, can be put into correspondence in this way with another Hamiltonian with conformally modified metric. Such a construction could account for part of the requirements of Bekenstein for achieving the MOND theory of Milgrom in the post-Newtonian limit. The constraints on the MOND theory imposed by the galactic rotation curves, through this correspondence, would then imply constraints on the structure of the world scalar field. We then use the fact that a Hamiltonian with vector gauge fields results, through such a conformal map, in a Kaluza-Klein type theory, and indicate how the TeVeS structure of Bekenstein and Saunders can be put into this framework. We exhibit a class of infinitesimal gauge transformations on the gauge fields {mathcal{U}}_{μ}(x) which preserve the Bekenstein-Sanders condition {mathcal{U}}_{μ}{mathcal{U}}^{μ}=-1. The underlying quantum structure giving rise to these gauge fields is a Hilbert bundle, and the gauge transformations induce a non-commutative behavior to the fields, i.e. they become of Yang-Mills type. Working in the infinitesimal gauge neighborhood of the initial Abelian theory we show that in the Abelian limit the Yang-Mills field equations provide residual nonlinear terms which may avoid the caustic singularity found by Contaldi et al.

  8. Serum alkaline phosphatase negatively affects endothelium-dependent vasodilation in naïve hypertensive patients.

    PubMed

    Perticone, Francesco; Perticone, Maria; Maio, Raffaele; Sciacqua, Angela; Andreucci, Michele; Tripepi, Giovanni; Corrao, Salvatore; Mallamaci, Francesca; Sesti, Giorgio; Zoccali, Carmine

    2015-10-01

    Tissue nonspecific alkaline phosphatase, promoting arterial calcification in experimental models, is a powerful predictor of total and cardiovascular mortality in general population and in patients with renal or cardiovascular diseases. For this study, to evaluate a possible correlation between serum alkaline phosphatase levels and endothelial function, assessed by strain gauge plethysmography, we enrolled 500 naïve hypertensives divided into increasing tertiles of alkaline phosphatase. The maximal response to acetylcholine was inversely related to alkaline phosphatase (r=−0.55; P<0.001), and this association was independent (r=−0.61; P<0.001) of demographic and classical risk factors, body mass index, estimated glomerular filtration rate, serum phosphorus and calcium, C-reactive protein, and albuminuria. At multiple logistic regression analysis, the risk of endothelial dysfunction was ≈3-fold higher in patients in the third tertile than that of patients in the first tertile. We also tested the combined role of alkaline phosphatase and serum phosphorus on endothelial function. The steepness of the alkaline phosphatase/vasodilating response to acetylcholine relationship was substantially attenuated (P<0.001) in patients with serum phosphorus above the median value when compared with patients with serum phosphorus below the median (−5.0% versus −10.2% per alkaline phosphatase unit, respectively), and this interaction remained highly significant (P<0.001) after adjustment of all the previously mentioned risk factors. Our data support a strong and significant inverse relationship between alkaline phosphatase and endothelium-dependent vasodilation, which was attenuated by relatively higher serum phosphorus levels. PMID:26324506

  9. Lateralizing Cortical Excitability in Drug Naïve Patients with Generalized or Focal Epilepsy

    PubMed Central

    Lee, Jung Hwa; Joo, Eun Yeon; Seo, Dae Won; Hong, Seung Bong

    2015-01-01

    Background and Purpose: Numerous transcranial magnetic stimulation (TMS) studies have defined the characteristic features of TMS in epilepsy. TME parameters were expected to classify the epilepsy syndrome or drug responses. However, the results such as cortical silent periods (CSP) are variable according to conditions of patients. Here, we investigate whether specific TMS parameters have localizing or lateralizing values in drug-naïve epilepsy patients. Methods: We recruited 148 consecutive untreated patients with epilepsy (idiopathic generalized epilepsy (IGE) 38, focal epilepsy (FE) 110, mean age 31.4 years) and 38 age- and gender-matched normal subjects. We obtained resting motor threshold (RMT), motor-evoked potential (MEP), CSP, short interval intracortical inhibition (SICI, inter-stimuli interval 2–5 ms), and intracortical facilitation (ICF, inter-stimuli interval 10–20 ms). TMS were performed during a seizure-free state of more than 48 h. Results: In IGE, no interhemispheric difference in CSP was found (p > 0.05). However, the mean CSP was longer in IGE patients than in normal controls at all stimulus intensities (p < 0.05). The mean CSP in ipsilateral hemisphere (IH) of FE was significantly longer at all stimulus intensities than that in normal controls (p < 0.001). The CSP in IH was longer than that in the contralateral hemisphere of FE. There was no significant difference in CSP between FE and IGE. SICI was significantly reduced only in the IH of FE versus normal subjects. RMT, MEP amplitudes, and ICF did not differ among IGE, FE, and normal controls. Conclusions: We found that prolonged CSP and reduced SICI in FE indicate asymmetrically increased cortical inhibition and excitation in the epileptic hemispheres. It suggests that CSP among TMS parameters has a crucial role to lateralize the epileptic hemisphere in FE. PMID:26819939

  10. A combined DTI and structural MRI study in medicated-naïve chronic schizophrenia.

    PubMed

    Liu, Xiaoyi; Lai, Yunyao; Wang, Xijin; Hao, Chuanxi; Chen, Lei; Zhou, Zhenyu; Yu, Xin; Hong, Nan

    2014-01-01

    Disconnection in white matter (WM) pathway and alterations in gray matter (GM) structure have been hypothesized as pathogenesis in schizophrenia. However, the relationship between the abnormal WM integrity and the alteration of GM in anatomically connected areas remains uncertain. Moreover, the potential influence of antipsychotic medication on WM anisotropy and cortical morphology was not excluded in previous studies. In this study, a total number of 34 subjects were enrolled, including 17 medicated-naïve chronic schizophrenia patients and 17 healthy controls. Tract-based spatial statistics (TBSS) were applied to investigate the level of WM integrity. The FreeSurfer surface-based analysis was used to determine GM volume, cortical thickness and the surface area of GM regions which corresponded to abnormal WM fiber tracts. We observed that patients possessed lower fractional anisotropy (FA) values in the left inferior fronto-occipital fasciculus (IFOF) and left inferior longitudinal fasciculus (ILF), along with smaller GM volume and cortical thinning in temporal lobe than the healthy controls, which reflected the underlying WM and GM disruption that contributed to the disease. In the patient population, the lower connectivity of ILF and IFOF was positively associated with cortical thickness in left lateral orbitofrontal cortex, superior temporal gyrus and lingual gyrus in males, and positively correlated with GM volume in left lateral orbitofrontal cortex in females. On the other hand, it was negatively correlated with cortical area of middle temporal gyrus in males and temporal pole in females respectively, but not when genders were combined. These findings suggested that abnormal WM integrity and anatomical correspondence of GM alterations in schizophrenia were interdependent on gender-separated analysis in patients with schizophrenia. Moreover, combining TBSS and FreeSurfer might be a useful method to provide significant insight into interacting processes

  11. Mismatched anti-predator behavioral responses in predator-naïve larval anurans.

    PubMed

    Albecker, Molly; Vance-Chalcraft, Heather D

    2015-01-01

    Organisms are adept at altering behaviors to balance the tradeoff between foraging and predation risk in spatially and temporally shifting predator environments. In order to optimize this tradeoff, prey need to be able to display an appropriate response based on degree of predation risk. To be most beneficial in the earliest life stages in which many prey are vulnerable to predation, innate anti-predator responses should scale to match the risk imposed by predators until learned anti-predator responses can occur. We conducted an experiment that examined whether tadpoles with no previous exposure to predators (i.e., predator-naive) exhibit innate antipredator behavioral responses (e.g., via refuge use and spatial avoidance) that match the actual risk posed by each predator. Using 7 treatments (6 free-roaming, lethal predators plus no-predator control), we determined the predation rates of each predator on Lithobates sphenocephalus tadpoles. We recorded behavioral observations on an additional 7 nonlethal treatments (6 caged predators plus no-predator control). Tadpoles exhibited innate responses to fish predators, but not non-fish predators, even though two non-fish predators (newt and crayfish) consumed the most tadpoles. Due to a mismatch between innate response and predator consumption, tadpoles may be vulnerable to greater rates of predation at the earliest life stages before learning can occur. Thus, naïve tadpoles in nature may be at a high risk to predation in the presence of a novel predator until learned anti-predator responses provide additional defenses to the surviving tadpoles. PMID:26664805

  12. Mismatched anti-predator behavioral responses in predator-naïve larval anurans

    PubMed Central

    Vance-Chalcraft, Heather D.

    2015-01-01

    Organisms are adept at altering behaviors to balance the tradeoff between foraging and predation risk in spatially and temporally shifting predator environments. In order to optimize this tradeoff, prey need to be able to display an appropriate response based on degree of predation risk. To be most beneficial in the earliest life stages in which many prey are vulnerable to predation, innate anti-predator responses should scale to match the risk imposed by predators until learned anti-predator responses can occur. We conducted an experiment that examined whether tadpoles with no previous exposure to predators (i.e., predator-naive) exhibit innate antipredator behavioral responses (e.g., via refuge use and spatial avoidance) that match the actual risk posed by each predator. Using 7 treatments (6 free-roaming, lethal predators plus no-predator control), we determined the predation rates of each predator on Lithobates sphenocephalus tadpoles. We recorded behavioral observations on an additional 7 nonlethal treatments (6 caged predators plus no-predator control). Tadpoles exhibited innate responses to fish predators, but not non-fish predators, even though two non-fish predators (newt and crayfish) consumed the most tadpoles. Due to a mismatch between innate response and predator consumption, tadpoles may be vulnerable to greater rates of predation at the earliest life stages before learning can occur. Thus, naïve tadpoles in nature may be at a high risk to predation in the presence of a novel predator until learned anti-predator responses provide additional defenses to the surviving tadpoles. PMID:26664805

  13. ERP Correlates of Proactive and Reactive Cognitive Control in Treatment-Naïve Adult ADHD.

    PubMed

    Grane, Venke Arntsberg; Brunner, Jan Ferenc; Endestad, Tor; Aasen, Ida Emilia S; Kropotov, Juri; Knight, Robert Thomas; Solbakk, Anne-Kristin

    2016-01-01

    This study investigated whether treatment naïve adults with Attention Deficit Hyperactivity Disorder (ADHD; n = 33; 19 female) differed from healthy controls (n = 31; 17 female) in behavioral performance, event-related potential (ERP) indices of preparatory attention (CueP3 and late CNV), and reactive response control (Go P3, NoGo N2, and NoGo P3) derived from a visual cued Go/NoGo task. On several critical measures, Cue P3, late CNV, and NoGo N2, there were no significant differences between the groups. This indicated normal preparatory processes and conflict monitoring in ADHD patients. However, the patients had attenuated Go P3 and NoGoP3 amplitudes relative to controls, suggesting reduced allocation of attentional resources to processes involved in response control. The patients also had a higher rate of Go signal omission errors, but no other performance decrements compared with controls. Reduced Go P3 and NoGo P3 amplitudes were associated with poorer task performance, particularly in the ADHD group. Notably, the ERPs were not associated with self-reported mood or anxiety. The results provide electrophysiological evidence for reduced effortful engagement of attentional resources to both Go and NoGo signals when reactive response control is needed. The absence of group differences in ERP components indexing proactive control points to impairments in specific aspects of cognitive processes in an untreated adult ADHD cohort. The associations between ERPs and task performance provided additional support for the altered electrophysiological responses. PMID:27448275

  14. Proceedings of the XXII A.I.VE.LA. National Meeting

    NASA Astrophysics Data System (ADS)

    Primo Tomasini, Enrico

    2015-11-01

    A.I.VE.LA. - the Italian Association of Laser Velocimetry and non-invasive diagnostics - is a non-profit cultural association whose objective is to promote and support research in the field of non-contact or minimally invasive measurement techniques, particularly electromagnetic-based techniques and optical techniques. Through its Annual Meeting, AIVELA aims to create an active and stimulating forum where current research results and technical advances can be exchanged and the development of new systems for laboratory use, field testing and industrial application can be promoted. The techniques covered include Laser Doppler Anemometry - LDA, Phase Doppler Anemometry - PDA, Image Velocimetry - PIV, Flow visualization techniques, Spectroscopic measurement techniques (LIF, Raman, etc.), Laser Doppler Vibrometry - LDV, Speckle Pattern Interferometry - ESPI, Holographic techniques, Shearography, Digital Image Correlation - DIC, Moiré techniques, Structured light techniques, Infrared imaging, Photoelasticity, Image based measurement techniques, Ultrasonic sensing, Acoustic and Aeroacoustic measurements, etc. The first Annual Meeting was held back in October 1992 and since then there has been a large consensus among the research and scientific communities that the papers presented at the event are of a high scientific interest. The XXII AIVELA Annual Meeting was held at the Faculty of Engineering of University of Rome Tor Vergata on 15-16 December 2014 and was organised in collaboration with the International Master Courses in "Protection Against CBRNe Events". This volume contains a selection of the papers presented at the event. The detailed Programme of the Meeting can be found at: http://www.aivela.org/XXII_Convegno/index.html Trusting our Association and its initiatives will meet your interest, I wish to thank you in advance for your kind attention and hope to meet you soon at one of our events.

  15. Almotriptan in triptan-naïve patients: new evidence of benefits.

    PubMed

    Pascual, J

    2008-09-01

    Although triptans represent the standard of care for migraine that is severe, disabling and/or suboptimally responsive to migraine non-specific analgesia, they are often underused in clinical practice. Simple analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) may provide effective treatment in some patients, but it is an inadequate response to these drugs that drives the therapeutic progression to triptans at the end of the traditional 'step-care' approach. However, there are several disadvantages to this approach. It may cause patients to lose confidence in their physician during this hierarchical 'trial-and-error' search for optimal treatment when prescribed medications are ineffective, leading them to cease consulting before triptans are tried. It may also result in a protracted time interval of suboptimal treatment, with unnecessary suffering in patients who are triptan candidates. The alternative approach of 'stratified care', in which medication is prescribed according to the severity of symptoms, enables triptans to be used earlier in the treatment plan, especially when triptan candidates are given a choice between simple analgesic/NSAID and triptan medication from the start. This raises the question about the efficacy of triptans in triptan-naïve (TN) patients. A recent exploratory post-hoc analysis compared the effect of almotriptan 12.5 mg in TN patients (n = 342) with that in triptan-experienced patients (n = 237). Almotriptan was effective in both cohorts with a consistent trend in favour of the efficacy of almotriptan in TN patients, notably for sustained pain freedom (SPF) and SPF plus no adverse events. Moreover, both headache recurrence at 24 h and the use of rescue medication was lower in the TN patients, whereas tolerability was equally good in both cohorts. These findings indicate that TN patients can expect excellent symptom control when they progress from non-specific analgesia to treatment with almotriptan and support the earlier

  16. ERP Correlates of Proactive and Reactive Cognitive Control in Treatment-Naïve Adult ADHD

    PubMed Central

    Endestad, Tor; Aasen, Ida Emilia S.; Kropotov, Juri; Knight, Robert Thomas

    2016-01-01

    This study investigated whether treatment naïve adults with Attention Deficit Hyperactivity Disorder (ADHD; n = 33; 19 female) differed from healthy controls (n = 31; 17 female) in behavioral performance, event-related potential (ERP) indices of preparatory attention (CueP3 and late CNV), and reactive response control (Go P3, NoGo N2, and NoGo P3) derived from a visual cued Go/NoGo task. On several critical measures, Cue P3, late CNV, and NoGo N2, there were no significant differences between the groups. This indicated normal preparatory processes and conflict monitoring in ADHD patients. However, the patients had attenuated Go P3 and NoGoP3 amplitudes relative to controls, suggesting reduced allocation of attentional resources to processes involved in response control. The patients also had a higher rate of Go signal omission errors, but no other performance decrements compared with controls. Reduced Go P3 and NoGo P3 amplitudes were associated with poorer task performance, particularly in the ADHD group. Notably, the ERPs were not associated with self-reported mood or anxiety. The results provide electrophysiological evidence for reduced effortful engagement of attentional resources to both Go and NoGo signals when reactive response control is needed. The absence of group differences in ERP components indexing proactive control points to impairments in specific aspects of cognitive processes in an untreated adult ADHD cohort. The associations between ERPs and task performance provided additional support for the altered electrophysiological responses. PMID:27448275

  17. Long-Term Clinical Remission in Biologically Naïve Crohn's Disease Patients with Adalimumab Therapy, Including Analyses of Switch from Adalimumab to Infliximab

    PubMed Central

    Mizoshita, Tsutomu; Tanida, Satoshi; Ozeki, Keiji; Katano, Takahito; Shimura, Takaya; Mori, Yoshinori; Kubota, Eiji; Kataoka, Hiromi; Kamiya, Takeshi; Joh, Takashi

    2016-01-01

    There is little evidence regarding the maintenance of long-term clinical remission by adalimumab (ADA) therapy in Crohn's disease (CD) patients naïve to anti-tumor necrosis factor treatment (naïve CD patients), since most CD patients are treated with ADA after infliximab (IFX) therapy. The long-term clinical response to ADA was retrospectively analyzed in 17 naïve CD patients for at least 24 months, and the serum trough IFX levels were evaluated in patients switching from ADA to IFX. Of the 17 naïve CD patients, 14 (82.4%) maintained long-term clinical remission with ADA therapy for at least 24 months, without serious adverse events. The clinical condition of 7 patients was observed for more than 36 months, and 3, 1, 1, and 2 cases maintained remission at months 42, 48, 54, and 60 after ADA therapy, respectively. Three patients (17.6%) switched from ADA to IFX less than 24 months after the start of ADA therapy, and they had remission, retaining trough levels of IFX higher than 1 μg/ml, occasionally by dose escalation. In conclusion, maintenance ADA therapy achieves long-term clinical remission in naïve CD patients. Switching from ADA to IFX is an important therapeutic option in CD patients showing loss of response to ADA, occasionally with dose escalation, based on the analysis of serum IFX trough levels.

  18. Activation of human naïve Th cells increases surface expression of GD3 and induces neoexpression of GD2 that colocalize with TCR clusters.

    PubMed

    Villanueva-Cabello, Tania M; Mollicone, Rosella; Cruz-Muñoz, Mario E; López-Guerrero, Delia V; Martínez-Duncker, Iván

    2015-12-01

    CD4+ T helper lymphocytes (Th) orchestrate the immune response after their activation by antigen-presenting cells. Activation of naïve Th cells is reported to generate the reduction in surface epitopes of sialic acid (Sia) in α2,3 and α2,6 linkages. In this work, we report that in spite of this glycophenotype, anti-CD3/anti-CD28-activated purified human naïve Th cells show a significant increase in surface Sia, as assessed by metabolic labeling, compared with resting naïve Th cells, suggesting an increased flux of Sia toward Siaα2,8 glycoconjugates. To understand this increase as a result of ganglioside up-regulation, we observed that very early after activation, human naïve Th cells show an increased expression in surface GD3 and neoexpression of surface GD2 gangliosides, the latter clustering with the T cell receptor (TCR). Also, we report that in contrast to GM2/GD2 synthase null mice, lentiviral vector-mediated silencing of the GM2/GD2 synthase in activated human naïve Th cells reduced efficient TCR clustering and downstream signaling, as assessed by proliferation assays and IL-2 and IL-2R expression, pointing to an important role of this enzyme in activation of human naive Th cells. PMID:26263924

  19. Privacy-Preserving Patient-Centric Clinical Decision Support System on Naïve Bayesian Classification.

    PubMed

    Liu, Ximeng; Lu, Rongxing; Ma, Jianfeng; Chen, Le; Qin, Baodong

    2016-03-01

    Clinical decision support system, which uses advanced data mining techniques to help clinician make proper decisions, has received considerable attention recently. The advantages of clinical decision support system include not only improving diagnosis accuracy but also reducing diagnosis time. Specifically, with large amounts of clinical data generated everyday, naïve Bayesian classification can be utilized to excavate valuable information to improve a clinical decision support system. Although the clinical decision support system is quite promising, the flourish of the system still faces many challenges including information security and privacy concerns. In this paper, we propose a new privacy-preserving patient-centric clinical decision support system, which helps clinician complementary to diagnose the risk of patients' disease in a privacy-preserving way. In the proposed system, the past patients' historical data are stored in cloud and can be used to train the naïve Bayesian classifier without leaking any individual patient medical data, and then the trained classifier can be applied to compute the disease risk for new coming patients and also allow these patients to retrieve the top- k disease names according to their own preferences. Specifically, to protect the privacy of past patients' historical data, a new cryptographic tool called additive homomorphic proxy aggregation scheme is designed. Moreover, to leverage the leakage of naïve Bayesian classifier, we introduce a privacy-preserving top- k disease names retrieval protocol in our system. Detailed privacy analysis ensures that patient's information is private and will not be leaked out during the disease diagnosis phase. In addition, performance evaluation via extensive simulations also demonstrates that our system can efficiently calculate patient's disease risk with high accuracy in a privacy-preserving way. PMID:26960216

  20. Parental substance abuse and function of the motivation and behavioral inhibition systems in drug-naïve youth.

    PubMed

    Ivanov, Iliyan; Liu, Xun; Shulz, Kurt; Fan, Jin; London, Edythe; Friston, Karl; Halperin, Jeffrey M; Newcorn, Jeffrey H

    2012-02-28

    It is hypothesized that the development of substance abuse (SA) may be due to imbalance in functions of the motivation-reward and behavioral inhibition systems in the brain. This speaks to the search for biological risk factors for SA in drug-naïve children who also exhibit motivational and inhibitory control deficits; however, this type of research is currently lacking. The objective of this study was to establish a neurobiological basis for addiction vulnerability using functional magnetic resonance imaging (fMRI) in drug-naïve youth with attention deficit/hyperactivity disorder (ADHD). We hypothesized that children with ADHD alone would show higher activity in regions of the motivation-reward and behavioral inhibition systems than children with ADHD and a parental history of SA. Toward this goal we scanned 20 drug-naïve children with ADHD ages 8-13 while performing an event-related reward task. High (N=10) and low (N=10) risk subjects were identified, based on parental history of SA. The effects of anticipation, conflict, and reward were assessed with appropriate linear contrasts, and between-group differences were assessed using statistical parametric mapping. The two groups did not differ on behavioral measures of the task. The fMRI results show heightened activation in the brain motivational-reward system and reduced activation of the inhibitory control system in high-risk compared to low-risk children. These results suggest that a functional mismatch between these two systems may represent one possible biological underpinning of SA risk, which is conferred by a parental history of addiction. PMID:22386967

  1. The transition from naïve to primed nociceptive state: A novel wind-up protocol in mice.

    PubMed

    Ziv, Nadav Y; Tal, Michael; Shavit, Yehuda

    2016-01-01

    Wind-up (WU) is a progressive, frequency-dependent facilitation of spinal cord neurons in response to repetitive nociceptive stimulation of constant intensity. We identified a new WU-associated phenomenon in naïve mice (not exposed to noxious stimulation immediately prior to WU stimulation), which were subjected to a novel experimental protocol composed of three consecutive trains of WU stimulation. The 1st train produced a typical linear 'wind-up' curve as expected following a repeating series of stimuli; in addition, this 1st train sensitized ('primed') the nociceptive system so that the responses to two subsequent trains (inter-train interval of 10 min) were significantly amplified compared with the response to the 1st train. We named this augmented response potentiation-of-windup, or "PoW". The PoW phenomenon appears to be centrally mediated, as the augmented response was suppressed by administration of an NMDA receptor antagonist (MK-801) and by cutting the spinal cord. Furthermore, the PoW protocol is accompanied by enhanced pain behavior. The 'priming' effect of the 1st train could be mimicked by exposure to natural noxious stimuli prior to the PoW protocol. Presumably, the PoW phenomenon has not been previously reported due to a procedural reason: typically, WU protocols have been executed in 'primed' rather than naïve animals, i.e., animals exposed to nociceptive stimulation prior to the actual WU recording. Our findings indicate that the PoW paradigm can distinguish between 'naïve' and 'primed' states, suggesting its use as a tool for the assessment of central sensitization. PMID:26439312

  2. Comparison of Serum Lipid Profile in HIV Positive Patients on ART with ART Naïve Patients

    PubMed Central

    V, Vijay; Shekhanawar, M.S.; Rajeshwari; M, Amareshwaras; D, Shantala

    2014-01-01

    Introduction: The widespread use of effective highly active antiretroviral therapy (HAART) in HIV patients has coincided with increasing reports of complications like HIV-associated lipodystrophy syndrome and the metabolic alterations, affecting the lipid and glucose metabolism. Evidences in support of lipodystrophy and dyslipidaemia associated with First- line HAART in our area is scarce. The aim of the present study was 1) to study and compare Lipid profile in HIV positive patients on ART with that of freshly diagnosed HIV positive patients who were yet to be started on ART. 2) To assess lipodystrophy syndrome in patients on ART. Materials and Methods: Hundred newly diagnosed HIV positive patients who were yet to be started on ART were taken as controls (ART-Naïve).Hundred randomly selected HIV+ patients who were already on First-line ART regimen (Stavudine/Zudovudine + Lamivudine + Nevirapine) for more than 12 months were taken as cases (ART). This study was conducted for a period of 12 months at the VIMS ART centre, Bellary, Karnataka, India. Results: There was a significant increase (p<0.001) in serum Total Cholesterol, LDL-C, TG, VLDL, Non-HDL -C & TC/HDL-C ratio in ART patients compared to ART-naïve patients. Of the 100 ART patients 23 had lipodystrophy syndrome (buffalo hump, abnormal fat deposition around neck & back, buccal fat resorption, increase in abdominal fat). Conclusion: To conclude, it is evident from our study that there is increase in lipid profile (except HDL) in ART patients compared to ART Naïve group and 23 ART patients showed lipodystrophy syndrome. Hence it appears reasonable to measure fasting lipid levels before and 3-6 months after antiretroviral therapy is initiated or when ART regimen is changed. PMID:25478335

  3. G alpha12 interaction with alphaSNAP induces VE-cadherin localization at endothelial junctions and regulates barrier function.

    PubMed

    Andreeva, Alexandra V; Kutuzov, Mikhail A; Vaiskunaite, Rita; Profirovic, Jasmina; Meigs, Thomas E; Predescu, Sanda; Malik, Asrar B; Voyno-Yasenetskaya, Tatyana

    2005-08-26

    The involvement of heterotrimeric G proteins in the regulation of adherens junction function is unclear. We identified alphaSNAP as an interactive partner of G alpha12 using yeast two-hybrid screening. Glutathione S-transferase pull-down assays showed the selective interaction of alphaSNAP with G alpha12 in COS-7 as well as in human umbilical vein endothelial cells. Using domain swapping experiments, we demonstrated that the N-terminal region of G alpha12 (1-37 amino acids) was necessary and sufficient for its interaction with alphaSNAP. G alpha13 with its N-terminal extension replaced by that of G alpha12 acquired the ability to bind to alphaSNAP, whereas G alpha12 with its N terminus replaced by that of G alpha13 lost this ability. Using four point mutants of alphaSNAP, which alter its ability to bind to the SNARE complex, we determined that the convex rather than the concave surface of alphaSNAP was involved in its interaction with G alpha12. Co-transfection of human umbilical vein endothelial cells with G alpha12 and alphaSNAP stabilized VE-cadherin at the plasma membrane, whereas down-regulation of alphaSNAP with siRNA resulted in the loss of VE-cadherin from the cell surface and, when used in conjunction with G alpha12 overexpression, decreased endothelial barrier function. Our results demonstrate a direct link between the alpha subunit of G12 and alphaSNAP, an essential component of the membrane fusion machinery, and implicate a role for this interaction in regulating the membrane localization of VE-cadherin and endothelial barrier function. PMID:15980433

  4. A randomized controlled trial adding fluvastatin to peginterferon and ribavirin for naïve genotype 1 hepatitis C patients.

    PubMed

    Bader, T; Hughes, L D; Fazili, J; Frost, B; Dunnam, M; Gonterman, A; Madhoun, M; Aston, C E

    2013-09-01

    Fluvastatin or simvastatin has demonstrable antiviral activity against hepatitis C virus (HCV) as monotherapy. The safety and efficacy of adding fluvastatin or simvastatin to peginterferon/ribavirin for 48 weeks was tested in HCV genotype 1 naïve-to-treatment veterans. Thirty-seven naïve-to-treatment genotype 1 HCV patients were randomized to either a control group (n = 20) to receive peginterferon alfa plus ribavirin or an experimental group (n = 18) to similarly receive peginterferon alfa plus ribavirin as well as fluvastatin 20 mg/day. In addition, seven patients who presented for HCV treatment already were on simvastatin and could not be withdrawn. These simvastatin users were not randomized but were entered into a concurrent prospective pilot arm. There were no unique safety issues with fluvastatin or simvastatin when these drugs were given with peginterferon/ribavirin for 48 weeks. Thirteen of 25 statin patients achieved sustained viral response (SVR), while 5 of 20 control patients achieved SVR. Analysis of SVR by intention-to-treat showed P = 0.078. In this phase 2 study, there were no safety issues with the addition of fluvastatin or simvastatin to peginterferon and ribavirin for 48 weeks. There was a trend towards improvement in SVR when fluvastatin or simvastatin was administered with peginterferon/ribavirin. The size of the groups did not reach the prestudy size thought needed to show significant difference (type II error). These results support the significant results of two other larger randomized controlled trials reported using the same dose of fluvastatin in naïve-to-treatment genotype 1 HCV patients. PMID:23910646

  5. Naturally occurring dominant resistance mutations to HCV protease and polymerase inhibitors in treatment-naïve patients

    PubMed Central

    Kuntzen, Thomas; Timm, Joerg; Berical, Andrew; Lennon, Niall; Berlin, Aaron M.; Young, Sarah K.; Lee, Bongshin; Heckerman, David; Carlson, Jonathan; Reyor, Laura L.; Kleyman, Marianna; McMahon, Cory M.; Birch, Christopher; Wiesch, Julian Schulze zur; Ledlie, Timothy; Koehrsen, Michael; Kodira, Chinnappa; Roberts, Andrew D.; Lauer, Georg M.; Rosen, Hugo R.; Bihl, Florian; Cerny, Andreas; Spengler, Ulrich; Liu, Zhimin; Kim, Arthur Y.; Xing, Yanming; Schneidewind, Arne; Madey, Margaret A.; Fleckenstein, Jaquelyn F.; Park, Vicki M.; Galagan, James E.; Nusbaum, Chad; Walker, Bruce D.; Lake-Bakaar, Gerond V.; Daar, Eric S.; Jacobson, Ira M.; Gomperts, Edward D.; Edlin, Brian R.; Donfield, Sharyne M.; Chung, Raymond T.; Talal, Andrew H.; Marion, Tony; Birren, Bruce W.; Henn, Matthew R.; Allen, Todd M.

    2008-01-01

    Resistance mutations to HCV NS3 protease inhibitors in <1% of the viral quasispecies may still allow >1000-fold viral load reductions upon treatment, consistent with their reported reduced replicative fitness in vitro. Recently, however, an R155K protease mutation was reported as the dominant quasispecies in a treatment-naïve individual, raising concerns about possible full drug resistance. To investigate the prevalence of dominant STAT-C resistance mutations in the population we analyzed HCV genome sequences from 507 treatment-naïve HCV genotype 1 infected patients from the US, Germany and Switzerland. Phylogenetic sequence analysis and viral load data were used to identify the possible spread of replication competent, drug resistant viral strains in the population and to infer the consequences of these mutations upon viral replication in vivo. Mutations described to confer resistance to the protease inhibitors Telaprevir, BILN2061, ITMN-191, SCH6 and Boceprevir, the NS5B polymerase inhibitor AG-021541, and to the NS4A antagonist ACH-806 were observed mostly as sporadic, unrelated cases, at frequencies between 0.3% and 2.8% in the population, including two patients with possible multi-drug resistance. Collectively, however, 8.6% of the genotype 1a and 1.4% of the genotype 1b infected patients carried at least one dominant resistance mutation. Viral loads were high in the majority of these patients, suggesting that drug resistant viral strains might achieve replication levels comparable to non-resistant viruses in vivo. Conclusion: Naturally occurring dominant STAT-C resistance mutations are common in HCV genotype 1 infected treatment-naïve patients. Their influence on treatment outcome should further be characterized to evaluate possible benefits of drug resistance testing for individual tailoring of drug combinations when treatment options are limited due to previous non-response to peginterferon and ribavirin. PMID:19026009

  6. Transcription Profiling of Malaria-Naïve and Semi-immune Colombian Volunteers in a Plasmodium vivax Sporozoite Challenge

    PubMed Central

    Rojas-Peña, Monica L.; Vallejo, Andres; Herrera, Sócrates; Gibson, Greg; Arévalo-Herrera, Myriam

    2015-01-01

    Background Continued exposure to malaria-causing parasites in endemic regions of malaria induces significant levels of acquired immunity in adult individuals. A better understanding of the transcriptional basis for this acquired immunological response may provide insight into how the immune system can be boosted during vaccination, and into why infected individuals differ in symptomology. Methodology/Principal Findings Peripheral blood gene expression profiles of 9 semi-immune volunteers from a Plasmodium vivax malaria prevalent region (Buenaventura, Colombia) were compared to those of 7 naïve individuals from a region with no reported transmission of malaria (Cali, Colombia) after a controlled infection mosquito bite challenge with P. vivax. A Fluidigm nanoscale quantitative RT-PCR array was used to survey altered expression of 96 blood informative transcripts at 7 timepoints after controlled infection, and RNASeq was used to contrast pre-infection and early parasitemia timepoints. There was no evidence for transcriptional changes prior to the appearance of blood stage parasites at day 12 or 13, at which time there was a strong interferon response and, unexpectedly, down-regulation of transcripts related to inflammation and innate immunity. This differential expression was confirmed with RNASeq, which also suggested perturbations of aspects of T cell function and erythropoiesis. Despite differences in clinical symptoms between the semi-immune and malaria naïve individuals, only subtle differences in their transcriptomes were observed, although 175 genes showed significantly greater induction or repression in the naïve volunteers from Cali. Conclusion/Significance Gene expression profiling of whole blood reveals the type and duration of the immune response to P. vivax infection, and highlights a subset of genes that may mediate adaptive immunity. PMID:26244760

  7. An evaluation of entecavir treatment among nucleos(t)ide-naïve Moroccan patients with chronic hepatitis B

    PubMed Central

    Chakkor, Amal; Rouibaa, Fedoua; Elaboudi, Safiaa; Aourarh, Aziz

    2016-01-01

    Objective To analyse the efficacy and safety of entecavir (ETV) treatment in nucleos(t)ide (NUC)-naïve Moroccan patients with chronic hepatitis B. Methods We retrospectively analysed 41 NUT-naïve Moroccan patients with chronic hepatitis B who received ETV 0,5 mg/day monotherapy for at least 3 months, of whom 3 were HBV envelope antigen (HbeAg) positive and 38 were HBeAg negative. The primary end point was the proportion of patients achieving virological response. Secondary end points included biochemical response (alanine transaminase (ALT) normalisation), serological response (HbeAg and HBV surface antigen (HBsAg) loss or seroconversion) and safety. Results The median follow-up duration was 74 weeks (48–144 weeks) and mean age was 43.8 years. Of 41 patients, 6 were primary non-responders and 2 achieved partial virological response at week 48, whereas 35 achieved undetectable hepatitis B virus (HBV) DNA at month 12. Viral suppression was maintained in 97.6% of patients after 3 years of ETV treatment. One patient experienced a virological breakthrough at month 12 of treatment. ALT normalisation occurred in 100% of the patients after 1 year of treatment. Only three patients in our study were HbeAg positive, of whom one has experienced seroconversion at month 12 of treatment. However, HBsAg loss or seroconversion was not achieved during the period of the study. No serious adverse event was reported. Conclusions These preliminary results showed that ETV is a safe and potent inhibitor of HBV in NUC-naïve Moroccan patients, but we need to observe more patients for a longer period of time, in order to assess the long-term effectiveness, safety, resistance profile and predictive factors for virological and serological response of ETV. PMID:27195127

  8. Advantages of Karhunen Loève transform over fast Fourier transform for planetary radar and space debris detection

    NASA Astrophysics Data System (ADS)

    Maccone, Claudio

    2007-04-01

    The present article describes that the range of any radiotelescope (and radar in general) may be increased by virtue of software, if one replaces the fast Fourier transform by the Karhunen Loève transform. The range increases with the inverse of the fourth root of the signal-to-noise ratio when this ratio decreases. Thus, the range on any radiotelescope (and radar) may be increased without changing the hardware at all, but by changing the software only. This improvement in the range of the radiotelescope is currently implemented at the 32-m antenna located at Medicina, near Bologna, in Italy, for both SETI and general radioastronomy.

  9. Olodaterol attenuates citric acid-induced cough in naïve and ovalbumin-sensitized and challenged guinea pigs.

    PubMed

    Wex, Eva; Bouyssou, Thierry

    2015-01-01

    Excessive coughing is a common feature of airway diseases. Different G-protein coupled receptors, including β2-adrenergic receptors (β2-AR), have been implicated in the molecular mechanisms underlying the cough reflex. However, the potential antitussive property of β2-AR agonists in patients with respiratory disease is a matter of ongoing debate. The aim of our study was to test the efficacy of the long-acting β2-AR agonist olodaterol with regard to its antitussive property in a pre-clinical model of citric acid-induced cough in guinea pigs and to compare the results to different clinically relevant β2-AR agonists. In our study β2-AR agonists were intratracheally administered, as dry powder, into the lungs of naïve or ovalbumin-sensitized guinea pigs 15 minutes prior to induction of cough by exposure to citric acid. Cough events were counted over 15 minutes during the citric acid exposure. Olodaterol dose-dependently inhibited the number of cough events in naïve and even more potently and with a greater maximal efficacy in ovalbumin-sensitized guinea pigs (p < 0.01). Formoterol and salmeterol showed a trend towards reducing cough. On the contrary, indacaterol demonstrated pro-tussive properties as it significantly increased the number of coughs, both in naïve and ovalbumin-sensitized animals (p < 0.001). In conclusion, olodaterol, at doses eliciting bronchodilation, showed antitussive properties in a model of citric acid-induced cough in naïve and ovalbumin-sensitized guinea pigs. This is in agreement with pre-clinical and clinical studies showing antitussive efficacy of β2-AR agonists. Indacaterol increased the number of coughs in this model, which concurs with clinical data where a transient cough has been observed after indacaterol inhalation. While the antitussive properties of β2-AR agonists can be explained by their ability to lead to the cAMP-induced hyperpolarization of the neuron membrane thereby inhibiting sensory nerve activation and the

  10. Olodaterol Attenuates Citric Acid-Induced Cough in Naïve and Ovalbumin-Sensitized and Challenged Guinea Pigs

    PubMed Central

    Wex, Eva; Bouyssou, Thierry

    2015-01-01

    Excessive coughing is a common feature of airway diseases. Different G-protein coupled receptors, including β2-adrenergic receptors (β2-AR), have been implicated in the molecular mechanisms underlying the cough reflex. However, the potential antitussive property of β2-AR agonists in patients with respiratory disease is a matter of ongoing debate. The aim of our study was to test the efficacy of the long-acting β2-AR agonist olodaterol with regard to its antitussive property in a pre-clinical model of citric acid-induced cough in guinea pigs and to compare the results to different clinically relevant β2-AR agonists. In our study β2-AR agonists were intratracheally administered, as dry powder, into the lungs of naïve or ovalbumin-sensitized guinea pigs 15 minutes prior to induction of cough by exposure to citric acid. Cough events were counted over 15 minutes during the citric acid exposure. Olodaterol dose-dependently inhibited the number of cough events in naïve and even more potently and with a greater maximal efficacy in ovalbumin-sensitized guinea pigs (p < 0.01). Formoterol and salmeterol showed a trend towards reducing cough. On the contrary, indacaterol demonstrated pro-tussive properties as it significantly increased the number of coughs, both in naïve and ovalbumin-sensitized animals (p < 0.001). In conclusion, olodaterol, at doses eliciting bronchodilation, showed antitussive properties in a model of citric acid-induced cough in naïve and ovalbumin-sensitized guinea pigs. This is in agreement with pre-clinical and clinical studies showing antitussive efficacy of β2-AR agonists. Indacaterol increased the number of coughs in this model, which concurs with clinical data where a transient cough has been observed after indacaterol inhalation. While the antitussive properties of β2-AR agonists can be explained by their ability to lead to the cAMP-induced hyperpolarization of the neuron membrane thereby inhibiting sensory nerve activation and the

  11. Assembly and rf-properties of the VE-RFQ-project for the ISL-cyclotron at HMI

    NASA Astrophysics Data System (ADS)

    Engels, O.; Häuser, J.; Homeyer, H.; Pelzer, W.; Schempp, A.

    1998-04-01

    The HMI (Hahn-Meitner-Institut) in Berlin changes one of the injectors of the ISL (Ionen-Strahl-Labor)-Cyclotron, as described in several papers before (e.g. O. Engels et al., Nucl. Instr. and Meth. B 113 (1996) 16). The former Tandem-injector will be replaced by a combination of an ECR-source and two VE (Variable Energy)-RFQs. The results of the set-up as well as the first measured low level and high power rf-properties of the RFQs will be discussed.

  12. Experimental transmission of avian‐like swine H1N1 influenza virus between immunologically naïve and vaccinated pigs

    PubMed Central

    Lloyd, Lucy E.; Jonczyk, Magdalena; Jervis, Carley M.; Flack, Deborah J.; Lyall, John; Foote, Alasdair; Mumford, Jennifer A.; Brown, Ian H.; Wood, James L.; Elton, Debra M.

    2011-01-01

    Please cite this paper as: Lloyd et al. (2011) Experimental transmission of avian‐like swine H1N1 influenza virus between immunologically naïve and vaccinated pigs. Influenza and Other Respiratory Viruses 5(5), 357–364. Background  Infection of pigs with swine influenza has been studied experimentally and in the field; however, little information is available on the natural transmission of this virus in pigs. Two studies in an experimental transmission model are presented here, one in immunologically naïve and one in a combination of vaccinated and naïve pigs. Objectives  To investigate the transmission of a recent ‘avian‐like’ swine H1N1 influenza virus in naive piglets, to assess the antibody response to a commercially available vaccine and to determine the efficiency of transmission in pigs after vaccination. Methods  Transmission chains were initiated by intranasal challenge of two immunologically naïve pigs. Animals were monitored daily for clinical signs and virus shedding. Pairs of pigs were sequentially co‐housed, and once virus was detected in recipients, prior donors were removed. In the vaccination study, piglets were vaccinated and circulating antibody levels were monitored by haemagglutination inhibition assay. To study transmission in vaccinates, a pair of infected immunologically naïve animals was co‐housed with vaccinated recipient pigs and further pairs of vaccinates were added sequentially as above. The chain was completed by the addition of naive pigs. Results and conclusions  Transmission of the H1N1 virus was achieved through a chain of six pairs of naïve piglets and through four pairs of vaccinated animals. Transmission occurred with minimal clinical signs and, in vaccinates, at antibody levels higher than previously reported to protect against infection. PMID:21668691

  13. A model to investigate the optimal seeder-to-naïve ratio for successful natural Mycoplasma hyopneumoniae gilt exposure prior to entering the breeding herd.

    PubMed

    Roos, Luiza R; Fano, Eduardo; Homwong, Nitipong; Payne, Brian; Pieters, Maria

    2016-02-29

    Due to the significance of Mycoplasma hyopneumoniae as a swine respiratory pathogen, acclimation measures are taken into consideration when obtaining replacement gilts from negative sources to be introduced to endemically infected herds. The aim of this study was to evaluate the optimum seeder-to-naïve gilt ratio in a 4-week period for successful natural exposure to M. hyopneumoniae. Sixty gilts were divided in two groups, 21 2-week old seeder gilts were inoculated with M. hyopneumoniae, and 39 aged-matched naïve gilts were exposed to the seeders during a 4-week period. The exposure was set by dividing the gilts into six groups of 10 with different ratios of seeder-to-naïve, from 1:9 until 6 seeders and 4 naïve gilts. Laryngeal swabs, oral fluids and blood samples were collected from all gilts prior to, during and after inoculation and exposure. Infection in seeders was confirmed by development of clinical signs, seroconversion post-inoculation, and detection of M. hyopneumoniae genetic material. Naïve were considered positive after 4 weeks if M. hyopneumoniae was detected on bronchial swab or fixed lung tissue. As result, 33% (3/9) naïve gilts were positive in the 1:9 ratio, 75% (6/8) in 2:8, 28% (2/7) in 3:7, 33% (2/6) in 4:6, 80% (4/5) in 5:5 and 100% (4/4) in the 6:4 ratio. The estimated transmission rate (β) and expected probability of infection (ψ) were 1.28 per pig/week and 0.6, respectively. In this study, six seeders were required in a group of 10 gilts for successful exposure to M. hyopneumoniae in a 4-week exposure period. PMID:26854344

  14. İhtimaller Hesabına Dayalı İstanbul ve Çevresindeki Deprem Tehlikesi (Seismic hazard assessment of Istanbul and its surroundings)

    USGS Publications Warehouse

    Gulkan, Polat; Kalkan, E.

    2010-01-01

    Bu yazının amacı, İstanbul ve yakın çevresinin maruz olduğu deprem tehlikesine dair 1999 depremlerinden bu yana devam eden tartışmalara bilimsel verilere ve hesaplara dayanan ve mümkün olduğu ölçüde kolay anlaşılır bir açıklama getirmektir. Depremlerin bir bölgede yaratabileceği tehlike, yani yerin sarsılması yüzünden yapılar üzerinde doğacak deprem etkileri, bölgenin deprem riskine, yani o bölgede olabilecek en yüksek deprem büyüklüğüne ve bölgenin zemin durumuna bağlıdır. Bu çalışmada, deprem oluşturma potansiyeline sahip aktif faylar ve son 500 yılda meydana gelmiş depremler ihtimal hesapları kullanılarak ilişkilendirilmiş ve Marmara Bölgesi’nde deprem sonucu doğacak yer hareketi şiddetinin dağılımı haritalanmıştır. Sunulan yeni deprem tehlike haritaları önceki bölgesel tehlike haritaları ile karşılaştırıldığında, Marmara Bölgesi’nde hissedilebilecek yer hareketi şiddetinde, benzer çalışmalara oranla % 10 ila % 15 arası artış görülmektedir.

  15. Aspergillus flavus VelB acts distinctly from VeA in conidiation and may coordinate with FluG to modulate sclerotial production.

    PubMed

    Chang, Perng-Kuang; Scharfenstein, Leslie L; Li, Ping; Ehrlich, Kenneth C

    2013-01-01

    The proteins VeA, VelB and LaeA of Aspergillus nidulans form a heterotrimeric complex (the velvet complex) in the dark to coordinate sexual development and production of some secondary metabolites. VeA and VelB of A. nidulans and Aspergillus fumigatus also are repressors of conidiation, but VeA of Aspergillus flavus in studied strains acts positively on conidiation. In the present study, we show via yeast-two hybrid assays that interactions among A. flavus VeA, VelB, and LaeA are conserved as in the A. nidulans velvet complex. We found that FluG, which is required for conidiophore formation in A. nidulans but whose deletion in A. flavus delays onset of conidiation, was probably an interacting partner of VelB. Deletion of velB in A. flavus CA14 severely impaired conidiation in the dark although to a lesser extent than deletion of veA. In both mutants fluG deletion resulted in further decreased conidiation even in the light. Deletion of fluG in the ΔlaeA strain, however, did not affect conidiation. All mutant types were unable to produce aflatoxin and sclerotia. Cross-complementation of the ΔvelB strain with gpdA::veA restored conidiation but not aflatoxin production although aflR, the aflatoxin pathway regulatory gene, was expressed at a normal level. Cross-complementation of the ΔveA strain with gpdA::velB failed to restore conidiation and aflatoxin production. The ΔvelB strain complemented with or a wild type transformed by gpdA::velB had elevated sclerotial production as the ΔfluG strain. Concerted interactions of A. flavus VeA and VelB with LaeA are critical for conidiation and aflatoxin biosynthesis. VelB may have a dual role and likely coordinates with FluG to modulate sclerotial production. PMID:23994319

  16. Estimation of rate constant for VE excitation of the С2(D1Σ) state in Не-СО-О2 discharge plasma

    NASA Astrophysics Data System (ADS)

    Grigorian, G.; Cenian, Adam

    2013-01-01

    The paper discusses the experimental results pointing to the efficient channel of the CO vibrational to the C2 electronic energy-transfer. The radiation spectra D1Σu - X1Σg , known as Mulliken bands, are investigated and the relation of their kinetics to a vibrational excitation of CO molecules in the He-CO-O2 plasma is discussed. The rate constant for VE process ( CO(v >= 25) + C2 → CO(v - 25) + C2(D1Σu) ) is estimated, kVE ~ 10-14 см3/с.

  17. Zinc finger protein Zfp335 is required for the formation of the naïve T cell compartment

    PubMed Central

    Han, Brenda Y; Wu, Shuang; Foo, Chuan-Sheng; Horton, Robert M; Jenne, Craig N; Watson, Susan R; Whittle, Belinda; Goodnow, Chris C; Cyster, Jason G

    2014-01-01

    The generation of naïve T lymphocytes is critical for immune function yet the mechanisms governing their maturation remain incompletely understood. We have identified a mouse mutant, bloto, that harbors a hypomorphic mutation in the zinc finger protein Zfp335. Zfp335bloto/bloto mice exhibit a naïve T cell deficiency due to an intrinsic developmental defect that begins to manifest in the thymus and continues into the periphery, affecting T cells that have recently undergone thymic egress. The effects of Zfp335bloto are multigenic and cannot be attributed to altered thymic selection, proliferation or Bcl2-dependent survival. Zfp335 binds to promoter regions via a consensus motif, and its target genes are enriched in categories related to protein metabolism, mitochondrial function, and transcriptional regulation. Restoring the expression of one target, Ankle2, partially rescues T cell maturation. These findings identify Zfp335 as a transcription factor and essential regulator of late-stage intrathymic and post-thymic T cell maturation. DOI: http://dx.doi.org/10.7554/eLife.03549.001 PMID:25343476

  18. A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia.

    PubMed

    O'Brien, Susan M; Lamanna, Nicole; Kipps, Thomas J; Flinn, Ian; Zelenetz, Andrew D; Burger, Jan A; Keating, Michael; Mitra, Siddhartha; Holes, Leanne; Yu, Albert S; Johnson, David M; Miller, Langdon L; Kim, Yeonhee; Dansey, Roger D; Dubowy, Ronald L; Coutre, Steven E

    2015-12-17

    Idelalisib is a first-in-class oral inhibitor of PI3Kδ that has shown substantial activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). To evaluate idelalisib as initial therapy, 64 treatment-naïve older patients with CLL or small lymphocytic leukemia (median age, 71 years; range, 65-90) were treated with rituximab 375 mg/m(2) weekly ×8 and idelalisib 150 mg twice daily continuously for 48 weeks. Patients completing 48 weeks without progression could continue to receive idelalisib on an extension study. The median time on treatment was 22.4 months (range, 0.8-45.8+). The overall response rate (ORR) was 97%, including 19% complete responses. The ORR was 100% in patients with del(17p)/TP53 mutations and 97% in those with unmutated IGHV. Progression-free survival was 83% at 36 months. The most frequent (>30%) adverse events (any grade) were diarrhea (including colitis) (64%), rash (58%), pyrexia (42%), nausea (38%), chills (36%), cough (33%), and fatigue (31%). Elevated alanine transaminase/aspartate transaminase was seen in 67% of patients (23% grade ≥3). The combination of idelalisib and rituximab was highly active, resulting in durable disease control in treatment-naïve older patients with CLL. These results support the further development of idelalisib as initial treatment of CLL. This study is registered at ClinicalTrials.gov as #NCT01203930. PMID:26472751

  19. Dermatoglyphic correlates of hippocampus volume: Evaluation of aberrant neurodevelopmental markers in antipsychotic-naïve schizophrenia.

    PubMed

    Kalmady, Sunil V; Shivakumar, Venkataram; Gautham, S; Arasappa, Rashmi; Jose, Dania A; Venkatasubramanian, Ganesan; Gangadhar, B N

    2015-10-30

    Schizophrenia is a disorder of aberrant neurodevelopment is marked by abnormalities in brain structure and dermatoglyphic traits. However, the link between these two (i.e. dermatoglyphic parameters and brain structure) which share ectodermal origin and common developmental window has not been explored extensively. The current study examined dermatoglyphic correlates of hippocampal volume in antipsychotic-naïve schizophrenia patients in comparison with matched healthy controls. Ridge counts and asymmetry measures for palmar inter-digital areas (a-b, b-c, c-d) were obtained using high resolution digital scans of palms from 89 schizophrenia patients [M:F=48:41] and 48 healthy controls [M:F=30:18]. Brain scans were obtained for subset of subjects including 26 antipsychotic-naïve patients [M:F=13:13] and 29 healthy controls [M:F=19:10] using 3 T-MRI. Hippocampal volume and palmar ridge counts were measured by blinded raters with good inter-rater reliability using valid methods. Directional asymmetry (DA) of b-c and bilateral hippocampal volume were significantly lower in patients than controls. Significant positive correlation was found between DA and ridge count of b-c with bilateral anterior hippocampal volume. Study demonstrates the utility of dermatoglyphic markers in identifying structural changes in the brain which may form the basis for neurodevelopmental pathogenesis in schizophrenia. PMID:26385539

  20. Mental models or methodological artefacts? Adults' 'naïve' responses to a test of children's conceptions of the earth.

    PubMed

    Nobes, Gavin; Panagiotaki, Georgia

    2009-05-01

    Vosniadou and Brewer (1992) claim that children's drawings and answers to questions show that they have naive, theory-like 'mental models' of the earth; for example, they believe it to be flat, or hollow with people inside. However, recent studies that have used different methods have found little or no evidence of these misconceptions. The contrasting accounts, and possible reasons for the inconsistent findings, were tested by giving adults (N = 484) either the original task (designed for 5-year olds) or a new version in which the same drawing instructions and questions were rephrased and clarified. Many adults' responses to the original version were identical to children's 'naïve' drawings and answers. The new version elicited substantially fewer non-scientific responses. These findings indicate that even adults find the original instructions and questions ambiguous and confusing, and that this is the principal reason for their non-scientific drawings and answers. Since children must find the task even more confusing than adults, this explanation very probably applies to many of their non-scientific responses, too, and therefore accounts for the discrepant findings of previous research. 'Naïve' responses result largely from misinterpretation of Vosniadou and Brewer's apparently simple task, rather than from mental models of the earth. PMID:18680639

  1. A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia

    PubMed Central

    Lamanna, Nicole; Kipps, Thomas J.; Flinn, Ian; Zelenetz, Andrew D.; Burger, Jan A.; Keating, Michael; Mitra, Siddhartha; Holes, Leanne; Yu, Albert S.; Johnson, David M.; Miller, Langdon L.; Kim, Yeonhee; Dansey, Roger D.; Dubowy, Ronald L.; Coutre, Steven E.

    2015-01-01

    Idelalisib is a first-in-class oral inhibitor of PI3Kδ that has shown substantial activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). To evaluate idelalisib as initial therapy, 64 treatment-naïve older patients with CLL or small lymphocytic leukemia (median age, 71 years; range, 65-90) were treated with rituximab 375 mg/m2 weekly ×8 and idelalisib 150 mg twice daily continuously for 48 weeks. Patients completing 48 weeks without progression could continue to receive idelalisib on an extension study. The median time on treatment was 22.4 months (range, 0.8-45.8+). The overall response rate (ORR) was 97%, including 19% complete responses. The ORR was 100% in patients with del(17p)/TP53 mutations and 97% in those with unmutated IGHV. Progression-free survival was 83% at 36 months. The most frequent (>30%) adverse events (any grade) were diarrhea (including colitis) (64%), rash (58%), pyrexia (42%), nausea (38%), chills (36%), cough (33%), and fatigue (31%). Elevated alanine transaminase/aspartate transaminase was seen in 67% of patients (23% grade ≥3). The combination of idelalisib and rituximab was highly active, resulting in durable disease control in treatment-naïve older patients with CLL. These results support the further development of idelalisib as initial treatment of CLL. This study is registered at ClinicalTrials.gov as #NCT01203930. PMID:26472751

  2. Different genome stability proteins underpin primed and naïve adaptation in E. coli CRISPR-Cas immunity

    PubMed Central

    Ivančić-Baće, Ivana; Cass, Simon D; Wearne, Stephen J; Bolt, Edward L

    2015-01-01

    CRISPR-Cas is a prokaryotic immune system built from capture and integration of invader DNA into CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) loci, termed ‘Adaptation’, which is dependent on Cas1 and Cas2 proteins. In Escherichia coli, Cascade-Cas3 degrades invader DNA to effect immunity, termed ‘Interference’. Adaptation can interact with interference (‘primed’), or is independent of it (‘naïve’). We demonstrate that primed adaptation requires the RecG helicase and PriA protein to be present. Genetic analysis of mutant phenotypes suggests that RecG is needed to dissipate R-loops at blocked replication forks. Additionally, we identify that DNA polymerase I is important for both primed and naive adaptation, and that RecB is needed for naïve adaptation. Purified Cas1-Cas2 protein shows specificity for binding to and nicking forked DNA within single strand gaps, and collapsing forks into DNA duplexes. The data suggest that different genome stability systems interact with primed or naïve adaptation when responding to blocked or collapsed invader DNA replication. In this model, RecG and Cas3 proteins respond to invader DNA replication forks that are blocked by Cascade interference, enabling DNA capture. RecBCD targets DNA ends at collapsed forks, enabling DNA capture without interference. DNA polymerase I is proposed to fill DNA gaps during spacer integration. PMID:26578567

  3. Silver nanoparticles interact with the cell membrane and increase endothelial permeability by promoting VE-cadherin internalization.

    PubMed

    Sun, Xia; Shi, Junpeng; Zou, Xiaoyan; Wang, Chengcheng; Yang, Yi; Zhang, Hongwu

    2016-11-01

    The toxicological risks of silver nanoparticles (AgNPs) have attracted widespread attention, and many studies have been published that have contributed to understanding AgNPs-induced toxicity. However, little attention has been paid to the low-dose effects of AgNPs and the related toxicological mechanism is still unclear. Here, we show that short-term exposure to AgNPs at low doses induces a substantial increase in human umbilical vein endothelial cells (HUVECs) monolayer permeability, whereas Ag ions at low doses do not induce an observable increase in monolayer permeability. This effect is independent of oxidative stress and apoptosis. Scanning electron microscopy confirms that AgNPs adhere to the cell membrane after 1h exposure. Furthermore, adhesion of AgNPs to the cell membrane can trigger vascular endothelial (VE)-cadherin phosphorylation at Y658 followed by VE-cadherin internalization, which lead to the increase in endothelial monolayer permeability. Our data show that surface interactions of AgNPs with the cell membrane, in other words, the particle effect, is a major factor leading to endothelial dysfunction following low-dose and short-term exposure. Our findings will contribute to understanding the health effects and the toxicological mechanisms of AgNPs. PMID:27344258

  4. Design and construction of a new human naïve single-chain fragment variable antibody library, IORISS1.

    PubMed

    Pasello, Michela; Zamboni, Silvia; Mallano, Alessandra; Flego, Michela; Picci, Piero; Cianfriglia, Maurizio; Scotlandi, Katia

    2016-04-20

    Human monoclonal antibodies are a powerful tool with increasingly successful exploitations and the single chain fragment variable format can be considered the building block for the implementation of more complex and effective antibody-based constructs. Phage display is one of the best and most efficient methods to isolate human antibodies selected from an efficient and variable phage display library. We report a method for the construction of a human naïve single-chain variable fragment library, termed IORISS1. Many different sets of oligonucleotide primers as well as optimized electroporation and ligation reactions were used to generate this library of 1.2×10(9) individual clones. The key difference is the diversity of variable gene templates, which was derived from only 15 non-immunized human donors. The method described here, was used to make a new human naïve single-chain fragment variable phage display library that represents a valuable source of diverse antibodies that can be used as research reagents or as a starting point for the development of therapeutics. Using biopanning, we determined the ability of IORISS1 to yield antibodies. The results we obtained suggest that, by using an optimized protocol, an efficient phage antibody library can be generated. PMID:26945728

  5. Project VeSElkA: results of abundance analysis I - HD 71030, HD 95608, HD 116235 and HD 186568

    NASA Astrophysics Data System (ADS)

    LeBlanc, F.; Khalack, V.; Yameogo, B.; Thibeault, C.; Gallant, I.

    2015-11-01

    A portion of main-sequence stars, called chemically peculiar (CP) stars, show important abundance anomalies mainly due to atomic diffusion of the species within these stars. Certain CP stars have hydrodynamically stable atmospheres where atomic diffusion may dominate and lead to vertical abundance stratification there. Recently, Project VeSElkA (a word meaning rainbow in Ukrainian and standing for `Vertical Stratification of Element Abundances') was initiated with the goal to detect vertical stratification of chemical abundances in selected CP stars using high-resolution spectra with large signal-to-noise ratios. The first extensive and detailed series of results from atomic-line analysis is presented here for four stars of Project VeSElkA: HD 71030, HD 95608, HD 116235 and HD 186568. These stars were recently observed with ESPaDOnS at Canada-France-Hawaii Telescope. Strong evidence of iron stratification in the atmospheres of HD 95608 and HD 116235 was found. Chromium also shows a steep abundance gradient in the upper atmospheres of these two stars. No evidence of stratification is found for HD 71030 and HD 186568.

  6. Water-resources reconnaissance of Île de la Gonâve, Haiti

    NASA Astrophysics Data System (ADS)

    Troester, Joseph W.; Turvey, Michael D.

    Île de la Gonâve is a 750-km2 island off the coast of Haiti. The depth to the water table ranges from less than 30 m in the Eocene and Upper Miocene limestones to over 60 m in the 300-m-thick Quaternary limestone. Annual precipitation ranges from 800-1,400 mm. Most precipitation is lost through evapotranspiration and there is virtually no surface water. Roughly estimated from chloride mass balance, about 4% of the precipitation recharges the karst aquifer. Cave pools and springs are a common source for water. Hand-dug wells provide water in coastal areas. Few productive wells have been drilled deeper than 60 m. Reconnaissance field analyses indicate that groundwater in the interior is a calcium-bicarbonate type, whereas water at the coast is a sodium-chloride type that exceeds World Health Organization recommended values for sodium and chloride. Tests for the presence of hydrogen sulfide-producing bacteria were negative in most drilled wells, but positive in cave pools, hand-dug wells, and most springs, indicating bacterial contamination of most water sources. Because of the difficulties in obtaining freshwater, the 110,000 inhabitants use an average of only 7 L per person per day. L'Île de la Gonâve est une île de 750 km2 au large de la côte d'Haïti. La profondeur de la nappe varie entre moins de 30 m dans les calcaires de l'Éocène et du Miocène supérieur à plus de 60 m dans les calcaires quaternaires épais de 300 m. Les précipitations annuelles sont comprises entre 800-1.400 mm. La plus grande partie des précipitations est perdue par évapotranspiration et il n'y a pratiquement pas d'eau de surface. Le bilan de masse des chlorures permet d'estimer à 4% des précipitations le montant de la recharge de l'aquifère karstique. Des bassins dans les grottes et des sources sont la source d'eau courante. Des puits creusés à la main fournissent de l'eau dans les zones côtières. Quelques puits productifs ont été forés dépassant 60 m de profondeur. L

  7. Water-resources reconnaissance of Île de la Gonâve, Haiti

    NASA Astrophysics Data System (ADS)

    Troester, Joseph W.; Turvey, Michael D.

    Île de la Gonâve is a 750-km2 island off the coast of Haiti. The depth to the water table ranges from less than 30 m in the Eocene and Upper Miocene limestones to over 60 m in the 300-m-thick Quaternary limestone. Annual precipitation ranges from 800-1,400 mm. Most precipitation is lost through evapotranspiration and there is virtually no surface water. Roughly estimated from chloride mass balance, about 4% of the precipitation recharges the karst aquifer. Cave pools and springs are a common source for water. Hand-dug wells provide water in coastal areas. Few productive wells have been drilled deeper than 60 m. Reconnaissance field analyses indicate that groundwater in the interior is a calcium-bicarbonate type, whereas water at the coast is a sodium-chloride type that exceeds World Health Organization recommended values for sodium and chloride. Tests for the presence of hydrogen sulfide-producing bacteria were negative in most drilled wells, but positive in cave pools, hand-dug wells, and most springs, indicating bacterial contamination of most water sources. Because of the difficulties in obtaining freshwater, the 110,000 inhabitants use an average of only 7 L per person per day. L'Île de la Gonâve est une île de 750 km2 au large de la côte d'Haïti. La profondeur de la nappe varie entre moins de 30 m dans les calcaires de l'Éocène et du Miocène supérieur à plus de 60 m dans les calcaires quaternaires épais de 300 m. Les précipitations annuelles sont comprises entre 800-1.400 mm. La plus grande partie des précipitations est perdue par évapotranspiration et il n'y a pratiquement pas d'eau de surface. Le bilan de masse des chlorures permet d'estimer à 4% des précipitations le montant de la recharge de l'aquifère karstique. Des bassins dans les grottes et des sources sont la source d'eau courante. Des puits creusés à la main fournissent de l'eau dans les zones côtières. Quelques puits productifs ont été forés dépassant 60 m de profondeur. L

  8. Endothelial tyrosine kinase receptor B prevents VE-cadherin cleavage and protects against atherosclerotic lesion development in ApoE−/− mice

    PubMed Central

    Jiang, Hong; Huang, Shuhong; Li, Xinyun; Li, Xian; Huang, Shanying; Zhang, Yun; Chen, Zhe-Yu

    2015-01-01

    Tyrosine kinase receptor B (TrkB) is a high-affinity receptor for brain-derived neurotrophic factor (BDNF). In addition to its nervous system functions, TrkB is also expressed in the aortic endothelium. However, the effects of endothelial TrkB signaling on atherosclerosis remained unknown. Immunofluorescence analysis revealed that TrkB expression is downregulated in the endothelium of atherosclerotic lesions from ApoE−/− mice compared with the atheroma-free aorta of WT mice. Endothelial TrkB knockdown led to increased lesion size, lipid deposition and inflammatory responses in the atherosclerotic lesions of the ApoE−/− mice compared with the control mice. Mechanistic studies showed that TrkB activation prevented VE-cadherin shedding by enhancing the interaction between vascular endothelial protein tyrosine phosphatase and VE-cadherin, maintaining VE-cadherin in a dephosphorylated state. Our data demonstrate that TrkB is an endothelial injury-response molecule in atherogenesis. Endothelial BDNF/TrkB signaling reduces VE-cadherin shedding and protects against atherosclerotic lesion development in ApoE−/− mice. PMID:26431274

  9. Aspergillus flavus VelB acts distinctly from VeA in conidiation and may coordinate with FluG to modulate sclerotial production

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Asexual and sexual differentiation in Aspergillus nidulans involve complex control by a number of factors and is light-dependent. The velvet protein, VeA, in A. nidulans is a negative regulator of conidiation and a positive regulator of sexual development. It forms a complex with VelB and LaeA to co...

  10. Parameters of glucose and lipid metabolism at the fasted state in drug-naïve first-episode patients with psychosis: Evidence for insulin resistance.

    PubMed

    Petrikis, Petros; Tigas, Stelios; Tzallas, Alexandros T; Papadopoulos, Ioannis; Skapinakis, Petros; Mavreas, Venetsanos

    2015-10-30

    Diabetes and dyslipidemia are common in patients with psychosis; this association may be partly related to adverse metabolic effects of antipsychotic medications. We assessed glucose and lipid metabolism during the fasted state in drug-naïve patients with psychosis. Fasting serum concentrations of total cholesterol, triglycerides, high density lipoprotein (HDL), glucose, insulin, connecting peptide (C-peptide), homeostatic model assessment index (HOMA-IR), glycated hemoglobin (HbA1C) and serum cortisol were compared between a group of 40 newly diagnosed drug-naïve, first-episode patients with psychosis and a group of 40 healthy controls, matched for age, sex and BMI. Total cholesterol, triglycerides and fasting glucose levels were similar, whereas insulin and C-peptide levels were higher and HDL marginally lower in the patients' group compared to those in healthy controls. Drug-naïve patients with psychosis were more insulin resistant (as assessed by the HOMA-R index) compared to healthy controls. Serum cortisol did not differ between the two groups. There is evidence that drug-naïve, first-episode patients with psychosis are more insulin resistant compared to healthy controls. PMID:26279127

  11. Altered pattern of Naïve and memory B cells and B1 cells in patients with chronic granulomatous disease.

    PubMed

    Mohsenzadegan, Monireh; Fattahi, Fahimeh; Fattahi, Fatemeh; Mirshafiey, Abbas; Fazlollahi, Mohammad Reza; Naderi Beni, Fariba; Movahedi, Masoud; Pourpak, Zahra

    2014-06-01

    Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder characterized by a greatly increased susceptibility to severe fungal and bacterial infections caused by defects in NADPH oxidase of phagocytic cells. We aimed to investigate immunophenotype alterations of naïve and memory B cells and B1a cells in peripheral whole blood from Iranian patients with CGD. Flow cytometric analysis was performed on peripheral blood samples from 31 CGD patients and 23 healthy controls (HC) to study naïve (IgD+/CD27-), memory (CD27+) B and B1a (CD5+) cells. Soluble CD27 (sCD27) and immunoglobulins were also measured by ELISA and the nephelometric method, respectively. We found significantly higher levels of naïve B cells and B1a cells but lower levels of memory B cells in CGD patients compared to HC.. There was no significant difference in soluble CD27 (sCD27) alteration between CGD patients and HC. Our findings suggested a role for NADPH oxidase in process of B cell differentiation and impairing conversion of naïve B cells to memory B cells and altered B1a cells in CGD patients. Increased susceptibility of CGD patients to opportunistic infections and autoimmune disorders could be partly explained by the altered phenotype of B lymphocytes in these patients. PMID:24659119

  12. Having Students Create Short Video Clips to Help Transition from Naïve Conceptions about Mechanics to True Newtonian Physics

    ERIC Educational Resources Information Center

    Corten-Gualtieri, Pascale; Ritter, Christian; Plumat, Jim; Keunings, Roland; Lebrun, Marcel; Raucent, Benoit

    2016-01-01

    Most students enter their first university physics course with a system of beliefs and intuitions which are often inconsistent with the Newtonian frame of reference. This article presents an experiment of collaborative learning aiming at helping first-year students in an engineering programme to transition from their naïve intuition about dynamics…

  13. Transcriptome analysis of Aspergillus flavus reveals veA-dependent regulation of secondary metabolite gene clusters, including the novel aflavarin cluster

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The global regulatory veA gene governs development and secondary metabolism in numerous fungal species, including Aspergillus flavus. This is especially relevant since A. flavus infects crops of agricultural importance worldwide, contaminating them with potent mycotoxins. The most well-known are afl...

  14. The cortical actin determines different susceptibility of naïve and memory CD4+ T cells to HIV-1 cell-to-cell transmission and infection.

    PubMed

    Permanyer, Marc; Pauls, Eduardo; Badia, Roger; Esté, José A; Ballana, Ester

    2013-01-01

    Memory CD4+ T cells are preferentially infected by HIV-1 compared to naïve cells. HIV-1 fusion and entry is a dynamic process in which the cytoskeleton plays an important role by allowing virion internalization and uncoating. Here, we evaluate the role of the cortical actin in cell-to-cell transfer of virus antigens and infection of target CD4+ T cells. Using different actin remodeling compounds we demonstrate that efficiency of HIV-internalization was proportional to the actin polymerization of the target cell. Naïve (CD45RA+) and memory (CD45RA-) CD4+ T cells could be phenotypically differentiated by the degree of cortical actin density and their capacity to capture virus. Thus, the higher cortical actin density of memory CD4+ T cells was associated to increased efficiency of HIV-antigen internalization and the establishment of a productive infection. Conversely, the lower cortical actin density in naïve CD4+ T cells restricted viral antigen transfer and consequently HIV-1 infection. In conclusion, the cortical actin density differentially affects the susceptibility to HIV-1 infection in naïve and memory CD4+ T cells by modulating the efficiency of HIV antigen internalization. PMID:24244453

  15. Transmitted drug resistance to rilpivirine among antiretroviral-naïve patients living with HIV from northern Poland

    PubMed Central

    Parczewski, Miłosz; Urbańska, Anna; Maciejewska, Katarzyna; Witak-Jȩdra, Magdalena; Leszczyszyn-Pynka, Magdalena

    2014-01-01

    Introduction Rilpivirine (RPV) is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) that was recently approved for the treatment of antiretroviral-naïve individuals with HIV-1 viral load of <100,000 copies/ml. As transmission of the drug resistance mutations to this NNRTI may affect treatment outcomes, the frequency of primary, RPV-associated drug resistance mutations was assessed in this study. Methods For the study, 244 viral genome sequences from antiretroviral-naïve individuals were obtained by bulk sequencing. RPV-associated mutations were divided into RPV resistance mutations (K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, Y188L, H221Y, F227C and M230I/L) according to the International AIDS Society-USA (IAS-USA) mutation list and variants potentially affecting RPV susceptibility (L100I, K101H/T, E138S, V179F/D/G/T, G190A/E/S, F227L and M230V) based on the in vitro and in vivo data. Results IAS-USA RPV drug resistance mutations were found in 5.3% sequences, with E138A and E138G being the most common (3.7 and 0.8%, respectively), followed by K101E (0.4%) and Y181C (0.4%), with no significant differences in the frequency between subtype B and non-B clades. Mutations potentially reducing RPV susceptibility were found in 2.5% of sequences, and they included V179D (1.6%) and G190A (0.8%), with equal distribution among non-B (n=2, 2.5%) and subtype B (n=4, 2.5%) clades. Clustering of RPV mutations was infrequent. Conclusions Prevalence of RPV-associated drug resistance mutations was low in the analysed sample and did not vary across the subtypes. The frequency of variants with potential influence on RPV susceptibility was similar among non-B variants if compared to B clades. Transmitted drug resistance to RPV is uncommon, which makes this a good option for the treatment of ARV-naïve patients; however, genotype resistance testing should remain compulsory before starting an RPV-based regimen. PMID:24746180

  16. Drug usage analysis and health care resources consumption in naïve patients with rheumatoid arthritis

    PubMed Central

    Sangiorgi, Diego; Benucci, Maurizio; Nappi, Carmela; Perrone, Valentina; Buda, Stefano; Degli Esposti, Luca

    2015-01-01

    Objectives The use of biologic agents has revolutionized the management of rheumatoid arthritis (RA) in the past 2 decades. These biologic agents directly target molecules and cells involved in the pathogenesis of RA. The purpose of this study was to assess the usage of biologic agents in terms of persistence to treatment, dose escalation, and consumption of health care resources (hospitalizations, drugs, and outpatients service) in the real clinical practice in naïve patients with RA. Methods We conducted a real-world, retrospective, observational cohort study based on data obtained from administrative databases of three Local Health Units in Italy. The population included adults diagnosed with RA who had at least one prescription between January 1, 2009 and December 31, 2011, for a biologic that was approved for treatment of RA. The patients were followed for 12 months after enrollment. The clinical characteristics of the patients enrolled in this study were also investigated in the 1-year period before the index date. The main and secondary endpoints were evaluated only in biologic-naïve patients without switches. The overall health care costs for patients were evaluated. Results A total of 594 patients met the study criteria (mean age 53.5±13.5, female:male ratio =3:1). Thirty-nine percent received etanercept, 25% adalimumab, 14% infliximab, 10% abatacept, 9% tocilizumab, and 3% golimumab. After 1 year of observation, patients showed similar use of other RA-related medication. For the naïve patients without switches, the persistence levels were: 78% for etanercept, 72% for tocilizumab, 71% for adalimumab, 69% for infliximab, and 64% for abatacept. For all agents, dose escalation was 21.4% for infliximab, 11.5% for adalimumab, 5.6% for abatacept, 4% for tocilizumab, and 3.8% for etanercept. The annual costs per treated patients were €12,803 for adalimumab, €11,924 for etanercept, €11,830 for tocilizumab, €11,201 for infliximab, and €10,943 for

  17. HIV research trials versus standard clinics for antiretroviral-naïve patients: the outcomes differ but do the patients?

    PubMed

    Williams, A J; Wallis, E; Orkin, C

    2016-06-01

    Exclusion criteria for HIV treatment-naïve drug trials can be stringent and selection bias exists, making it difficult to extrapolate results into the 'real world' clinical situation. We aim to compare the demographics, virological outcomes and psychosocial complexity in adult HIV-infected treatment-naïve patients from our cohort initiating combination antiretroviral therapy (cART) in research trials versus standard clinics. In our unit from 2006 to 2011, 1202 standard clinic and 69 research trial patients initiated cART; every eighth standard clinics patient was included to create a standard clinics:research trials patient ratio of 2:1. Notes were retrospectively reviewed for patient demographics, attendance rates and virological outcomes. Data from 221 antiretroviral-naïve patients starting cART were analysed: 152 standard clinic patients and 69 from research trials. In the research trials group, there was an overrepresentation of men (p = 0.041), men who have sex with men (p < 0.001), patients of white ethnicity (p = 0.01), employed patients (p = 0.01) and patients using excessive alcohol (p = 0.02). There was equal representation of drug use, depression and referral to psychology, psychiatry and social work in both groups. The research trials group at baseline had significantly higher CD4 counts (p < 0.001), lower viral loads (p = 0.01) and more patients achieved undetectable viral loads at three (p < 0.001), six (p < 0.001) and 24 months (p = 0.033). There is a prevailing common preconception that participants in clinical trials are uncomplicated, unlike their 'real-life' counterparts. We demonstrated important similarities in psychosocial complexity as well as differences in demographics and virological outcomes in trial and non-trial patients. Clinicians need to be aware of these discrepancies to ensure the facilitation of a heterogeneous population participating in research trials. PMID:25999167

  18. Clinical activity of enzalutamide in docetaxel-naïve and docetaxel-pretreated patients with metastatic castration-resistant prostate cancer

    PubMed Central

    Nadal, Rosa; Zhang, Zhe; Rahman, Hibba; Schweizer, Michael T.; Denmeade, Samuel R.; Paller, Channing J.; Carducci, Michael A.; Eisenberger, Mario A.; Antonarakis, Emmanuel S.

    2014-01-01

    Background Two randomized clinical trials have demonstrated a survival advantage with enzalutamide over placebo in both docetaxel (D)-pretreated and D-naïve metastatic castration-resistant prostate cancer (mCRPC) patients. Cross-resistance between androgen receptor-directed therapies and taxanes has been suggested, possibly leading to lower efficacy of enzalutamide in the post-D setting. Material and Methods We aimed to examine the impact of prior D treatment on the clinical activity of enzalutamide in patients with mCRPC. We retrospectively reviewed an institutional database to identify men with mCRPC treated with standard-of-care enzalutamide. Patients were classified as D-naïve or D-pretreated. The efficacy end points were prostate-specific antigen (PSA) response rates (≥50% PSA decline), time to PSA progression (TTPP) and clinical/radiographic progression-free survival (PFS) in response to enzalutamide. Differences between groups (D-naïve and D-pretreated) were assessed by univariate and multivariable analyses using logistic and Cox regression models. Results One-hundred-seven (107) consecutive patients were included: 60 were D-pretreated and 47 were D-naïve. PSA responses were 43.2% in D-naïve patients and 25.4% in D-pretreated patients (P=0.089). Median TTPP was 7.2 months (95% CI=4.5–17.2) in the D-naïve group versus 2.6 mo (95% CI=1.9–3.5) in the D-pretreated group (P<0.0001). Median PFS was not reached for D-naïve men and was 3.3 mo (95% CI=2.5–4.8) for D-pretreated men (P<0.0001). After adjusting for potential confounders including prior abiraterone use, differences remained statistically significant for TTPP (HR=2.32; 95% CI=1.19–4.50; P=0.013) and marginally significant for PFS (HR=1.90; 95% CI=0.94–3.84; P=0.073) in multivariable analyses. Among patients who achieved a PSA response to enzalutamide (n=34), results suggested a trend towards shorter duration of response in D-pretreated patients. Conclusions The clinical activity of

  19. Platelet-activating factor increases VE-cadherin tyrosine phosphorylation in mouse endothelial cells and its association with the PtdIns3'-kinase

    PubMed Central

    Hudry-Clergeon, Hélène; Stengel, Dominique; Ninio, Ewa; Vilgrain, Isabelle

    2005-01-01

    Platelet-activating-Factor (PAF), a potent inflammatory mediator, is involved in endothelial permeability. This study was designed to characterize PAF receptor (PAF-R) expression and its specific contribution to the modifications of adherens junctions in mouse endothelial cells. We demonstrated that PAF-R was expressed in mouse endothelial cells and was functionally active in stimulating p42/p44 MAPK and phosphatidylinositol 3-kinase (PtdIns3′-kinase)/Akt activities. Treatment of cells with PAF induced a rapid, time- and dose-dependent (10−7 to 10−10M) increase in tyrosine phosphorylation of a subset of proteins ranging from 90 kDa to 220 kDa, including the VE-cadherin, the latter effect being prevented by the tyrosine kinase inhibitors, herbimycin A and bis-tyrphostin. Furthermore, we demonstrated that PAF promoted formation of multimeric aggregates of VE-cadherin with PtdIns3′-kinase which was also inhibited by herbimycin and bis-tyrphostin. Finally, we showed by immunostaining of endothelial cells VE-cadherin, that PAF dissociated adherens junctions. The present data provide the first evidence that the treatment of endothelial cells with PAF promoted activation of tyrosine kinases and the VE-cadherin tyrosine phosphorylation and PtdIns3′-kinase association, that ultimately lead to the dissociation of adherens junctions. Physical association between PtdIns3′-kinase, serving as a docking protein, and VE-cadherin may thus provide an efficient mechanism for amplification and perpetuation of PAF-induced cellular activation. PMID:15791001

  20. Frontal-Subcortical Volumetric Deficits in Single Episode, Medication-Naïve Depressed Patients and the Effects of 8 Weeks Fluoxetine Treatment: A VBM-DARTEL Study

    PubMed Central

    Kong, Lingtao; Wu, Feng; Tang, Yanqing; Ren, Ling; Kong, Dongyan; Liu, Ying; Xu, Ke; Wang, Fei

    2014-01-01

    Background Convergent studies suggest that morphological abnormalities of frontal-subcortical circuits which involved with emotional and cognitive processing may contribute to the pathophysiology of major depressive disorder (MDD). Antidepressant treatment which has been reported to reverse the functional abnormalities of frontal-subcortical circuits in MDD may have treating effects to related brain morphological abnormalities. In this study, we used voxel-based morphometry method to investigate whole brain structural abnormalities in single episode, medication-naïve MDD patients. Furthermore, we investigated the effects of an 8 weeks pharmacotherapy with fluoxetine. Methods 28 single episode, medication-naïve MDD participants and 28 healthy controls (HC) acquired the baseline high-resolution structural magnetic resonance imaging (sMRI) scan. 24 MDD participants acquired a follow-up sMRI scan after 8 weeks antidepressant treatment. Gray matter volumetric (GMV) difference between groups was examined. Results Medication-naïve MDD had significantly decreased GMV in the right dorsolateral prefrontal cortex and left middle frontal gyrus as well as increased GMV in the left thalamus and right insula compared to HC (P<0.05, corrected). Moreover, treated MDD had significantly increased GMV in the left middle frontal gyrus and right orbitofrontal cortex compared to HC (P<0.05, corrected). No difference on GMV was detected between medication-naïve MDD group and treated MDD group. Conclusions This study of single episode, medication-naïve MDD subjects demonstrated structural abnormalities of frontal-subcortical circuitsin the early stage of MDD and the effects of 8 weeks successful antidepressant treatment, suggesting these abnormalities may play an important role in the neuropathophysiology of MDD at its onset. PMID:24427263

  1. Long antibody HCDR3s from HIV-naïve donors presented on a PG9 neutralizing antibody background mediate HIV neutralization.

    PubMed

    Willis, Jordan R; Finn, Jessica A; Briney, Bryan; Sapparapu, Gopal; Singh, Vidisha; King, Hannah; LaBranche, Celia C; Montefiori, David C; Meiler, Jens; Crowe, James E

    2016-04-19

    Development of broadly neutralizing antibodies (bnAbs) against HIV-1 usually requires prolonged infection and induction of Abs with unusual features, such as long heavy-chain complementarity-determining region 3 (HCDR3) loops. Here we sought to determine whether the repertoires of HIV-1-naïve individuals contain Abs with long HCDR3 loops that could mediate HIV-1 neutralization. We interrogated at massive scale the structural properties of long Ab HCDR3 loops in HIV-1-naïve donors, searching for structured HCDR3s similar to those of the HIV-1 bnAb PG9. We determined the nucleotide sequences encoding 2.3 × 10(7)unique HCDR3 amino acid regions from 70 different HIV-1-naïve donors. Of the 26,917 HCDR3 loops with 30-amino acid length identified, we tested 30 for further study that were predicted to have PG9-like structure when chimerized onto PG9. Three of these 30 PG9 chimeras bound to the HIV-1 gp120 monomer, and two were neutralizing. In addition, we found 14 naturally occurring HCDR3 sequences that acquired the ability to bind to the HIV-1 gp120 monomer when adding 2- to 7-amino acid mutations via computational design. Of those 14 designed Abs, 8 neutralized HIV-1, with IC50values ranging from 0.7 to 98 µg/mL. These data suggest that the repertoire of HIV-1-naïve individuals contains rare B cells that encode HCDR3 loops that bind or neutralize HIV-1 when presented on a PG9 background with relatively few or no additional mutations. Long HCDR3 sequences are present in the HIV-naïve B-cell repertoire, suggesting that this class of bnAbs is a favorable target for rationally designed preventative vaccine efforts. PMID:27044078

  2. G0S2 modulates homeostatic proliferation of naïve CD8+ T cells and inhibits oxidative phosphorylation in mitochondria

    PubMed Central

    Lee, Ping-Hsien; Yamada, Takeshi; Park, Chun Shik; Shen, Ye; Puppi, Monica; Lacorazza, H. Daniel

    2015-01-01

    Since its discovery, diverse functions have been attributed to the G0/G1 switch gene 2 (G0S2), from lipid metabolism to control of cell proliferation. Our group showed for the first time that G0S2 promotes quiescence in hematopoietic stem cells by interacting with and retaining nucleolin around the nucleus. Herein, we report the role of G0S2 in the differentiation and function of CD8+ T cells examined in mice with an embryonic deletion of the G0s2 gene. G0S2 expression in naïve CD8+ T cells decreased immediately after T-cell receptor activation downstream of the MAPK, calcium/calmodulin, PI3K, and mTOR pathways. Surprisingly, G0S2-null naïve CD8+ T cells displayed increased basal and spare respiratory capacity that was not associated with increased mitochondrial biogenesis but with increased phosphorylation of AMPKα. Naïve CD8+ T cells showed increased proliferation in response to in vitro activation and in vivo lymphopenia; however, naïve CD8+ T cells expressing the OT-1 transgene exhibited normal differentiation of naïve cells to effector and memory CD8+ T cells upon infection with Listeria monocytogenes in a wild type or a G0s2-null environment, with increased circulating levels of free fatty acids. Collectively, our results suggest that G0S2 inhibits energy production by oxidative phosphorylation to fine-tune proliferation in homeostatic conditions. PMID:25666096

  3. G0S2 modulates homeostatic proliferation of naïve CD8⁺ T cells and inhibits oxidative phosphorylation in mitochondria.

    PubMed

    Lee, Ping-Hsien; Yamada, Takeshi; Park, Chun Shik; Shen, Ye; Puppi, Monica; Lacorazza, H Daniel

    2015-08-01

    Since its discovery, diverse functions have been attributed to the G0/G1 switch gene 2 (G0S2), from lipid metabolism to control of cell proliferation. Our group showed for the first time that G0S2 promotes quiescence in hematopoietic stem cells by interacting with and retaining nucleolin around the nucleus. Herein, we report the role of G0S2 in the differentiation and function of CD8(+) T cells examined in mice with an embryonic deletion of the G0s2 gene. G0S2 expression in naïve CD8(+) T cells decreased immediately after T-cell receptor activation downstream of the mitogen-activated protein kinase, calcium/calmodulin, phosphatidylinositol 3'-kinase and mammalian target of rapamycin pathways. Surprisingly, G0S2-null naïve CD8(+) T cells displayed increased basal and spare respiratory capacity that was not associated with increased mitochondrial biogenesis but with increased phosphorylation of AMP-activated protein kinase α. Naïve CD8(+) T cells showed increased proliferation in response to in vitro activation and in vivo lymphopenia; however, naïve CD8(+) T cells expressing the OT-1 transgene exhibited normal differentiation of naïve cells to effector and memory CD8(+) T cells upon infection with Listeria monocytogenes in a wild-type or a G0s2-null environment, with increased circulating levels of free fatty acids. Collectively, our results suggest that G0S2 inhibits energy production by oxidative phosphorylation to fine-tune proliferation in homeostatic conditions. PMID:25666096

  4. HMGN proteins modulate chromatin regulatory sites and gene expression during activation of naïve B cells

    PubMed Central

    Zhang, Shaofei; Zhu, Iris; Deng, Tao; Furusawa, Takashi; Rochman, Mark; Vacchio, Melanie S.; Bosselut, Remy; Yamane, Arito; Casellas, Rafael; Landsman, David; Bustin, Michael

    2016-01-01

    The activation of naïve B lymphocyte involves rapid and major changes in chromatin organization and gene expression; however, the complete repertoire of nuclear factors affecting these genomic changes is not known. We report that HMGN proteins, which bind to nucleosomes and affect chromatin structure and function, co-localize with, and maintain the intensity of DNase I hypersensitive sites genome wide, in resting but not in activated B cells. Transcription analyses of resting and activated B cells from wild-type and Hmgn−/− mice, show that loss of HMGNs dampens the magnitude of the transcriptional response and alters the pattern of gene expression during the course of B-cell activation; defense response genes are most affected at the onset of activation. Our study provides insights into the biological function of the ubiquitous HMGN chromatin binding proteins and into epigenetic processes that affect the fidelity of the transcriptional response during the activation of B cell lymphocytes. PMID:27112571

  5. Discordance Between Cobas BRAF V600 Testing and VE1 Immunohistochemistry in a Melanoma Patient With Bone Marrow Metastases.

    PubMed

    Rapisuwon, Suthee; Busam, Klaus J; Parks, Kellie; Chapman, Paul B; Lee, Elsie; Atkins, Michael B

    2016-09-01

    False negative result remains an ongoing problem in direct gene sequencing of cancers. It is important to use the appropriate mutation detection method most appropriate to each circumstance and the available tissue. Here, we report a patient with melanoma of unknown primary with metastases to spleen and bone marrow, who was tested negative for Cobas BRAF V600E mutation, whose cancer progressed on antiprogrammed death 1 (PD1) receptor monoclonal antibody therapy. Subsequent VE1 immunohistochemistry was positive for BRAF V600E mutation, and the tumor responded dramatically to v-Raf murine sarcoma viral oncogene homolog B (BRAF)/Mitogen-activated protein kinase inhibitor combination therapy. This demonstrates how alternative BRAF testing methodology could produce results that can influence treatment choice and the outcome. PMID:27541170

  6. Characterization of the Psychological, Physiological and EEG Profile of Acute Betel Quid Intoxication in Naïve Subjects

    PubMed Central

    Osborne, Peter G.; Chou, Tung-Shan; Shen, Tsu-Wang

    2011-01-01

    Betel quid use and abuse is wide spread in Asia but the physiological basis of intoxication and addiction are unknown. In subjects naïve to the habit of betel quid intoxication, the psychological and physiological profile of intoxication has never been reported. We compared the effect of chewing gum or chewing betel quid, and subsequent betel quid intoxication, on psychological assessment, prospective time interval estimation, numerical and character digit span, computerized 2 choice tests and mental tasks such as reading and mathematics with concurrent monitoring of ECG, EEG and face temperature in healthy, non-sleep deprived, male subjects naïve to the habit of chewing betel quid. Betel quid intoxication, dose dependently induced tachycardia (max 30 bpm) and elevated face temperature (0.7°C) (P<0.001) above the effects observed in response to chewing gum (max 12 bpm and 0.3°C) in 12 subjects. Gross behavioral indices of working memory such as numerical or character digit span in 8 subjects, or simple visual-motor performance such as reaction speed or accuracy in a two choice scenario in 8 subjects were not affected by betel quid intoxication. Betel quid intoxication strongly influenced the psychological aspects of perception such as slowing of the prospective perception of passage of a 1 minute time interval in 8 subjects (P<0.05) and perceived increased arousal (P<0.01) and perceived decreased ability to think (P<0.05) in 31 subjects. The EEG spectral profile recorded from mental states associated with open and closed eyes, and mental tasks such as reading and eyes closed mental arithmetic were significantly modified (P<0.05) relative to chewing gum by betel quid intoxication in 10 subjects. The prevalence of betel quid consumption across a range of social and work settings warrants greater investigation of this widespread but largely under researched drug. PMID:21909371

  7. Overt and occult hepatitis B virus infection among treatment-naïve HIV-infected patients in Brazil.

    PubMed

    Oliveira, Marina Pedroso; Lemes, Pollyanne Sousa; Matos, Márcia Alves Dias; Del-Rios, Nativa Helena Alves; Carneiro, Megmar Aparecida Santos; Silva, Ágabo Macedo Costa; Lopes, Carmen Luci Rodrigues; Teles, Sheila Araújo; Aires, Rodrigo Sebba; Lago, Bárbara Vieira; Araujo, Natalia Motta; Martins, Regina Maria Bringel

    2016-07-01

    Although hepatitis B virus (HBV) and human immunodeficiency virus (HIV) co-infection is common, only few data are available on HBV among HIV patients including occult hepatitis B infection (OBI), regardless of serological markers. This study aims to determine the prevalence of OBI and overall HBV infection, associated factors, HBV genotypes, and surface (S) gene mutations in a population of treatment-naïve HIV-infected patients in Brazil. A cross-sectional study was conducted in treatment-naïve HIV-infected patients in Central Brazil. All samples were tested for HBV serological markers and HBV DNA. Sequence analysis of the S gene and overlapping polymerase gene was preformed. Overall, 25.1% (127/505) of the patients had markers of current or previous HBV infection, which was associated with age over 40 years, history of injection drug use, and homosexual sex. The hepatitis B surface antigen (HBsAg) seroprevalence was 4.9% (25/505). HBV DNA was detected in 39 out of 505 patients: 20 of them were HBsAg-positive and 19 were HBsAg-negative, resulting in an OBI prevalence of 3.8%. Patients with OBI had significantly higher HCV seropositivity rate compared to HBsAg-positive patients. Sequencing of the S gene revealed Y100C, T131N, and D144A mutations. One patient had the M204I and L180M drug-resistance mutations (polymerase). HBV genotypes A (A1, A2), D (D2, D3), and F (F2) were identified. In conclusion, OBI represented almost half of all HBV infections with detectable HBV DNA, suggesting that hepatitis B diagnosis in HIV patients should include in addition to serological markers the detection of HBV DNA. PMID:27061406

  8. Neurocognitive Function in Acromegaly after Surgical Resection of GH-Secreting Adenoma versus Naïve Acromegaly

    PubMed Central

    Martín-Rodríguez, Juan Francisco; Madrazo-Atutxa, Ainara; Venegas-Moreno, Eva; Benito-López, Pedro; Gálvez, María Ángeles; Cano, David A.; Tinahones, Francisco J.; Torres-Vela, Elena; Soto-Moreno, Alfonso; Leal-Cerro, Alfonso

    2013-01-01

    Patients with active untreated acromegaly show mild to moderate neurocognitive disorders that are associated to chronic exposure to growth hormone (GH) and insulin-like growth factor (IGF-I) hypersecretion. However, it is unknown whether these disorders improve after controlling GH/IGF-I hypersecretion. The aim of this study was to compare neurocognitive functions of patients who successfully underwent GH-secreting adenoma transsphenoidal surgery (cured patients) with patients with naive acromegaly. In addition, we wanted to determine the impact of different clinical and biochemical variables on neurocognitive status in patients with active disease and after long-term cure. A battery of six standardized neuropsychological tests assessed attention, memory and executive functioning. In addition, a quantitative electroencephalography with Low-Resolution Electromagnetic Tomography (LORETA) solution was performed to obtain information about the neurophysiological state of the patients. Neurocognitive data was compared to that of a healthy control group. Multiple linear regression analysis was also conducted using clinical and hormonal parameters to obtain a set of independent predictors of neurocognitive state before and after cure. Both groups of patients scored significantly poorer than the healthy controls on memory tests, especially those assessing visual and verbal recall. Patients with cured acromegaly did not obtain better cognitive measures than naïve patients. Furthermore memory deficits were associated with decreased beta activity in left medial temporal cortex in both groups of patients. Regression analysis showed longer duration of untreated acromegaly was associated with more severe neurocognitive complications, regardless of the diagnostic group, whereas GH levels at the time of assessment was related to neurocognitive outcome only in naïve patients. Longer duration of post-operative biochemical remission of acromegaly was associated with better

  9. Association between brain volumes and HAND in cART naïve HIV+ individuals from Thailand

    PubMed Central

    Heaps, Jodi M.; Sithinamsuwan, Pasiri; Paul, Robert; Clifford, David; Pothisri, Mantana; Luerdlum, Sukalaya; Catella, Stephanie; Busovaca, Edgar; Raudabaugh, Benjamin; Ratto-Kim, Silvia; Tipsuk, Somporn; Fletcher, James LK; Valcour, Victor; Ananworanich, Jintanat

    2015-01-01

    This study aimed to determine the effects of human immunodeficiency virus (HIV) on brain structure in HIV-infected individuals with and without HIV-associated neurocognitive disorders (HAND). Twenty-nine HIV-uninfected controls, 37 HIV+, treatment naïve, individuals with HAND (HIV+HAND+; 16 ANI, 12 MND, and 9 HAD) and 37 HIV+, treatment naïve, individuals with normal cognitive function (HIV+HAND−) underwent magnetic resonance imaging (MRI) and neuropsychological assessment. The HIV-infected participants had a mean (SD) age of 35(7) years, mean (IQR) CD4 count of 221(83-324) and mean (IQR) log10 plasma viral load of 4.81(4.39-5.48). Six regions of interest were selected for analyses including total and subcortical gray matter, total white matter, caudate, corpus callosum, and thalamus. The HIV+/HAND+ group exhibited significantly smaller brain volumes compared to the HIV-uninfected group in subcortical gray and total gray matter; however, there were no statistically significant differences in brain volumes between the HIV+HAND+ and HIV+HAND− groups or between HIV+/HAND− and controls. CD4 count at time of cART initiation was associated with total and subcortical gray matter volumes, but not with cognitive measures. Plasma viral load correlated with neuropsychological performance, but not brain volumes. The lack of significant differences in brain volumes between HIV+HAND+ and HIV+HAND− suggests that brain atrophy is not a sensitive measure of HAND in subjects without advanced immunosuppression. Alternatively, current HAND diagnostic criteria may not sufficiently distinguish patients based on MRI measures of brain volumes. PMID:25604494

  10. Generation of Naïve Bovine Induced Pluripotent Stem Cells Using PiggyBac Transposition of Doxycycline-Inducible Transcription Factors

    PubMed Central

    Kawaguchi, Takamasa; Tsukiyama, Tomoyuki; Kimura, Koji; Matsuyama, Shuichi; Minami, Naojiro; Yamada, Masayasu; Imai, Hiroshi

    2015-01-01

    Generation of pluripotent stem cells (PSCs) in large domestic animals has achieved only limited success; most of the PSCs obtained to date have been classified as primed PSCs, which possess very little capacity to produce chimeric offspring. By contrast, mouse PSCs have been classified as naïve PSCs that can contribute to most of the tissues of chimeras, including germ cells. Here, we describe the generation of two different types of bovine induced pluripotent stem cells (biPSCs) from amnion cells, achieved through introduction of piggyBac vectors containing doxycycline-inducible transcription factors (Oct3/4, Sox2, Klf4, and c-Myc). One type of biPSCs, cultured in medium supplemented with knockout serum replacement (KSR), FGF2, and bovine leukemia inhibitory factor (bLIF), had a flattened morphology like human PSCs; these were classified as primed-type. The other type biPSCs, cultured in KSR, bLIF, Mek/Erk inhibitor, GSK3 inhibitor and forskolin, had a compact morphology like mouse PSCs; these were classified as naïve-type. Cells could easily be switched between these two types of biPSCs by changing the culture conditions. Both types of biPSCs had strong alkaline phosphatase activity, expressed pluripotent markers (OCT3/4, NANOG, REX1, ESRRβ, STELLA, and SOCS3), and formed embryoid bodies that gave rise to differentiated cells from all three embryonic germ layers. However, only naïve-type biPSCs showed the hallmarks of naïve mouse PSCs, such as LIF-dependent proliferation, lack of FGF5 expression, and active XIST expression with two active X chromosomes. Furthermore, naïve-type biPSCs could contribute to the inner cell mass (ICM) of host blastocysts and most tissues within chimeric embryos. This is the first report of generation of biPSCs with several characteristics similar to those of naïve mouse PSCs and a demonstrated potential to contribute to chimeras. PMID:26287611

  11. Efficacy of a preservative-free formulation of fixed-combination bimatoprost and timolol (Ganfort PF) in treatment-naïve patients vs previously treated patients

    PubMed Central

    Cordeiro, M Francesca; Goldberg, Ivan; Schiffman, Rhett; Bernstein, Paula; Bejanian, Marina

    2015-01-01

    Purpose To evaluate, using subgroup analysis, the effect of treatment status on the intraocular pressure (IOP)-lowering efficacy of a preservative-free formulation of fixed-combination bimatoprost 0.03%/timolol 0.5% (FCBT PF). Methods A primary, multicenter, randomized, double-masked, 12-week study compared the efficacy and safety of FCBT PF with preserved FCBT (Ganfort®) in 561 patients diagnosed with glaucoma or ocular hypertension. For this analysis, eligible patients were treatment-naïve or had inadequate IOP lowering and underwent a washout of previous treatment. IOP (8 am, 10 am, and 4 pm) was measured at baseline and weeks 2, 6, and 12. Subgroup analysis of the FCBT PF arm assessed changes in average eye IOP from baseline in treatment-naïve vs previously treated patients. To evaluate the effect of treatment status at baseline (treatment-naïve vs previously treated) on IOP reduction in the FCBT PF treatment group, an analysis of covariance model was used with treatment status and investigator as fixed effects, and baseline average eye IOP, age, glaucoma diagnosis, and baseline average eye corneal thickness as covariates. P-values and the 95% confidence intervals were determined using the model. Results In the FCBT PF arm, IOP mean changes from baseline ranged from −8.7 mmHg to −9.8 mmHg in treatment-naïve patients (N=50), compared with −7.3 mmHg to −8.5 mmHg in previously treated patients (N=228). Baseline IOP, age, glaucoma diagnosis, and corneal thickness significantly affected IOP reduction in the FCBT PF group. Adjusting for these covariates, FCBT PF had a greater IOP-lowering effect (0.8–1.7 mmHg) in treatment-naïve patients than previously treated patients, which was statistically significant (P≤0.05) at seven of nine time points. Conclusion In this subgroup analysis, FCBT PF reduced IOP more effectively in treatment-naïve than in previously treated patients possibly due, in part, to altered responsiveness or tachyphylaxis that has

  12. Generation of Naïve Bovine Induced Pluripotent Stem Cells Using PiggyBac Transposition of Doxycycline-Inducible Transcription Factors.

    PubMed

    Kawaguchi, Takamasa; Tsukiyama, Tomoyuki; Kimura, Koji; Matsuyama, Shuichi; Minami, Naojiro; Yamada, Masayasu; Imai, Hiroshi

    2015-01-01

    Generation of pluripotent stem cells (PSCs) in large domestic animals has achieved only limited success; most of the PSCs obtained to date have been classified as primed PSCs, which possess very little capacity to produce chimeric offspring. By contrast, mouse PSCs have been classified as naïve PSCs that can contribute to most of the tissues of chimeras, including germ cells. Here, we describe the generation of two different types of bovine induced pluripotent stem cells (biPSCs) from amnion cells, achieved through introduction of piggyBac vectors containing doxycycline-inducible transcription factors (Oct3/4, Sox2, Klf4, and c-Myc). One type of biPSCs, cultured in medium supplemented with knockout serum replacement (KSR), FGF2, and bovine leukemia inhibitory factor (bLIF), had a flattened morphology like human PSCs; these were classified as primed-type. The other type biPSCs, cultured in KSR, bLIF, Mek/Erk inhibitor, GSK3 inhibitor and forskolin, had a compact morphology like mouse PSCs; these were classified as naïve-type. Cells could easily be switched between these two types of biPSCs by changing the culture conditions. Both types of biPSCs had strong alkaline phosphatase activity, expressed pluripotent markers (OCT3/4, NANOG, REX1, ESRRβ, STELLA, and SOCS3), and formed embryoid bodies that gave rise to differentiated cells from all three embryonic germ layers. However, only naïve-type biPSCs showed the hallmarks of naïve mouse PSCs, such as LIF-dependent proliferation, lack of FGF5 expression, and active XIST expression with two active X chromosomes. Furthermore, naïve-type biPSCs could contribute to the inner cell mass (ICM) of host blastocysts and most tissues within chimeric embryos. This is the first report of generation of biPSCs with several characteristics similar to those of naïve mouse PSCs and a demonstrated potential to contribute to chimeras. PMID:26287611

  13. The TCR’s sensitivity to self-peptide–MHC dictates the ability of naïve CD8+ T cells to respond to foreign antigens

    PubMed Central

    Fulton, Ross B.; Hamilton, Sara E.; Xing, Yan; Best, J. Adam; Goldrath, Ananda W.; Hogquist, Kristin A.; Jameson, Stephen C.

    2014-01-01

    The strength of self-peptide–major histocompatibility complex (MHC) recognition dictates naïve CD8+ T cell homeostasis, but its effect on foreign antigen reactivity is controversial. As CD5 expression correlates with self-recognition, we studied CD5lo and CD5hi naïve CD8+ T cells. Gene expression characteristics suggested CD5hi cells were better poised for reactivity and differentiation compared to the CD5lo population, and we found that the CD5hi pool exhibited more efficient clonal recruitment and expansion, as well as enhanced reactivity to inflammatory cues, during recognition of foreign antigen. Yet foreign peptide–MHC recognition was similar for both subsets. Thus, CD8+ T cells with higher self-reactivity dominate the immune response against foreign antigens, with implications for T cell repertoire diversity and autoimmunity. PMID:25419629

  14. Temporary Threshold Shifts in Naïve and Experienced Belugas: Can Dampening of the Effects of Fatiguing Sounds Be Learned?

    PubMed

    Popov, Vladimir; Supin, Alexander; Nechaev, Dmitry; Sysueva, Evgenia; Rozhnov, Viatcheslav

    2016-01-01

    In belugas (Delphinapterus leucas), substantial (10-15 dB) differences in temporary threshold shifts (TTSs) were observed between the first and subsequent experimental sessions in the same subjects. In the first session (naïve subject state), the TTSs produced by exposure to fatiguing noises were larger than the TTSs produced in subsequent sessions (experienced subject state). After one to two sessions, the TTSs stabilized. The baseline hearing thresholds did not differ between the naïve and experienced states. One possible explanation for this effect is that the animals learned to dampen their hearing during exposure to fatiguing noises and thus mitigate the impact of those noises. PMID:26611042

  15. Bayesian Estimation of Mixture Models with Prespecified Elements to Compare Drug Resistance in Treatment-Naïve and Experienced Tuberculosis Cases

    PubMed Central

    Izu, Alane; Cohen, Ted; DeGruttola, Victor

    2013-01-01

    We propose a Bayesian approach for estimating branching tree mixture models to compare drug-resistance pathways (i.e. patterns of sequential acquisition of resistance to individual antibiotics) that are observed among Mycobacterium tuberculosis isolates collected from treatment-naïve and treatment-experienced patients. Resistant pathogens collected from treatment-naïve patients are strains for which fitness costs of resistance were not sufficient to prevent transmission, whereas those collected from treatment-experienced patients reflect both transmitted and acquired resistance, the latter of which may or may not be associated with lower transmissibility. The comparison of the resistance pathways constructed from these two groups of drug-resistant strains provides insight into which pathways preferentially lead to the development of multiple drug resistant strains that are transmissible. We apply the proposed statistical methods to data from worldwide surveillance of drug-resistant tuberculosis collected by the World Health Organization over 13 years. PMID:23555210

  16. Drop out Estimation Students based on the Study Period: Comparisonbetween Naïve Bayes and Support Vector Machines Algorithm Methods

    NASA Astrophysics Data System (ADS)

    Harwati; Ikha Virdyanawaty, Riezky; Mansur, Agus

    2016-01-01

    Industrial Engineering is one of the departments in Faculty of Industrial Technology. It has more than 200 reshmen in every academic year. However, many students are dropped out because they couldn't complete their study in appropriate time. Variables that influence the drop out case are not yet studied. The objective of this paper is discovering the highest accuracy level between the two methods used, i.e. Naïve Bayesand Support Vector Machines algorithms. The method with the highest accuracy will be discovered from the patterns forms and parameters of every attribute which most influence the students’ length of study period. The result shows that the highest accuracy method is Naïve Bayes Algorithm with accuracy degree of 80.67%. Discussion of this paper emphasizes on the variables that influence the students’ study period.

  17. Sevoflurane prevents lipopolysaccharide-induced barrier dysfunction in human lung microvascular endothelial cells: Rho-mediated alterations of VE-cadherin.

    PubMed

    Huang, Yiran; Tan, Qindong; Chen, Rui; Cao, Biao; Li, Wenhong

    Acute lung injury (ALI) mainly occurs as increased permeability of lung tissue and pleural effusion. Inhaled anesthetic sevoflurane has been demonstrated to alleviate lung permeability by upregulating junction proteins after ischemia-reperfusion. However, the exact mechanisms of its protective effect on reperfusion injury remain elusive. The aim of this study was to assess possible preconditioning with sevoflurane in an in vitro model of lipopolysaccharide (LPS)-induced barrier dysfunction in human lung microvascular endothelial cells (HMVEC-Ls). In this study, HMVEC-Ls were exposed to minimum alveolar concentration of sevoflurane for 2 h. LPS significantly increased the permeability of HMVEC-L. Moreover, the distribution of junction protein, vascular endothelial (VE)-cadherin, in cell-cell junction area and the total expression in HMVEC-Ls were significantly decreased by LPS treatment. However, the abnormal distribution and decreased expression of VE-cadherin and hyperpermeability of HMVEC-Ls were significantly reversed by pretreatment with sevoflurane. Furthermore, LPS-induced activation of the RhoA/ROCK signaling pathway was significantly inhibited with sevoflurane. Such activation, abnormal distribution and decreased expression of VE-cadherin and hyperpermeability of HMVEC-Ls were significantly inhibited with sevoflurane pretreatment or knockdown of RhoA or ROCK-2. In conclusion, sevoflurane prevented LPS-induced rupture of HMVEC-L monolayers by suppressing the RhoA/ROCK-mediated VE-cadherin signaling pathway. Our results may explain, at least in part, some beneficial effects of sevoflurane on pulmonary dysfunction such as ischemia-reperfusion injury. PMID:26529544

  18. Polychlorinated biphenyl quinone induces endothelial barrier dysregulation by setting the cross talk between VE-cadherin, focal adhesion, and MAPK signaling.

    PubMed

    Zhang, Pu; Feng, Shan; Bai, Huiyuan; Zeng, Panying; Chen, Feng; Wu, Chengxiang; Peng, Yi; Zhang, Qin; Zhang, Qiuyao; Ye, Qichao; Xue, Qiang; Xu, Xiaoyu; Song, Erqun; Song, Yang

    2015-05-15

    Environmental hazardous material polychlorinated biphenyl (PCB) exposure is associated with vascular endothelial dysfunction, which may increase the risk of cardiovascular diseases and cancer metastasis. Our previous studies illustrated the cytotoxic, antiproliferative, and genotoxic effects of a synthetic, quinone-type, highly reactive metabolite of PCB, 2,3,5-trichloro-6-phenyl-[1,4]benzoquinone (PCB29-pQ). Here, we used it as the model compound to investigate its effects on vascular endothelial integrity and permeability. We demonstrated that noncytotoxic doses of PCB29-pQ induced vascular endothelial (VE)-cadherin junction disassembly by increasing the phosphorylation of VE-cadherin at Y658. We also found that focal adhesion assembly was required for PCB29-pQ-induced junction breakdown. Focal adhesion site-associated actin stress fibers may serve as holding points for cytoskeletal tension to regulate the cellular contractility. PCB29-pQ exposure promoted the association of actin stress fibers with paxillin-containing focal adhesion sites and enlarged the size/number of focal adhesions. In addition, PCB29-pQ treatment induced phosphorylation of paxillin at Y118. By using pharmacological inhibition, we further demonstrated that p38 activation was necessary for paxillin phosphorylation, whereas extracellular signal-regulated kinases-1/2 activation regulated VE-cadherin phosphorylation. In conclusion, these results indicated that PCB29-pQ stimulates endothelial hyperpermeability by mediating VE-cadherin disassembly, junction breakdown, and focal adhesion formation. Intervention strategies targeting focal adhesion and MAPK signaling could be used as therapeutic approaches for preventing adverse cardiovascular health effects induced by environmental toxicants such as PCBs. PMID:25770237

  19. Heightened self-reactivity associated with selective survival, but not expansion, of naïve virus-specific CD8+ T cells in aged mice

    PubMed Central

    Quinn, Kylie M.; Zaloumis, Sophie G.; Cukalac, Tania; Kan, Wan-Ting; Sng, Xavier Y. X.; Mirams, Michiko; Watson, Katherine A.; Doherty, Peter C.; Thomas, Paul G.; Handel, Andreas; La Gruta, Nicole L.

    2016-01-01

    In advanced age, decreased CD8+ cytotoxic T-lymphocyte (CTL) responses to novel pathogens and cancer is paralleled by a decline in the number and function of naïve CTL precursors (CTLp). Although the age-related fall in CD8+ T-cell numbers is well established, neither the underlying mechanisms nor the extent of variation for different epitope specificities have been defined. Furthermore, naïve CD8+ T cells expressing high levels of CD44 accumulate with age, but it is unknown whether this accumulation reflects their preferential survival or an age-dependent driver of CD8+ T-cell proliferation. Here, we track the number and phenotype of four influenza A virus (IAV)-specific CTLp populations in naïve C57BL/6 (B6) mice during aging, and compare T-cell receptor (TCR) clonal diversity for the CD44hi and CD44lo subsets of one such population. We show differential onset of decline for several IAV-specific CD8+ T-cell populations with advanced age that parallel age-associated changes in the B6 immunodominance hierarchy, suggestive of distinct impacts of aging on different epitope-specific populations. Despite finding no evidence of clonal expansions in an aged, epitope-specific TCR repertoire, nonrandom alterations in TCR usage were observed, along with elevated CD5 and CD8 coreceptor expression. Collectively, these data demonstrate that naïve CD8+ T cells expressing markers of heightened self-recognition are selectively retained, but not clonally expanded, during aging. PMID:26787864

  20. ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses.

    PubMed

    Jossé, Rozenn; Martin, Scott E; Guha, Rajarshi; Ormanoglu, Pinar; Pfister, Thomas D; Reaper, Philip M; Barnes, Christopher S; Jones, Julie; Charlton, Peter; Pollard, John R; Morris, Joel; Doroshow, James H; Pommier, Yves

    2014-12-01

    Camptothecin and its derivatives, topotecan and irinotecan, are specific topoisomerase I (Top1) inhibitors and potent anticancer drugs killing cancer cells by producing replication-associated DNA double-strand breaks, and the indenoisoquinoline LMP-400 (indotecan) is a novel Top1 inhibitor in clinical trial. To develop novel drug combinations, we conducted a synthetic lethal siRNA screen using a library that targets nearly 7,000 human genes. Depletion of ATR, the main transducer of replication stress, came as a top candidate gene for camptothecin synthetic lethality. Validation studies using ATR siRNA and the ATR inhibitor VE-821 confirmed marked antiproliferative synergy with camptothecin and even greater synergy with LMP-400. Single-cell analyses and DNA fiber combing assays showed that VE-821 abrogates the S-phase replication elongation checkpoint and the replication origin-firing checkpoint induced by camptothecin and LMP-400. As expected, the combination of Top1 inhibitors with VE-821 inhibited the phosphorylation of ATR and Chk1; however, it strongly induced γH2AX. In cells treated with the combination, the γH2AX pattern changed over time from the well-defined Top1-induced damage foci to an intense peripheral and diffuse nuclear staining, which could be used as response biomarker. Finally, the clinical derivative of VE-821, VX-970, enhanced the in vivo tumor response to irinotecan without additional toxicity. A key implication of our work is the mechanistic rationale and proof of principle it provides to evaluate the combination of Top1 inhibitors with ATR inhibitors in clinical trials. PMID:25269479

  1. ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase I inhibitors by disabling DNA replication initiation and fork elongation responses

    PubMed Central

    Jossé, Rozenn; Martin, Scott E.; Guha, Rajarshi; Ormanoglu, Pinar; Pfister, Thomas D.; Reaper, Philip M.; Barnes, Christopher S.; Jones, Julie; Charlton, Peter; Pollard, John R.; Morris, Joel; Doroshow, James H.; Pommier, Yves

    2014-01-01

    Camptothecin and its derivatives, topotecan and irinotecan are specific topoisomerase I (Top1) inhibitors and potent anticancer drugs killing cancer cells by producing replication-associated DNA double-strand breaks, and the indenoisoquinoline LMP-400 (indotecan) is a novel Top1 inhibitor in clinical trial. To develop novel drug combinations, we conducted a synthetic lethal siRNA screen using a library that targets nearly 7,000 human genes. Depletion of ATR, the main transducer of replication stress came as a top candidate gene for camptothecin synthetic lethality. Validation studies using ATR siRNA and the ATR inhibitor VE-821, confirmed marked antiproliferative synergy with camptothecin, and even greater synergy with LMP-400. Single cell analyses and DNA fiber combing assays showed that VE-821 abrogates the S-phase replication elongation checkpoint and the replication origin-firing check point induced by camptothecin and LMP-400. As expected, the combination ofTop1 inhibitors with VE-821 inhibited the phosphorylation of ATR and Chk1; however, it strongly induced γH2AX. In cells treated with the combination, the γH2AX pattern changed overtime from the well-defined Top1-induced damage foci to an intense peripheral and diffuse nuclear staining, which could be used as response biomarker. Finally, the clinical derivative of VE-821, VX-970 enhanced the in vivo tumor response to irinotecan without additional toxicity. Akey implication of our work is the mechanistic rationale and proof-of-principle it provides to evaluate the combination of Top1 inhibitors with ATR inhibitors in clinical trials. PMID:25269479

  2. Heightened self-reactivity associated with selective survival, but not expansion, of naïve virus-specific CD8+ T cells in aged mice.

    PubMed

    Quinn, Kylie M; Zaloumis, Sophie G; Cukalac, Tania; Kan, Wan-Ting; Sng, Xavier Y X; Mirams, Michiko; Watson, Katherine A; McCaw, James M; Doherty, Peter C; Thomas, Paul G; Handel, Andreas; La Gruta, Nicole L

    2016-02-01

    In advanced age, decreased CD8(+) cytotoxic T-lymphocyte (CTL) responses to novel pathogens and cancer is paralleled by a decline in the number and function of naïve CTL precursors (CTLp). Although the age-related fall in CD8(+) T-cell numbers is well established, neither the underlying mechanisms nor the extent of variation for different epitope specificities have been defined. Furthermore, naïve CD8(+) T cells expressing high levels of CD44 accumulate with age, but it is unknown whether this accumulation reflects their preferential survival or an age-dependent driver of CD8(+) T-cell proliferation. Here, we track the number and phenotype of four influenza A virus (IAV)-specific CTLp populations in naïve C57BL/6 (B6) mice during aging, and compare T-cell receptor (TCR) clonal diversity for the CD44hi and CD44lo subsets of one such population. We show differential onset of decline for several IAV-specific CD8(+) T-cell populations with advanced age that parallel age-associated changes in the B6 immunodominance hierarchy, suggestive of distinct impacts of aging on different epitope-specific populations. Despite finding no evidence of clonal expansions in an aged, epitope-specific TCR repertoire, nonrandom alterations in TCR usage were observed, along with elevated CD5 and CD8 coreceptor expression. Collectively, these data demonstrate that naïve CD8(+) T cells expressing markers of heightened self-recognition are selectively retained, but not clonally expanded, during aging. PMID:26787864

  3. Distinct Kinetics of Effector CD8+ Cytotoxic T Cells after Infection with Trypanosoma cruzi in Naïve or Vaccinated Mice

    PubMed Central

    Tzelepis, Fanny; de Alencar, Bruna C. G.; Penido, Marcus L. O.; Gazzinelli, Ricardo T.; Persechini, Pedro M.; Rodrigues, Mauricio M.

    2006-01-01

    The kinetics of effector CD8+-T-cell responses to specific Trypanosoma cruzi epitopes was investigated after challenge. Our results suggest that the delayed kinetics differs from that observed in other microbial infections and facilitates the establishment of the disease in naïve mice. In contrast, in vaccinated mice, the swift CD8+-T-cell response helps host survival after challenge. PMID:16552083

  4. Characteristics of antiretroviral therapy-naïve patients lost-to-care in HIV clinics in Democratic Republic of Congo, Cameroon, and Burundi.

    PubMed

    Stolka, Kristen; Iriondo-Perez, Jeniffer; Kiumbu, Modeste; Atibu, Joseph; Azinyue, Innocent; Akam, Wilfred; Balimba, Ashue; Mfangam Molu, Brigitte; Mukumbi, Henri; Niyongabo, Theodore; Twizere, Christelle; Newman, Jamie; Hemingway-Foday, Jennifer

    2016-07-01

    Antiretroviral therapy (ART)-naïve patients are vulnerable to becoming lost-to-care (LTC) because they are not monitored as often as patients on treatment. We examined data from 19,461 HIV positive adults at 10 HIV clinics in Democratic Republic of Congo (DRC), Cameroon, and Burundi participating in the Phase 1 International epidemiologic Databases to Evaluate AIDS Central Africa (IeDEA-CA) study. Patients were LTC if they were ART-naïve and did not return within 7 months of the end of data collection. Logistic regression was used to obtain odds ratios (ORs) and 95% confidence intervals (CIs) for risk factors associated with LTC. Of 5353 ART-naïve patients, 4420 (83%) were LTC and 933 (17%) were in-care. The odds of being LTC were greatest among patients from DRC (OR = 2.16, CI: 1.64-2.84, p < .0001), males (OR = 1.39, CI: 1.15-1.69, p = .0009), and ages 18-49 (OR = 1.45, CI: 1.16-1.82, p = .001). The odds of being LTC were least among patients with a WHO Clinical Stage of 1 or 2 (OR = 0.65, CI: 0.55-0.77, p < .0001) and in a perceived concordant relationship (OR = 0.61, CI: 0.43-0.87, p < .0001). LTC patients were more likely to have characteristics associated with higher risk for HIV transmission and progression. Many entered care at advanced stages and were less likely to know their partner's serostatus. Greater efforts to retain ART-naïve patients may increase earlier initiation of ART. PMID:26855169

  5. [Data on rilpivirine in treatment-naïve patients. Lessons from ECHO, THRIVE and STaR].

    PubMed

    Domingo, Pere; Ribera, Esteban

    2013-06-01

    Rilpivirine (RPV) is a new, second-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) that has been recently approved for use in the initial antiretroviral therapy (ART) of treatment-naïve HIV-infected patients, combined with two nucleoside/nucleotide reverse transcriptase inhibitors (NRTI). The approved dose is 25mg once daily with food. RPV has been assessed in a phase IIb study (TMC278-C204) and in three phase III trials (ECHO, THRIVE and STaR). In all of them, RPV was compared with the gold standard, efavirenz (EFV); these studies enrolled a large number of patients (n=1,349 on RPV). RPV was non-inferior to EFV at 48 and 96 weeks. In all the studies and study arms, the tolerability of RPV was better than that of EFV, especially for neuropsychiatric adverse effects, rash, and lipid profile. An analysis of the combined data from the ECHO and THRIVE trials showed marked differences, depending on baseline viral load. The therapeutic efficacy of RPV was superior to that of EFV in patients with a baseline viral load ≤ 100,000 copies/mL, due to a similar virological efficacy and a better tolerability profile. However, in patients with a baseline viral load ≥ 100,000 copies/mL, virological failure was more frequent in the RPV arm, especially in patients with a viral load ≥ 500,000 copies/mL. Emerging resistance mutations to RPV were commonly detected in patients with virological failure, especially in those with a higher baseline viral load. In view of these results, the European Medications Agency and the US Food and Drug Administration have approved the use of RPV in treatment-naïve patients with a baseline viral load ≤ 100,000 copies/mL. Some treatment guidelines have already included RPV among their recommendations. The guidelines of the US Department of Health and Human Services (DHSS) and the International Antiviral Society-USA ((IAS-USA), while awaiting additional data, consider RPV-based regimens as an alternative regimen. The Gesida

  6. Transmitted Drug Resistance Mutations in Antiretroviral-Naïve Injection Drug Users with Chronic HIV-1 Infection in Iran

    PubMed Central

    Memarnejadian, Arash; Menbari, Shahoo; Vahabpour, Rouhollah; Aghasadeghi, Mohammad Reza; Mostafavi, Ehsan; Abdi, Mohammad

    2015-01-01

    The growing incidence and transmission of drug resistant HIV-1 strains due to widespread use of antiretroviral therapy (ART) can jeopardize the success of first-line ART. While there is a known moderate prevalence of transmitted drug resistance (TDR) among newly infected Iranians, no data exist about the rate of these primary resistance mutations among the ART-naïve, chronically infected individuals who are, in fact, the main candidates for ART initiation. To address this issue, we collected blood samples from 40 ART-naïve injection drug-users (IDUs) with chronic HIV-1 infection (seroconversion time ranging from 2 to 9 years) living in Sanandaj, Iran, followed by sequencing of the protease and reverse-transcriptase regions from their HIV-1 genome. Phylogenetic analyses of the sequenced regions revealed that all samples were CRF35_AD. Transmitted resistance mutations were interpreted as surveillance drug-resistant mutations (SDRMs) based on the world health organization (WHO) algorithm. The frequency of SDRMs to any class of antiretroviral drugs was 15%, which included mutations to nucleoside reverse transcriptase inhibitors (NRTIs, 10%), with M41L and M184V as the most common (5%), and non-nucleoside reverse transcriptase inhibitors (NNRTIs, 5%), with K103N as the only detected mutation (5%). Although not in the WHO SDRMs list, several minor protease inhibitor resistant mutations listed in the International Antiviral Society-USA panel were identified, of which M36I, H69K, L89M/V/I (each one 100%) and K20R/T (92.5%) can be considered as polymorphic signatures for CRF35_AD.The relatively high rate of TDR mutations in our study raises concerns about the risk of treatment failure in chronically infected IDUs of Sanandaj city. These results suggest that routine resistance testing should be considered before the therapy initiation in this area. Additional surveillance studies are required to generalize this deduction to other cities of Iran. PMID:25962088

  7. Transmitted Drug Resistance Mutations in Antiretroviral-Naïve Injection Drug Users with Chronic HIV-1 Infection in Iran.

    PubMed

    Memarnejadian, Arash; Menbari, Shahoo; Mansouri, Seyed Ali; Sadeghi, Leila; Vahabpour, Rouhollah; Aghasadeghi, Mohammad Reza; Mostafavi, Ehsan; Abdi, Mohammad

    2015-01-01

    The growing incidence and transmission of drug resistant HIV-1 strains due to widespread use of antiretroviral therapy (ART) can jeopardize the success of first-line ART. While there is a known moderate prevalence of transmitted drug resistance (TDR) among newly infected Iranians, no data exist about the rate of these primary resistance mutations among the ART-naïve, chronically infected individuals who are, in fact, the main candidates for ART initiation. To address this issue, we collected blood samples from 40 ART-naïve injection drug-users (IDUs) with chronic HIV-1 infection (seroconversion time ranging from 2 to 9 years) living in Sanandaj, Iran, followed by sequencing of the protease and reverse-transcriptase regions from their HIV-1 genome. Phylogenetic analyses of the sequenced regions revealed that all samples were CRF35_AD. Transmitted resistance mutations were interpreted as surveillance drug-resistant mutations (SDRMs) based on the world health organization (WHO) algorithm. The frequency of SDRMs to any class of antiretroviral drugs was 15%, which included mutations to nucleoside reverse transcriptase inhibitors (NRTIs, 10%), with M41L and M184V as the most common (5%), and non-nucleoside reverse transcriptase inhibitors (NNRTIs, 5%), with K103N as the only detected mutation (5%). Although not in the WHO SDRMs list, several minor protease inhibitor resistant mutations listed in the International Antiviral Society-USA panel were identified, of which M36I, H69K, L89M/V/I (each one 100%) and K20R/T (92.5%) can be considered as polymorphic signatures for CRF35_AD.The relatively high rate of TDR mutations in our study raises concerns about the risk of treatment failure in chronically infected IDUs of Sanandaj city. These results suggest that routine resistance testing should be considered before the therapy initiation in this area. Additional surveillance studies are required to generalize this deduction to other cities of Iran. PMID:25962088

  8. Addressing secondary students' naïve ideas about freshwater springs in order to develop an instructional tool to promote conceptual reconstruction

    NASA Astrophysics Data System (ADS)

    Reinfried, S.; Tempelmann, S.; Aeschbacher, U.

    2012-02-01

    "Water knowledge" has now become a socio-political and future-orientated necessity. Erroneous notions or preconceptions of hydrology can have a deleterious effect on our understanding of the scientific facts and their interrelations that are of relevance to sustainable water management. This explorative pilot study shows that erroneous and naïve ideas about the origin of freshwater springs are common at the lower secondary level. The purpose of this study was two-fold: (1) to investigate the nature of misconceptions about freshwater springs among 13-year-old students, and (2) to develop an efficient instructional tool that promotes conceptual reconstruction in the learners' minds. To assess students' naïve ideas we conducted interviews, examined student work, and asked students to fill in a questionnaire. The identified naïve ideas were used to construct an instructional tool based on the findings of learning psychology aiming at promoting deep learning, thus facilitating a lasting conceptual reconstruction of the concept of freshwater springs.

  9. Systemizers Are Better Code-Breakers: Self-Reported Systemizing Predicts Code-Breaking Performance in Expert Hackers and Naïve Participants

    PubMed Central

    Harvey, India; Bolgan, Samuela; Mosca, Daniel; McLean, Colin; Rusconi, Elena

    2016-01-01

    Studies on hacking have typically focused on motivational aspects and general personality traits of the individuals who engage in hacking; little systematic research has been conducted on predispositions that may be associated not only with the choice to pursue a hacking career but also with performance in either naïve or expert populations. Here, we test the hypotheses that two traits that are typically enhanced in autism spectrum disorders—attention to detail and systemizing—may be positively related to both the choice of pursuing a career in information security and skilled performance in a prototypical hacking task (i.e., crypto-analysis or code-breaking). A group of naïve participants and of ethical hackers completed the Autism Spectrum Quotient, including an attention to detail scale, and the Systemizing Quotient (Baron-Cohen et al., 2001, 2003). They were also tested with behavioral tasks involving code-breaking and a control task involving security X-ray image interpretation. Hackers reported significantly higher systemizing and attention to detail than non-hackers. We found a positive relation between self-reported systemizing (but not attention to detail) and code-breaking skills in both hackers and non-hackers, whereas attention to detail (but not systemizing) was related with performance in the X-ray screening task in both groups, as previously reported with naïve participants (Rusconi et al., 2015). We discuss the theoretical and translational implications of our findings. PMID:27242491

  10. Polysomnographic Assessment of Sleep Comorbidities in Drug-Naïve Narcolepsy-Spectrum Disorders--A Japanese Cross-Sectional Study.

    PubMed

    Sasai-Sakuma, Taeko; Kinoshita, Akihiko; Inoue, Yuichi

    2015-01-01

    This is a large cross-sectional study which aimed to investigate comorbidity rate, degree of sleep-related breathing disorder, polysomnigraphically diagnosible rapid eye movement sleep behavior disorder/rapid eye movement sleep without atonia and periodic limb movements during sleep in Japanese drug-naïve patients with narcolepsy-spectrum disorders. A total of 158 consecutive drug naïve patients with narcolepsy with cataplexy, 295 patients with narcolepsy without cataplexy and 395 patients with idiopathic hypersomnia without long sleep time were enrolled. From retrospectively analyzed data of nocturnal polysomnography and multiple sleep latency test, higher rates of periodic limb movements during sleep (> = 15 h(-1)) (10.2%) and polysomnographically diagnosable rapid eye movement sleep behavior disorder (1.9%) were found in patients with narcolepsy with cataplexy. They had more severe periodic limb movements during sleep especially during rapid eye movement sleep and higher percentages of rapid eye movement sleep without atonia than the other two patient groups. In the present large sample study, Japanese drug naïve patients with narcolepsy with cataplexy showed the highest comorbidity rates of periodic limb movements during sleep, polysomnographically diagnosable rapid eye movement sleep behavior disorder and rapid eye movement sleep without atonia among those with the other narcolepsy-spectrum disorders; the rates were lower than those for Western patients. PMID:26322978

  11. Peripheral Tissue Homing Receptor Control of Naïve, Effector, and Memory CD8 T Cell Localization in Lymphoid and Non-Lymphoid Tissues

    PubMed Central

    Brinkman, C. Colin; Peske, J. David; Engelhard, Victor Henry

    2013-01-01

    T cell activation induces homing receptors that bind ligands on peripheral tissue vasculature, programing movement to sites of infection and injury. There are three major types of CD8 effector T cells based on homing receptor expression, which arise in distinct lymphoid organs. Recent publications indicate that naïve, effector, and memory T cell migration is more complex than once thought; while many effectors enter peripheral tissues, some re-enter lymph nodes (LN), and contain central memory precursors. LN re-entry can depend on CD62L or peripheral tissue homing receptors. Memory T cells in LN tend to express the same homing receptors as their forebears, but often are CD62Lneg. Homing receptors also control CD8 T cell tumor entry. Tumor vasculature has low levels of many peripheral tissue homing receptor ligands, but portions of it resemble high endothelial venules (HEV), enabling naïve T cell entry, activation, and subsequent effector activity. This vasculature is associated with positive prognoses in humans, suggesting it may sustain ongoing anti-tumor responses. These findings reveal new roles for homing receptors expressed by naïve, effector, and memory CD8 T cells in controlling entry into lymphoid and non-lymphoid tissues. PMID:23966998

  12. Peripheral tissue homing receptor control of naïve, effector, and memory CD8 T cell localization in lymphoid and non-lymphoid tissues.

    PubMed

    Brinkman, C Colin; Peske, J David; Engelhard, Victor Henry

    2013-01-01

    T cell activation induces homing receptors that bind ligands on peripheral tissue vasculature, programing movement to sites of infection and injury. There are three major types of CD8 effector T cells based on homing receptor expression, which arise in distinct lymphoid organs. Recent publications indicate that naïve, effector, and memory T cell migration is more complex than once thought; while many effectors enter peripheral tissues, some re-enter lymph nodes (LN), and contain central memory precursors. LN re-entry can depend on CD62L or peripheral tissue homing receptors. Memory T cells in LN tend to express the same homing receptors as their forebears, but often are CD62Lneg. Homing receptors also control CD8 T cell tumor entry. Tumor vasculature has low levels of many peripheral tissue homing receptor ligands, but portions of it resemble high endothelial venules (HEV), enabling naïve T cell entry, activation, and subsequent effector activity. This vasculature is associated with positive prognoses in humans, suggesting it may sustain ongoing anti-tumor responses. These findings reveal new roles for homing receptors expressed by naïve, effector, and memory CD8 T cells in controlling entry into lymphoid and non-lymphoid tissues. PMID:23966998

  13. Systemizers Are Better Code-Breakers: Self-Reported Systemizing Predicts Code-Breaking Performance in Expert Hackers and Naïve Participants.

    PubMed

    Harvey, India; Bolgan, Samuela; Mosca, Daniel; McLean, Colin; Rusconi, Elena

    2016-01-01

    Studies on hacking have typically focused on motivational aspects and general personality traits of the individuals who engage in hacking; little systematic research has been conducted on predispositions that may be associated not only with the choice to pursue a hacking career but also with performance in either naïve or expert populations. Here, we test the hypotheses that two traits that are typically enhanced in autism spectrum disorders-attention to detail and systemizing-may be positively related to both the choice of pursuing a career in information security and skilled performance in a prototypical hacking task (i.e., crypto-analysis or code-breaking). A group of naïve participants and of ethical hackers completed the Autism Spectrum Quotient, including an attention to detail scale, and the Systemizing Quotient (Baron-Cohen et al., 2001, 2003). They were also tested with behavioral tasks involving code-breaking and a control task involving security X-ray image interpretation. Hackers reported significantly higher systemizing and attention to detail than non-hackers. We found a positive relation between self-reported systemizing (but not attention to detail) and code-breaking skills in both hackers and non-hackers, whereas attention to detail (but not systemizing) was related with performance in the X-ray screening task in both groups, as previously reported with naïve participants (Rusconi et al., 2015). We discuss the theoretical and translational implications of our findings. PMID:27242491

  14. Prolonged exposure of naïve CD8+ T cells to interleukin-7 or interleukin-15 stimulates proliferation without differentiation or loss of telomere length.

    PubMed

    Wallace, Diana L; Bérard, Marion; Soares, Maria V D; Oldham, Janine; Cook, Joanne E; Akbar, Arne N; Tough, David F; Beverley, Peter C L

    2006-10-01

    Interleukin (IL)-7 and IL-15 are cytokines implicated in homeostatic control of the peripheral CD8 T-cell pool. We compared the effects of IL-7 and IL-15 on survival and proliferation of purified human CD8+ T-cell subsets. Low concentrations of either cytokine reduced the spontaneous apoptosis of all subsets, and enhancement of survival corresponded to the extent of Bcl-2 up-regulation. Surprisingly, although minimal proliferation of naïve CD8+ T cells was observed during the first week of culture with cytokines, a marked expansion of these cells occurred at later time points, particularly in response to IL-15. This occurred largely without phenotypic change or acquisition of effector function, indicating a dissociation of differentiation from proliferation. Notably, progression of naïve CD8+ T cells through several cell divisions resulted in up-regulation of telomerase and the maintenance of telomere length. These data show that IL-7 and IL-15 induce cell proliferation and rescue from apoptosis in a concentration, time and subset-dependent manner, and have implications for the homeostatic expansion of the naïve CD8+ T-cell pool. PMID:17005004

  15. Naïve CD8(+) T cell derived tumor-specific cytotoxic effectors as a potential remedy for overcoming TGF-β immunosuppression in the tumor microenvironment.

    PubMed

    Nguyen, Hong Hanh; Kim, Therasa; Song, Sang Yun; Park, Somang; Cho, Hyang Hee; Jung, Sung-Hoon; Ahn, Jae-Sook; Kim, Hyeoung-Joon; Lee, Je-Jung; Kim, Hee-Ok; Cho, Jae-Ho; Yang, Deok-Hwan

    2016-01-01

    Despite of the potential implications for cancer immunotherapy, conventional approaches using in vitro expanded CD8(+) T cells have suboptimal outcomes, mostly due to loss of functionality from cellular exhaustion. We therefore investigated the phenotypic and functional differences among in vitro activated CD8(+) T cells of three different sources, namely naïve (NTeff), memory (MTeff) and tumor-infiltrating lymphocytes (TILeff) from human and mice, to better understand mechanisms behind potent effector functions and potential for overcoming current limitations. In line with the greater proliferation activity and longer telomere lengths of NTeff populations, cells of naïve origin exhibited significantly less amounts of T cell exhaustion markers than those of MTeff and TILeff, and moreover, acquired distinct expression patterns of memory-promoting transcription factors, T-bet and Eomes, induced in a rapid and sustainable manner. NTeff cells appeared to have lower expression of Foxp1 and were refractory to apoptosis upon TGF-β conditioning, implying better survival potential and resistance to tumor-induced immune suppression. Of CD8(+) T cell pools activated to tumor-specific CTLs, naïve cell generated effectors possessed the most potent cytotoxic activity, validating implications for use in rational design of adoptive immunotherapy. PMID:27306834

  16. Compartment resolved reference proteome map from highly purified naïve, activated, effector, and memory CD8⁺ murine immune cells.

    PubMed

    Zanker, Damien; Otto, Wolfgang; Chen, Weisan; von Bergen, Martin; Tomm, Janina M

    2015-06-01

    Differentiation of CD8(+) T lymphocytes into effector and memory cells is key for an adequate immune response and relies on complex interplay of pathways that convey signals from the cell surface to the nucleus. In this study, we investigated the proteome of four cytotoxic T-cell subtypes; naïve, recently activated effector, effector, and memory cells. Cells were fractionated into membrane, cytosol, soluble nuclear, chromatin-bound, and cytoskeletal compartments. Following LC-MS/MS analysis, identified peptides were analyzed via MaxQuant. Compartment fractionation and gel-LC-MS separation resulted in 2399 proteins identified in total. Comparison between the different subsets resulted in 146 significantly regulated proteins for naïve and effector cells, followed by 116 for activated, and 55 for memory cells. Besides Granzyme B signaling (for activated and/ or effector cells vs. naïve cells), the most prominent changes occurred in the TCA cycle and aspartate degradation. These changes suggest that correct balancing of metabolism is key for differentiation processes. All MS data have been deposited in the ProteomeXchange with identifier PXD001065 (http://proteomecentral.proteomexchange.org/dataset/PXD001065). PMID:25643623

  17. Differential expression of proteins in naïve and IL-2 stimulated primary human NK cells identified by global proteomic analysis

    PubMed Central

    Ma, Di; Felder, Mildred; Scarlett, Cameron O.; Patankar, Manish S.; Li, Lingjun

    2015-01-01

    Natural killer (NK) cells efficiently cytolyse tumors and virally infected cells. Despite the important role that interleukin (IL)-2 plays in stimulating the proliferation of NK cells and increasing NK cell activity, little is known about the alterations in the global NK cell proteome following IL-2 activation. To compare the proteomes of naïve and IL-2-activated primary NK cells and identify key cellular pathways involved in IL-2 signaling, we isolated proteins from naïve and IL-2-activated NK cells from healthy donors, the proteins were trypsinized and the resulting peptides were analyzed by 2D LC ESI-MS/MS followed by label-free quantification. In total, more than 2000 proteins were identified from naïve and IL-2-activated NK cells where 383 proteins were found to be differentially expressed following IL-2 activation. Functional annotation of IL-2 regulated proteins revealed potential targets for future investigation of IL-2 signaling in human primary NK cells. A pathway analysis was performed and revealed several pathways that were not previously known to be involved in IL-2 response, including ubiquitin proteasome pathway, integrin signaling pathway, platelet derived growth factor (PDGF) signaling pathway, epidermal growth factor receptor (EGFR) signaling pathway and Wnt signaling pathway. PMID:23806757

  18. Polysomnographic Assessment of Sleep Comorbidities in Drug-Naïve Narcolepsy-Spectrum Disorders—A Japanese Cross-Sectional Study

    PubMed Central

    2015-01-01

    This is a large cross-sectional study which aimed to investigate comorbidity rate, degree of sleep-related breathing disorder, polysomnigraphically diagnosible rapid eye movement sleep behavior disorder/rapid eye movement sleep without atonia and periodic limb movements during sleep in Japanese drug-naïve patients with narcolepsy-spectrum disorders. A total of 158 consecutive drug naïve patients with narcolepsy with cataplexy, 295 patients with narcolepsy without cataplexy and 395 patients with idiopathic hypersomnia without long sleep time were enrolled. From retrospectively analyzed data of nocturnal polysomnography and multiple sleep latency test, higher rates of periodic limb movements during sleep (> = 15 h-1) (10.2%) and polysomnographically diagnosable rapid eye movement sleep behavior disorder (1.9%) were found in patients with narcolepsy with cataplexy. They had more severe periodic limb movements during sleep especially during rapid eye movement sleep and higher percentages of rapid eye movement sleep without atonia than the other two patient groups. In the present large sample study, Japanese drug naïve patients with narcolepsy with cataplexy showed the highest comorbidity rates of periodic limb movements during sleep, polysomnographically diagnosable rapid eye movement sleep behavior disorder and rapid eye movement sleep without atonia among those with the other narcolepsy-spectrum disorders; the rates were lower than those for Western patients. PMID:26322978

  19. CMV-Specific T-cells Generated From Naïve T-cells Recognize Atypical Epitopes And May Be Protective in Vivo

    PubMed Central

    Hanley, Patrick J.; Melenhorst, Jan J.; Nikiforow, Sarah; Scheinberg, Phillip; Blaney, James W.; Demmler-Harrison, Gail; Cruz, C. Russell; Lam, Sharon; Krance, Robert A.; Leung, Kathryn S.; Martinez, Caridad A.; Liu, Hao; Heslop, Helen E.; Rooney, Cliona M.; Shpall, Elizabeth J.; Barrett, A. John; Rodgers, John R.; Bollard, Catherine M.

    2015-01-01

    Adoptive transfer of adult-seropositive, cytomegalovirus (CMV)-specific T-cells can effectively restore antiviral immunity after transplantation. Lack of CMV-specific memory T-cells in blood from CMV-seronegative adult and cord blood (CB) donors restricts the availability of donor-derived virus-specific T-cells for immunoprophylaxis. Here we demonstrate the feasibility of naïve-donor-derived CMV-specific T-cell therapy for transplant recipients. Primed naïve T-cells recognized only atypical epitopes and with a similar avidity to CMV-seropositive-derived T-cells recognizing typical epitopes, but T-cells from CMV-seropositive donors recognizing atypical epitopes had a lower avidity suggesting the loss of high-avidity T-cells over time. Clonotypic analysis revealed T-cells recognizing atypical CMVpp65 epitopes in the peripheral blood of recipients of CB grafts who did not develop CMV. T-cell receptors from atypical epitopes were most common in unmanipulated CB units explaining why these T-cells expanded. When infused to recipients, naïve donor-derived virus specific T-cells that recognized atypical epitopes were associated with prolonged periods of CMV-free survival and complete remission. PMID:25925682

  20. Naïve CD8+ T cell derived tumor-specific cytotoxic effectors as a potential remedy for overcoming TGF-β immunosuppression in the tumor microenvironment

    PubMed Central

    Nguyen, Hong Hanh; Kim, Therasa; Song, Sang Yun; Park, Somang; Cho, Hyang Hee; Jung, Sung-Hoon; Ahn, Jae-Sook; Kim, Hyeoung-Joon; Lee, Je-Jung; Kim, Hee-Ok; Cho, Jae-Ho; Yang, Deok-Hwan

    2016-01-01

    Despite of the potential implications for cancer immunotherapy, conventional approaches using in vitro expanded CD8+ T cells have suboptimal outcomes, mostly due to loss of functionality from cellular exhaustion. We therefore investigated the phenotypic and functional differences among in vitro activated CD8+ T cells of three different sources, namely naïve (NTeff), memory (MTeff) and tumor-infiltrating lymphocytes (TILeff) from human and mice, to better understand mechanisms behind potent effector functions and potential for overcoming current limitations. In line with the greater proliferation activity and longer telomere lengths of NTeff populations, cells of naïve origin exhibited significantly less amounts of T cell exhaustion markers than those of MTeff and TILeff, and moreover, acquired distinct expression patterns of memory-promoting transcription factors, T-bet and Eomes, induced in a rapid and sustainable manner. NTeff cells appeared to have lower expression of Foxp1 and were refractory to apoptosis upon TGF-β conditioning, implying better survival potential and resistance to tumor-induced immune suppression. Of CD8+ T cell pools activated to tumor-specific CTLs, naïve cell generated effectors possessed the most potent cytotoxic activity, validating implications for use in rational design of adoptive immunotherapy. PMID:27306834

  1. Behavioural response of sexually naïve and experienced male rats to the smell of 6-methyl-5-hepten-2-one and female rat faeces.

    PubMed

    Nielsen, Birte L; Jerôme, Nathalie; Saint-Albin, Audrey; Rampin, Olivier; Maurin, Yves

    2013-08-15

    Sexually experienced male rats display penile erections when exposed to faeces from mammalian females in oestrus (Rampin et al., Behav Brain Res, 172:169, 2006), suggesting that specific odours indicate female receptiveness across species. However, it is unknown to what extent the sexual response observed results from an odorous conditioning acquired during sexual experience. We tested the behavioural response of male Brown Norway rats both when sexually naïve and experienced to four odours, including oestrous rat faeces and 6-methyl-5-hepten-2-one (methylheptenone; a molecule found in higher concentrations during oestrus in female rats, foxes and horses). Odour had a significant effect on the sexual response of the naïve rats, with oestrus faeces provoking significantly more erections than herb odour, and with methylheptenone and di-oestrus faeces being intermediate. This indicates that sexually naïve male rats have an unconditioned ability to detect oestrous mediated via odour. After gaining sexual experience, the response to methylheptenone, di- and oestrus faeces was significantly higher than that observed with herb odour. These results strongly suggest that methylheptenone is part of the odorous bouquet of oestrus and contributes to the olfactory determination of female receptiveness. PMID:23911690

  2. An Automatic Multidocument Text Summarization Approach Based on Naïve Bayesian Classifier Using Timestamp Strategy

    PubMed Central

    Ramanujam, Nedunchelian; Kaliappan, Manivannan

    2016-01-01

    Nowadays, automatic multidocument text summarization systems can successfully retrieve the summary sentences from the input documents. But, it has many limitations such as inaccurate extraction to essential sentences, low coverage, poor coherence among the sentences, and redundancy. This paper introduces a new concept of timestamp approach with Naïve Bayesian Classification approach for multidocument text summarization. The timestamp provides the summary an ordered look, which achieves the coherent looking summary. It extracts the more relevant information from the multiple documents. Here, scoring strategy is also used to calculate the score for the words to obtain the word frequency. The higher linguistic quality is estimated in terms of readability and comprehensibility. In order to show the efficiency of the proposed method, this paper presents the comparison between the proposed methods with the existing MEAD algorithm. The timestamp procedure is also applied on the MEAD algorithm and the results are examined with the proposed method. The results show that the proposed method results in lesser time than the existing MEAD algorithm to execute the summarization process. Moreover, the proposed method results in better precision, recall, and F-score than the existing clustering with lexical chaining approach. PMID:27034971

  3. Intragenic Deletion in the LIFR Gene in a Long-Term Survivor with Stüve-Wiedemann Syndrome

    PubMed Central

    Hatagami Marques, Júlia; Lopes Yamamoto, Guilherme; de Cássia Testai, Larissa; da Costa Pereira, Alexandre; Kim, Chong Ae; Passos-Bueno, Maria R.; Romeo Bertola, Débora

    2015-01-01

    Stüve-Wiedemann syndrome (SWS, OMIM 601559) is a rare autosomal recessive bent-bone dysplasia, caused by loss-of-function mutations in the leukemia inhibitory factor receptor (LIFR) gene, which usually leads to early death. Only few patients with long-term survival have been described in the literature. We report on a 5-year-old boy from a consanguineous marriage with molecular analysis for the LIFR gene. Sanger and next-generation sequencing (NGS) of LIFR were performed. Copy number variation analysis with NGS showed a novel mutation as the cause for the syndrome: an intragenic homozygous deletion in LIFR, involving exons 15-20. Bridging PCR was carried out to confirm the intragenic deletion. This is the first description of a large deletion in LIFR, broadening the spectrum of mutations in SWS. Besides the reported allelic heterogeneity, further studies such as exome sequencing are required to identify a novel gene in order to confirm the locus heterogeneity in SWS. PMID:26279654

  4. Assessing sandy beach macrofaunal patterns along large-scale environmental gradients: A Fuzzy Naïve Bayes approach

    NASA Astrophysics Data System (ADS)

    Bozzeda, Fabio; Zangrilli, Maria Paola; Defeo, Omar

    2016-06-01

    A Fuzzy Naïve Bayes (FNB) classifier was developed to assess large-scale variations in abundance, species richness and diversity of the macrofauna inhabiting fifteen Uruguayan sandy beaches affected by the effects of beach morphodynamics and the estuarine gradient generated by Rio de la Plata. Information from six beaches was used to estimate FNB parameters, while abiotic data of the remaining nine beaches were used to forecast abundance, species richness and diversity. FNB simulations reproduced the general increasing trend of target variables from inner estuarine reflective beaches to marine dissipative ones. The FNB model also identified a threshold value of salinity range beyond which diversity markedly increased towards marine beaches. Salinity range is suggested as an ecological master factor governing distributional patterns in sandy beach macrofauna. However, the model: 1) underestimated abundance and species richness at the innermost estuarine beach, with the lowest salinity, and 2) overestimated species richness in marine beaches with a reflective morphodynamic state, which is strongly linked to low abundance, species richness and diversity. Therefore, future modeling efforts should be refined by giving a dissimilar weigh to the gradients defined by estuarine (estuarine beaches) and morphodynamic (marine beaches) variables, which could improve predictions of target variables. Our modeling approach could be applied to a wide spectrum of issues, ranging from basic ecology to social-ecological systems. This approach seems relevant, given the current challenge to develop predictive methodologies to assess the simultaneous and nonlinear effects of anthropogenic and natural impacts in coastal ecosystems.

  5. Continuation maintenance therapy with S-1 in chemotherapy-naïve patients with advanced squamous cell lung cancer.

    PubMed

    Suzuki, Seiichiro; Karayama, Masato; Inui, Naoki; Fujisawa, Tomoyuki; Enomoto, Noriyuki; Nakamura, Yutaro; Kuroishi, Shigeki; Matsuda, Hiroyuki; Yokomura, Koshi; Koshimizu, Naoki; Toyoshima, Mikio; Imokawa, Shiro; Asada, Kazuhiro; Masuda, Masafumi; Yamada, Takashi; Watanabe, Hiroshi; Suda, Takafumi

    2016-08-01

    Objectives Maintenance therapy is a standard therapeutic strategy in non-squamous non-small-cell lung cancer. However, there is no consensus regarding the benefit of maintenance therapy for patients with squamous cell lung cancer. We assessed maintenance therapy with S-1, an oral fluoropyrimidine agent, following induction therapy with carboplatin and S-1 in patients with squamous cell lung cancer. Methods In this phase II trial, chemotherapy-naïve patients with squamous cell lung cancer were enrolled to induction therapy with four cycles of carboplatin (at an area under the curve of 5 on day 1) and S-1 (80 mg/m(2)/day on days 1-14) in a 28-day cycle. Patients who achieved disease control after induction therapy received maintenance therapy with S-1 in a 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival after administration of maintenance therapy. Results Fifty-one patients were enrolled in the study. The median progression-free survival from the start of maintenance therapy was 3.0 months (95 % confidence interval, 2.5-3.5). The most common toxicities associated with maintenance therapy were anemia, thrombocytopenia, and fatigue, but they were not severe. Conclusion S-1 maintenance therapy might be a feasible treatment option in patients with squamous cell lung cancer. PMID:27279143

  6. An Automatic Multidocument Text Summarization Approach Based on Naïve Bayesian Classifier Using Timestamp Strategy.

    PubMed

    Ramanujam, Nedunchelian; Kaliappan, Manivannan

    2016-01-01

    Nowadays, automatic multidocument text summarization systems can successfully retrieve the summary sentences from the input documents. But, it has many limitations such as inaccurate extraction to essential sentences, low coverage, poor coherence among the sentences, and redundancy. This paper introduces a new concept of timestamp approach with Naïve Bayesian Classification approach for multidocument text summarization. The timestamp provides the summary an ordered look, which achieves the coherent looking summary. It extracts the more relevant information from the multiple documents. Here, scoring strategy is also used to calculate the score for the words to obtain the word frequency. The higher linguistic quality is estimated in terms of readability and comprehensibility. In order to show the efficiency of the proposed method, this paper presents the comparison between the proposed methods with the existing MEAD algorithm. The timestamp procedure is also applied on the MEAD algorithm and the results are examined with the proposed method. The results show that the proposed method results in lesser time than the existing MEAD algorithm to execute the summarization process. Moreover, the proposed method results in better precision, recall, and F-score than the existing clustering with lexical chaining approach. PMID:27034971

  7. Event-related potentials in drug-naïve pediatric patients with obsessive-compulsive disorder.

    PubMed

    Yamamuro, Kazuhiko; Ota, Toyosaku; Nakanishi, Yoko; Matsuura, Hiroki; Okazaki, Kosuke; Kishimoto, Naoko; Takahashi, Hiroyuki; Iwasaka, Hidemi; Iida, Junzo; Kishimoto, Toshifumi

    2015-12-15

    Obsessive-compulsive disorder (OCD) is one of the most common mental health disorders, characterized by obsessive thoughts and/or compulsive behaviors, which may involve specific disorders in cognition and/or information processing. Event-related potentials (ERPs) are commonly used as physiological measures of cognitive function as they are easily measured and noninvasive. In the present study, 20 drug-naïve pediatric patients with OCD were compared with 20 healthy control participants who were age- and sex-matched to perform the ERP. Based on the guidelines for evoked potential measurement, the P300 and mismatch negativity (MMN) were obtained by auditory odd-ball tasks. We found that the amplitudes of the P300 components in the Fz, Cz, Pz, C3, and C4 regions were significantly smaller in the OCD group compared with the control group. There were no between-group differences in P300 latency, MMN amplitude, or MMN latency. Moreover, we found significant correlations between scores on the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) and P300 amplitudes at Cz, Pz, and C3. The present study is the first to report smaller P300s and the associations between P300 abnormalities and CY-BOCS scores. PMID:26410771

  8. Utilizing computerized entertainment education in the development of decision aids for lower literate and naïve computer users.

    PubMed

    Jibaja-Weiss, Maria L; Volk, Robert J

    2007-01-01

    Decision aids have been developed by using various delivery methods, including interactive computer programs. Such programs, however, still rely heavily on written information, health and digital literacy, and reading ease. We describe an approach to overcome these potential barriers for low-literate, underserved populations by making design considerations for poor readers and naïve computer users and by using concepts from entertainment education to engage the user and to contextualize the content for the user. The system design goals are to make the program both didactic and entertaining and the navigation and graphical user interface as simple as possible. One entertainment education strategy, the soap opera, is linked seamlessly to interactive learning modules to enhance the content of the soap opera episodes. The edutainment decision aid model (EDAM) guides developers through the design process. Although designing patient decision aids that are educational, entertaining, and targeted toward poor readers and those with limited computer skills is a complex task, it is a promising strategy for aiding this population. Entertainment education may be a highly effective approach to promoting informed decision making for patients with low health literacy. PMID:17934944

  9. Individual heritable differences result in unique cell lymphocyte receptor repertoires of naïve and antigen-experienced cells.

    PubMed

    Rubelt, Florian; Bolen, Christopher R; McGuire, Helen M; Vander Heiden, Jason A; Gadala-Maria, Daniel; Levin, Mikhail; Euskirchen, Ghia M; Mamedov, Murad R; Swan, Gary E; Dekker, Cornelia L; Cowell, Lindsay G; Kleinstein, Steven H; Davis, Mark M

    2016-01-01

    The adaptive immune system's capability to protect the body requires a highly diverse lymphocyte antigen receptor repertoire. However, the influence of individual genetic and epigenetic differences on these repertoires is not typically measured. By leveraging the unique characteristics of B, CD4(+) T and CD8(+) T-lymphocyte subsets from monozygotic twins, we quantify the impact of heritable factors on both the V(D)J recombination process and on thymic selection. We show that the resulting biases in both V(D)J usage and N/P addition lengths, which are found in naïve and antigen experienced cells, contribute to significant variation in the CDR3 region. Moreover, we show that the relative usage of V and J gene segments is chromosomally biased, with ∼1.5 times as many rearrangements originating from a single chromosome. These data refine our understanding of the heritable mechanisms affecting the repertoire, and show that biases are evident on a chromosome-wide level. PMID:27005435

  10. Spectral Line Measurements in Exceptionally Low SNR Achieved by Virtue of the KLT (Karhunen-Loève Transform)

    NASA Astrophysics Data System (ADS)

    Maccone, C.; Pluchino, S.; Schillirò, F.

    2009-12-01

    A little-known tool for spectral line measurements is the KLT (Karhunen-Loève Transform). This mathematical algorithm is superior to the classical FFT in that: 1) The KLT can filter signals out of the background noise over both wide and narrow bands. On the contrary, the FFT rigorously applies to narrow-band signals only. 2) The KLT can be applied to random functions that are non-stationary in time, i.e. whose autocorrelation is a function of the two independent variables t1 and t2 separately. Again, this is a sheer advantage of the KLT over the FFT, since the FFT rigorously applies to stationary processes only, i.e. when the autocorrelation is a function of the absolute value of the difference of t1 and t2. 3) The KLT can detect signals embedded in noise to unbelievably small values of the Signal-to-Noise Ratio (SNR), like 10-3 or so. This particular feature of the KLT is described in detail in this paper.

  11. Nicotine absorption from electronic cigarette use: comparison between experienced consumers (vapers) and naïve users (smokers)

    PubMed Central

    Farsalinos, Konstantinos E.; Spyrou, Alketa; Stefopoulos, Christos; Tsimopoulou, Kalliroi; Kourkoveli, Panagiota; Tsiapras, Dimitris; Kyrzopoulos, Stamatis; Poulas, Konstantinos; Voudris, Vassilis

    2015-01-01

    Electronic cigarettes (ECs) are nicotine delivery devices that are proposed as tobacco harm reduction products to smokers. Nicotine delivery from ECs is potentially important in their efficacy as smoking substitutes. Herein, nicotine delivery from using a new-generation EC device (variable-wattage, set at 9 W) was evaluated, comparing experienced (vapers) with naïve users (smokers). Twenty-four vapers and 23 smokers participated to the study. They were asked to obtain 10 puffs in 5 minutes and then use the EC ad lib for 60 more minutes (total duration of use: 65 minutes). An 18 mg/mL nicotine-containing liquid was used. Blood samples were obtained at baseline, 5-minutes and every 15 minutes thereafter, while number of puffs and average puff duration were recorded. Although at baseline both groups had similar plasma nicotine levels, smokers consistently exhibited lower levels at all time-periods; at 5-minutes the levels were lower by 46%, while during the subsequent period they were lower by 43% (at 65-minutes) to 54% (at 20-minutes). Both groups took similar number of puffs, but smokers had average puff duration of 2.3 s compared to 3.5 s in vapers. Even in vapers, plasma nicotine levels at 5 minutes were lower than those observed after smoking 1 tobacco cigarette. PMID:26082330

  12. ATAC-seq on biobanked specimens defines a unique chromatin accessibility structure in naïve SLE B cells

    PubMed Central

    Scharer, Christopher D.; Blalock, Emily L.; Barwick, Benjamin G.; Haines, Robert R.; Wei, Chungwen; Sanz, Ignacio; Boss, Jeremy M.

    2016-01-01

    Biobanking is a widespread practice for storing biological samples for future studies ranging from genotyping to RNA analysis. However, methods that probe the status of the epigenome are lacking. Here, the framework for applying the Assay for Transposase Accessible Sequencing (ATAC-seq) to biobanked specimens is described and was used to examine the accessibility landscape of naïve B cells from Systemic Lupus Erythematosus (SLE) patients undergoing disease flares. An SLE specific chromatin accessibility signature was identified. Changes in accessibility occurred at loci surrounding genes involved in B cell activation and contained motifs for transcription factors that regulate B cell activation and differentiation. These data provide evidence for an altered epigenetic programming in SLE B cells and identify loci and transcription factor networks that potentially impact disease. The ability to determine the chromatin accessibility landscape and identify cis-regulatory elements has broad application to studies using biorepositories and offers significant advantages to improve the molecular information obtained from biobanked samples. PMID:27249108

  13. Continuous Viral Escape and Selection by Autologous Neutralizing Antibodies in Drug-Naïve Human Immunodeficiency Virus Controllers▿

    PubMed Central

    Mahalanabis, Madhumita; Jayaraman, Pushpa; Miura, Toshiyuki; Pereyra, Florencia; Chester, E. Michael; Richardson, Barbra; Walker, Bruce; Haigwood, Nancy L.

    2009-01-01

    We assessed differences in the character and specificity of autologous neutralizing antibodies (ANAbs) against individual viral variants of the quasispecies in a cohort of drug-naïve subjects with long-term controlled human immunodeficiency virus type 1 (HIV-1) infection and moderate levels of broad heterologous neutralizing antibodies (HNAb). Functional plasma virus showed continuous env evolution despite a short time frame and low levels of viral replication. Neutralization-sensitive variants dominated in subjects with intermittent viral blips, while neutralization-resistant variants predominated in elite controllers. By sequence analysis of this panel of autologous variants with various sensitivities to neutralization, we identified more than 30 residues in envelope proteins (Env) associated with resistance or sensitivity to ANAbs. The appearance of new sensitive variants is consistent with a model of continuous selection and turnover. Strong ANAb responses directed against autologous Env variants are present in long-term chronically infected individuals, suggesting a role for these responses in contributing to the durable control of HIV replication. PMID:18987151

  14. Reduction of Caudate Nucleus Volumes in Neuroleptic-Naïve Female Subjects with Schizotypal Personality Disorder

    PubMed Central

    Koo, Min-Seong; Levitt, James J.; McCarley, Robert W.; Seidman, Larry J.; Dickey, Chandlee C.; Niznikiewicz, Margaret A.; Voglmaier, Martina M.; Zamani, Payman; Long, Katherine R.; Kim, Sunnie S.; Shenton, Martha E.

    2009-01-01

    Background The caudate nucleus might contribute to the psychopathological and cognitive deficits observed in schizotypal personality disorder (SPD), a schizophrenia spectrum disorder. Here we focused on female patients, because this group is underrepresented in studies of SPD and schizophrenia, and we might learn more about the caudate and clinical and cognitive impairments that are unique to female patients diagnosed with SPD. Methods Magnetic resonance imaging scans, obtained on a 1.5-T magnet with 1.5-mm contiguous slices, were used to measure the caudate in 32 neuroleptic-naïve women with SPD and in 29 female normal comparison subjects. Subjects were group-matched for age, parental socioeconomic status, and intelligence quotient. Results We found significantly reduced left and right caudate relative volume (8.3%, 7.7%) in female SPD subjects compared with normal comparison subjects. In female SPD subjects, we found significant correlations between smaller total caudate relative volume and worse performance on the Wisconsin Card Sorting test (nonperseverative errors) and on the California Verbal Learning Test (verbal memory and learning), and significant correlations between smaller total caudate relative volume and both positive and negative symptoms on the Structured Interview for Schizotypy. Conclusions These findings demonstrate that, for female SPD subjects, smaller caudate volume is associated with poorer cognitive performance and more schizotypal symptomatology. PMID:16460694

  15. Pressure Distribution over a Wing and Tail Rib of a VE-7 and of a TS Airplane in Flight

    NASA Technical Reports Server (NTRS)

    Crowley, J W , Jr

    1928-01-01

    This investigation was made to determine the pressure distribution over a rib of the wing and over a rib of the horizontal tail surface of an airplane in flight and to obtain information as to the time correlation of the loads occurring on these ribs. Two airplanes, VE-7 and TS, were selected in order to obtain the information for a thin and a thick wing section. In each case the pressure distribution was recorded for the full range of angle of attack in level flight and throughout violent maneuvers. The results show: (a) that the present rib load specifications in use by the Army Air Corps and the Bureau of Aeronautics, Navy Department, are in fair agreement with the loads actually occurring in flight, but could be slightly improved; (b) that there appears to be no definite sequence in which wing and tail surface ribs reach their respective maximum loads in different maneuvers; (c) that in accelerated flight, at air speeds less than or equal to 60 per cent of the maximum speed, the accelerations measured agree very closely with the theoretically possible maximum accelerations. In maneuvers at higher air speeds the observed accelerations were smaller than those theoretically possible. (author)

  16. Neural correlates of mindful self-awareness in mindfulness meditators and meditation-naïve subjects revisited.

    PubMed

    Lutz, J; Brühl, A B; Scheerer, H; Jäncke, L; Herwig, U

    2016-09-01

    Mindful self-awareness is central to mindfulness meditation and plays a key role in its salutary effects. It has been related to decreased activation in cortical midline structures (CMS) and amygdala, and increased activation in somatosensory regions. However, findings in untrained individuals are contradictory, and scarce in experienced meditators. Using fMRI, we investigated experienced mindfulness meditators (LTM, n=21, average 4652 practice-hours) and matched meditation-naïve participants (MNP, n=19) during short periods of mindful self-awareness (FEEL) and self-referential thinking (THINK). We report somatosensory activations and decreases in CMS during FEEL for both groups, but significantly stronger decreases in prefrontal CMS in LTM. LTM further showed decreases in language-related and amygdala regions, but the latter was not significantly different between groups. Overall, higher activations in amygdala and mid-line regions during FEEL were related to levels of depressiveness. Neural patterns of mindful self-awareness emerge already in MNP but more pronounced in LTM. Specifically, meditation training might reduce self-reference and verbalization during mindful awareness. We further corroborate the suggested link between mindfulness and healthy self-related functions on the neural level. Longitudinal studies need to corroborate these findings. PMID:27377788

  17. ATAC-seq on biobanked specimens defines a unique chromatin accessibility structure in naïve SLE B cells.

    PubMed

    Scharer, Christopher D; Blalock, Emily L; Barwick, Benjamin G; Haines, Robert R; Wei, Chungwen; Sanz, Ignacio; Boss, Jeremy M

    2016-01-01

    Biobanking is a widespread practice for storing biological samples for future studies ranging from genotyping to RNA analysis. However, methods that probe the status of the epigenome are lacking. Here, the framework for applying the Assay for Transposase Accessible Sequencing (ATAC-seq) to biobanked specimens is described and was used to examine the accessibility landscape of naïve B cells from Systemic Lupus Erythematosus (SLE) patients undergoing disease flares. An SLE specific chromatin accessibility signature was identified. Changes in accessibility occurred at loci surrounding genes involved in B cell activation and contained motifs for transcription factors that regulate B cell activation and differentiation. These data provide evidence for an altered epigenetic programming in SLE B cells and identify loci and transcription factor networks that potentially impact disease. The ability to determine the chromatin accessibility landscape and identify cis-regulatory elements has broad application to studies using biorepositories and offers significant advantages to improve the molecular information obtained from biobanked samples. PMID:27249108

  18. The lipoprotein La7 contributes to Borrelia burgdorferi persistence in ticks and their transmission to naïve hosts.

    PubMed

    Yang, Xiuli; Hegde, Shylaja; Shroder, Deborah Y; Smith, Alexis A; Promnares, Kamoltip; Neelakanta, Girish; Anderson, John F; Fikrig, Erol; Pal, Utpal

    2013-01-01

    La7, an immunogenic outer membrane lipoprotein of Borrelia burgdorferi, produced during infection, has been shown to play a redundant role in mammalian infectivity. Here we show that La7 facilitates pathogen survival in all tested phases of the vector-specific spirochete life cycle, including tick-to-host transmission. Unlike wild type or la7-complemented isolates, isogenic La7-deficient spirochetes are severely impaired in their ability to persist within feeding ticks during acquisition from mice, in quiescent ticks during larval-nymphal inter-molt, and in subsequent pathogen transmission from ticks to naïve hosts. Analysis of gene expression during the major stages of the tick-rodent infection cycle showed increased expression of la7 in the vector and a swift downregulation in the mammalian hosts. Co-immunoprecipitation studies coupled with liquid chromatography-mass spectrometry analysis further suggested that La7, a highly conserved and abundant inner membrane protein, is involved in protein-protein interaction with a discrete set of borrelial ligands although biological significance of such interactions remains unclear. Further characterization of vector-induced membrane antigens like La7 and its interacting partners will likely aid in our understanding of the molecular details of B. burgdorferi persistence and transmission through a complex enzootic cycle. PMID:23774694

  19. A Randomized Trial of Pharmacogenetic Warfarin Dosing in Naïve Patients with Non-Valvular Atrial Fibrillation

    PubMed Central

    Fogar, Paola; Padoan, Andrea; Nante, Giovanni; Pelloso, Michela; Moz, Stefania; Frigo, Anna Chiara; Groppa, Francesca; Bozzato, Dania; Tiso, Enrico; Gnatta, Elisa; Denas, Gentian; Padayattil Jose, Seena; Padrini, Roberto; Basso, Daniela; Plebani, Mario

    2015-01-01

    Genotype-guided warfarin dosing have been proposed to improve patient’s management. This study is aimed to determine whether a CYP2C9- VKORC1- CYP4F2-based pharmacogenetic algorithm is superior to a standard, clinically adopted, pharmacodynamic method. Two-hundred naïve patients with non-valvular atrial fibrillation were randomized to trial arms and 180 completed the study. No significant differences were found in the number of out-of-range INRs (INR<2.0 or >3.0) (p = 0.79) and in the mean percentage of time spent in the therapeutic range (TTR) after 19 days in the pharmacogenetic (51.9%) and in the control arm (53.2%, p = 0.71). The percentage of time spent at INR>4.0 was significantly lower in the pharmacogenetic (0.7%) than in the control arm (1.8%) (p = 0.02). Genotype-guided warfarin dosing is not superior in overall anticoagulation control when compared to accurate clinical standard of care. Trial Registration ClinicalTrials.gov NCT01178034 PMID:26710337

  20. Karhunen-Loève treatment to remove noise and facilitate data analysis in sensing, spectroscopy and other applications.

    PubMed

    Zaharov, V V; Farahi, R H; Snyder, P J; Davison, B H; Passian, A

    2014-11-21

    Resolving weak spectral variations in the dynamic response of materials that are either dominated or excited by stochastic processes remains a challenge. Responses that are thermal in origin are particularly relevant examples due to the delocalized nature of heat. Despite its inherent properties in dealing with stochastic processes, the Karhunen-Loève expansion has not been fully exploited in measurement of systems that are driven solely by random forces or can exhibit large thermally driven random fluctuations. Here, we present experimental results and analysis of the archetypes (a) the resonant excitation and transient response of an atomic force microscope probe by the ambient random fluctuations and nanoscale photothermal sample response, and (b) the photothermally scattered photons in pump-probe spectroscopy. In each case, the dynamic process is represented as an infinite series with random coefficients to obtain pertinent frequency shifts and spectral peaks and demonstrate spectral enhancement for a set of compounds including the spectrally complex biomass. The considered cases find important applications in nanoscale material characterization, biosensing, and spectral identification of biological and chemical agents. PMID:25252650

  1. Influence of Perspective of Action Observation Training on Residual Limb Control in Naïve Prosthesis Usage.

    PubMed

    Lawson, Delisa T; Cusack, William F; Lawson, Regan; Hardy, Ashley; Kistenberg, Robert; Wheaton, Lewis A

    2016-01-01

    Prior work in amputees and partial limb immobilization have shown improved neural and behavioral outcomes in using their residual limb with prosthesis when undergoing observation-based training with a prosthesis-using actor compared to an intact limb. It was posited that these improvements are due to an alignment of user with the actor. It may be affected by visual angles that allow emphasis of critical joint actions which may promote behavioral changes. The purpose of this study was to examine how viewing perspective of observation-based training effects prosthesis adaptation in naïve device users. Twenty nonamputated prosthesis users learned how to use an upper extremity prosthetic device while viewing a training video from either a sagittal or coronal perspective. These views were chosen as they place visual emphasis on different aspects of task performance to the device. The authors found that perspective of actions has a significant role in adaptation of the residual limb while using upper limb prostheses. Perspectives that demonstrate elbow adaptations to prosthesis usage may enhance the functional motor outcomes of action observation therapy. This work has potential implications on how prosthetic device operation is conveyed to persons adapting to prostheses through action observation based therapy. PMID:27253208

  2. Dissociated large-scale functional connectivity networks of the precuneus in medication-naïve first-episode depression.

    PubMed

    Peng, Daihui; Liddle, Elizabeth B; Iwabuchi, Sarina J; Zhang, Chen; Wu, Zhiguo; Liu, Jun; Jiang, Kaida; Xu, Lin; Liddle, Peter F; Palaniyappan, Lena; Fang, Yiru

    2015-06-30

    An imbalance in neural activity within large-scale networks appears to be an important pathophysiological aspect of depression. Yet, there is little consensus regarding the abnormality within the default mode network (DMN) in major depressive disorder (MDD). In the present study, 16 first-episode, medication-naïve patients with MDD and 16 matched healthy controls underwent functional magnetic resonance imaging (fMRI) at rest. With the precuneus (a central node of the DMN) as a seed region, functional connectivity (FC) was measured across the entire brain. The association between the FC of the precuneus and overall symptom severity was assessed using the Hamilton Depression Rating Scale. Patients with MDD exhibited a more negative relationship between the precuneus and the non-DMN regions, including the sensory processing regions (fusiform gyrus, postcentral gyrus) and the secondary motor cortex (supplementary motor area and precentral gyrus). Moreover, greater severity of depression was associated with greater anti-correlation between the precuneus and the temporo-parietal junction as well as stronger positive connectivity between the precuneus and the dorsomedial prefrontal cortex. These results indicate that dissociated large-scale networks of the precuneus may contribute to the clinical expression of depression in MDD. PMID:25957017

  3. Direct Contra Naïve-Indirect Comparison of Clinical Failure Rates between High-Viscosity GIC and Conventional Amalgam Restorations: An Empirical Study

    PubMed Central

    Mickenautsch, Steffen; Yengopal, Veerasamy

    2013-01-01

    Background Naïve-indirect comparisons are comparisons between competing clinical interventions’ evidence from separate (uncontrolled) trials. Direct comparisons are comparisons within randomised control trials (RCTs). The objective of this empirical study is to test the null-hypothesis that trends and performance differences inferred from naïve-indirect comparisons and from direct comparisons/RCTs regarding the failure rates of amalgam and direct high-viscosity glass-ionomer cement (HVGIC) restorations in permanent posterior teeth have similar direction and magnitude. Methods A total of 896 citations were identified through systematic literature search. From these, ten and two uncontrolled clinical longitudinal studies for HVGIC and amalgam, respectively, were included for naïve-indirect comparison and could be matched with three out twenty RCTs. Summary effects sizes were computed as Odds ratios (OR; 95% Confidence intervals) and compared with those from RCTs. Trend directions were inferred from 95% Confidence interval overlaps and direction of point estimates; magnitudes of performance differences were inferred from the median point estimates (OR) with 25% and 75% percentile range, for both types of comparison. Mann-Whitney U test was applied to test for statistically significant differences between point estimates of both comparison types. Results Trends and performance differences inferred from naïve-indirect comparison based on evidence from uncontrolled clinical longitudinal studies and from direct comparisons based on RCT evidence are not the same. The distributions of the point estimates differed significantly for both comparison types (Mann–Whitney U  =  25, nindirect  =  26; ndirect  =  8; p  =  0.0013, two-tailed). Conclusion The null-hypothesis was rejected. Trends and performance differences inferred from either comparison between HVGIC and amalgam restorations failure rates in permanent posterior teeth are not the same. It is

  4. Recombinant Bivalent Fusion Protein rVE Induces CD4+ and CD8+ T-Cell Mediated Memory Immune Response for Protection Against Yersinia enterocolitica Infection

    PubMed Central

    Singh, Amit K.; Kingston, Joseph J.; Gupta, Shishir K.; Batra, Harsh V.

    2015-01-01

    Studies investigating the correlates of immune protection against Yersinia infection have established that both humoral and cell mediated immune responses are required for the comprehensive protection. In our previous study, we established that the bivalent fusion protein (rVE) comprising immunologically active regions of Y. pestis LcrV (100–270 aa) and YopE (50–213 aa) proteins conferred complete passive and active protection against lethal Y. enterocolitica 8081 challenge. In the present study, cohort of BALB/c mice immunized with rVE or its component proteins rV, rE were assessed for cell mediated immune responses and memory immune protection against Y. enterocolitica 8081. rVE immunization resulted in extensive proliferation of both CD4 and CD8 T cell subsets; significantly high antibody titer with balanced IgG1: IgG2a/IgG2b isotypes (1:1 ratio) and up-regulation of both Th1 (TNF-α, IFN-γ, IL-2, and IL-12) and Th2 (IL-4) cytokines. On the other hand, rV immunization resulted in Th2 biased IgG response (11:1 ratio) and proliferation of CD4+ T-cell; rE group of mice exhibited considerably lower serum antibody titer with predominant Th1 response (1:3 ratio) and CD8+ T-cell proliferation. Comprehensive protection with superior survival (100%) was observed among rVE immunized mice when compared to the significantly lower survival rates among rE (37.5%) and rV (25%) groups when IP challenged with Y. enterocolitica 8081 after 120 days of immunization. Findings in this and our earlier studies define the bivalent fusion protein rVE as a potent candidate vaccine molecule with the capability to concurrently stimulate humoral and cell mediated immune responses and a proof of concept for developing efficient subunit vaccines against Gram negative facultative intracellular bacterial pathogens. PMID:26733956

  5. Prevalence of Hypertension in HIV/AIDS Patients on Highly Active Antiretroviral Therapy (HAART) Compared with HAART-Naïve Patients at the Limbe Regional Hospital, Cameroon

    PubMed Central

    Dimala, Christian Akem; Atashili, Julius; Mbuagbaw, Josephine C.; Wilfred, Akam; Monekosso, Gottlieb L.

    2016-01-01

    Background Highly active antiretroviral therapy (HAART) has greatly reduced the morbidity and mortality of HIV/AIDS patients but has also been associated with increased metabolic complications and cardiovascular diseases. Data on the association between HAART and hypertension (HTN) in Africa are scarce. Objectives Primarily to compare the prevalence of HTN in HIV/AIDS patients on HAART and HAART-naïve patients in Limbe, Cameroon; and secondarily to assess other socio-demographic and clinical factors associated with HTN in this population. Methods A cross-sectional study was conducted at the Limbe Regional Hospital HIV treatment center between April and June 2013, involving 200 HIV/AIDS patients (100 on first-line HAART regimens for at least 12 months matched by age and sex to 100 HAART-naïve patients). HTN was defined as a systolic blood pressure (BP) ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg. Results The prevalence of HTN in patients on HAART was twice (38%; 95% CI: 28.5–48.3) that of the HAART-naïve patients (19%; 95% CI, 11.8–28.1), p = 0.003. In multivariate analyses adjusted for age, gender, smoking, family history of HTN, and BMI-defined overweight, HAART was associated with HTN, the adjusted odds ratio of the HAART-treated versus HAART-naïve group was 2.20 (95% CI: 1.07–4.52), p = 0.032. HTN was associated with older age and male gender, in the HAART group and with BMI-defined overweight in the HAART-naïve group. Conclusion The prevalence of hypertension in HIV/AIDS patients in Limbe stands out to be elevated, higher in patients on HAART compared to those not on treatment. Blood pressure and cardiovascular risk factors should be routinely monitored. Other factors such as diet, weight control and physical exercise should also be considered. PMID:26862763

  6. TEMEL ETİK KURAMLAR AÇISINDAN ADALET ve SAĞLIK HAKKI KAVRAMLARININ DEĞERLENDİRMESİ1,2

    PubMed Central

    Ekmekçi, Perihan Elif; Arda, Berna

    2015-01-01

    Sağlık hakkı temel bir insan hakkıdır. Ancak günümüzde sağlık hakkının hayata geçmesi, sağlık sunumunda gereksinim duyulan kaynakların kısıtlı olması nedeniyle engeller ile karşılaşmaktadır. Ayrıca tıp alanındaki hızlı teknolojik ilerlemeler, tanı ve tedavi imkânlarının her geçen gün gelişmesine yol açmaktadır. Bu durum, sağlık hizmetlerinin sunumunu dağıtıcı adaletin bir süjesi haline getirmektedir. Adalet kavramının tanımlanabilmesi için öncelikle, birey ya da toplulukların bir şeye ilişkin hak talebinde bulunmalarının koşullarını tanımlanmalı daha sonra hak edilenin kim tarafından ve nasıl verileceğinin belirlenmelidir. Etik kuramlar, etik açıdan doğru eyleyebilmek için hangi dayanak noktalarından yola çıkarak hangi değerleri önceleyerek karar vermek gerektiği konusunda kendi paradigmalarını oluşturmuşlardır. Adalet ve sağlık hakkı gibi temel kavramlar, temel etik kuramlar tarafından, o kuramın bağlamı içinde değerlendirilmekte ve anlam kazanmaktadır. Sağlık hakkı bazı etik kuramlar tarafından insan varlığının doğal bir bileşeni olarak tanımlanırken, bazı etik kuramlar tarafından bağlamsal olarak kabul edilmekte bazıları tarafından ise reddedilmekte, adalet kavramı ve bağlantılı olarak adaletin materyal ve formal ilkeleri gibi kavramların içerikleri ve taşıdıkları değerler içinden bakılan etik kuramın paradigmasına bağlı olarak farklıklar içermektedir. Etik kuramların paradigmaları sadece kavramların tanımlanmasında değil, aynı zamanda pratik uygulamalarda da farklı yaklaşımları gerektirmektedir. Bu çalışmada, erdem etiği, faydacı etik kuram, ödev etiği, liberal etik kuram ve kommuniteryan etik kuramın adalet ve sağlık hakkını nasıl kavramsallaştırdıklarını ortaya konmaktır. Bu amaçla öncelikle her bir etik kuramın genel çerçevesi tanımlanmış ve bu çerçevenin çizdiği teorik paradigma i

  7. The transition of mouse pluripotent stem cells from the naïve to the primed state requires Fas signaling through 3-O sulfated heparan sulfate structures recognized by the HS4C3 antibody

    SciTech Connect

    Hirano, Kazumi; Van Kuppevelt, Toin H.; Nishihara, Shoko

    2013-01-18

    Highlights: ► Fas transcript increases during the transition from the naïve to the primed state. ► 3OST-5 transcript, the HS4C3 epitope synthesis gene, increases during the transition. ► Fas signaling regulates the transition from the naïve to the primed state. ► HS4C3-binding epitope regulates the transition from the naïve to the primed state. ► Fas signaling is regulated by the HS4C3 epitope during the transition. -- Abstract: The characteristics of pluripotent embryonic stem cells of human and mouse are different. The properties of human embryonic stem cells (hESCs) are similar to those of mouse epiblast stem cells (mEpiSCs), which are in a later developmental pluripotency state, the so-called “primed state” compared to mouse embryonic stem cells (mESCs) which are in a naïve state. As a result of the properties of the primed state, hESCs proliferate slowly, cannot survive as single cells, and can only be transfected with genes at low efficiency. Generating hESCs in the naïve state is necessary to overcome these problems and allow their application in regenerative medicine. Therefore, clarifying the mechanism of the transition between the naïve and primed states in pluripotent stem cells is important for the establishment of stable methods of generating naïve state hESCs. However, the signaling pathways which contribute to the transition between the naïve and primed states are still unclear. In this study, we carried out induction from mESCs to mEpiSC-like cells (mEpiSCLCs), and observed an increase in the activation of Fas signaling during the induction. The expression of Fgf5, an epiblast marker, was diminished by inhibition of Fas signaling using the caspase-8 and -3 blocking peptides, IETD and DEVD, respectively. Furthermore, during the induction, we observed increased expression of 3-O sulfated heparan sulfate (HS) structures synthesized by HS 3-O-sulfotransferase (3OST), which are recognized by the HS4C3 antibody (HS4C3-binding epitope

  8. Evidence for Persistence of Ectromelia Virus in Inbred Mice, Recrudescence Following Immunosuppression and Transmission to Naïve Mice

    PubMed Central

    Sakala, Isaac G.; Chaudhri, Geeta; Scalzo, Anthony A.; Eldi, Preethi; Newsome, Timothy P.; Buller, Robert M.; Karupiah, Gunasegaran

    2015-01-01

    Orthopoxviruses (OPV), including variola, vaccinia, monkeypox, cowpox and ectromelia viruses cause acute infections in their hosts. With the exception of variola virus (VARV), the etiological agent of smallpox, other OPV have been reported to persist in a variety of animal species following natural or experimental infection. Despite the implications and significance for the ecology and epidemiology of diseases these viruses cause, those reports have never been thoroughly investigated. We used the mouse pathogen ectromelia virus (ECTV), the agent of mousepox and a close relative of VARV to investigate virus persistence in inbred mice. We provide evidence that ECTV causes a persistent infection in some susceptible strains of mice in which low levels of virus genomes were detected in various tissues late in infection. The bone marrow (BM) and blood appeared to be key sites of persistence. Contemporaneous with virus persistence, antiviral CD8 T cell responses were demonstrable over the entire 25-week study period, with a change in the immunodominance hierarchy evident during the first 3 weeks. Some virus-encoded host response modifiers were found to modulate virus persistence whereas host genes encoded by the NKC and MHC class I reduced the potential for persistence. When susceptible strains of mice that had apparently recovered from infection were subjected to sustained immunosuppression with cyclophosphamide (CTX), animals succumbed to mousepox with high titers of infectious virus in various organs. CTX treated index mice transmitted virus to, and caused disease in, co-housed naïve mice. The most surprising but significant finding was that immunosuppression of disease-resistant C57BL/6 mice several weeks after recovery from primary infection generated high titers of virus in multiple tissues. Resistant mice showed no evidence of a persistent infection. This is the strongest evidence that ECTV can persist in inbred mice, regardless of their resistance status. PMID

  9. Evidence for Persistence of Ectromelia Virus in Inbred Mice, Recrudescence Following Immunosuppression and Transmission to Naïve Mice.

    PubMed

    Sakala, Isaac G; Chaudhri, Geeta; Scalzo, Anthony A; Eldi, Preethi; Newsome, Timothy P; Buller, Robert M; Karupiah, Gunasegaran

    2015-12-01

    Orthopoxviruses (OPV), including variola, vaccinia, monkeypox, cowpox and ectromelia viruses cause acute infections in their hosts. With the exception of variola virus (VARV), the etiological agent of smallpox, other OPV have been reported to persist in a variety of animal species following natural or experimental infection. Despite the implications and significance for the ecology and epidemiology of diseases these viruses cause, those reports have never been thoroughly investigated. We used the mouse pathogen ectromelia virus (ECTV), the agent of mousepox and a close relative of VARV to investigate virus persistence in inbred mice. We provide evidence that ECTV causes a persistent infection in some susceptible strains of mice in which low levels of virus genomes were detected in various tissues late in infection. The bone marrow (BM) and blood appeared to be key sites of persistence. Contemporaneous with virus persistence, antiviral CD8 T cell responses were demonstrable over the entire 25-week study period, with a change in the immunodominance hierarchy evident during the first 3 weeks. Some virus-encoded host response modifiers were found to modulate virus persistence whereas host genes encoded by the NKC and MHC class I reduced the potential for persistence. When susceptible strains of mice that had apparently recovered from infection were subjected to sustained immunosuppression with cyclophosphamide (CTX), animals succumbed to mousepox with high titers of infectious virus in various organs. CTX treated index mice transmitted virus to, and caused disease in, co-housed naïve mice. The most surprising but significant finding was that immunosuppression of disease-resistant C57BL/6 mice several weeks after recovery from primary infection generated high titers of virus in multiple tissues. Resistant mice showed no evidence of a persistent infection. This is the strongest evidence that ECTV can persist in inbred mice, regardless of their resistance status. PMID

  10. Knocking on Heaven's Door: Are Novel Invaders Necessarily Facing Naïve Native Species on Islands?

    PubMed

    Gérard, Agathe; Jourdan, Hervé; Millon, Alexandre; Vidal, Eric

    2016-01-01

    The impact of alien predator species on insular native biota has often been attributed to island prey naïveté (i.e. lack of, or inefficient, anti-predator behavior). Only rarely, however, has the concept of island prey naïveté been tested, and then only a posteriori (i.e. hundreds or thousands of years after alien species introduction). The presence of native or anciently introduced predators or competitors may be crucial for the recognition and development of adaptive behavior toward unknown predators or competitors of the same archetype (i.e. a set of species that occupy a similar ecological niche and show similar morphological and behavioral traits when interacting with other species). Here, we tested whether two squamates endemic to New Caledonia, a skink, Caledoniscincus austrocaledonicus, and a gecko, Bavayia septuiclavis, recognized and responded to the odor of two major invaders introduced into the Pacific islands, but not yet into New Caledonia. We chose one predator, the small Indian mongoose Herpestes javanicus and one competitor, the cane toad Rhinella marina, which belong respectively to the same archetype as the following two species already introduced into New Caledonia in the nineteenth century: the feral cat Felis catus and the golden bell frog Litoria aurea. Our experiment reveals that geckos are naïve with respect to the odors of both an unknown predator and an unknown competitor, as well as to the odors of a predator and a competitor they have lived with for centuries. In contrast, skinks seem to have lost some naïveté regarding the odor of a predator they have lived with for centuries and seem "predisposed" to avoid the odor of an unknown potential competitor. These results indicate that insular species living in contact with invasive alien species for centuries may be, although not systematically, predisposed toward developing adaptive behavior with respect to species belonging to the same archetype and introduced into their native

  11. Accessibility and Quality of Online Cancer-Related Clinical Trial Information for Naïve Searchers.

    PubMed

    Abel, Gregory A; Cronin, Angel M; Earles, Kristofer; Gray, Stacy W

    2015-10-01

    Although the Internet may help to increase cancer patients' awareness of clinical trials, little is known about the accessibility and quality of online clinical trial information. We simulated the experience of a naïve cancer patient without clinical trial knowledge by searching three popular search engines for treatment information for breast, lung, and prostate cancer, and myelodysplastic syndromes (MDS). Two coders independently evaluated website content for accessibility and quality. We screened 120 websites and identified 40 unique sites for analysis. Overall, 85% [95% confidence interval (CI), 70%-94%] of sites mentioned clinical trials on the landing page and 68% (51%-81%) included links to specific trials. Overall readability was poor. Approximately half of websites (36%-68%) included information on the potential benefits and risks of clinical trials and 40% provided information about when the site had been updated (25%-57%). Among sites with links to specific clinical trials, only 44% (25%-65%) provided an interactive interface that would allow patients to customize search results; breast (100%) and prostate (50%) sites were more interactive than lung (25%) and MDS (14%; P = 0.007). Although cancer clinical trial information is widely available on the Internet, its quality is highly variable. Given the fact that many emerging cancer therapeutics are personalized based on disease or genomic characteristics, interactive web-based interfaces could serve as powerful vehicles to help patients locate appropriate clinical trials. Without enhanced efforts to ensure greater interactivity of cancer treatment websites, patient awareness of relevant clinical trials may remain low. PMID:26265204

  12. Discovery of Influenza A virus neuraminidase inhibitors using support vector machine and Naïve Bayesian models.

    PubMed

    Lian, Wenwen; Fang, Jiansong; Li, Chao; Pang, Xiaocong; Liu, Ai-Lin; Du, Guan-Hua

    2016-05-01

    Neuraminidase (NA) is a critical enzyme in the life cycle of influenza virus, which is known as a successful paradigm in the design of anti-influenza agents. However, to date there are no classification models for the virtual screening of NA inhibitors. In this work, we built support vector machine and Naïve Bayesian models of NA inhibitors and non-inhibitors, with different ratios of active-to-inactive compounds in the training set and different molecular descriptors. Four models with sensitivity or Matthews correlation coefficients greater than 0.9 were chosen to predict the NA inhibitory activities of 15,600 compounds in our in-house database. We combined the results of four optimal models and selected 60 representative compounds to assess their NA inhibitory profiles in vitro. Nine NA inhibitors were identified, five of which were oseltamivir derivatives with large C-5 substituents exhibiting potent inhibition against H1N1 NA with [Formula: see text] values in the range of 12.9-185.0 nM, and against H3N2 NA with [Formula: see text] values between 18.9 and 366.1 nM. The other four active compounds belonged to novel scaffolds, with [Formula: see text] values ranging 39.5-63.8 [Formula: see text]M against H1N1 NA and 44.5-114.1 [Formula: see text]M against H3N2 NA. This is the first time that classification models of NA inhibitors and non-inhibitors are built and their prediction results validated experimentally using in vitro assays. PMID:26689205

  13. Stellar Activity at the End of the Main Sequence: GHRS Observations of the M8 Ve Star VB 10

    NASA Technical Reports Server (NTRS)

    Linsky, Jeffrey L.; Wood, Brian E.; Brown, Alexander; Giampapa, Mark S.; Ambruster, Carol

    1995-01-01

    We present Goddard High Resolution Spectrograph observations of the M8 Ve star VB 10 (equal to G1 752B), located very near the end of the stellar main sequence, and its dM3.5 binary companion G1 752A. These coeval stars provide a test bed for studying whether the outer atmospheres of stars respond to changes in internal structure as stars become fully convective near mass 0.3 solar mass (about spectral type M5), where the nature of the stellar magnetic dynamo presumably changes, and near the transition from red to brown dwarfs near mass 0.08 solar mass (about spectral type M9), when hydrogen burning ceases at the end of the main sequence. We obtain upper limits for the quiescent emission of VB 10 but observe a transition region spectrum during a large flare, which indicates that some type of magnetic dynamo must be present. Two indirect lines of evidence-scaling from the observed X-ray emission and scaling from a time-resolved flare on AD Leo suggest that the fraction of the stellar bolometric luminosity that heats the transition region of VB 10 outside of obvious flares is comparable to, or larger than, that for G1 752A. This suggests an increase in the magnetic heating rates, as measured by L(sub line)/L(sub bol) ratios, across the radiative/convective core boundary and as stars approach the red/brown dwarf boundary. These results provide new constraints for dynamo models and models of coronal and transition-region heating in late-type stars.

  14. Mismatch negativity in tobacco-naïve cannabis users and its alteration with acute nicotine administration.

    PubMed

    Impey, Danielle; El-Marj, Nicole; Parks, Andrea; Choueiry, Joelle; Fisher, Derek; Knott, Verner J

    2015-09-01

    Chronic cannabis use may interact with factors, such as age of onset of cannabis use, family history, and genetic factors, to elicit schizophrenia (SZ)-like symptoms, including sensory and cognitive deficits. However, evidence of a relationship between cannabis use and cognitive impairment is confounded by concomitant use of tobacco. The objective of this study was to compare tobacco-naïve cannabis users with individuals without a history of tobacco/cannabis use on the auditory mismatch negativity (MMN) event-related potential (ERP), a neural measure of auditory deviance detection which is diminished in SZ. An exploratory arm of the study, conducted within a randomized, double-blind, placebo controlled design, examined the acute effects of nicotine gum (6mg) on MMN in cannabis users. MMN was recorded in response to 5 deviant stimuli within an optimal MMN paradigm in 44 healthy, non-tobacco smoking volunteers aged 18-26. Cannabis users (n=21) started smoking cannabis prior to age 17, at least 1 joint per month. To examine the effects of chronicity, users were grouped into relatively heavy long-term (HLT; n=11) users and light short-term (LST; n=10) users. Impaired deviance detection was shown in cannabis users vs. nonusers as reflected by a smaller MMN to duration deviants. Chronicity of use was also associated with MMN alterations, as HLTs displayed a reduced duration and gap MMN vs. LSTs. Compared with placebo, nicotine treatment enhanced select MMN deviants in cannabis user subgroups. As deficits associated with early and persistent cannabis use are similar to those seen in SZ, these dose-dependant disturbances in early sensory processing with cannabis use may be one cognitive pathway which mediates an increased risk for SZ in vulnerable youth, and be influenced by concurrent cigarette smoking behavior. PMID:26188167

  15. Visual targeting of components of floral colour patterns in flower-naïve bumblebees ( Bombus terrestris; Apidae)

    NASA Astrophysics Data System (ADS)

    Lunau, Klaus; Fieselmann, Gabriele; Heuschen, Britta; van de Loo, Antje

    2006-07-01

    Floral colour patterns are contrasting colour patches on flowers, a part of the signalling apparatus that was considered to display shape and colour signals used by flower-visitors to detect flowers and locate the site of floral reward. Here, we show that flower-naïve bumblebees ( Bombus terrestris) spontaneously direct their approach towards the outside margin of artificial flowers, which provides contrast between these dummy flowers and the background. If no floral guides are present, the bumblebees continue to approach the margin and finally touch the marginal area of the dummy flower with the tips of their antennae. Whilst approaching dummy flowers that also have a central floral guide, the bumblebees change their direction of flight: Initially, they approach the margin, later they switch to approaching the colour guide, and finally they precisely touch the floral guide with their antennae. Variation of the shape of equally sized dummy flowers did not alter the bumblebees’ preferential orientation towards the guide. Using reciprocal combinations of guide colour and surrounding colour, we showed that the approach from a distance towards the corolla and the antennal contact with the guide are elicited by the same colour parameter: spectral purity. As a consequence, the dummy flowers eliciting the greatest frequency of antennal reactions at the guide are those that combine a floral guide of high spectral purity with a corolla of less spectral purity. Our results support the hypothesis that floral guides direct bumblebees’ approaches to the site of first contact with the flower, which is achieved by the tips of the antennae.

  16. Work productivity among treatment-naïve patients with genotype 1 chronic hepatitis C infection receiving telaprevir combination treatment.

    PubMed

    Aggarwal, J; Vera-Llonch, M; Donepudi, M; Suthoff, E; Younossi, Z; Goss, T F

    2015-01-01

    Work productivity is impacted in hepatitis C virus (HCV)-infected patients and has been linked to treatment. In two Phase 3 trials, ADVANCE and ILLUMINATE, treatment-naïve genotype 1 chronic HCV-infected patients received 12-week telaprevir (T) with 24 (T12PR24)- or 48 (T12PR48)-week peginterferon alfa-2a/ribavirin. The objective of this analysis was to examine the impact of chronic HCV infection and its treatment with combination therapy on work productivity. The 5-item, self-reported work productivity questionnaire (WPQ) was administered in Phase 3 trials to assess unemployment status, days unable to work due to HCV/treatment, reduced hours worked and impact on productivity in prior 4 weeks. Descriptive statistics and multivariate regression analyses were employed in analyses of pooled trial data. About 1147 patients were included; 22% (n = 255) were unemployed at baseline, with 8% being unemployed due to health reasons. At week 12, there were no differences by treatment regimen in the number of days unable to work. At week 48, improvements were observed earlier among patients receiving the shorter duration of T combination treatment. Mean (95% CI) change from baseline in days unable to work was -0.48 (-0.85, -0.11) days for T12PR24, 1.43 (0.63, 2.24) days for T12PR48 and 1.24 (0.18, 2.30) days for PR48 with placebo. Predictors of days unable to work were identified and include demographic characteristics, pretreatment and on-treatment levels of fatigue, as well regional variation. In post hoc analyses of the ADVANCE and ILLUMINATE trials, work productivity decreased during the initial 12 weeks regardless of treatment group. PMID:24528927

  17. Multimodal Magnetic Resonance Imaging Study of Treatment-Naïve Adults with Attention-Deficit/Hyperactivity Disorder

    PubMed Central

    Chaim, Tiffany M.; Zhang, Tianhao; Zanetti, Marcus V.; da Silva, Maria Aparecida; Louzã, Mário R.; Doshi, Jimit; Serpa, Mauricio H.; Duran, Fabio L. S.; Caetano, Sheila C.; Davatzikos, Christos; Busatto, Geraldo F.

    2014-01-01

    Background Attention-Deficit/Hiperactivity Disorder (ADHD) is a prevalent disorder, but its neuroanatomical circuitry is still relatively understudied, especially in the adult population. The few morphometric magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) studies available to date have found heterogeneous results. This may be at least partly attributable to some well-known technical limitations of the conventional voxel-based methods usually employed to analyze such neuroimaging data. Moreover, there is a great paucity of imaging studies of adult ADHD to date that have excluded patients with history of use of stimulant medication. Methods A newly validated method named optimally-discriminative voxel-based analysis (ODVBA) was applied to multimodal (structural and DTI) MRI data acquired from 22 treatment-naïve ADHD adults and 19 age- and gender-matched healthy controls (HC). Results Regarding DTI data, we found higher fractional anisotropy in ADHD relative to HC encompassing the white matter (WM) of the bilateral superior frontal gyrus, right middle frontal left gyrus, left postcentral gyrus, bilateral cingulate gyrus, bilateral middle temporal gyrus and right superior temporal gyrus; reductions in trace (a measure of diffusivity) in ADHD relative to HC were also found in fronto-striatal-parieto-occipital circuits, including the right superior frontal gyrus and bilateral middle frontal gyrus, right precentral gyrus, left middle occipital gyrus and bilateral cingulate gyrus, as well as the left body and right splenium of the corpus callosum, right superior corona radiata, and right superior longitudinal and fronto-occipital fasciculi. Volumetric abnormalities in ADHD subjects were found only at a trend level of significance, including reduced gray matter (GM) in the right angular gyrus, and increased GM in the right supplementary motor area and superior frontal gyrus. Conclusions Our results suggest that adult ADHD is associated with

  18. Evolution of an Eurasian avian-like influenza virus in naïve and vaccinated pigs.

    PubMed

    Murcia, Pablo R; Hughes, Joseph; Battista, Patrizia; Lloyd, Lucy; Baillie, Gregory J; Ramirez-Gonzalez, Ricardo H; Ormond, Doug; Oliver, Karen; Elton, Debra; Mumford, Jennifer A; Caccamo, Mario; Kellam, Paul; Grenfell, Bryan T; Holmes, Edward C; Wood, James L N

    2012-01-01

    Influenza viruses are characterized by an ability to cross species boundaries and evade host immunity, sometimes with devastating consequences. The 2009 pandemic of H1N1 influenza A virus highlights the importance of pigs in influenza emergence, particularly as intermediate hosts by which avian viruses adapt to mammals before emerging in humans. Although segment reassortment has commonly been associated with influenza emergence, an expanded host-range is also likely to be associated with the accumulation of specific beneficial point mutations. To better understand the mechanisms that shape the genetic diversity of avian-like viruses in pigs, we studied the evolutionary dynamics of an Eurasian Avian-like swine influenza virus (EA-SIV) in naïve and vaccinated pigs linked by natural transmission. We analyzed multiple clones of the hemagglutinin 1 (HA1) gene derived from consecutive daily viral populations. Strikingly, we observed both transient and fixed changes in the consensus sequence along the transmission chain. Hence, the mutational spectrum of intra-host EA-SIV populations is highly dynamic and allele fixation can occur with extreme rapidity. In addition, mutations that could potentially alter host-range and antigenicity were transmitted between animals and mixed infections were commonplace, even in vaccinated pigs. Finally, we repeatedly detected distinct stop codons in virus samples from co-housed pigs, suggesting that they persisted within hosts and were transmitted among them. This implies that mutations that reduce viral fitness in one host, but which could lead to fitness benefits in a novel host, can circulate at low frequencies. PMID:22693449

  19. Replication Capacity in Relation to Immunologic and Virologic Outcomes in HIV-1 infected, Treatment-Naïve Subjects

    PubMed Central

    Skowron, Gail; Spritzler, John G.; Weidler, Jodi; Robbins, Gregory K.; Johnson, Victoria A.; Chan, Ellen S.; Asmuth, David M.; Gandhi, Rajesh T.; Lie, Yolanda; Bates, Michael; Pollard, Richard B.

    2012-01-01

    Objectives To evaluate the association between baseline (BL) replication capacity (RC) [RCBL] and immunologic/virologic parameters (at BL and after 48 weeks on therapy) in HIV-1 infected subjects initiating antiretroviral therapy. Methods RCBL was determined using a modified Monogram PhenoSense HIV drug susceptibility assay on plasma HIV-1 from 321 treatment-naïve subjects from ACTG384. Univariate and multivariable analyses were performed to determine the association of RCBL with BL and on-therapy virologic and immunologic outcomes. Results Higher RCBL was associated with lower baseline CD4 (CD4BL) (r=−0.23, p<0.0001), higher baseline HIV-1 (RNABL) (r=0.25, p<0.0001), higher CD4BL activation percent (r=0.23, p<0.0001) and lower CD4BL memory count (r=−0.21, p=0.0002). In a multivariable model, week 48 CD4 increase (ΔCD448) was associated with lower CD4BL memory count and higher CD4BL naive percent (p=0.004, p=0.015, respectively). The interaction between CD4BL and RCBL was significant (p=0.018), with a positive association between RCBL and ΔCD448 in subjects with higher CD4BL, and a negative association at lower absCD4BL. Conclusions At baseline, higher RC was significantly associated with higher HIV-1 RNA, higher CD4 cell activation, lower CD4 cell count, and lower CD4 memory cell count. These factors may interact, directly or indirectly, to modify the extent to which CD4 recovery occurs in patients starting antiretroviral therapy at different baseline CD4 counts. PMID:19194319

  20. Liver Enzymes Abnormalities among Highly Active Antiretroviral Therapy Experienced and HAART Naïve HIV-1 Infected Patients at Debre Tabor Hospital, North West Ethiopia: A Comparative Cross-Sectional Study

    PubMed Central

    Tulu, Ketema Tafess; Zegeye, Amtatachew Moges; Wubante, Amarech Asratie

    2016-01-01

    Liver disease has emerged as the most common non-AIDS-related cause of death in HIV patients. However, there is limited data regarding this condition including our setting in Ethiopia. Hence, liver enzyme abnormalities among highly active antiretroviral therapy (HAART) experienced and HAART naïve patients were assessed in this study. A total of 164 HAART experienced and 164 HAART naïve patients were studied. Blood specimen was collected to determine alanine aminotransferase (ALT) and aspartate aminotransferase (AST), CD4 count, and viral hepatitis. The prevalence of liver enzyme abnormality was 20.1% and 22.0% among HAART experienced and HAART naïve patients, respectively. The HAART experienced patients had higher mean ALT than HAART naïve patients (P = 0.002). Viral hepatitis (AOR = 6.02; 95% CI = 1.87–19.39), opportunistic infections (AOR = 2.91; 95% CI = 1.04–8.19), current CD4 count <200 cells/mm3 (AOR = 2.16; 95% CI = 1.06–4.39), and male sex (AOR = 1.83; 95% CI = 1.001–3.33) were associated with elevated ALT and/or AST. In conclusion, liver enzyme abnormalities were high in both HAART experienced and HAART naïve HIV-1 infected patients. Hence, monitoring and management of liver enzyme abnormalities in HIV-1 infected patients are important in our setting. PMID:27493798

  1. Striatal D(2/3) Binding Potential Values in Drug-Naïve First-Episode Schizophrenia Patients Correlate With Treatment Outcome.

    PubMed

    Wulff, Sanne; Pinborg, Lars Hageman; Svarer, Claus; Jensen, Lars Thorbjørn; Nielsen, Mette Ødegaard; Allerup, Peter; Bak, Nikolaj; Rasmussen, Hans; Frandsen, Erik; Rostrup, Egill; Glenthøj, Birte Yding

    2015-09-01

    One of best validated findings in schizophrenia research is the association between blockade of dopamine D2 receptors and the effects of antipsychotics on positive psychotic symptoms. The aim of the present study was to examine correlations between baseline striatal D(2/3) receptor binding potential (BP(p)) values and treatment outcome in a cohort of antipsychotic-naïve first-episode schizophrenia patients. Additionally, we wished to investigate associations between striatal dopamine D(2/3) receptor blockade and alterations of negative symptoms as well as functioning and subjective well-being. Twenty-eight antipsychotic-naïve schizophrenia patients and 26 controls were included in the study. Single-photon emission computed tomography (SPECT) with [(123)I]iodobenzamide ([(123)I]-IBZM) was used to examine striatal D(2/3) receptor BP(p). Patients were examined before and after 6 weeks of treatment with the D(2/3) receptor antagonist amisulpride. There was a significant negative correlation between striatal D(2/3) receptor BP(p) at baseline and improvement of positive symptoms in the total group of patients. Comparing patients responding to treatment to nonresponders further showed significantly lower baseline BP(p) in the responders. At follow-up, the patients demonstrated a negative correlation between the blockade and functioning, whereas no associations between blockade and negative symptoms or subjective well-being were observed. The results show an association between striatal BP(p) of dopamine D(2/3) receptors in antipsychotic-naïve first-episode patients with schizophrenia and treatment response. Patients with a low BP(p) have a better treatment response than patients with a high BP(p). The results further suggest that functioning may decline at high levels of dopamine receptor blockade. PMID:25698711

  2. CD4+ cell count recovery in naïve patients initiating cART, who achieved and maintained plasma HIV-RNA suppression

    PubMed Central

    Costagliola, Dominique; Lacombe, Jean-Marc; Ghosn, Jade; Delaugerre, Constance; Pialoux, Gilles; Cuzin, Lise; Launay, Odile; Ménard, Amélie; de Truchis, Pierre; Mary-Krause, Murielle; Weiss, Laurence; Delfraissy, Jean-François

    2014-01-01

    Introduction A key objective of combined antiretroviral therapy (cART) is to reach and maintain high CD4 cell counts to provide long-term protection against AIDS-defining opportunistic infections and malignancies, as well as other comorbidities. However, a high proportion of patients present late for care. Our objective was to assess CD4 cell count recovery up to seven years in naïve patients initiating cART with at least three drugs in usual clinical care. Methods From the French Hospital Database on HIV, we selected naïve individuals initiating cART from 2000 with at least two years of follow-up. Participants were further required to have achieved viral load suppression by six months after initiating cART and were censored in case of virological failure. We calculated the proportion of patients (Kaplan-Meier estimates) who achieved CD4 recovery to >500/mm3 according to baseline CD4 cell count. Results A total of 15,025 patients were analyzed with a median follow-up on ART of 65.5 months (IQR: 42.3–96.0). At cART initiation, the median age was 38.6 years (IQR: 32.2–46.0), 9734 (64.8%) were men, median CD4 cell count was 239 (IQR: 130–336) and 2668 (17.8%) had a prior AIDS event. Results are presented in the Table 1. Conclusions This study shows that CD4 cell counts continue to increase seven years after cART initiation, whatever the baseline CD4 cell count. Failing to achieve CD4 recovery with continuous viral load suppression is rare for naïve patients initiating cART in routine clinical practice, but takes substantially longer in patients who initiate antiretroviral therapy at low CD4 cell counts. PMID:25393990

  3. Abnormal white matter integrity in antipsychotic-naïve first-episode psychosis patients assessed by a DTI principal component analysis

    PubMed Central

    Alvarado-Alanis, Patricia; León-Ortiz, Pablo; Reyes-Madrigal, Francisco; Favila, Rafael; Rodríguez-Mayoral, Oscar; Nicolini, Humberto; Azcárraga, Mariana; Graff-Guerrero, Ariel; Rowland, Laura M.; de la Fuente-Sandoval, Camilo

    2015-01-01

    Introduction Diffusion tensor imaging (DTI) studies in patients with schizophrenia have shown abnormalities in the microstructure of white matter tracts. Specifically, reduced fractional anisotropy (FA) has been described across multiple white matter tracts, in studies that have mainly included patients treated with antipsychotic medications. Objective To compare FA in antipsychotic-naïve patients experiencing a first episode of psychosis (FEP) to FA in healthy controls to demonstrate that the variance of FA can be grouped, in a coincidental manner, in four predetermined factors in accordance with a theoretical partition of the white matter tracts, using a principal components analysis (PCA). Methods Thirty-five antipsychotic-naïve FEP patients and 35 age- and gender-matched healthy controls underwent DTI at 3T. Analysis was performed using a tract-based spatial statistics (TBSS) method and exploratory PCA. Results DTI analysis showed extensive FA reduction in white matter tracts in FEP patients compared with the control group. The PCA grouped the white matter tracts into four factors explaining 66% of the total variance. Comparison of the FA values within each factor highlighted the differences between FEP patients and controls. Discussion Our study confirms extensive white matter tracts anomalies in patients with schizophrenia, more specifically, in drug-naïve FEP patients. The results also indicate that a small number of white matter tracts share common FA anomalies that relate to deficit symptoms in FEP patients. Our study adds to a growing body of literature emphasizing the need for treatments targeting white matter function and structure in FEP patients. PMID:25620120

  4. Effects of Blocking D2/D3 Receptors on Mismatch Negativity and P3a Amplitude of Initially Antipsychotic Naïve, First Episode Schizophrenia Patients

    PubMed Central

    Glenthøj, Birte Yding; Oranje, Bob

    2016-01-01

    Background: Reduced mismatch negativity and P3a amplitude have been suggested to be among the core deficits in schizophrenia since the late 1970s. Blockade of dopamine D2 receptors play an important role in the treatment of schizophrenia. In addition, there is some evidence indicating that deficits in mismatch negativity and P3a amplitude are related to increased dopaminergic activity. This is the first study investigating the effect of amisulpride, a potent D2-antagonist, on mismatch negativity and P3a amplitude in a large group of antipsychotic-naïve, first-episode schizophrenia patients. Methods: Fifty-one antipsychotic-naïve, first-episode schizophrenia patients were tested in a mismatch negativity paradigm at baseline and after 6 weeks of treatment with amisulpride. We further examined 48 age- and gender-matched controls in this paradigm. Results: At baseline, the patients showed significantly reduced P3a amplitude compared with healthy controls, but no differences in mismatch negativity. Although the treatment with amisulpride significantly improved the patients’ psychopathological (PANSS) and functional (GAF) scores, it did not influence their mismatch negativity amplitude, while also their reduced P3a amplitude persisted. Conclusion: Our findings show that antipsychotic naïve, first-episode patients with schizophrenia have normal mismatch negativity yet reduced P3a amplitude compared with healthy controls. In spite of the fact that the 6-week amisulpride treatment improved the patients both clinically and functionally, it had no effect on either mismatch negativity or P3a amplitude. This suggests that even though there is a dopaminergic involvement in global functioning and symptomatology in schizophrenia, there is no such involvement in these particular measures of early information processing. PMID:26453696

  5. HIV-1 drug resistance in recently HIV-infected pregnant mother’s naïve to antiretroviral therapy in Dodoma urban, Tanzania

    PubMed Central

    2013-01-01

    Background HIV resistance affects virological response to therapy and efficacy of prophylaxis in mother-to-child-transmission. The study aims to assess the prevalence of HIV primary resistance in pregnant women naïve to antiretrovirals. Methods Cross sectional baseline analysis of a cohort of HIV + pregnant women (HPW) enrolled in the study entitled Antiretroviral Management of Antenatal and Natal HIV Infection (AMANI, peace in Kiswahili language). The AMANI study began in May 2010 in Dodoma, Tanzania. In this observational cohort, antiretroviral treatment was provided to all women from the 28th week of gestation until the end of the breastfeeding period. Baseline CD4 cell count, viral load and HIV drug-resistance genotype were collected. Results Drug-resistance analysis was performed on 97 naïve infected-mothers. The prevalence of all primary drug resistance and primary non-nucleoside reverse-transcriptase inhibitors resistance was 11.9% and 7.5%, respectively. K103S was found in two women with no M184V detection. HIV-1 subtype A was the most commonly identified, with a high prevalence of subtype A1, followed by C, D, C/D recombinant, A/C recombinant and A/D recombinant. HIV drug- resistance mutations were detected in A1 and C subtypes. Conclusion Our study reports an 11.9% prevalence rate of primary drug resistance in naïve HIV-infected pregnant women from a remote area of Tanzania. Considering that the non-nucleoside reverse-transcriptase inhibitors are part of the first-line antiretroviral regimen in Tanzania and all of Africa, resistance surveys should be prioritized in settings where antiretroviral therapy programs are scaled up. PMID:24053581

  6. Low-frequency NNRTI-resistant HIV-1 variants and relationship to mutational load in antiretroviral-naïve subjects.

    PubMed

    Gupta, Shaili; Lataillade, Max; Kyriakides, Tassos C; Chiarella, Jennifer; St John, Elizabeth P; Webb, Suzin; Moreno, Elizabeth A; Simen, Birgitte B; Kozal, Michael J

    2014-09-01

    Low-frequency HIV variants possessing resistance mutations against non‑nucleoside reverse transcriptase inhibitors (NNRTI), especially at HIV reverse transcriptase (RT) amino acid (aa) positions K103 and Y181, have been shown to adversely affect treatment response. Therapeutic failure correlates with both the mutant viral variant frequency and the mutational load. We determined the prevalence of NNRTI resistance mutations at several RT aa positions in viruses from 204 antiretroviral (ARV)-naïve HIV-infected individuals using deep sequencing, and examined the relationship between mutant variant frequency and mutational load for those variants. Deep sequencing to ≥0.4% levels found variants with major NNRTI-resistance mutations having a Stanford-HIVdb algorithm value ≥30 for efavirenz and/or nevirapine in 52/204 (25.5%) ARV-naïve HIV-infected persons. Eighteen different major NNRTI mutations were identified at 11 different positions, with the majority of variants being at frequency >1%. The frequency of these variants correlated strongly with the mutational load, but this correlation weakened at low frequencies. Deep sequencing detected additional major NNRTI-resistant viral variants in treatment-naïve HIV-infected individuals. Our study suggests the significance of screening for mutations at all RT aa positions (in addition to K103 and Y181) to estimate the true burden of pre-treatment NNRTI-resistance. An important finding was that variants at low frequency had a wide range of mutational loads (>100-fold) suggesting that frequency alone may underestimate the impact of specific NNRTI-resistant variants. We recommend further evaluation of all low-frequency NNRTI-drug resistant variants with special attention given to the impact of mutational loads of these variants on treatment outcomes. PMID:25256391

  7. Temporal studies into attachment, VE-cadherin perturbation, and paracellular migration of human umbilical mesenchymal stem cells across umbilical vein endothelial monolayers.

    PubMed

    Ebrahim, Neven A; Leach, Lopa

    2015-02-15

    Mesenchymal stem cells from Wharton's jelly of human umbilical cords (WJ-MSC) are a valuable alternate source of stem cells. Their role in situ and whether they can interact and cross intact endothelial monolayers requires elucidation. The aim of this study was to investigate the dynamic interactions between WJ-MSC and human umbilical vein endothelial cells (HUVEC), including attachment, transit times, extravasation pathway, and the effects of WJ-MSC on junctional vascular endothelial (VE)-cadherin. HUVEC were grown to near confluence in endothelial media and to full confluence in mixed media before the addition of PKH26-labelled WJ-MSC. Time lapse fluorescence microscopy showed stem cells undergoing membrane blebbing followed by amoeboid movement on HUVEC monolayers before rounding up and changing shape toward the spindle-shaped morphology during/after transmigration to subendothelial positions. Cells demonstrated a time lag of 60 min before paracellular extravasation, confirmed by confocal microscopy. Forty-six percent of attached cells crossed in the first 2 h. By 16 h, a majority of cells had transmigrated with >96% of cells crossing by 22 h. There were concomitant changes in endothelial junctional VE-cadherin with statistically significant increases in discontinuous staining at 2 h, return to control values at 16 h, even as from 22 h onward HUVEC displayed increased percentage of junctions with continuous staining and upregulation of protein. Our data suggests that WJ-MSC crosses the endothelial barrier through the paracellular pathway and can influence junctional organization of HUVEC with discreet perturbation of VE-cadherin preceding transmigration followed by upregulation once the adluminal side is reached. The latter may reflect a perivascular support function of WJ-MSC in the umbilical cord. PMID:25317631

  8. Efficacy of Once Daily Darunavir/Ritonavir in PI-Naïve, NNRTI-Experienced Patients in the ODIN Trial

    PubMed Central

    Geretti, Anna Maria; Moeketsi, Mathe; Demasi, Ralph; van Delft, Yvon; Mohammed, Perry

    2015-01-01

    Background. An exploratory subanalysis of the ODIN trial was performed to evaluate the efficacy of darunavir/ritonavir (DRV/r) 800/100 mg OD versus 600/100 mg BID in patients who were NNRTI-experienced but PI-naïve. Methods. ODIN was a phase III, 48-week study comparing DRV/r OD versus BID in 590 treatment-experienced patients with no DRV resistance-associated mutations (RAMs) at screening. Patients received DRV/r 800/100 mg OD or DRV/r 600/100 mg BID plus ≥2 NRTIs. Of the 590 patients randomized, 272 (46%) were NNRTI-experienced but PI-naïve. Results. Overall, 272 patients received DRV/r OD (n = 135) or BID (n = 137) plus ≥2 optimised NRTIs. The mean age was 39 years; 35% were female; 27% were Black, 24% Caucasian, 26% Oriental/Asian, and 23% other races; 17% were recruited in South Africa; and 48% had non-B HIV-1 subtypes. Mean baseline plasma HIV-1 RNA load was 4.10 log10⁡ copies/mL; median CD4 cell count was 258 cells/μL. At week 48, 111/135 (82%) of DRV/r OD and 109/137 (80%) of DRV/r BID patients achieved an HIV-1 RNA load <50 copies/mL. No patient developed primary PI RAMs. Conclusion. DRV/r 800/100 mg OD in combination with ≥2 optimised NRTIs led to virological suppression <50 copies/mL in 82% of NNRTI-experienced, PI-naïve patients by week 48. PMID:26357568

  9. Modulation of the Default Mode Network in First-Episode, Drug-Naïve Major Depressive Disorder via Acupuncture at Baihui (GV20) Acupoint

    PubMed Central

    Deng, Demao; Liao, Hai; Duan, Gaoxiong; Liu, Yanfei; He, Qianchao; Liu, Huimei; Tang, Lijun; Pang, Yong; Tao, Jien

    2016-01-01

    Background: Previous neuroimaging studies have revealed that acupuncture modulates the default mode network (DMN) in healthy subjects and patients with certain disorder. However, few studies have been performed to investigate whether or not acupuncture might modulate the DMN in patients with major depressive disorder (MDD). Thereby, the aim of the present study was to assess alterations of the DMN induced by acupuncture stimulation in patients with first-episode, drug-naïve MDD. Materials and Methods: Twenty nine patients with first-episode, drug-naïve MDD and 29 healthy subjects were enrolled in this study. All the healthy subjects underwent 6-min resting-state functional magnetic resonance imaging (R-fMRI) scan. While patients underwent acupuncture stimulation for 20-min electro-acupuncture stimulation (EAS) at Baihui acupoint (GV20) and two 6-min R-fMRI scans before and after EAS. Based on the precuneus/posterior cingulate cortex (PC/PCC) as the seed region, functional connectivity (FC) method was adopted to examine abnormal DMN in patients by comparing with healthy subjects and to evaluate the influence of EAS on intrinsic connectivity within the DMN in patients with MDD. Results: Compared to healthy subjects, MDD patients had abnormal DMN. Moreover, results showed that EAS at GV20 induced increased FC between the PC/PCC and bilateral anterior cingulate cortex (ACC), and decreased FC between the PC/PCC and left middle prefrontal cortex, left angualr gyrus and bilateral hippocampus/parahippocampus (HIPP/paraHIPP) in patients with MDD, which were the main brain regions showing significant differences between the patients and healthy subjects. Conclusion: Our findings provide imaging evidence to support that GV20-related acupuncture stimulation may modulate the DMN in patients with first-episode, drug-naïve MDD. This study may partly interpret the neural mechanisms of acupuncture at GV20 which is used to treat patients with MDD in clinical. PMID:27242492

  10. Genome-wide DNA methylation patterns in naïve CD4+ T cells from patients with primary Sjögren’s syndrome

    PubMed Central

    Altorok, Nezam; Coit, Patrick; Hughes, Travis; Koelsch, Kristi A.; Stone, Donald U.; Rasmussen, Astrid; Radfar, Lida; Scofield, R. Hal; Sivils, Kathy L.; Farris, A. Darise; Sawalha, Amr H.

    2013-01-01

    Objective Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease with incompletely understood etiology. Very little is known about the role of epigenetic dysregulation in the pathogenesis of pSS. Methods We performed a genome-wide DNA methylation study in naïve CD4+ T cells in eleven pSS patients compared to age-, sex-, and ethnicity-matched healthy controls. Cytosine methylation was quantified using the Illumina Infinium HumanMethylation450 BeadChip array and validated using bisulfite sequencing. Results We identified 553 hypomethylated and 200 hypermethylated CpG sites in naïve CD4+ T cells from pSS patients compared to healthy matched controls, representing 311 hypomethylated and 115 hypermethylated gene regions. Hypomethylated genes in pSS include LTA, coding for Lymphotoxin α. Other relevant genes such as CD247, TNFRSF25, PTPRC, GSTM1 and PDCD1 were also hypomethylated. The interferon signature pathway was represented by hypomethylation of STAT1, IFI44L, USP18 and IFITM1. A group of genes encoding for members of the solute carrier proteins were differentially methylated. In addition, the transcription factor RUNX1 was hypermethylated in patients, suggesting a possible connection to lymphoma predisposition. Gene ontology (GO) analysis of hypomethylated genes demonstrated enrichment of genes involved in lymphocyte activation and immune response. GO terms for hypermethylated genes included antigen processing and presentation. Conclusion This is the first epigenome-wide DNA methylation study in pSS. Our data highlight a role for DNA methylation in pSS and identify disease-associated DNA methylation changes in several genes and pathways in naïve CD4+ T cells in pSS that may be involved in the pathogenesis of this disease. PMID:24574234

  11. Disrupted Structural and Functional Connectivity in Prefrontal-Hippocampus Circuitry in First-Episode Medication-Naïve Adolescent Depression

    PubMed Central

    Geng, Haiyang; Wu, Feng; Kong, Lingtao; Tang, Yanqing; Zhou, Qian; Chang, Miao; Zhou, Yifang; Jiang, Xiaowei; Li, Songbai; Wang, Fei

    2016-01-01

    Background Evidence implicates abnormalities in prefrontal-hippocampus neural circuitry in major depressive disorder (MDD). This study investigates the potential disruptions in prefrontal-hippocampus structural and functional connectivity, as well as their relationship in first-episode medication-naïve adolescents with MDD in order to investigate the early stage of the illness without confounds of illness course and medication exposure. Methods Diffusion tensor imaging and resting-state functional magnetic resonance imaging (rs-fMRI) data were acquired from 26 first-episode medication-naïve MDD adolescents and 31 healthy controls (HC). Fractional anisotropy (FA) values of the fornix and the prefrontal-hippocampus functional connectivity was compared between MDD and HC groups. The correlation between the FA value of fornix and the strength of the functional connectivity in the prefrontal cortex (PFC) region showing significant differences between the two groups was identified. Results Compared with the HC group, adolescent MDD group had significant lower FA values in the fornix, as well as decreased functional connectivity in four PFC regions. Significant negative correlations were observed between fornix FA values and functional connectivity from hippocampus to PFC within the HC group. There was no significant correlation between the fornix FA and the strength of functional connectivity within the adolescent MDD group. Conclusions First-episode medication-naïve adolescent MDD showed decreased structural and functional connectivity as well as deficits of the association between structural and functional connectivity shown in HC in the PFC-hippocampus neural circuitry. These findings suggest that abnormal PFC-hippocampus neural circuitry may present in the early onset of MDD and play an important role in the neuropathophysiology of MDD. PMID:26863301

  12. Demonstration of Sustained Drug-Resistant Human Immunodeficiency Virus Type 1 Lineages Circulating among Treatment-Naïve Individuals▿ †

    PubMed Central

    Hué, Stéphane; Gifford, Robert J.; Dunn, David; Fernhill, Esther; Pillay, Deenan

    2009-01-01

    Transmission of human immunodeficiency virus (HIV) drug resistance is well-recognized and compromises response to first-line therapy. However, the population dynamics of transmitted resistance remains unclear, although previous models have assumed that such transmission reflects direct infection from treated individuals. We investigated whether population-based phylogenetic analyses would uncover lineages of resistant viruses circulating in untreated individuals. Through the phylogenetic analysis of 14,061 HIV type 1 (HIV-1) pol gene sequences generated in the United Kingdom from both treatment-naïve and -experienced individuals, we identified five treatment-independent viral clusters containing mutations conferring cross-resistance to antiretroviral drugs prescribed today in the United Kingdom. These viral lineages represent sustainable reservoirs of resistance among new HIV infections, independent of treatment. Dated phylogenies reconstructed through Bayesian Markov chain Monte Carlo inference indicated that these reservoirs originated between 1997 and 2003 and have persisted in the HIV-infected population for up to 8 years. Since our cohort does not represent all infected individuals within the United Kingdom, our results are likely to underestimate the number and size of the resistant reservoirs circulating among drug-naïve patients. The existence of sustained reservoirs of resistance in the absence of treatment has the capacity to threaten the long-term efficacy of antiretroviral therapy and suggests there is a limit to the decline of transmitted drug resistance. Given the current decrease in resistance transmitted from treated individuals, a greater proportion of resistance is likely to come from drug-naïve lineages. These findings provide new insights for the planning and management of treatment programs in resource-rich and developing countries. PMID:19158238

  13. Caffeine affects CD8+ lymphocyte apoptosis and migration differently in naïve and familiar individuals following moderate intensity exercise.

    PubMed

    Navalta, James W; Fedor, Elizabeth A; Schafer, Mark A; Lyons, T Scott; Tibana, Ramires A; Pereira, Guilherme B; Prestes, Jonato

    2016-06-01

    The purpose of this investigation was to determine the lymphocyte subset response to 30 min of moderate treadmill exercise during caffeine supplemented (6.0 mg.kg(-1)) and placebo conditions in caffeine-naïve and -familiar individuals. Seventeen individuals participated (caffeine-familiar = 8, caffeine-naïve = 9) completing two exercise bouts (caffeine supplemented and placebo control) 48 h apart in a counterbalanced and double-blinded fashion. Individuals were classified as follows: caffeine-naive <50 mg.d(-1) and caffeine-familiar >200 mg.d(-1) Whole blood samples were obtained at rest, 30 min after caffeine or placebo ingestion, immediately following exercise, and 1 h post exercise. Blood was used to analyze apoptosis (annexin V) and cellular migration (CX3CR1) responses in lymphocyte subsets (CD4+, CD8+, CD19+). Absolute changes from rest values were calculated and differences between conditions were determined through Chi-squared analysis with significance accepted at P <0.05. With regard to CD4+ and CD19+ lymphocytes, the interaction of caffeine and exercise did not affect naïve individuals to a greater extent immediately post exercise when compared to familiar, as similar apoptotic and migratory responses were observed (P >0.05). However, CD8+ lymphocyte cell death and migration responses were observed to be significantly greater at each sampling point in caffeine-familiar individuals (P <0.05). It is possible that chronic caffeine supplementation may prime CD8+ cell receptors for responsiveness to apoptosis and migration and the consequence of this form of immunosuppression in the post-exercise period should be determined. PMID:26684634

  14. HIV-1 Antiretroviral Drug Resistance Mutations in Treatment Naïve and Experienced Panamanian Subjects: Impact on National Use of EFV-Based Schemes.

    PubMed

    Mendoza, Yaxelis; Castillo Mewa, Juan; Martínez, Alexander A; Zaldívar, Yamitzel; Sosa, Néstor; Arteaga, Griselda; Armién, Blas; Bautista, Christian T; García-Morales, Claudia; Tapia-Trejo, Daniela; Ávila-Ríos, Santiago; Reyes-Terán, Gustavo; Bello, Gonzalo; Pascale, Juan M

    2016-01-01

    The use of antiretroviral therapy in HIV infected subjects prevents AIDS-related illness and delayed occurrence of death. In Panama, rollout of ART started in 1999 and national coverage has reached 62.8% since then. The objective of this study was to determine the level and patterns of acquired drug resistance mutations of clinical relevance (ADR-CRM) and surveillance drug resistance mutations (SDRMs) from 717 HIV-1 pol gene sequences obtained from 467 ARV drug-experienced and 250 ARV drug-naïve HIV-1 subtypes B infected subjects during 2007-2013, respectively. The overall prevalence of SDRM and of ADR-CRM during the study period was 9.2% and 87.6%, respectively. The majority of subjects with ADR-CRM had a pattern of mutations that confer resistance to at least two classes of ARV inhibitors. The non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations K103N and P225H were more prevalent in both ARV drug-naïve and ARV drug-experienced subjects. The nucleoside reverse transcriptase inhibitor (NRTI) mutation M184V was more frequent in ARV drug-experienced individuals, while T215YFrev and M41L were more frequent in ARV drug-naïve subjects. Prevalence of mutations associated to protease inhibitors (PI) was lower than 4.1% in both types of subjects. Therefore, there is a high level of resistance (>73%) to Efavirenz/Nevirapine, Lamivudine and Azidothymidine in ARV drug-experienced subjects, and an intermediate to high level of resistance (5-10%) to Efavirenz/Nevirapine in ARV drug-naïve subjects. During the study period, we observed an increasing trend in the prevalence of ADR-CRM in subjects under first-line schemes, but not significant changes in the prevalence of SDRM. These results reinforce the paramount importance of a national surveillance system of ADR-CRM and SDRM for national management policies of subjects living with HIV. PMID:27119150

  15. Comparison of efavirenz and protease inhibitor based combination antiretroviral therapy regimens in treatment-naïve people living with HIV with baseline resistance.

    PubMed

    Lim, Charlotte; McFaul, Katie; Kabagambe, Samuel; Sonecha, Sonali; Jones, Rachael; Asboe, David; Pozniak, Anton; Nwokolo, Nneka; Boffito, Marta

    2016-07-17

    A retrospective cohort analysis comparing the efficacy of boosted protease inhibitor-based and efavirenz-based combination antiretroviral therapy in treatment-naïve people living with HIV with baseline resistance found that efavirenz-based treatment led to a shorter mean time to undetectable viral load. A higher proportion of patients with nonnucleoside reverse transcriptase inhibitor related baseline resistance mutations in the efavirenz-treatment group achieved an undetectable viral load at both 6 and 12 months post-treatment initiation, compared with the boosted protease-inhibitor-treatment group.Supplementary content: http://links.lww.com/QAD/A930. PMID:27139315

  16. Increasing HIV-1 pretreatment drug resistance among antiretroviral-naïve adults initiating treatment between 2006 and 2014 in Nairobi, Kenya.

    PubMed

    Chung, Michael H; Silverman, Rachel; Beck, Ingrid A; Yatich, Nelly; Dross, Sandra; McKernan-Mullin, Jennifer; Bii, Stephen; Tapia, Kenneth; Stern, Joshua; Chohan, Bhavna; Sakr, Samah R; Kiarie, James N; Frenkel, Lisa M

    2016-06-19

    Antiretroviral-naïve adults initiating antiretroviral therapy in Nairobi, Kenya were tested for HIV-1 drug resistance at codons K103N, Y181C, G190A, M184V, and K65R using an oligonucleotide ligation assay. Prevalence of pretreatment drug resistance increased from 3.89% in 2006 to 10.93% in 2014 (P < 0.001), and 95% of those with resistance had at least one nonnucleoside reverse transcriptase inhibitor mutation. Resistance to tenofovir (K65R) was found in 2014 but not in 2006. PMID:27058353

  17. Quantitative hepatitis B core antibody level is associated with inflammatory activity in treatment-naïve chronic hepatitis B patients.

    PubMed

    Li, Min-Ran; Lu, Jian-Hua; Ye, Li-Hong; Sun, Xing-Li; Zheng, Yan-Hua; Liu, Zhi-Quan; Zhang, Hai-Cong; Liu, Yun-Yan; Lv, Ying; Huang, Yan; Dai, Er-Hei

    2016-08-01

    Previous studies have shown that hepatitis B core antibody (anti-HBc) levels vary during different phases of disease in treatment-naïve chronic hepatitis B (CHB) patients and can be used as a predictor of both interferon-α and nucleoside analogue therapy response. However, there is no information on the association between the quantitative serum anti-HBc (qAnti-HBc) level and liver inflammation in CHB patients. Therefore, we investigated these relationships in a large cohort of treatment-naïve CHB patients. A total of 624 treatment-naïve CHB patients were included in the study. The serum qAnti-HBc level was moderately correlated with ALT and AST levels (P < 0.001) in both hepatitis B e antigen-positive (HBeAg [+]) and HBeAg-negative (HBeAg [-]) CHB patients. CHB patients with no to mild inflammation (G0-1) had significantly lower serum qAnti-HBc levels than patients with moderate to severe inflammation (G2-4) (P < 0.001). Receiver operating characteristic analysis suggested that a serum qAnti-HBc cut-off value of 4.36 log10 IU/mL provided a sensitivity of 71.68%, specificity of 73.81%, positive predictive value of 78.43%, and negative predictive value of 66.24% in HBeAg (+) CHB patients with moderate to severe inflammation (G≥2). A cut-off value of 4.62 log10 IU/mL provided a sensitivity of 54.29%, specificity of 90.00%, positive predictive value of 95.00%, and negative predictive value of 36.00% in HBeAg (-) CHB patients with moderate to severe inflammation (G≥2). Serum qAnti-HBc levels were positively associated with liver inflammation grade. Furthermore, we identified optimal serum qAnti-HBc cut-off values for the prediction of inflammation activity in both HBeAg (+) and HBeAg (-) treatment-naïve CHB patients. PMID:27559949

  18. Experimental application of the Karhunen-Lo{grave e}ve decomposition to the study of modal interactions in a mechanical oscillator

    SciTech Connect

    Cusumano, J.P.

    1996-06-01

    The results of an experimental study of a magnetically-kicked flexible-beam oscillator are presented. The dynamics of the autonomous system are observed using nine strain gauges distributed along the length of the beam. The Karhunen-Lo{grave e}ve decomposition is used to study the dimensionality of the system in terms of modal interactions. Two modes which interact to produce the observed dynamics over a wide range of the system{close_quote}s bifurcation parameter are found. It is concluded that a two degree of freedom model is adequate to describe the observed steady-state phenomena. {copyright} {ital 1996 American Institute of Physics.}

  19. HIV-1 Antiretroviral Drug Resistance Mutations in Treatment Naïve and Experienced Panamanian Subjects: Impact on National Use of EFV-Based Schemes

    PubMed Central

    Mendoza, Yaxelis; Castillo Mewa, Juan; Martínez, Alexander A.; Zaldívar, Yamitzel; Sosa, Néstor; Arteaga, Griselda; Armién, Blas; Bautista, Christian T.; García-Morales, Claudia; Tapia-Trejo, Daniela; Ávila-Ríos, Santiago; Reyes-Terán, Gustavo; Bello, Gonzalo; Pascale, Juan M.

    2016-01-01

    The use of antiretroviral therapy in HIV infected subjects prevents AIDS-related illness and delayed occurrence of death. In Panama, rollout of ART started in 1999 and national coverage has reached 62.8% since then. The objective of this study was to determine the level and patterns of acquired drug resistance mutations of clinical relevance (ADR-CRM) and surveillance drug resistance mutations (SDRMs) from 717 HIV-1 pol gene sequences obtained from 467 ARV drug-experienced and 250 ARV drug-naïve HIV-1 subtypes B infected subjects during 2007–2013, respectively. The overall prevalence of SDRM and of ADR-CRM during the study period was 9.2% and 87.6%, respectively. The majority of subjects with ADR-CRM had a pattern of mutations that confer resistance to at least two classes of ARV inhibitors. The non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations K103N and P225H were more prevalent in both ARV drug-naïve and ARV drug-experienced subjects. The nucleoside reverse transcriptase inhibitor (NRTI) mutation M184V was more frequent in ARV drug-experienced individuals, while T215YFrev and M41L were more frequent in ARV drug-naïve subjects. Prevalence of mutations associated to protease inhibitors (PI) was lower than 4.1% in both types of subjects. Therefore, there is a high level of resistance (>73%) to Efavirenz/Nevirapine, Lamivudine and Azidothymidine in ARV drug-experienced subjects, and an intermediate to high level of resistance (5–10%) to Efavirenz/Nevirapine in ARV drug-naïve subjects. During the study period, we observed an increasing trend in the prevalence of ADR-CRM in subjects under first-line schemes, but not significant changes in the prevalence of SDRM. These results reinforce the paramount importance of a national surveillance system of ADR-CRM and SDRM for national management policies of subjects living with HIV. PMID:27119150

  20. Immunologic response in treatment-naïve HIV-2-infected patients: the IeDEA West Africa cohort

    PubMed Central

    Balestre, Eric; Ekouevi, Didier Koumavi; Tchounga, Boris; Eholie, Serge Paul; Messou, Eugène; Sawadogo, Adrien; Thiébaut, Rodolphe; May, Margaret T; Sterne, Jonathan Ac; Dabis, François

    2016-01-01

    Introduction Response to antiretroviral therapy (ART) among individuals infected with HIV-2 is poorly described. We compared the immunological response among patients treated with three nucleoside reverse-transcriptase inhibitors (NRTIs) to boosted protease inhibitor (PI) and unboosted PI-based regimens in West Africa. Methods This prospective cohort study enrolled treatment-naïve HIV-2-infected patients within the International Epidemiological Databases to Evaluate AIDS collaboration in West Africa. We used mixed models to compare the CD4 count response to treatment over 12 months between regimens. Results Of 422 HIV-2-infected patients, 285 (67.5%) were treated with a boosted PI-based regimen, 104 (24.6%) with an unboosted PI-based regimen and 33 (7.8%) with three NRTIs. Treatment groups were comparable with regard to gender (54.5% female) and median age at ART initiation (45.3 years; interquartile range 38.3 to 51.8). Treatment groups differed by clinical stage (21.2%, 16.8% and 17.3% at CDC Stage C or World Health Organization Stage IV for the triple NRTI, boosted PI and unboosted PI groups, respectively, p=0.02), median length of follow-up (12.9, 17.7 and 44.0 months for the triple NRTI, the boosted PI and the unboosted PI groups, respectively, p<0.001) and baseline median CD4 count (192, 173 and 129 cells/µl in the triple NRTI, the boosted PI and the unboosted PI-based regimen groups, respectively, p=0.003). CD4 count recovery at 12 months was higher for patients treated with boosted PI-based regimens than those treated with three NRTIs or with unboosted PI-based regimens (191 cells/µl, 95% CI 142 to 241; 110 cells/µl, 95% CI 29 to 192; 133 cells/µl, 95% CI 80 to 186, respectively, p=0.004). Conclusions In this observational study using African data, boosted PI-containing regimens had better immunological response compared to triple NRTI combinations and unboosted PI-based regimens at 12 months. A randomized clinical trial is still required to determine

  1. The KLT (Karhunen-Loève Transform) to extend SETI searches to broad-band and extremely feeble signals

    NASA Astrophysics Data System (ADS)

    Maccone, Claudio

    2010-12-01

    The KLT (acronym for Karhunen-Loève Transform) is a mathematical algorithm superior to the classical FFT in many regards: The KLT can filter signals out of the background noise over both wide and narrow bands. This is in sharp contrast to the FFT that rigorously applies to narrow-band signals only. The KLT can be applied to random functions that are non-stationary in time, i.e. whose autocorrelation is a function of the two independent variables t1 and t2 separately. Again, this is a sheer advantage of the KLT over the FFT, inasmuch as the FFT rigorously applies to stationary processes only, i.e. processes whose autocorrelation is a function of the absolute value of the difference of t1 and t2 only. The KLT can detect signals embedded in noise to unbelievably small values of the Signal-to-Noise Ratio (SNR), like 10 -3 or so. This particular feature of the KLT is studied in detail in this paper. An excellent filtering algorithm like the KLT, however, comes with a cost that one must be ready to pay for especially in SETI: its computational burden is much higher than for the FFT. In fact, it can be shown that no fast KLT transform can possibly exist and, for an autocorrelation matrix of size N, the calculations must be of the order of N2, rather than N log( N). Nevertheless, for moderate values of N (in the hundreds), the KLT dominates over the FFT, as shown by the numerical simulations. Finally, an important and recent (2007-2008) development in the KLT theory, called the "Bordered Autocorrelation Method" (BAM), is presented. This BAM-KLT method gets around the difficulty of the N2 brunt calculations and ends up in the following unexpected theorem: the KLT of a feeble sinusoidal carrier embedded into a lot of white stationary noise is given by the Fourier transform of the derivative of the largest KLT eigenvalue with respect to the bordering index. This basic result is fully proved analytically in the final sections of this paper by virtue of a new theorem

  2. Naïve Learners Show Cross-Domain Transfer after Distributional Learning: The Case of Lexical and Musical Pitch.

    PubMed

    Ong, Jia Hoong; Burnham, Denis; Stevens, Catherine J; Escudero, Paola

    2016-01-01

    Experienced listeners of a particular acoustic cue in either speech or music appear to have an advantage when perceiving a similar cue in the other domain (i.e., they exhibit cross-domain transfer). One explanation for cross-domain transfer relates to the acquisition of the foundations of speech and music: if acquiring pitch-based elements in speech or music results in heightened attention to pitch in general, then cross-domain transfer of pitch may be observed, which may explain the cross-domain phenomenon seen among listeners of a tone language and listeners with musical training. Here, we investigate this possibility in naïve adult learners, who were trained to acquire pitch-based elements using a distributional learning paradigm, to provide a proof-of-concept for the explanation. Learners were exposed to a stimulus distribution spanning either a Thai lexical tone minimal pair or a novel musical chord minimal pair. Within each domain, the distribution highlights pitch to facilitate learning of two different sounds (Bimodal distribution) or the distribution minimizes pitch so that the input is inferred to be from a single sound (Unimodal distribution). Learning was assessed before and after exposure to the distribution using discrimination tasks with both Thai tone and musical chord minimal pairs. We hypothesize: (i) distributional learning for learners in both the tone and the chord distributions, that is, pre-to-post improvement in discrimination after exposure to the Bimodal but not the Unimodal distribution; and (ii) for both the tone and chord conditions, learners in the Bimodal conditions but not those in the Unimodal conditions will show cross-domain transfer, as indexed by improvement in discrimination of test items in the domain other than what they were trained on. The results support both hypotheses, suggesting that distributional learning is not only used to acquire the foundations of speech and music, but may also play a role in cross

  3. Antibody and cellular immune responses of naïve mares to repeated vaccination with an inactivated equine herpesvirus vaccine.

    PubMed

    Wagner, B; Goodman, L B; Babasyan, S; Freer, H; Torsteinsdóttir, S; Svansson, V; Björnsdóttir, S; Perkins, G A

    2015-10-13

    Equine herpesvirus type 1 (EHV-1) continues to cause severe outbreaks of abortions or myeloencephalopathy in horses despite widely used vaccination. The aim of this work was to determine the effects of frequent vaccination with an inactivated EHV vaccine on immune development in horses. Fifteen EHV-1 naïve mares were vaccinated a total of 5 times over a period of 8 months with intervals of 20, 60, 90 and 60 days between vaccine administrations. Total antibody and antibody isotype responses were evaluated with a new sensitive EHV-1 Multiplex assay to glycoprotein C (gC) and gD for up to 14 months after initial vaccination. Antibodies peaked after the first two vaccine doses and then declined despite a third administration of the vaccine. The fourth vaccine dose was given at 6 months and the gC and gD antibody titers increased again. Mixed responses with increasing gC but decreasing gD antibody values were observed after the fifth vaccination at 8 months. IgG4/7 isotype responses mimicked the total Ig antibody production to vaccination most closely. Vaccination also induced short-lasting IgG1 antibodies to gC, but not to gD. EHV-1-specific cellular immunity induced by vaccination developed slower than antibodies, was dominated by IFN-γ producing T-helper 1 (Th1) cells, and was significantly increased compared to pre-vaccination values after administration of 3 vaccine doses. Decreased IFN-γ production and reduced Th1-cell induction were also observed after the second and fourth vaccination. Overall, repeated EHV vaccine administration did not always result in increasing immunity. The adverse effects on antibody and cellular immunity that were observed here when the EHV vaccine was given in short intervals might in part explain why EHV-1 outbreaks are observed worldwide despite widely used vaccination. The findings warrant further evaluation of immune responses to EHV vaccines to optimize vaccination protocols for different vaccines and horse groups at risk. PMID

  4. Knocking on Heaven's Door: Are Novel Invaders Necessarily Facing Naïve Native Species on Islands?

    PubMed Central

    Gérard, Agathe; Jourdan, Hervé; Millon, Alexandre; Vidal, Eric

    2016-01-01

    The impact of alien predator species on insular native biota has often been attributed to island prey naïveté (i.e. lack of, or inefficient, anti-predator behavior). Only rarely, however, has the concept of island prey naïveté been tested, and then only a posteriori (i.e. hundreds or thousands of years after alien species introduction). The presence of native or anciently introduced predators or competitors may be crucial for the recognition and development of adaptive behavior toward unknown predators or competitors of the same archetype (i.e. a set of species that occupy a similar ecological niche and show similar morphological and behavioral traits when interacting with other species). Here, we tested whether two squamates endemic to New Caledonia, a skink, Caledoniscincus austrocaledonicus, and a gecko, Bavayia septuiclavis, recognized and responded to the odor of two major invaders introduced into the Pacific islands, but not yet into New Caledonia. We chose one predator, the small Indian mongoose Herpestes javanicus and one competitor, the cane toad Rhinella marina, which belong respectively to the same archetype as the following two species already introduced into New Caledonia in the nineteenth century: the feral cat Felis catus and the golden bell frog Litoria aurea. Our experiment reveals that geckos are naïve with respect to the odors of both an unknown predator and an unknown competitor, as well as to the odors of a predator and a competitor they have lived with for centuries. In contrast, skinks seem to have lost some naïveté regarding the odor of a predator they have lived with for centuries and seem “predisposed” to avoid the odor of an unknown potential competitor. These results indicate that insular species living in contact with invasive alien species for centuries may be, although not systematically, predisposed toward developing adaptive behavior with respect to species belonging to the same archetype and introduced into their native

  5. Naïve Learners Show Cross-Domain Transfer after Distributional Learning: The Case of Lexical and Musical Pitch

    PubMed Central

    Ong, Jia Hoong; Burnham, Denis; Stevens, Catherine J.; Escudero, Paola

    2016-01-01

    Experienced listeners of a particular acoustic cue in either speech or music appear to have an advantage when perceiving a similar cue in the other domain (i.e., they exhibit cross-domain transfer). One explanation for cross-domain transfer relates to the acquisition of the foundations of speech and music: if acquiring pitch-based elements in speech or music results in heightened attention to pitch in general, then cross-domain transfer of pitch may be observed, which may explain the cross-domain phenomenon seen among listeners of a tone language and listeners with musical training. Here, we investigate this possibility in naïve adult learners, who were trained to acquire pitch-based elements using a distributional learning paradigm, to provide a proof-of-concept for the explanation. Learners were exposed to a stimulus distribution spanning either a Thai lexical tone minimal pair or a novel musical chord minimal pair. Within each domain, the distribution highlights pitch to facilitate learning of two different sounds (Bimodal distribution) or the distribution minimizes pitch so that the input is inferred to be from a single sound (Unimodal distribution). Learning was assessed before and after exposure to the distribution using discrimination tasks with both Thai tone and musical chord minimal pairs. We hypothesize: (i) distributional learning for learners in both the tone and the chord distributions, that is, pre-to-post improvement in discrimination after exposure to the Bimodal but not the Unimodal distribution; and (ii) for both the tone and chord conditions, learners in the Bimodal conditions but not those in the Unimodal conditions will show cross-domain transfer, as indexed by improvement in discrimination of test items in the domain other than what they were trained on. The results support both hypotheses, suggesting that distributional learning is not only used to acquire the foundations of speech and music, but may also play a role in cross

  6. Do patients with active RA have differences in disease activity and perceptions if anti-TNF naïve versus anti-TNF experienced? Baseline results of the optimization of adalimumab trial

    PubMed Central

    Pope, Janet; Thorne, J. Carter; Haraoui, Boulos Paul; Psaradellis, Eliofotisti; Sampalis, John

    2012-01-01

    Summary Background The chance of a good response in RA is attenuated in previous anti-TNF users who start new anti-TNF therapy compared to biologic naïve patients. In active RA, those with previous anti-TNF exposure compared to anti-TNF naïve may have different baseline disease activity and patient perceptions when starting a new anti-TNF treatment that could explain the observed response differences. Material/Methods The aim of this study was a post hoc analysis of baseline characteristics of patients enrolled in the Optimization of Adalimumab study that was a treat to target vs. routine care study in patients initiating adalimumab. As per the protocol, a maximum of 20% anti-TNF experienced patients were enrolled in the 300 patient trial. Twelve (4.0%) were excluded who previously used other biologics. Baseline characteristics including age, gender, tender and swollen joint counts, disease activity (DAS28), function (HAQ-DI), patient global assessment, patient satisfaction with current treatment, and inflammatory markers (CRP, ESR), were compared between previously anti-TNF experienced [etanercept or infliximab (EXP)], and anti-TNF naïve patients (NAÏVE). Results The mean (SD) age was 54.8 (13.3) years; 81.0% were female, and 237 (79.0%) were anti-TNF naïve while 51 (17.0%) patients were anti-TNF experienced (29 with etanercept, 16 with infliximab, and 6 for both). The mean (SD) baseline in EXP versus NAÏVE groups respectively was: CRP=21.7(32.9) vs. 17.5(20.7); ESR=28.7(22.5) vs. 29.8(20.4); SJC=10.5(6.0) vs. 10.7(5.6); TJC=12.8(7.1) vs. 12.3(7.3); and DAS28=6.0(1.2) vs. 5.8(1.1). None of the between-group differences were statistically significant, however, the HAQ-DI in EXP was 1.7(0.6) compared to 1.5(0.7) for the NAÏVE (P=0.021). Additionally, EXP patients had a higher patient global score [71.3(26.1) vs. 61.9(26.2), P=0.021]. Conclusions Although anti-TNF naïve and experienced patients who initiated adalimumab were similar, with respect to several

  7. Chilades pandava mothers discriminate among Cycas species during oviposition choice tests, but only in an endemic naïve population.

    PubMed

    Marler, Thomas E; Lindström, Anders J; Marler, Paris N

    2016-08-01

    Host and non-host plant species communicate with insect herbivores to influence oviposition decisions. We studied if Chilades pandava female adults expressed oviposition preferences among host Cycas species in 2 choice tests, counting 39,420 eggs among assays from 4 butterfly populations. A naïve butterfly population from Cycas nongnoochiae habitat oviposited 2.2-fold more eggs on leaves of Cycas species that are susceptible to butterfly herbivory than on leaves of its native host Cycas nongnoochiae. In contrast, Chilades pandava populations experienced with novel Cycas species in Thailand, Philippines, and Guam exhibited no preference in choice tests between leaves of susceptible versus leaves of minimally damaged Cycas species. The results indicated that oviposition deterrents and/or stimulants partly mediate the sustainable relationship between an endemic Cycas species and the naïve Chilades pandava population from its habitat. Alternatively, differences in infochemicals among Cycas species do not enable discrimination in oviposition choices for Chilades pandava populations that have experienced Cycas species exhibiting no evolutionary history with Chilades pandava. PMID:27391307

  8. Ginkgolide B Inhibits JAM-A, Cx43, and VE-Cadherin Expression and Reduces Monocyte Transmigration in Oxidized LDL-Stimulated Human Umbilical Vein Endothelial Cells

    PubMed Central

    Liu, Xueqing; Sun, Wenjia; Zhao, Yanyang; Chen, Beidong; Wu, Wei; Bao, Li; Qi, Ruomei

    2015-01-01

    Aim. To investigate the effect of ginkgolide B on junction proteins and the reduction of monocyte migration in oxidized low-density lipoprotein- (ox-LDL-) treated endothelial cells. Methods. Human umbilical vein endothelial cells (HUVECs) were used in the present study. Immunofluorescence and Western blot were performed to determine the expression of junctional adhesion molecule-A (JAM-A), connexin 43 (Cx43), and vascular endothelial cadherin (VE-cadherin). Monocyte migration was detected by the Transwell assay. Results. ox-LDL stimulation increased JAM-A expression by 35%, Cx43 expression by 24%, and VE-cadherin expression by 37% in HUVECs. Ginkgolide B (0.2, 0.4, and 0.6 mg/mL) dose-dependently abolished the expression of these junction proteins. The monocyte transmigration experiments showed that the level of monocyte migration was sixfold higher in the ox-LDL-treated group than in the control group. Ginkgolide B (0.6 mg/mL) nearly completely abolished monocyte migration. Both ginkgolide B and LY294002 suppressed Akt phosphorylation and the expression of these junction proteins in ox-LDL-treated endothelial cells. These results suggest that the ginkgolide B-induced inhibition of junction protein expression is associated with blockade of the PI3K/Akt pathway. Conclusion. Ginkgolide B suppressed junction protein expression and reduced monocyte transmigration that was induced by ox-LDL. Ginkgolide B may improve vascular permeability in atherosclerosis. PMID:26246869

  9. Telomere elongation and naïve pluripotent stem cells achieved from telomerase haplo-insufficient cells by somatic cell nuclear transfer

    PubMed Central

    Sung, Li-Ying; Chang, Wei-Fang; Zhang, Qian; Liu, Chia-Chia; Liou, Jun-Yang; Chang, Chia-Chun; Ou-Yang, Huan; Guo, Renpeng; Fu, Haifeng; Cheng, Winston T.K.; Ding, Shih-Torng; Chen, Chuan-Mu; Okuka, Maja; Keefe, David L; Chen, Y. Eugene; Liu, Lin; Xu, Jie

    2014-01-01

    Haplo-insufficiency of telomerase genes in humans leads to telomere syndromes such as dyskeratosis congenital and idiopathic pulmonary fibrosis. Generation of pluripotent stem cells from telomerase haplo-insufficient donor cells would provide unique opportunities towards the realization of patient-specific stem cell therapies. Recently, pluripotent human embryonic stem cells (ntESCs) have been efficiently achieved by somatic cell nuclear transfer (SCNT). We tested the hypothesis that SCNT could effectively elongate shortening telomeres of telomerase haplo-insufficient cells in the ntESCs using relevant mouse models. Indeed, telomeres of telomerase haplo-insufficient (Terc+/−) mouse cells are elongated in ntESCs. Moreover, ntESCs derived from Terc+/− cells exhibit naïve pluripotency as evidenced by generation of Terc+/−ntESC clone pups by tetraploid embryo complementation (TEC), the most stringent test of naïve pluripotency. These data suggest that SCNT could offer a powerful tool to reprogram telomeres and to discover the factors for robust restoration of telomeres and pluripotency of telomerase haplo-insufficient somatic cells. PMID:25464850

  10. Raltegravir and Abacavir/Lamivudine in Japanese Treatment-Naïve and Treatment-Experienced Patients with HIV Infection: a 48-Week Retrospective Pilot Analysis.

    PubMed

    Suzuki, Akihito; Uehara, Yuki; Saita, Mizue; Inui, Akihiro; Isonuma, Hiroshi; Naito, Toshio

    2016-01-01

    Abacavir/lamivudine (ABC/3TC) is a nucleoside reverse transcriptase inhibitor used for treating human immunodeficiency viral (HIV) infections. Hypersensitivity reactions such as skin eruptions caused by ABC are well-known, but rarely occur in Asians. Raltegravir (RAL) is an integrase strand transfer inhibitor, that is now increasingly, used for treating HIV infections because it has few adverse effects. This retrospective analysis assessed the efficacy and safety of combined ABC/3TC and RAL in both treatment-naïve and -experienced Japanese patients with HIV infections. In all 11 treatment-naïve patients (100%), virological suppression to undetectable level was achieved. Liver transaminases, renal function, and serum lipid profiles showed no exacerbations up to 48 weeks of treatment. In 12 patients who were switched from previous regimens to ABC/3TC and RAL, HIV viral load was undetectable in 11 patients (91.6%), but remained detectable in 1 patient with poor adherence. Major reasons for switching regimens to ABC/3TC and RAL were hyperlipidemia and nausea. After switching, these adverse effects improved, and no new adverse effects were observed. Despite the small number of participants in this study, the results support the combination of ABC/3TC and RAL as a possible treatment choice in Japanese individuals with HIV-infection. PMID:25971320

  11. TCR sequences and tissue distribution discriminate the subsets of naïve and activated/memory Treg cells in mice.

    PubMed

    Bergot, Anne-Sophie; Chaara, Wahiba; Ruggiero, Eliana; Mariotti-Ferrandiz, Encarnita; Dulauroy, Sophie; Schmidt, Manfred; von Kalle, Christof; Six, Adrien; Klatzmann, David

    2015-05-01

    Analyses of the regulatory T (Treg) cell TCR repertoire should help elucidate the nature and diversity of their cognate antigens and thus how Treg cells protect us from autoimmune diseases. We earlier identified CD44(hi) CD62L(low) activated/memory (am) Treg cells as a Treg-cell subset with a high turnover and possible self-specificity. We now report that amTreg cells are predominantly distributed in lymph nodes (LNs) draining deep tissues. Multivariate analyses of CDR3 spectratyping first revealed that amTreg TCR repertoire is different from that of naïve Treg cells (nTreg cells) and effector T (Teff) cells. Furthermore, in deep- versus superficial LNs, TCR-β deep sequencing further revealed diversified nTreg-cell and amTreg-cell repertoires, although twofold less diverse than that of Teff cells, and with repertoire richness significantly lower in deep-LN versus superficial-LN Treg cells. Importantly, expanded clonotypes were mostly detected in deep-LN amTreg cells, some accounting for 20% of the repertoire. Strikingly, these clonotypes were absent from nTreg cells, but found at low frequency in Teff cells. Our results, obtained in nonmanipulated mice, indicate different antigenic targets for naïve and amTreg cells and that amTreg cells are self-specific. The data we present are consistent with an instructive component in Treg-cell differentiation. PMID:25726757

  12. Naïve adult stem cells from patients with Hutchinson-Gilford progeria syndrome express low levels of progerin in vivo.

    PubMed

    Wenzel, Vera; Roedl, Daniela; Gabriel, Diana; Gordon, Leslie B; Herlyn, Meenhard; Schneider, Reinhard; Ring, Johannes; Djabali, Karima

    2012-06-15

    Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare disorder characterized by segmental accelerated aging and early death from coronary artery disease or stroke. Nearly 90% of HGPS sufferers carry a G608G mutation within exon 11 of LMNA, producing a truncated form of prelamin A, referred to as "progerin". Here, we report the isolation of naïve multipotent skin-derived precursor (SKP) cells from dermal fibroblast cultures from HGPS donors. These cells form spheres and express the neural crest marker, nestin, in addition to the multipotent markers, OCT4, Sox2, Nanog and TG30; these cells can self-renew and differentiate into smooth muscle cells (SMCs) and fibroblasts. The SMCs derived from the HGPS-SKPs accumulate nuclear progerin with increasing passages. A subset of the HGPS-naïve SKPs express progerin in vitro and in situ in HGPS skin sections. This is the first in vivo evidence that progerin is produced in adult stem cells, and implies that this protein could induce stem cells exhaustion as a mechanism contributing to aging. Our study provides a basis on which to explore therapeutic applications for HGPS stem cells and opens avenues for investigating the pathogenesis of other genetic diseases. PMID:23213444

  13. Wood identification of Dalbergia nigra (CITES Appendix I) using quantitative wood anatomy, principal components analysis and naïve Bayes classification

    PubMed Central

    Gasson, Peter; Miller, Regis; Stekel, Dov J.; Whinder, Frances; Ziemińska, Kasia

    2010-01-01

    Background and Aims Dalbergia nigra is one of the most valuable timber species of its genus, having been traded for over 300 years. Due to over-exploitation it is facing extinction and trade has been banned under CITES Appendix I since 1992. Current methods, primarily comparative wood anatomy, are inadequate for conclusive species identification. This study aims to find a set of anatomical characters that distinguish the wood of D. nigra from other commercially important species of Dalbergia from Latin America. Methods Qualitative and quantitative wood anatomy, principal components analysis and naïve Bayes classification were conducted on 43 specimens of Dalbergia, eight D. nigra and 35 from six other Latin American species. Key Results Dalbergia cearensis and D. miscolobium can be distinguished from D. nigra on the basis of vessel frequency for the former, and ray frequency for the latter. Principal components analysis was unable to provide any further basis for separating the species. Naïve Bayes classification using the four characters: minimum vessel diameter; frequency of solitary vessels; mean ray width; and frequency of axially fused rays, classified all eight D. nigra correctly with no false negatives, but there was a false positive rate of 36·36 %. Conclusions Wood anatomy alone cannot distinguish D. nigra from all other commercially important Dalbergia species likely to be encountered by customs officials, but can be used to reduce the number of specimens that would need further study. PMID:19884155

  14. The VeTOOLS Project: an example of how to strengthen collaboration between scientists and Civil Protections in disaster risk reduction

    NASA Astrophysics Data System (ADS)

    Marti, Joan; Bartolini, Stefania; Becerril, Laura

    2016-04-01

    VeTOOLS is a project funded by the European Commission's Humanitarian Aid and Civil Protection department (ECHO), and aims at creating an integrated software platform specially designed to assess and manage volcanic risk. The project facilitates interaction and cooperation between scientists and Civil Protection Agencies in order to share, unify, and exchange procedures, methodologies and technologies to effectively reduce the impacts of volcanic disasters. The project aims at 1) improving and developing volcanic risk assessment and management capacities in active volcanic regions; 2) developing universal methodologies, scenario definitions, response strategies and alert protocols to cope with the full range of volcanic threats; 4) improving quantitative methods and tools for vulnerability and risk assessment; and 5) defining thresholds and protocols for civil protection. With these objectives, the VeTOOLS project points to two of the Sendai Framework resolutions for implementing it: i) Provide guidance on methodologies and standards for risk assessments, disaster risk modelling and the use of data; ii) Promote and support the availability and application of science and technology to decision-making, and offers a good example on how a close collaboration between science and civil protection is an effective way to contribute to DRR. European Commission ECHO Grant SI2.695524

  15. Activation Outcomes Induced in Naïve CD8 T-Cells by Macrophages Primed via “Phagocytic” and Nonphagocytic Pathways

    PubMed Central

    Olazabal, Isabel María; Martín-Cofreces, Noa Beatriz; Mittelbrunn, María; Martínez del Hoyo, Gloria; Alarcón, Balbino

    2008-01-01

    The array of phagocytic receptors expressed by macrophages make them very efficient at pathogen clearance, and the phagocytic process links innate with adaptive immunity. Primary macrophages modulate antigen cross-presentation and T-cell activation. We assessed ex vivo the putative role of different phagocytic receptors in immune synapse formation with CD8 naïve T-cells from OT-I transgenic mice and compared this with the administration of antigen as a soluble peptide. Macrophages that have phagocytosed antigen induce T-cell microtubule-organizing center and F-actin cytoskeleton relocalization to the contact site, as well as the recruitment of proximal T-cell receptor signals such as activated Vav1 and PKCθ. At the same doses of loaded antigen (1 μM), “phagocytic” macrophages were more efficient than peptide-antigen–loaded macrophages at forming productive immune synapses with T-cells, as indicated by active T-cell TCR/CD3 conformation, LAT phosphorylation, IL-2 production, and T-cell proliferation. Similar T-cell proliferation efficiency was obtained when low doses of soluble peptide (3–30 nM) were loaded on macrophages. These results suggest that the pathway used for antigen uptake may modulate the antigen density presented on MHC-I, resulting in different signals induced in naïve CD8 T-cells, leading either to CD8 T-cell activation or anergy. PMID:18077558

  16. A practical tool for public health surveillance: Semi-automated coding of short injury narratives from large administrative databases using Naïve Bayes algorithms.

    PubMed

    Marucci-Wellman, Helen R; Lehto, Mark R; Corns, Helen L

    2015-11-01

    Public health surveillance programs in the U.S. are undergoing landmark changes with the availability of electronic health records and advancements in information technology. Injury narratives gathered from hospital records, workers compensation claims or national surveys can be very useful for identifying antecedents to injury or emerging risks. However, classifying narratives manually can become prohibitive for large datasets. The purpose of this study was to develop a human-machine system that could be relatively easily tailored to routinely and accurately classify injury narratives from large administrative databases such as workers compensation. We used a semi-automated approach based on two Naïve Bayesian algorithms to classify 15,000 workers compensation narratives into two-digit Bureau of Labor Statistics (BLS) event (leading to injury) codes. Narratives were filtered out for manual review if the algorithms disagreed or made weak predictions. This approach resulted in an overall accuracy of 87%, with consistently high positive predictive values across all two-digit BLS event categories including the very small categories (e.g., exposure to noise, needle sticks). The Naïve Bayes algorithms were able to identify and accurately machine code most narratives leaving only 32% (4853) for manual review. This strategy substantially reduces the need for resources compared with manual review alone. PMID:26412196

  17. ve-SEQ: Robust, unbiased enrichment for streamlined detection and whole-genome sequencing of HCV and other highly diverse pathogens

    PubMed Central

    Trebes, Amy; Brown, Anthony; Klenerman, Paul; Buck, David; Piazza, Paolo; Barnes, Eleanor; Bowden, Rory

    2015-01-01

    The routine availability of high-depth virus sequence data would allow the sensitive detection of resistance-associated variants that can jeopardize HIV or hepatitis C virus (HCV) treatment. We introduce ve-SEQ, a high-throughput method for sequence-specific enrichment and characterization of whole-virus genomes at up to 20% divergence from a reference sequence and 1,000-fold greater sensitivity than direct sequencing. The extreme genetic diversity of HCV led us to implement an algorithm for the efficient design of panels of oligonucleotide probes to capture any sequence among a defined set of targets without detectable bias. ve-SEQ enables efficient detection and sequencing of any HCV genome, including mixtures and intra-host variants, in a single experiment, with greater tolerance of sequence diversity than standard amplification methods and greater sensitivity than metagenomic sequencing, features that are directly applicable to other pathogens or arbitrary groups of target organisms, allowing the combination of sensitive detection with sequencing in many settings. PMID:27092241

  18. Tumor-associated mesenchymal stem cells inhibit naïve T cell expansion by blocking cysteine export from dendritic cells.

    PubMed

    Ghosh, Tithi; Barik, Subhasis; Bhuniya, Avishek; Dhar, Jesmita; Dasgupta, Shayani; Ghosh, Sarbari; Sarkar, Madhurima; Guha, Ipsita; Sarkar, Koustav; Chakrabarti, Pinak; Saha, Bhaskar; Storkus, Walter J; Baral, Rathindranath; Bose, Anamika

    2016-11-01

    Mesenchymal stem cells (MSCs) represent an important cellular constituent of the tumor microenvironment, which along with tumor cells themselves, serve to regulate protective immune responses in support of progressive disease. We report that tumor MSCs prevent the ability of dendritic cells (DC) to promote naïve CD4(+) and CD8(+) T cell expansion, interferon gamma secretion and cytotoxicity against tumor cells, which are critical to immune-mediated tumor eradication. Notably, tumor MSCs fail to prevent DC-mediated early T cell activation events or the ability of responder T cells to produce IL-2. The immunoregulatory activity of tumor MSCs is IL-10- and STAT3-dependent, with STAT3 repressing DC expression of cystathionase, a critical enzyme that converts methionine-to-cysteine. Under cysteine-deficient priming conditions, naïve T cells exhibit defective cellular metabolism and proliferation. Bioinformatics analyses as well as in vitro observations suggest that STAT3 may directly bind to a GAS-like motif within the cystathionase promoter (-269 to -261) leading to IL-10-STAT3 mediated repression of cystathionase gene transcription. Our collective results provide evidence for a novel mechanism of tumor MSC-mediated T cell inhibition within tumor microenvironment. PMID:27405489

  19. The RNA-binding protein quaking maintains endothelial barrier function and affects VE-cadherin and β-catenin protein expression

    PubMed Central

    de Bruin, Ruben G.; van der Veer, Eric P.; Prins, Jurriën; Lee, Dae Hyun; Dane, Martijn J. C.; Zhang, Huayu; Roeten, Marko K.; Bijkerk, Roel; de Boer, Hetty C.; Rabelink, Ton J.; van Zonneveld, Anton Jan; van Gils, Janine M.

    2016-01-01

    Proper regulation of endothelial cell-cell contacts is essential for physiological functioning of the endothelium. Interendothelial junctions are actively involved in the control of vascular leakage, leukocyte diapedesis, and the initiation and progression of angiogenesis. We found that the RNA-binding protein quaking is highly expressed by endothelial cells, and that its expression was augmented by prolonged culture under laminar flow and the transcription factor KLF2 binding to the promoter. Moreover, we demonstrated that quaking directly binds to the mRNA of VE-cadherin and β-catenin and can induce mRNA translation mediated by the 3′UTR of these genes. Reduced quaking levels attenuated VE-cadherin and β-catenin expression and endothelial barrier function in vitro and resulted in increased bradykinin-induced vascular leakage in vivo. Taken together, we report that quaking is essential in maintaining endothelial barrier function. Our results provide novel insight into the importance of post-transcriptional regulation in controlling vascular integrity. PMID:26905650

  20. The RNA-binding protein quaking maintains endothelial barrier function and affects VE-cadherin and β-catenin protein expression.

    PubMed

    de Bruin, Ruben G; van der Veer, Eric P; Prins, Jurriën; Lee, Dae Hyun; Dane, Martijn J C; Zhang, Huayu; Roeten, Marko K; Bijkerk, Roel; de Boer, Hetty C; Rabelink, Ton J; van Zonneveld, Anton Jan; van Gils, Janine M

    2016-01-01

    Proper regulation of endothelial cell-cell contacts is essential for physiological functioning of the endothelium. Interendothelial junctions are actively involved in the control of vascular leakage, leukocyte diapedesis, and the initiation and progression of angiogenesis. We found that the RNA-binding protein quaking is highly expressed by endothelial cells, and that its expression was augmented by prolonged culture under laminar flow and the transcription factor KLF2 binding to the promoter. Moreover, we demonstrated that quaking directly binds to the mRNA of VE-cadherin and β-catenin and can induce mRNA translation mediated by the 3'UTR of these genes. Reduced quaking levels attenuated VE-cadherin and β-catenin expression and endothelial barrier function in vitro and resulted in increased bradykinin-induced vascular leakage in vivo. Taken together, we report that quaking is essential in maintaining endothelial barrier function. Our results provide novel insight into the importance of post-transcriptional regulation in controlling vascular integrity. PMID:26905650

  1. Serum Insulin-Like Growth Factor-1 in Patients with De Novo, Drug Naïve Parkinson’s Disease: A Meta-Analysis

    PubMed Central

    Quinn, Thomas J.; Liu, Jun

    2015-01-01

    Objective Insulin-like growth factor-1 (IGF-1) is reported to be neuroprotective in the setting of Parkinson’s disease (PD), and there is increasing interest in the possible association of serum IGF-1 levels with PD patients, but with conflicting results. Therefore, we conducted a meta-analysis to evaluate the association of serum IGF-1 levels in de novo, drug naïve PD patients compared with healthy controls. Methods Pubmed, ISI Web of Science, OVID, EMBASE, and Cochrane library databases from 1966 to October 2014 were utilized to identify candidate studies using Medical Subjective Headings without language restriction. A random-effects model was chosen, with subgroup analysis and sensitivity analysis conducted to reveal underlying heterogeneity among the included studies. Results In this meta-analysis, we found that PD patients had higher serum IGF-1 levels compared with healthy controls (summary mean difference [MD] = 17.75, 95%CI = 6.01, 29.48). Subgroup analysis demonstrated that the source of heterogeneity was population differences within the total group. Sensitivity analysis showed that the combined MD was consistent at any time omitting any one study. Conclusions The results of this meta-analysis demonstrate that serum IGF-1 levels were significantly higher in de novo, drug-naïve PD patients compared with healthy controls. Nevertheless, additional endeavors are required to further explore the association between serum IGF-1 levels and diagnosis, prognosis and early therapy for PD. PMID:26657015

  2. Anti-thymocyte globulin (ATG) differentially depletes naïve and memory T cells and permits memory-type regulatory T cells in nonobese diabetic mice

    PubMed Central

    2012-01-01

    Background ATG has been employed to deplete T cells in several immune-mediated conditions. However, whether ATG administration affects naïve and memory T cell differently is largely unknown. The context and purpose of the study In this study, we assessed how murine ATG therapy affected T cell subsets in NOD mice, based on their regulatory and naïve or memory phenotype, as well as its influence on antigen-specific immune responses. Results Peripheral blood CD4+ and CD8+ T cells post-ATG therapy declined to their lowest levels at day 3, while CD4+ T cells returned to normal levels more rapidly than CD8+ T cells. ATG therapy failed to eliminate antigen-primed T cells. CD4+ T cell responses post-ATG therapy skewed to T helper type 2 (Th2) and possibly IL-10-producing T regulatory type 1 (Tr1) cells. Intriguingly, Foxp3+ regulatory T cells (Tregs) were less sensitive to ATG depletion and remained at higher levels following in vivo recovery compared to controls. Of note, the frequency of Foxp3+ Tregs with memory T cell phenotype was significantly increased in ATG-treated animals. Conclusion ATG therapy may modulate antigen-specific immune responses through inducing memory-like regulatory T cells as well as other protective T cells such as Th2 and IL-10-producing Tr1 cells. PMID:23237483

  3. An explanatory analysis of driver injury severity in rear-end crashes using a decision table/Naïve Bayes (DTNB) hybrid classifier.

    PubMed

    Chen, Cong; Zhang, Guohui; Yang, Jinfu; Milton, John C; Alcántara, Adélamar Dely

    2016-05-01

    Rear-end crashes are a major type of traffic crashes in the U.S. Of practical necessity is a comprehensive examination of its mechanism that results in injuries and fatalities. Decision table (DT) and Naïve Bayes (NB) methods have both been used widely but separately for solving classification problems in multiple areas except for traffic safety research. Based on a two-year rear-end crash dataset, this paper applies a decision table/Naïve Bayes (DTNB) hybrid classifier to select the deterministic attributes and predict driver injury outcomes in rear-end crashes. The test results show that the hybrid classifier performs reasonably well, which was indicated by several performance evaluation measurements, such as accuracy, F-measure, ROC, and AUC. Fifteen significant attributes were found to be significant in predicting driver injury severities, including weather, lighting conditions, road geometry characteristics, driver behavior information, etc. The extracted decision rules demonstrate that heavy vehicle involvement, a comfortable traffic environment, inferior lighting conditions, two-lane rural roadways, vehicle disabled damage, and two-vehicle crashes would increase the likelihood of drivers sustaining fatal injuries. The research limitations on data size, data structure, and result presentation are also summarized. The applied methodology and estimation results provide insights for developing effective countermeasures to alleviate rear-end crash injury severities and improve traffic system safety performance. PMID:26928291

  4. The inversion layer at the tropopause of the Venus atmosphere: new insights from the Radio Science Experiment (VeRa) onboard Venus Express

    NASA Astrophysics Data System (ADS)

    Herrmann, M.; Oschlisniok, J.; Remus, S.; Tellmann, S.; Häusler, B.; Pätzold, M.

    2015-10-01

    The inversion layer at the tropopause of the Venus atmosphere is a very common and prominent feature in the vertical temperature profile at higher latitudes. The inversion layer is of particular interest because it separates the stratified troposphere from the highly variable mesosphere. The altitude range of the inversion layer is therefore a likely location for the formation of gravity waves [1]. The Radio Science Experiment (VeRa) onboard Venus Express [2,3] is capable to sound the Venus atmosphere from 100 km downward to 40 km [4,5] and delivered more than 800 vertical profiles of temperature, pressure and neutral number density at almost all local times and latitudes. The tropopause is typically located at 60 km altitude. Spatial changes of the refractive index over a short altitude range lead to multi-path effects which cannot be fully retrieved with common closed-loop recording methods. The development of a new data processing tool based on VeRa open loop data sets provided the necessary frequency resolution to fully resolve multipath effects occurring along a short range of 2 km at the tropopause location. The inversion layer presents itself up to 15K colder than commonly thought. The new results shall help to find a consistent picture of the Venus' thermal atmosphere structure and therefore help to improve atmospheric models.

  5. Inability to demonstrate fish-to-fish transmission of Ichthyophonus from laboratory infected Pacific herring Clupea pallasii to naïve conspecifics

    USGS Publications Warehouse

    Gregg, J.L.; Grady, C.A.; Friedman, C.S.; Hershberger, P.K.

    2012-01-01

    The parasite Ichthyophonus is enzootic in many marine fish populations of the northern Atlantic and Pacific Oceans. Forage fishes are a likely source of infection for higher trophic level predators; however, the processes that maintain Ichthyophonus in forage fish populations (primarily clupeids) are not well understood. Lack of an identified intermediate host has led to the convenient hypothesis that the parasite can be maintained within populations of schooling fishes by waterborne fish-to-fish transmission. To test this hypothesis we established Ichthyophonus infections in Age-1 and young-of-the-year (YOY) Pacific herring Clupea pallasii (Valenciennes) via intraperitoneal (IP) injection and cohabitated these donors with naïve conspecifics (sentinels) in the laboratory. IP injections established infection in 75 to 84% of donor herring, and this exposure led to clinical disease and mortality in the YOY cohort. However, after cohabitation for 113 d no infections were detected in naïve sentinels. These data do not preclude the possibility of fish-to-fish transmission, but they do suggest that other transmission processes are necessary to maintain Ichthyophonus in wild Pacific herring populations.

  6. Work and power reduced in L-dopa naïve patients in the early-stages of Parkinson's disease.

    PubMed

    Lima, Lidiane Oliveira; Cardoso, Francisco; Teixeira-Salmela, Luci Fuscaldi; Rodrigues-de-Paula, Fátima

    2016-04-01

    Studies which have investigated muscular performance during the initial stages of Parkinson´s disease (PD) without L-dopa treatments were not found. Objective to assess whether muscular performance, work and power, of the trunk and lower limbs in L-dopa naïve patients in the early stages of PD was lower than those of healthy subjects and to compare muscular performance between the lower limbs. Method Ten subjects with PD, Hoehn and Yahr (HY) I-II, L-dopa naïve and 10 subjects in the control group were assessed with the isokinetic dynamometer. Results ANOVAs revealed that work and power measures of the trunk, hip, knee, and ankle muscular groups were lower in PD compared with the control group (p < 0.05). There were no significant differences in muscular performance between the lower limbs. Conclusion The results suggested the use of specific exercises, as rehabilitation strategies, to improve the ability to produce work and power with this population. PMID:27097000

  7. Long-term efficacy and safety results of taliglucerase alfa up to 36 months in adult treatment-naïve patients with Gaucher disease.

    PubMed

    Zimran, Ari; Durán, Gloria; Mehta, Atul; Giraldo, Pilar; Rosenbaum, Hanna; Giona, Fiorina; Amato, Dominick J; Petakov, Milan; Muñoz, Eduardo Terreros; Solorio-Meza, Sergio Eduardo; Cooper, Peter A; Varughese, Sheeba; Chertkoff, Raul; Brill-Almon, Einat

    2016-07-01

    Taliglucerase alfa is an intravenous enzyme replacement therapy approved for treatment of type 1 Gaucher disease (GD), and is the first available plant cell-expressed recombinant therapeutic protein. Herein, we report long-term safety and efficacy results of taliglucerase alfa in treatment-naïve adult patients with GD. Patients were randomized to receive taliglucerase alfa 30 or 60 U/kg every other week, and 23 patients completed 36 months of treatment. Taliglucerase alfa (30 U/kg; 60 U/kg, respectively) resulted in mean decreases in spleen volume (50.1%; 64.6%) and liver volume (25.6%; 24.4%) with mean increases in hemoglobin concentration (16.0%; 35.8%) and platelet count (45.7%; 114.0%), and mean decreases in chitotriosidase activity (71.5%; 82.2%). All treatment-related adverse events were mild to moderate in intensity and transient. The most common adverse events were nasopharyngitis, arthralgia, upper respiratory tract infection, headache, pain in extremity, and hypertension. These 36-month results of taliglucerase alfa in treatment-naïve adult patients with GD demonstrate continued improvement in disease parameters with no new safety concerns. These findings extend the taliglucerase alfa clinical safety and efficacy dataset. www.clinicaltrials.gov identifier NCT00705939. Am. J. Hematol. 91:656-660, 2016. © 2016 Wiley Periodicals, Inc. PMID:27174694

  8. Rasgrp1 mutation increases naïve T-cell CD44 expression and drives mTOR-dependent accumulation of Helios+ T cells and autoantibodies

    PubMed Central

    Myers, Darienne R; Polakos, Noelle K; Enders, Anselm; Roots, Carla; Balakishnan, Bhavani; Miosge, Lisa A; Sjollema, Geoff; Bertram, Edward M; Field, Matthew A; Shao, Yunli; Andrews, T Daniel; Whittle, Belinda; Barnes, S Whitney; Walker, John R; Cyster, Jason G

    2013-01-01

    Missense variants are a major source of human genetic variation. Here we analyze a new mouse missense variant, Rasgrp1Anaef, with an ENU-mutated EF hand in the Rasgrp1 Ras guanine nucleotide exchange factor. Rasgrp1Anaef mice exhibit anti-nuclear autoantibodies and gradually accumulate a CD44hi Helios+ PD-1+ CD4+ T cell population that is dependent on B cells. Despite reduced Rasgrp1-Ras-ERK activation in vitro, thymocyte selection in Rasgrp1Anaef is mostly normal in vivo, although CD44 is overexpressed on naïve thymocytes and T cells in a T-cell-autonomous manner. We identify CD44 expression as a sensitive reporter of tonic mTOR-S6 kinase signaling through a novel mouse strain, chino, with a reduction-of-function mutation in Mtor. Elevated tonic mTOR-S6 signaling occurs in Rasgrp1Anaef naïve CD4+ T cells. CD44 expression, CD4+ T cell subset ratios and serum autoantibodies all returned to normal in Rasgrp1AnaefMtorchino double-mutant mice, demonstrating that increased mTOR activity is essential for the Rasgrp1Anaef T cell dysregulation. DOI: http://dx.doi.org/10.7554/eLife.01020.001 PMID:24336796

  9. Live imaging of X chromosome reactivation dynamics in early mouse development can discriminate naïve from primed pluripotent stem cells.

    PubMed

    Kobayashi, Shin; Hosoi, Yusuke; Shiura, Hirosuke; Yamagata, Kazuo; Takahashi, Saori; Fujihara, Yoshitaka; Kohda, Takashi; Okabe, Masaru; Ishino, Fumitoshi

    2016-08-15

    Pluripotent stem cells can be classified into two distinct states, naïve and primed, which show different degrees of potency. One difficulty in stem cell research is the inability to distinguish these states in live cells. Studies on female mice have shown that reactivation of inactive X chromosomes occurs in the naïve state, while one of the X chromosomes is inactivated in the primed state. Therefore, we aimed to distinguish the two states by monitoring X chromosome reactivation. Thus far, X chromosome reactivation has been analysed using fixed cells; here, we inserted different fluorescent reporter gene cassettes (mCherry and eGFP) into each X chromosome. Using these knock-in 'Momiji' mice, we detected X chromosome reactivation accurately in live embryos, and confirmed that the pluripotent states of embryos were stable ex vivo, as represented by embryonic and epiblast stem cells in terms of X chromosome reactivation. Thus, Momiji mice provide a simple and accurate method for identifying stem cell status based on X chromosome reactivation. PMID:27471261

  10. VE-Suite

    Energy Science and Technology Software Center (ESTSC)

    2006-10-01

    an open source virtual engineering software toolkit that simplifies information management so users can simultaneously interact with engineering analyses and graphical models to create a virtual decision-making environment.

  11. Effect of Linagliptin on Glycemic Control in Chinese Patients with Newly-Diagnosed, Drug-Naïve Type 2 Diabetes Mellitus: A Randomized Controlled Trial.

    PubMed

    Wu, Wenjun; Li, Ying; Chen, Xiong; Lin, Dini; Xiang, Songying; Shen, Feixia; Gu, Xuemei

    2015-01-01

    BACKGROUND This study aimed to evaluate the efficacy and safety of linagliptin (a novel dipeptidyl peptidase (DPP)-4 inhibitor) on glucose metabolism and β-cell function in Chinese patients with newly-diagnosed, drug-naïve type 2 diabetes mellitus (T2DM). MATERIAL AND METHODS Newly-diagnosed and drug-naïve T2DM patients were enrolled. After 4-week lifestyle modulation and 2-week placebo run-in, 57 patients were randomized to double-blind treatment with linagliptin (n=34) or placebo (n=23). The primary endpoint was the change from baseline in glycosylated hemoglobin A1c (HbA1c) after 24 weeks. Fasting plasma glucose (FPG), 2-h postprandial plasma glucose (2h-PPG), fasting insulin, proinsulin-to-insulin ratio, homeostasis model assessment of insulin resistance (HOMA-IR), and homeostasis model assessment of β-cell function (HOMA-β) were also evaluated. RESULTS Baseline characteristics were similar between the 2 groups. Compared with placebo, linagliptin therapy resulted in a significant decrease in HbA1C (-1.2±0.7% vs. -0.4±0.4%, P<0.001), FBG (-0.98±1.17 vs. -0.32±0.51 mmol/L, P=0.011, and 2h-PPG (-2.02±0.94 vs. -0.97±0.63 mmol/L, P<0.001). Significant differences were observed for the proinsulin/insulin ratio (P<0.001) and HOMA-β index (P=0.001). Rates of adverse events were similar between the 2 groups (30.3% vs. 27.3%). All adverse events were mild. One patient discontinued participation due to pregnancy. CONCLUSIONS Linagliptin treatment resulted in a significant and clinically meaningful improvement of glycemic control in drug-naïve Chinese patients with T2DM, as well as improved parameters of b-cell function. Linagliptin had an excellent safety profile. PMID:26350766

  12. Processing of blood samples influences PBMC viability and outcome of cell-mediated immune responses in antiretroviral therapy-naïve HIV-1-infected patients.

    PubMed

    Bourguignon, Patricia; Clément, Frédéric; Renaud, Frédéric; Le Bras, Vivien; Koutsoukos, Marguerite; Burny, Wivine; Moris, Philippe; Lorin, Clarisse; Collard, Alix; Leroux-Roels, Geert; Roman, François; Janssens, Michel; Vandekerckhove, Linos

    2014-12-01

    Intracellular cytokine staining (ICS) assay is increasingly used in vaccine clinical trials to measure antigen-specific T-cell mediated immune (CMI) responses in cryopreserved peripheral blood mononuclear cells (PBMCs) and whole blood. However, recent observations indicate that several parameters involved in blood processing can impact PBMC viability and CMI responses, especially in antiretroviral therapy (ART)-naïve HIV-1-infected individuals. In this phase I study (NCT01610427), we collected blood samples from 22 ART-naïve HIV-1-infected adults. PBMCs were isolated and processed for ICS assay. The individual and combined effects of the following parameters were investigated: time between blood collection and PBMC processing (time-to-process: 2, 7 or 24 h); time between PBMC thawing and initiation of in vitro stimulation with HIV-1 antigens (resting-time: 0, 2, 6 and 18 h); and duration of antigen-stimulation in PBMC cultures (stimulation-time: 6h or overnight). The cell recovery after thawing, cell viability after ICS and magnitude of HIV-specific CD8(+) T-cell responses were considered to determine the optimal combination of process conditions. The impact of time-to-process (2 or 4 h) on HIV-specific CD8(+) T-cell responses was also assessed in a whole blood ICS assay. A higher quality of cells in terms of recovery and viability (up to 81% and >80% respectively) was obtained with shorter time-to-process (less than 7 h) and resting-time (less than 2 h) intervals. Longer (overnight) rather than shorter (6 h) stimulation-time intervals increased the frequency of CD8(+)-specific T-cell responses using ICS in PBMCs without change of the functionality. The CD8(+) specific T-cell responses detected using fresh whole blood showed a good correlation with the responses detected using frozen PBMCs. Our results support the need of standardized procedures for the evaluation of CMI responses, especially in HIV-1-infected, ART-naïve patients. PMID:25224748

  13. Türk Lise Öğrencilerinde Okul Terkinin Yordanması: Aracı ve Etkileşim Değişkenleri ile Bir Model Testi

    PubMed Central

    Özer, Arif; Gençtanirim, Dilek; Ergene, Tuncay

    2011-01-01

    Bu araştırmada ilk olarak, dürtüsel davranma ile okulu terk etme riski arasındaki ilişkiye disiplin cezası almanın, antisosyal davranışların ve sigara-alkol kullanımının aracılık edip etmediği incelenmiştir. İkinci olarak, öğretmen desteği ve antisosyal davranış etkileşiminin okulu terk etme riski üzerindeki etkisi test edilmiştir. Araştırma grubunu 2009-2010 yılında Ankara İlinde genel liselere devam eden 478 öğrenci oluşturmuştur. Sonuçlar okulu terk etme riskini aile ve arkadaş desteğinin azalttığını, dürtüsel davranmanın ise artırdığını göstermiştir. Ayrıca disiplin cezası, alkol-sigara kullanma ve antisosyal davranışlar okulu terk etme riskini artıran aracı değişkenlerdir. Antisosyal davranışlarla okulu terk etme arasındaki ilişki öğretmen desteğine bağlı olarak değişmektedir. Öğrencilerin cinsiyet ve başarıları ile okulu terk etme riskleri arasında anlamlı bir ilişki bulunmamaktadır. PMID:22003257

  14. Serial follow-up of presurgical treatment using pasireotide long-acting release with or without octreotide long-acting release for naïve active acromegaly.

    PubMed

    Chang, Jan-Shun; Tseng, Ham-Min; Chang, Tien-Chun

    2016-06-01

    The aim of the present study was to evaluate the serial changes of GH and IGF-1 in seven patients with naïve, active acromegaly following presurgical treatment of the somatostatin analog pasireotide long-acting release (LAR) and octreotide LAR. The patients were treated with pasireotide LAR with or without octreotide LAR for two years and underwent transsphenoidal adenomectomy. After treatment with the somatostatin analogs, the surgical cure rate was similar to that in patients who underwent transsphenoidal surgery alone. Diabetes insipidus was not identified in any patients after the operation. Pasireotide LAR was effective on GH as well as IGF-1 suppression and tumor size decreasing when used as the primary therapy. Future large-population studies to investigate the surgical curative rate after presurgical treatment with somatostatin analogs in patients with acromegaly and macroadenomas close to the cavernous sinus are warranted. However, that hyperglycemia developed following pre-surgical treatment with pasireotide should take into consideration. PMID:27117887

  15. Response to antiretroviral therapy (ART): comparing women with previous use of zidovudine monotherapy (ZDVm) in pregnancy with ART naïve women

    PubMed Central

    2014-01-01

    Background Short-term zidovudine monotherapy (ZDVm) remains an option for some pregnant HIV-positive women not requiring treatment for their own health but may affect treatment responses once antiretroviral therapy (ART) is subsequently started. Methods Data were obtained by linking two UK studies: the UK Collaborative HIV Cohort (UK CHIC) study and the National Study of HIV in Pregnancy and Childhood (NSHPC). Treatment responses were assessed for 2028 women initiating ART at least one year after HIV-diagnosis. Outcomes were compared using logistic regression, proportional hazards regression or linear regression. Results In adjusted analyses, ART-naïve (n = 1937) and ZDVm-experienced (n = 91) women had similar increases in CD4 count and a similar proportion achieving virological suppression; both groups had a low risk of AIDS. Conclusions In this setting, antenatal ZDVm exposure did not adversely impact on outcomes once ART was initiated for the woman’s health. PMID:24593018

  16. Eosinophils from Murine Lamina Propria Induce Differentiation of Naïve T Cells into Regulatory T Cells via TGF-β1 and Retinoic Acid

    PubMed Central

    Ojcius, David M.; Hu, Wei-Lin; Ge, Yu-Mei; Lin, Xu’ai; Li, Lan-Juan; Pan, Jian-Ping; Yan, Jie

    2015-01-01

    Treg cells play a crucial role in immune tolerance, but mechanisms that induce Treg cells are poorly understood. We here have described eosinophils in lamina propria (LP) that displayed high aldehyde dehydrogenase (ALDH) activity, a rate-limiting step during all-trans retinoic acid (ATRA) synthesis, and expressed TGF-β1 mRNA and high levels of ATRA. Co-incubation assay confirmed that LP eosinophils induced the differentiation of naïve T cells into Treg cells. Differentiation promoted by LP eosinophils were inhibited by blocked either TGF-β1 or ATRA. Peripheral blood (PB) eosinophils did not produce ATRA and could not induce Treg differentiation. These data identifies LP eosinophils as effective inducers of Treg cell differentiation through a mechanism dependent on TGF-β1 and ATRA. PMID:26587591

  17. Resveratrol regulates naïve CD 8+ T-cell proliferation by upregulating IFN-γ-induced tryptophanyl-tRNA synthetase expression.

    PubMed

    Noh, Kyung Tae; Cho, Joon; Chun, Sung Hak; Jang, Jong-Hwa; Cha, Gil Sun; Jung, In Duk; Jang, Dong Deuk; Park, Yeong-Min

    2015-05-01

    We found that resveratrol enhances interferon (IFN)-γ-induced tryptophanyl-tRNA-synthetase (TTS) expression in bone marrow- derived dendritic cells (BMDCs). Resveratrol-induced TTS expression is associated with glycogen synthase kinase-3β (GSK-3β) activity. In addition, we found that resveratrol regulates naïve CD8+ T-cell polarization by modulating GSK-3β activity in IFN-γ-stimulated BMDCs, and that resveratol induces upregulation of TTS in CD8+ T-cells in the in vivo tumor environment. Taken together, resveratrol upregulates IFN-γ-induced TTS expression in a GSK-3β-dependent manner, and this TTS modulation is crucial for DC-mediated T-cell modulation. PMID:25248565

  18. Resveratrol regulates naïve CD 8+ T-cell proliferation by upregulating IFN-γ-induced tryptophanyl-tRNA synthetase expression

    PubMed Central

    Noh, Kyung Tae; Cho, Joon; Chun, Sung Hak; Jang, Jong-Hwa; Cha, Gil Sun; Jung, In Duk; Jang, Dong Deuk; Park, Yeong-Min

    2015-01-01

    We found that resveratrol enhances interferon (IFN)-γ-induced tryptophanyl-tRNA-synthetase (TTS) expression in bone marrow-derived dendritic cells (BMDCs). Resveratrol-induced TTS expression is associated with glycogen synthase kinase-3β (GSK-3β) activity. In addition, we found that resveratrol regulates naïve CD8+ T-cell polarization by modulating GSK-3β activity in IFN-γ-stimulated BMDCs, and that resveratol induces upregulation of TTS in CD8+ T-cells in the in vivo tumor environment. Taken together, resveratrol upregulates IFN-γ-induced TTS expression in a GSK-3β-dependent manner, and this TTS modulation is crucial for DC-mediated T-cell modulation. [BMB Reports 2015; 48(5): 283-288] PMID:25248565

  19. First episode drug-naïve major depressive disorder with panic disorder: gray matter deficits in limbic and default network structures.

    PubMed

    Lai, Chien-Han; Hsu, Yuan-Yu; Wu, Yu-Te

    2010-10-01

    This study was designed to investigate the structural differences in the brains of first episode, drug-naïve patients with major depressive disorder and panic disorder versus healthy control subjects. High-resolution brain magnetic resonance images were performed on patients and health control subjects (age, sex and handedness matched). Structural magnetic resonance images of brain were estimated by optimized voxel-based morphometry of FSL (FMRIB Software Library). Patients had deficits of gray matter volumes over right anterior cingulate cortex, right medial frontal gyrus, left posterior cingulate cortex, right parahippocampal gyrus, limbic areas, occipital lingual gyrus and bilateral cerebellums when compared to controls. These results suggested that this group of patients has possible deficits of gray matter volumes over the default-mode network, fronto-cingulate and limbic structures. The decline of gray matter volumes might have started since the first episode. PMID:20599363

  20. Safety, Immunogenicity and Efficacy of Modified Vaccinia Ankara (MVA) Against Dryvax® Challenge in Vaccinia-Naïve and Vaccinia-Immune Individuals

    PubMed Central

    Parrino, Janie; McCurdy, Lewis H.; Larkin, Brenda D.; Gordon, Ingelise J.; Rucker, Steven E.; Enama, Mary E.; Koup, Richard A.; Roederer, Mario; Bailer, Robert T.; Moodie, Zoe; Gu, Lin; Yan, Lihan; Graham, Barney S.

    2007-01-01

    Modified vaccinia Ankara (MVA) was evaluated as an alternative to Dryvax® in vaccinia-naïve and immune adult volunteers. Subjects received intramuscular MVA or placebo followed by Dryvax® challenge at 3 months. Two or more doses of MVA prior to Dryvax® reduced severity of lesion formation, decreased magnitude and duration of viral shedding, and augmented post-Dryvax® vaccinia-specific CD8+ T cell responses and extracellular enveloped virus protein-specific antibody responses. MVA vaccination is safe and immunogenic and improves the safety and immunogenicity of subsequent Dryvax® vaccination supporting the potential for using MVA as a vaccine in the general population to improve immunity to orthopoxviruses. PMID:17126963

  1. Having students create short video clips to help transition from naïve conceptions about mechanics to true Newtonian physics

    NASA Astrophysics Data System (ADS)

    Corten-Gualtieri, Pascale; Ritter, Christian; Plumat, Jim; Keunings, Roland; Lebrun, Marcel; Raucent, Benoit

    2016-07-01

    Most students enter their first university physics course with a system of beliefs and intuitions which are often inconsistent with the Newtonian frame of reference. This article presents an experiment of collaborative learning aiming at helping first-year students in an engineering programme to transition from their naïve intuition about dynamics to the Newtonian way of thinking. In a first activity, students were asked to critically analyse the contents of two video clips from the point of view of Newtonian mechanics. In a second activity, students had to design and realise their own video clip to illustrate a given aspect of Newtonian mechanics. The preparation of the scenario for the second activity required looking up and assimilating scientific knowledge. The efficiency of the activity was assessed on an enhanced version of the statistical analysis method proposed by Hestenes and Halloun, which relies on a pre-test and a post-test to measure individual learning.

  2. Behavioral responses of predator-naïve dwarf hamsters (Phodopus campbelli) to odor cues of the European ferret fed with different prey species.

    PubMed

    Apfelbach, Raimund; Soini, Helena A; Vasilieva, Nina Y; Novotny, Milos V

    2015-07-01

    Many mammalian predators are able to identify their prey by odors and, vice versa, numerous prey species recognize predator odors as well. The present paper reports on the behavioral responses of predator-naïve dwarf hamsters (Phodopus campbelli) towards the urine odors of carnivorous ferrets, which were raised on either a chicken, mouse or hamster diet. Chemical composition from ferret urines of the different diet groups was analyzed, while quantitative differences in urinary volatile constituents were observed through capillary gas chromatography–mass spectrometry. In a Y-maze arrangement, hamsters were offered several two-choice odor discrimination tasks and their behavior was quantified. Hamsters were easily able to discriminate the urine odor of ferrets fed with mice against ferrets fed with hamsters. This is probably the first report indicating that a prey species can distinguish urine odors of even an unknown predator species that has been fed different prey species. The analytical data complemented behavioral assays. PMID:26066723

  3. Loss of CCR2 expressing non-classical monocytes are associated with cognitive impairment in antiretroviral therapy-naïve HIV-infected Thais.

    PubMed

    Ndhlovu, Lishomwa C; D'Antoni, Michelle L; Ananworanich, Jintanat; Byron, Mary Margaret; Chalermchai, Thep; Sithinamsuwan, Pasiri; Tipsuk, Somporn; Ho, Erika; Slike, Bonnie M; Schuetz, Alexandra; Zhang, Guangxiang; Agsalda-Garcia, Melissa; Shiramizu, Bruce; Shikuma, Cecilia M; Valcour, Victor

    2015-11-15

    HIV DNA in monocytes has been linked to HIV-associated neurocognitive disorders (HAND), however, characterization of monocyte subsets associated with HAND remains unclear. We completed a prospective study of antiretroviral therapy-naïve, HIV-infected Thais, with varying degrees of cognitive impairment, compared to HIV-uninfected controls. Monocyte subsets' CCR2, CCR5 and CD163 expression were profiled and inflammatory markers in plasma and cerebrospinal fluid (CSF), measured. Lower numbers of CCR2(+)non-classical monocytes were associated with worse neuropsychological test performance (r=0.43, p=0.024). CCR2(+)non-classical monocyte count inversely correlated with CSF neopterin (r=-0.43, p=0.035) and plasma TNF-α levels (r=-0.40, p=0.041). These data benchmark CCR2(+)non-classical monocytes as an independent index of cognitive impairment. PMID:26531691

  4. Neutralizing inhibitors in the airways of naïve ferrets do not play a major role in modulating the virulence of H3 subtype influenza A viruses.

    PubMed

    Job, Emma R; Pizzolla, Angela; Nebl, Thomas; Short, Kirsty R; Deng, Yi-Mo; Carolan, Louise; Laurie, Karen L; Brooks, Andrew G; Reading, Patrick C

    2016-07-01

    Many insights regarding the pathogenesis of human influenza A virus (IAV) infections have come from studies in mice and ferrets. Surfactant protein (SP)-D is the major neutralizing inhibitor of IAV in mouse airway fluids and SP-D-resistant IAV mutants show enhanced virus replication and virulence in mice. Herein, we demonstrate that sialylated glycoproteins, rather than SP-D, represent the major neutralizing inhibitors against H3 subtype viruses in airway fluids from naïve ferrets. Moreover, while resistance to neutralizing inhibitors is a critical factor in modulating virus replication and disease in the mouse model, it does not appear to be so in the ferret model, as H3 mutants resistant to either SP-D or sialylated glycoproteins in ferret airway fluids did not show enhanced virulence in ferrets. These data have important implications for our understanding of pathogenesis and immunity to human IAV infections in these two widely used animal models of infection. PMID:27110707

  5. N-Acetylaspartate Reduction in the Medial Prefrontal Cortex Following 8 weeks of Risperidone Treatment in First-Episode Drug-Naïve Schizophrenia Patients

    PubMed Central

    Zong, Xiaofen; Hu, Maolin; Li, Zongchang; Cao, Hongbao; He, Ying; Liao, Yanhui; Zhou, Jun; Sang, Deen; Zhao, Hongzeng; Tang, Jinsong; Lv, Luxian; Chen, Xiaogang

    2015-01-01

    It is unclear whether N-acetylaspartate (NAA) depletions documented in schizophrenia patients might be due to the disease progression or medications. Here we investigated longitudinal NAA changes in drug-naïve first-episode patients (FEP) who are relatively free from chronicity. Forty-two drug-naïve FEP and 38 controls were enrolled in this study to explore the effect of 8-week risperidone monotherapy on NAA. All spectra were obtained from the medial prefrontal cortex (MPFC) on a 3.0 T MRI and analyzed with LCModel. At baseline, patients presented no significant differences in NAA (P = 0.084) or NAA/Cr + Pcr (P = 0.500) compared to controls; NAA levels were negatively correlated with PANSS total scores (P = 0.001) and WCST-PE (P = 0.041). After treatment, patients demonstrated significant reductions of NAA (P < 0.001) and NAA/Cr + Pcr (P < 0.001), and significant improvement in PANSS-P (P < 0.001) and PANSS-G (P < 0.001) symptoms. We detected no significant correlations between NAA alterations and PANSS-P (P = 0.679) or PANSS-G (P = 0.668) symptom changes; nor did NAA/Cr + Pcr changes with alterations in PANSS-P (P = 0.677) and PANSS-G (P = 0.616). This is the first evidence that short-term risperidone treatment induces an acute reduction of MPFC NAA during the early phase of schizophrenia, which may be a previously unavailable biomarker to indicate risperidone with a similar pharmacological mechanism, although the functional significance is still unclear. PMID:25778460

  6. Cytokine and Antibody Responses to Plasmodium falciparum in Naïve Individuals during a First Malaria Episode: Effect of Age and Malaria Exposure

    PubMed Central

    Jiménez, Alfons; Nhabomba, Augusto; Puyol, Laura; Manaca, Maria N.; Barrios, Diana; Cisteró, Pau; Guinovart, Caterina; Aguilar, Ruth; Bardají, Azucena; Pinazo, María-Jesús; Angov, Evelina; Dutta, Sheetij; Chitnis, Chetan E.; Muñoz, José; Gascón, Joaquim; Dobaño, Carlota

    2013-01-01

    Age- and exposure-dependent immune responses during a malaria episode may be key to understanding the role of these factors in the acquisition of immunity to malaria. Plasma/serum samples collected from naïve Mozambican children (n = 48), European adults (naïve travelers, n = 22; expatriates with few prior malaria exposures, n = 15) and Mozambican adults with long-life malaria exposure (n = 99) during and after a malaria episode were analyzed for IgG against merozoite proteins by Luminex and against infected erythrocytes by flow cytometry. Cytokines and chemokines were analyzed in plasmas/sera by suspension array technology. No differences were detected between children and adults with a primary infection, with the exception of higher IgG levels against 3D7 MSP-142 (P = 0.030) and a P. falciparum isolate (P = 0.002), as well as higher IL-12 (P = 0.020) in children compared to other groups. Compared to malaria-exposed adults, children, travelers and expatriates had higher concentrations of IFN-γ (P≤0.0090), IL-2 (P≤0.0379) and IL-8 (P≤0.0233). Children also had higher IL-12 (P = 0.0001), IL-4 (P = 0.003), IL-1β (P = 0.024) and TNF (P = 0.006) levels compared to malaria-exposed adults. Although IL-12 was elevated in children, overall the data do not support a role of age in immune responses to a first malaria episode. A TH1/pro-inflammatory response was the hallmark of non-immune subjects. PMID:23437061

  7. DNA methylation patterns in naïve CD4+ T cells identify epigenetic susceptibility loci for malar rash and discoid rash in systemic lupus erythematosus

    PubMed Central

    Renauer, Paul; Coit, Patrick; Jeffries, Matlock A; Merrill, Joan T; McCune, W Joseph; Maksimowicz-McKinnon, Kathleen; Sawalha, Amr H

    2015-01-01

    Objective Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterised by heterogeneous clinical manifestations, autoantibody production and epigenetic dysregulation in T cells. We sought to investigate the epigenetic contribution to the development of cutaneous manifestations in SLE. Methods We performed genome-wide DNA methylation analyses in patients with SLE stratified by a history of malar rash, discoid rash or neither cutaneous manifestation, and age, sex and ethnicity matched healthy controls. We characterised differentially methylated regions (DMRs) in naïve CD4+ T cells unique to each disease subset, and assessed functional relationships between DMRs using bioinformatic approaches. Results We identified 36 and 37 unique DMRs that contribute to the epigenetic susceptibility to malar rash and discoid rash, respectively. These DMRs were primarily localised to genes mediating cell proliferation and apoptosis. Hypomethylation of MIR886 and TRIM69, and hypermethylation of RNF39 were specific to patients with SLE with a history of malar rash. Hypomethylation of the cytoskeleton-related gene RHOJ was specific to patients with SLE with a history of discoid rash. In addition, discoid rash-specific hypomethylated DMRs were found in genes involved in antigen-processing and presentation such as TAP1 and PSMB8. Network analyses showed that DMRs in patients with SLE with but not without a history of cutaneous manifestations are associated with TAP-dependent processing and major histocompatibility-class I antigen cross-presentation (p=3.66×10−18 in malar rash, and 3.67×10−13 in discoid rash). Conclusions We characterised DNA methylation changes in naïve CD4+ T cells specific to malar rash and discoid rash in patients with SLE. These data suggest unique epigenetic susceptibility loci that predispose to or are associated with the development of cutaneous manifestations in SLE. PMID:26405558

  8. Epstein-Barr virus infection of naïve B cells in vitro frequently selects clones with mutated immunoglobulin genotypes: implications for virus biology.

    PubMed

    Heath, Emily; Begue-Pastor, Noelia; Chaganti, Sridhar; Croom-Carter, Debbie; Shannon-Lowe, Claire; Kube, Dieter; Feederle, Regina; Delecluse, Henri-Jacques; Rickinson, Alan B; Bell, Andrew I

    2012-01-01

    Epstein-Barr virus (EBV), a lymphomagenic human herpesvirus, colonises the host through polyclonal B cell-growth-transforming infections yet establishes persistence only in IgD⁺ CD27⁺ non-switched memory (NSM) and IgD⁻ CD27⁺ switched memory (SM) B cells, not in IgD⁺ CD27⁻ naïve (N) cells. How this selectivity is achieved remains poorly understood. Here we show that purified N, NSM and SM cell preparations are equally transformable in vitro to lymphoblastoid cells lines (LCLs) that, despite upregulating the activation-induced cytidine deaminase (AID) enzyme necessary for Ig isotype switching and Ig gene hypermutation, still retain the surface Ig phenotype of their parental cells. However, both N- and NSM-derived lines remain inducible to Ig isotype switching by surrogate T cell signals. More importantly, IgH gene analysis of N cell infections revealed two features quite distinct from parallel mitogen-activated cultures. Firstly, following 4 weeks of EBV-driven polyclonal proliferation, individual clonotypes then become increasingly dominant; secondly, in around 35% cases these clonotypes carry Ig gene mutations which both resemble AID products and, when analysed in prospectively-harvested cultures, appear to have arisen by sequence diversification in vitro. Thus EBV infection per se can drive at least some naïve B cells to acquire Ig memory genotypes; furthermore, such cells are often favoured during an LCL's evolution to monoclonality. Extrapolating to viral infections in vivo, these findings could help to explain how EBV-infected cells become restricted to memory B cell subsets and why EBV-driven lymphoproliferative lesions, in primary infection and/or immunocompromised settings, so frequently involve clones with memory genotypes. PMID:22589726

  9. Epstein-Barr Virus Infection of Naïve B Cells In Vitro Frequently Selects Clones with Mutated Immunoglobulin Genotypes: Implications for Virus Biology

    PubMed Central

    Croom-Carter, Debbie; Shannon-Lowe, Claire; Kube, Dieter; Feederle, Regina; Delecluse, Henri-Jacques; Rickinson, Alan B.; Bell, Andrew I.

    2012-01-01

    Epstein-Barr virus (EBV), a lymphomagenic human herpesvirus, colonises the host through polyclonal B cell-growth-transforming infections yet establishes persistence only in IgD+ CD27+ non-switched memory (NSM) and IgD− CD27+ switched memory (SM) B cells, not in IgD+ CD27− naïve (N) cells. How this selectivity is achieved remains poorly understood. Here we show that purified N, NSM and SM cell preparations are equally transformable in vitro to lymphoblastoid cells lines (LCLs) that, despite upregulating the activation-induced cytidine deaminase (AID) enzyme necessary for Ig isotype switching and Ig gene hypermutation, still retain the surface Ig phenotype of their parental cells. However, both N- and NSM-derived lines remain inducible to Ig isotype switching by surrogate T cell signals. More importantly, IgH gene analysis of N cell infections revealed two features quite distinct from parallel mitogen-activated cultures. Firstly, following 4 weeks of EBV-driven polyclonal proliferation, individual clonotypes then become increasingly dominant; secondly, in around 35% cases these clonotypes carry Ig gene mutations which both resemble AID products and, when analysed in prospectively-harvested cultures, appear to have arisen by sequence diversification in vitro. Thus EBV infection per se can drive at least some naïve B cells to acquire Ig memory genotypes; furthermore, such cells are often favoured during an LCL's evolution to monoclonality. Extrapolating to viral infections in vivo, these findings could help to explain how EBV-infected cells become restricted to memory B cell subsets and why EBV-driven lymphoproliferative lesions, in primary infection and/or immunocompromised settings, so frequently involve clones with memory genotypes. PMID:22589726

  10. Botulinum toxin type B vs. type A in toxin-naïve patients with cervical dystonia: Randomized, double-blind, noninferiority trial.

    PubMed

    Pappert, Eric J; Germanson, Terry

    2008-03-15

    The objective of this study was to compare efficacy, safety, and duration of botulinum toxin type A (BoNT-A) and type B (BoNT-B) in toxin-naïve cervical dystonia (CD) subjects. BoNT-naïve CD subjects were randomized to BoNT-A or BoNT-B and evaluated in a double-blind trial at baseline and every 4-weeks following one treatment. The primary measure was the change in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) from baseline to week 4 post-injection. Secondary measures included change in TWSTRS-subscale scores, pain, global impressions, and duration of response and safety assessments. The study was designed as a noninferiority trial of BoNT-B to BoNT-A. 111 subjects were randomized (55 BoNT-A; 56 BoNT-B). Improvement in TWSTRS-total scores 4 weeks after BoNT-B was noninferior to BoNT-A (adjusted means 11.0 (SE 1.2) and 8.8 (SE 1.2), respectively; per-protocol-population (PPP)). The median duration of effect of BoNT-A and BoNT-B was not different (13.1 vs. 13.7 weeks, respectively; P-value = 0.833; PPP). There were no significant differences in the occurrence of injection site pain and dysphagia. Mild dry mouth was more frequent with BoNT-B but there were no differences for moderate/severe dry mouth. In this study, both BoNT-A and B were shown to be effective and safe for the treatment of toxin-naive CD subjects. PMID:18098274

  11. Comprehensive evaluation of cortical structure abnormalities in drug-naïve, adult patients with obsessive-compulsive disorder: a surface-based morphometry study.

    PubMed

    Venkatasubramanian, Ganesan; Zutshi, Amit; Jindal, Sachin; Srikanth, Subbamma G; Kovoor, Jerry M E; Kumar, J Keshav; Janardhan Reddy, Y C

    2012-09-01

    The study objective was to comprehensively evaluate drug-naïve, adult patients with Obsessive Compulsive Disorder (OCD) for cortical structure abnormalities in comparison with healthy controls. In this cross-sectional study of case-control design, Magnetic Resonance Imaging (1-mm) was performed in drug-naïve OCD patients (N = 50) & age- sex-, education- and handedness-matched healthy controls (N = 40). We examined cortical volume, thickness, surface area & local Gyrification Index (LGI) through a completely automated surface-based morphometric analysis using FreeSurfer software. OCD symptoms and insight were assessed using Yale-Brown Obsessive Compulsive Symptom (Y-BOCS) check-list and severity scale. Illness severity was assessed using Clinical Global Impression Severity (CGI-S) Scale. OCD patients had significantly deficient volume, thickness and surface area of right anterior cingulate gyrus (ACG). Right lingual gyrus surface area was found to be significantly decreased in patients. Y-BOCS obsession score had significant negative correlation with left frontal pole volume. Y-BOCS compulsion score had significant negative correlations with right ACG volume and surface area and right lateral orbitofrontal cortex LGI. CGI-Severity score had significant negative correlations with right lingual gyrus volume, thickness and surface area as well as right lateral orbitofrontal area. Y-BOCS insight score showed a significant negative correlation with LGI of left medial OFC and left rostral ACG. Identification of novel deficits involving occipital brain regions and first-time observations of relevant correlations between various illness characteristics and cortical measures in OCD patients supports a network involving anterior cingulate, orbitofrontal and occipital brain regions in the pathogenesis of OCD. PMID:22770508

  12. Effect of BMI and fat mass on HIV disease progression in HIV-infected, antiretroviral treatment-naïve adults in Botswana.

    PubMed

    Martinez, S S; Campa, A; Bussmann, H; Moyo, S; Makhema, J; Huffman, F G; Williams, O D; Essex, M; Marlink, R; Baum, M K

    2016-06-01

    An obesity paradox has been proposed in many conditions including HIV. Studies conducted to investigate obesity and its effect on HIV disease progression have been inconclusive and are lacking for African settings. This study investigated the relationship between overweight/obesity (BMI≥25 kg/m2) and HIV disease progression in HIV+ asymptomatic adults not on antiretroviral treatment (ART) in Botswana over 18 months. A cohort study in asymptomatic, ART-naïve, HIV+ adults included 217 participants, 139 with BMI of 18·0-24·9 kg/m2 and seventy-eight participants with BMI≥25 kg/m2. The primary outcome was time to event (≥25 % decrease in cluster of differentiation 4 (CD4) cell count) during 18 months of follow-up; secondary outcomes were time to event of CD4 cell count<250 cells/µl and AIDS-defining conditions. Proportional survival hazard models were used to compare hazard ratios (HR) on time to events of HIV disease progression over 18 months. Higher baseline BMI was associated with significantly lower risk of an AIDS-defining condition during the follow-up (HR 0·218; 95 % CI 0·068, 0·701; P=0·011). Higher fat mass at baseline was also significantly associated with decreased risk of AIDS-defining conditions during the follow-up (HR 0·855; 95 % CI 0·741, 0·987; P=0·033) and the combined outcome of having CD4 cell count≤250/µl and AIDS-defining conditions, whichever occurred earlier (HR 0·918; 95 % CI 0·847, 0·994; P=0·036). All models were adjusted for covariates. Higher BMI and fat mass among the HIV-infected, ART-naïve participants were associated with slower disease progression. Mechanistic research is needed to evaluate the association between BMI, fat mass and HIV disease progression. PMID:27087233

  13. Natural Polymorphisms Conferring Resistance to HCV Protease and Polymerase Inhibitors in Treatment-Naïve HIV/HCV Co-Infected Patients in China

    PubMed Central

    Wang, Charles; Hu, Fengyu; Ning, Chuanyi; Lan, Yun; Tang, Xiaoping; Tucker, Joseph D.; Cai, Weiping

    2016-01-01

    Background The advent of direct-acting agents (DAAs) has improved treatment of HCV in HIV co-infection, but may be limited by primary drug resistance. This study reports the prevalence of natural polymorphisms conferring resistance to NS3/4A protease inhibitors and NS5B polymerase inhibitors in treatment-naïve HIV/HCV co-infected individuals in China. Methods Population based NS3/4A sequencing was completed for 778 treatment-naïve HIV/HCV co-infected patients from twelve provinces. NS3 sequences were amplified by nested PCR using in-house primers for genotypes 1–6. NS5B sequencing was completed for genotyping in 350 sequences. Resistance-associated variants (RAVs) were identified in positions associated with HCV resistance. Results Overall, 72.8% (566/778) of all HCV sequences had at least one RAV associated with HCV NS3/4A protease inhibitor resistance. Variants were found in 3.6% (7/193) of genotype 1, 100% (23/23) of genotype 2, 100% (237/237) of genotype 3 and 92% (299/325) of genotype 6 sequences. The Q80K variant was present in 98.4% of genotype 6a sequences. High-level RAVs were rare, occurring in only 0.8% of patients. 93% (64/69) patients with genotype 1b also carried the C316N variant associated with NS5B low-level resistance. Conclusions The low frequency of high-level RAVs associated with primary HCV DAA resistance among all genotypes in HIV/HCV co-infected patients is encouraging. Further phenotypic studies and clinical research are needed. PMID:27341031

  14. Different Variants in Reverse Transcriptase Domain Determined by Ultra-deep Sequencing in Treatment-naïve and Treated Indonesian Patients Infected with Hepatitis B Virus.

    PubMed

    Wasityastuti, Widya; Yano, Yoshihiko; Widasari, Dewiyani Indah; Yamani, Laura Navika; Ratnasari, Neneng; Heriyanto, Didik Setyo; Okada, Rina; Tanahashi, Toshihito; Murakami, Yoshiki; Azuma, Takeshi; Hayashi, Yoshitake

    2016-01-01

    A nucleos(t)ide analog (NA) is the common antiviral drug available for directly treating hepatitis B virus (HBV) infection. However, its application has led to the emergence of NA-resistant mutations mostly in a conserved region of the reverse transcriptase domain of HBV polymerase. Harboring NA-resistant mutations decreases drug effectiveness and increases the frequency of end-stage liver disease. The invention of next-generation sequencing that can generate thousands of sequences from viral complex mixtures provides opportunities to detect minor changes and early viral evolution under drug stress. The present study used ultra-deep sequencing to evaluate discrepant quasispecies in the reverse transcriptase domain of HBV including NA-resistant hotspots between seven treatment-naïve Indonesian patients infected with HBV and five at the early phase of treatment. The most common sub-genotype was HBV B3 (83.34%). The substitution rate of variants determined among amino acids with a ratio of ≥ 1% changes was higher among the population in conserved regions (23.19% vs. 4.59%, P = 0.001) and in the inter-reverse transcriptase domain (23.95% vs. 2.94%, P = 0.002) in treatment naïve, than in treated patients. Nine hotspots of antiviral resistance were identified in both groups, and the mean frequency of changes in all patients was < 1%. The known rtM204I mutation was the most frequent in both groups. The lower rate of variants in HBV quasispecies in patients undergoing treatment could be associated with virus elimination and the extinction of sensitive species by NA therapy. The present findings imply that HBV quasispecies dynamically change during treatment. PMID:27492206

  15. An observational study of bimatoprost 0.01% in treatment-naïve patients with primary open angle glaucoma or ocular hypertension: the CLEAR trial

    PubMed Central

    Nixon, Donald R; Simonyi, Susan; Bhogal, Meetu; Sigouin, Christopher S; Crichton, Andrew C; Discepola, Marino; Hutnik, Cindy ML; Yan, David B

    2012-01-01

    Background This study was designed to evaluate the occurrence and severity of ocular hyperemia in subjects with elevated intraocular pressure (IOP) due to primary open angle glaucoma (POAG) or ocular hypertension (OHT) following treatment with bimatoprost 0.01% in a real-world clinical setting. Methods This was an open-label, observational study conducted at 67 centers in Canada. Subjects with elevated IOP due to POAG or OHT instilled bimatoprost 0.01% topically as monotherapy once daily. Ocular hyperemia was graded by the investigator at baseline and weeks 6 and 12 using a photographic five-point grading scale. Change in IOP from baseline was also evaluated at these time points. This analysis includes only the subgroup of 522 subjects who were naïve to IOP-lowering medication prior to the study. Results After 12 weeks of treatment with bimatoprost 0.01%, hyperemia was graded as none-to-mild (grades 0, +0.5, or +1) for 93.3% of subjects and as moderate-to-severe (grades +2 or +3) for 6.7%. At weeks 6 and 12, most subjects (93.2% and 93.5%) had no change in hyperemia grade from baseline. IOP was reduced by 7.4 mmHg (29.8%) at week 6 and 7.7 mmHg (30.9%) at week 12 from baseline. Conclusion This real-world, observational study found that bimatoprost 0.01% instilled once daily reduced IOP by a mean of 30% from baseline without moderate or severe ocular hyperemia in 93% of treatment-naïve subjects with POAG or OHT. PMID:23269858

  16. An indirect comparison and cost per responder analysis of adalimumab, methotrexate and apremilast in the treatment of methotrexate-naïve patients with psoriatic arthritis.

    PubMed

    Betts, Keith A; Griffith, Jenny; Friedman, Alan; Zhou, Zheng-Yi; Signorovitch, James E; Ganguli, Arijit

    2016-04-01

    Objective Apremilast was recently approved for the treatment of active psoriatic arthritis (PsA). However, no studies compare apremilast with methotrexate or biologic therapies, so its relative comparative efficacy remains unknown. This study compared the response rates and incremental costs per responder associated with methotrexate, apremilast, and biologics for the treatment of active PsA. Methods A systematic literature review was performed to identify phase 3 randomized controlled clinical trials of approved biologics, methotrexate, and apremilast in the methotrexate-naïve PsA population. Using Bayesian methods, a network meta-analysis was conducted to indirectly compare rates of achieving a ≥20% improvement in American College of Rheumatology component scores (ACR20). The number needed to treat (NNT) and the incremental costs per ACR20 responder (2014 US$) relative to placebo were estimated for each of the therapies. Results Three trials (MIPA for methotrexate, PALACE-4 for apremilast, and ADEPT for adalimumab) met all inclusion criteria. The NNTs relative to placebo were 2.63 for adalimumab, 6.69 for apremilast, and 8.31 for methotrexate. Among methotrexate-naïve PsA patients, the 16 week incremental costs per ACR20 responder were $3622 for methotrexate, $26,316 for adalimumab, and $45,808 for apremilast. The incremental costs per ACR20 responder were $222,488 for apremilast vs. methotrexate. Conclusion Among methotrexate-naive PsA patients, adalimumab was found to have the lowest NNT for one additional ACR20 response and methotrexate was found to have the lowest incremental costs per ACR20 responder. There was no statistical evidence of greater efficacy for apremilast vs. methotrexate. A head-to-head trial between apremilast and methotrexate is recommended to confirm this finding. PMID:26743448

  17. Morphologic and Functional Connectivity Alterations of Corticostriatal and Default Mode Network in Treatment-Naïve Patients with Obsessive-Compulsive Disorder

    PubMed Central

    Hou, Jingming; Song, Lingheng; Zhang, Wei; Wu, Wenjing; Wang, Jian; Zhou, Daiquan; Qu, Wei; Guo, Junwei; Gu, Shanshan; He, Mei; Xie, Bing; Li, Haitao

    2013-01-01

    Background Previous studies have demonstrated that structural deficits and functional connectivity imbalances might underlie the pathophysiology of obsessive-compulsive disorder (OCD). The purpose of the present study was to investigate gray matter deficits and abnormal resting-state networks in patients with OCD and further investigate the association between the anatomic and functional alterations and clinical symptoms. Methods Participants were 33 treatment-naïve OCD patients and 33 matched healthy controls. Voxel-based morphometry was used to investigate the regions with gray matter abnormalities and resting-state functional connectivity analysis was further conducted between each gray matter abnormal region and the remaining voxels in the brain. Results Compared with healthy controls, patients with OCD showed significantly increased gray matter volume in the left caudate, left thalamus, and posterior cingulate cortex, as well as decreased gray matter volume in the bilateral medial orbitofrontal cortex, left anterior cingulate cortex, and left inferior frontal gyrus. By using the above morphologic deficits areas as seed regions, functional connectivity analysis found abnormal functional integration in the cortical-striatum-thalamic-cortical (CSTC) circuits and default mode network. Subsequent correlation analyses revealed that morphologic deficits in the left thalamus and increased functional connectivity within the CSTC circuits positively correlated with the total Y-BOCS score. Conclusion This study provides evidence that morphologic and functional alterations are seen in CSTC circuits and default mode network in treatment-naïve OCD patients. The association between symptom severity and the CSTC circuits suggests that anatomic and functional alterations in CSTC circuits are especially important in the pathophysiology of OCD. PMID:24358320

  18. Undernutrition and anaemia among HAART-naïve HIV infected children in Ile-Ife, Nigeria: a case-controlled, hospital based study

    PubMed Central

    Anyabolu, Henry Chineme; Adejuyigbe, Ebunoluwa Aderonke; Adeodu, Oluwagbemiga Oyewole

    2014-01-01

    Introduction Case control studies that assess the burden and factors associated with undernutrition and anaemia among HAART naïve HIV infected children in Nigeria is very sparse. This will help to formulate nutritional programs among these children. Methods Seventy HAART naive HIV infected children aged 18 months and above were as well as seventy age and sex matched HIV negative children were recruited from August 2007 to January 2009 at Paediatric Clinic of Obafemi Awolowo University Teaching Hospital Complex, Ile-Ife, Nigeria. Their bio data, WHO clinical stage, anthropometric measurements, haematocrit, serum albumin and CD4 counts were taken with other parameters according to a study proforma. Results The prevalence of stunting, underweight and wasting among the HIV infected subjects were 48. 6%,58. 6% and 31. 4% respectively which as significantly higher than 28. 1%, 7. 1% and 28. 1% among the HIV negative controls. 20. 1% of the HIV infected children were marasmic compared to 2. 3% of the controls. Triple anthropometric failure was found in 7. 1% of the subjects as compared to none among the controls. Anaemia is significantly more prevalent among the subjects than the controls (70. 0% vs 31. 4%; p<0. 001). The prevalence of anaemia was higher in the HIV infected subjects with undernutrition. Low socioeconomic status, hypoalbuminemia and severe immunosuppression are significantly associated with higher undernutrition prevalence. Conclusion Several years after availability of HAART, undernutrition and anaemia remain widely prevalent among newly presenting HAART naïve HIV infected Nigerian children. Nutritional supplementation and evaluation for anaemia still need close attention in the management of these children. PMID:25400844

  19. Stochastic uncertainty analysis for solute transport in randomly heterogeneous media using a Karhunen-Loève-based moment equation approach

    USGS Publications Warehouse

    Liu, Gaisheng; Lu, Zhiming; Zhang, Dongxiao

    2007-01-01

    A new approach has been developed for solving solute transport problems in randomly heterogeneous media using the Karhunen-Loève-based moment equation (KLME) technique proposed by Zhang and Lu (2004). The KLME approach combines the Karhunen-Loève decomposition of the underlying random conductivity field and the perturbative and polynomial expansions of dependent variables including the hydraulic head, flow velocity, dispersion coefficient, and solute concentration. The equations obtained in this approach are sequential, and their structure is formulated in the same form as the original governing equations such that any existing simulator, such as Modular Three-Dimensional Multispecies Transport Model for Simulation of Advection, Dispersion, and Chemical Reactions of Contaminants in Groundwater Systems (MT3DMS), can be directly applied as the solver. Through a series of two-dimensional examples, the validity of the KLME approach is evaluated against the classical Monte Carlo simulations. Results indicate that under the flow and transport conditions examined in this work, the KLME approach provides an accurate representation of the mean concentration. For the concentration variance, the accuracy of the KLME approach is good when the conductivity variance is 0.5. As the conductivity variance increases up to 1.0, the mismatch on the concentration variance becomes large, although the mean concentration can still be accurately reproduced by the KLME approach. Our results also indicate that when the conductivity variance is relatively large, neglecting the effects of the cross terms between velocity fluctuations and local dispersivities, as done in some previous studies, can produce noticeable errors, and a rigorous treatment of the dispersion terms becomes more appropriate.

  20. Clinical-scale selection and viral transduction of human naïve and central memory CD8+ T cells for adoptive cell therapy of cancer patients.

    PubMed

    Casati, Anna; Varghaei-Nahvi, Azam; Feldman, Steven Alexander; Assenmacher, Mario; Rosenberg, Steven Aaron; Dudley, Mark Edward; Scheffold, Alexander

    2013-10-01

    The adoptive transfer of lymphocytes genetically engineered to express tumor-specific antigen receptors is a potent strategy to treat cancer patients. T lymphocyte subsets, such as naïve or central memory T cells, selected in vitro prior to genetic engineering have been extensively investigated in preclinical mouse models, where they demonstrated improved therapeutic efficacy. However, so far, this is challenging to realize in the clinical setting, since good manufacturing practices (GMP) procedures for complex cell sorting and genetic manipulation are limited. To be able to directly compare the immunological attributes and therapeutic efficacy of naïve (T(N)) and central memory (T(CM)) CD8(+) T cells, we investigated clinical-scale procedures for their parallel selection and in vitro manipulation. We also evaluated currently available GMP-grade reagents for stimulation of T cell subsets, including a new type of anti-CD3/anti-CD28 nanomatrix. An optimized protocol was established for the isolation of both CD8(+) T(N) cells (CD4(-)CD62L(+)CD45RA(+)) and CD8(+) T(CM) (CD4(-)CD62L(+)CD45RA(-)) from a single patient. The highly enriched T cell subsets can be efficiently transduced and expanded to large cell numbers, sufficient for clinical applications and equivalent to or better than current cell and gene therapy approaches with unselected lymphocyte populations. The GMP protocols for selection of T(N) and T(CM) we reported here will be the basis for clinical trials analyzing safety, in vivo persistence and clinical efficacy in cancer patients and will help to generate a more reliable and efficacious cellular product. PMID:23903715

  1. Naïve hosts of avian brood parasites accept foreign eggs, whereas older hosts fine-tune foreign egg discrimination during laying

    PubMed Central

    2014-01-01

    Background Many potential hosts of social parasites recognize and reject foreign intruders, and reduce or altogether escape the negative impacts of parasitism. The ontogenetic basis of whether and how avian hosts recognize their own and the brood parasitic eggs remains unclear. By repeatedly parasitizing the same hosts with a consistent parasitic egg type, and contrasting the responses of naïve and older breeders, we studied ontogenetic plasticity in the rejection of foreign eggs by the great reed warbler (Acrocephalus arundinaceus), a host species of the common cuckoo (Cuculus canorus). Results In response to experimental parasitism before the onset of laying, first time breeding hosts showed almost no egg ejection, compared to higher rates of ejection in older breeders. Young birds continued to accept foreign eggs when they were subjected to repeated parasitism, whereas older birds showed even higher ejection rates later in the same laying cycle. Conclusions Our results are consistent with the hypotheses that (i) naïve hosts need to see and learn the appearance of their own eggs to discriminate and reject foreign eggs, whereas (ii) experienced breeders possess a recognition template of their own eggs and reject parasitic eggs even without having to see their own eggs. However, we cannot exclude the possibility that other external cues and internal processes, accumulated simply with increasing age, may also modify age-specific patterns in egg rejection (e.g. more sightings of the cuckoo by older breeders). Future research should specifically track the potential role of learning in responses of individual hosts between first and subsequent breeding attempts by testing whether imprinting on a parasitized clutch reduces the rates of rejecting foreign eggs in subsequent parasitized clutches. PMID:25024736

  2. A Comparison of the Diabetes Risk Score in HIV/AIDS Patients on Highly Active Antiretroviral Therapy (HAART) and HAART-Naïve Patients at the Limbe Regional Hospital, Cameroon

    PubMed Central

    Dimala, Christian Akem; Atashili, Julius; Mbuagbaw, Josephine C.; Wilfred, Akam; Monekosso, Gottlieb L.

    2016-01-01

    Background Highly active antiretroviral therapy (HAART) has been associated with dysglycaemia. However, there is scarce data on the risk of developing diabetes mellitus (DM) in HIV/AIDS patients in Africa. Objectives Primarily to quantify and compare the risk of having diabetes mellitus in HIV/AIDS patients on HAART and HAART-naïve patients in Limbe, Cameroon; and secondarily to determine if there is an association between HAART and increased DM risk. Methods A cross-sectional study was conducted at the Limbe Regional Hospital HIV treatment center between April and June 2013, involving 200 HIV/AIDS patients (100 on first-line HAART regimens for at least 12 months matched by age and gender to 100 HAART-naïve patients). The Diabetes Risk Score (DRS) was calculated using a clinically validated model based on routinely recorded primary care parameters. A DRS ≥ 7% was considered as indicative of an increased risk of developing DM. Results The median DRS was significantly higher in patients on HAART (2.30%) than in HAART-naïve patients (1.62%), p = 0.002. The prevalence of the increased DM risk (DRS ≥ 7%) was significantly higher in patients on HAART, 31% (95% CI: 22.13–41.03) than in HAART-naïve patients, 17% (95% CI: 10.23–25.82), p = 0.020. HAART was significantly associated with an increased DM risk, the odds ratio of the HAART group compared to the HAART-naïve group was 2.19 (95% CI: 1.12–4.30, p = 0.020). However, no association was found after adjusting for BMI-defined overweight, hypertension, age, sex, family history of DM and smoking (Odds ratio = 1.22, 95% CI: 0.42–3.59, p = 0.708). Higher BMI and hypertension accounted for the increased risk of DM in patients on HAART. Also, more than 82% of the participants were receiving or had ever used Zidovudine based HAART regimens. Conclusion HIV/AIDS patients on HAART could be at a greater risk of having DM than HAART-naïve patients as a result of the effect of HAART on risk factors of DM such as BMI

  3. Efficacy of Second Generation Direct-Acting Antiviral Agents for Treatment Naïve Hepatitis C Genotype 1: A Systematic Review and Network Meta-Analysis

    PubMed Central

    Sobhonslidsuk, Abhasnee; Thakkinstian, Ammarin; Teerawattananon, Yot

    2015-01-01

    Background The treatment of hepatitis C (HCV) infections has significantly changed in the past few years due to the introduction of direct-acting antiviral agents (DAAs). DAAs could improve the sustained virological response compared to pegylated interferon with ribavirin (PR). However, there has been no evidence from randomized controlled trials (RCTs) that directly compare the efficacy among the different regimens of DAAs. Aim Therefore, we performed a systematic review and network meta-analysis aiming to compare the treatment efficacy between different DAA regimens for treatment naïve HCV genotype 1. Methods Medline and Scopus were searched up to 25th May 2015. RCTs investigating the efficacy of second generation DAA regimens for treatment naïve HCV genotype 1 were eligible for the review. Due to the lower efficacy and more side effects of first generation DAAs, this review included only second generation DAAs approved by the US or EU Food and Drug Administration, that comprised of simeprevir (SMV), sofosbuvir (SOF), daclatasvir (DCV), ledipasvir (LDV), and paritaprevir/ritonavir/ombitasvir plus dasabuvir (PrOD). Primary outcomes were sustained virological response at weeks 12 (SVR12) and 24 (SVR24) after the end of treatment and adverse drug events (i.e. serious adverse events, anemia, and fatigue). Efficacy of all treatment regimens were compared by applying a multivariate random effect meta-analysis. Incidence rates of SVR12 and SVR24, and adverse drug events of each treatment regimen were pooled using ‘pmeta’ command in STATA program. Results Overall, 869 studies were reviewed and 16 studies were eligible for this study. Compared with the PR regimen, SOF plus PR, SMV plus PR, and DVC plus PR regimens yielded significantly higher probability of having SVR24 with pooled risk ratios (RR) of 1.98 (95% CI 1.24, 3.14), 1.46 (95% CI: 1.22, 1.75), and 1.68 (95% CI: 1.14, 2.46), respectively. Pooled incidence rates of SVR12 and SVR24 in all treatment regimens

  4. Evaluation of Dual Therapy in Real Life Setting in Treatment-Naïve Turkish Patients with HCV Infection: A Multicenter, Retrospective Study

    PubMed Central

    Gürbüz, Yunus; Tülek, Necla Eren; Tütüncü, Emin Ediz; Koruk, Süda Tekin; Aygen, Bilgehan; Demirtürk, Neşe; Kınıklı, Sami; Kaya, Ali; Yıldırmak, Taner; Süer, Kaya; Korkmaz, Fatime; Ural, Onur; Akhan, Sıla; Günal, Özgür; Tuna, Nazan; Köse, Şükran; Gönen, İbak; Örmen, Bahar; Türker, Nesrin; Saltoğlu, Neşe; Batırel, Ayşe; Tuncer, Günay; Bulut, Cemal; Sırmatel, Fatma; Ulçay, Asım; Karagöz, Ergenekon; Tosun, Derviş; Şener, Alper; Aynıoğlu, Aynur; Altunok, Elif Sargın

    2016-01-01

    Background: Before the introduction of direct-acting antivirals in the treatment of chronic hepatitis C patients, the combination of peginterferon alpha and ribavirin was the standard therapy. Observational studies that investigated sustained virological response (SVR) rates by these drugs yielded different outcomes. Aims: The goal of the study was to demonstrate real life data concerning SVR rate achieved by peginterferon alpha plus ribavirin in patients who were treatment-naïve. Study Design: A multicenter, retrospective observational study. Methods: The study was conducted retrospectively on 1214 treatment naïve-patients, being treated with peginterferon alpha-2a or 2b plus ribavirin in respect of the current guidelines between 2005 and 2013. The patients’ data were collected from 22 centers via a standard form, which has been prepared for this study. The data included demographic and clinical characteristics (gender, age, body weight, initial Hepatitis C virus RNA (HCV RNA) level, disease staging) as well as course of treatment (duration of treatment, outcomes, discontinuations and adverse events). Renal insufficiency, decompensated liver disease, history of transplantation, immunosuppressive therapy or autoimmune liver disease were exclusion criteria for the study. Treatment efficacy was assessed according to the patient’s demographic characteristics, baseline viral load, genotype, and fibrosis scores. Results: The mean age of the patients was 50.74 (±0.64) years. Most of them were infected with genotype 1 (91.8%). SVR was achieved in 761 (62.7%) patients. SVR rate was 59.1% in genotype 1, 89.4% in genotype 2, 93.8% in genotype 3, and 33.3% in genotype 4 patients. Patients with lower viral load yielded higher SVR (65.8% vs. 58.4%, p=0.09). SVR rates according to histologic severity were found to be 69.3%, 66.3%, 59.9%, 47.3%, and 45.5% in patients with fibrosis stage 0, 1, 2, 3 and 4, respectively. The predictors of SVR were male gender, genotype 2

  5. Clinical response to eliglustat in treatment-naïve patients with Gaucher disease type 1: Post-hoc comparison to imiglucerase-treated patients enrolled in the International Collaborative Gaucher Group Gaucher Registry.

    PubMed

    Ibrahim, Jennifer; Underhill, Lisa H; Taylor, John S; Angell, Jennifer; Peterschmitt, M Judith

    2016-09-01

    Eliglustat is a recently approved oral therapy in the United States and Europe for adults with Gaucher disease type 1 who are CYP2D6 extensive, intermediate, or poor metabolizers (> 90% of patients) that has been shown to decrease spleen and liver volume and increase hemoglobin concentrations and platelet counts in untreated adults with Gaucher disease type 1 and maintain these parameters in patients previously stabilized on enzyme replacement therapy. In a post-hoc analysis, we compared the results of eliglustat treatment in treatment-naïve patients in two clinical studies with the results of imiglucerase treatment among a cohort of treatment-naïve patients with comparable baseline hematologic and visceral parameters in the International Collaborative Gaucher Group Gaucher Registry. Organ volumes and hematologic parameters improved from baseline in both treatment groups, with a time course and degree of improvement in eliglustat-treated patients similar to imiglucerase-treated patients. PMID:27408819

  6. The cumulative effect of coffee and a mental stress task on heart rate, blood pressure, and mental alertness is similar in caffeine-naïve and caffeine-habituated females.

    PubMed

    Kennedy, Michael D; Galloway, Ashley V; Dickau, Leanne J; Hudson, Megan K

    2008-09-01

    Most North American workers drink coffee throughout their workday, although the cumulative effect of job stress and coffee is not well known. Research has shown that coffee affects the cardiovascular system and mental alertness primarily through the active ingredient caffeine; however, the dose of caffeine used in these studies is greater than a normal cup of coffee. In addition, these changes have been mostly determined in male caffeine-habituated consumers. Therefore, this study examined the effect of a normal cup of coffee on the cardiovascular and mental alertness response both before and after a mental stress task in 10 caffeine-naïve (23 +/- 5.0 years) and 10 caffeine-habituated (25 +/- 6 years) females. Blood pressure, heart rate, and mental alertness were taken at baseline (before coffee), 50 minutes after finishing coffee and immediately after a 9-minute mental stress task. The volume of coffee ingested for a 15-minute period was 350 mL (12 oz), which is equivalent to 140 mg of caffeine. The combined effect of coffee and mental stress significantly decreased diastolic blood pressure (Delta8 mm Hg) and increased heart rate (Delta6 beats per minute) and mental alertness (Delta67.3%) in caffeine-naïve and caffeine-habituated females, whereas systolic blood pressure (Delta10.3 mm Hg) only increased in the caffeine-naïve participants. Our results indicate that a normal cup of coffee can effect changes in blood pressure and mental alertness and that mental stress may alter the magnitude of change; however, the transient increase in systolic blood pressure after drinking coffee in caffeine-naïve participants requires further investigation. PMID:19083466

  7. HIV-1 Drug Resistance Mutations Among Antiretroviral-Naïve HIV-1–Infected Patients in Asia: Results From the TREAT Asia Studies to Evaluate Resistance-Monitoring Study

    PubMed Central

    Oyomopito, Rebecca; Sirivichayakul, Sunee; Sirisanthana, Thira; Kantipong, Pacharee; Lee, Christopher K. C.; Kamarulzaman, Adeeba; Messerschmidt, Liesl; Law, Matthew G.; Phanuphak, Praphan

    2011-01-01

    (See editorial commentary by Jordan on pages 1058–1060.) Of 682 antiretroviral-naïve patients initiating antiretroviral therapy in a prospective, multicenter human immunodeficiency virus type 1 (HIV-1) drug resistance monitoring study involving 8 sites in Hong Kong, Malaysia, and Thailand, the prevalence of patients with ≥1 drug resistance mutation was 13.8%. Primary HIV drug resistance is emerging after rapid scaling-up of antiretroviral therapy use in Asia. PMID:21460324

  8. Regarding: Rosenthal DI, Glatstein E. "We've Got a Treatment, but What's the Disease?" The Oncologist 1996;1.

    PubMed

    Lunsford; Flickinger; Larson

    1997-01-01

    To the Editors: We have read with interest and some concern the recently published editorial, "We've Got a Treatment, but What's the Disease," by Rosenthal and Glatstein. This editorial enunciates these common anxieties (? "mid-life") about radiosurgery: A) that thedure as currently practiced worldwide, even in the United States, does not in all cases rely on the talents of radiation oncologists; B) that the technique disregards fundamental (? proven) principles about radiobiology, and C) that the authors of the editorial have chosen to ignore a tremendous body of historical and clinical literature relative to outcomes. In fact, long-term clinical data have been published in a wide variety of reports during the last ten years. Their reference list does not include a single article published beyond 1992. Now let's address the first issue. While it is true that the advantages obtained by closed skull focused stereotactic single session irradiation of a small but well-defined intracranial target volume (radiosurgery) were first espoused and practiced by neuosurgeons, the goal was not to impact upon the turf of the radiation oncologist. The goal was to provide a minimally invasive treatment for many problems deep within the brain for which traditional neurosurgical procedures were neither satisfactory nor effective. The tools that allowed neurosurgeons to accomplish this goal included focused particle beams or photon beams generated by the gamma knife or by linear accelerators. The technique also required highly precise (<1 mm) intracranial guiding systems (stereotactic technology). The initial evolution of this technology was cautious. It was based on more than 30 years of experimental and clinical work that preceded its introduction into the worldwide medical community beginning in the mid-1980s. In the United States, the vast majority of centers provide this technology based on the multidisciplinary input of neurosurgeons, radiation oncologists and medical

  9. Renal Function Impairment and Associated Factors among HAART Naïve and Experienced Adult HIV Positive Individuals in Southwest Ethiopia: A Comparative Cross Sectional Study

    PubMed Central

    Mekuria, Yewulsew; Yilma, Daniel; Mekonnen, Zeleke; Kassa, Tesfaye; Gedefaw, Lealem

    2016-01-01

    Background Human immunodeficiency virus (HIV) infection and its treatment cause renal diseases. Renal disease is associated with an increasing cause of morbidity and mortality in HIV positive individuals than in the general population. It has been also associated with adverse outcomes, such as complications of decreased renal functions and progression to renal failure. Objective To determine the prevalence and factors associated with renal function impairment among highly active antiretroviral therapy (HAART) naive and HAART experienced adult HIV positive individuals. Methods A facility based comparative cross-sectional study was conducted in Jimma University Specialized Hospital (JUSH) from June to September 2014. HIV positive individuals who visited JUSH during the study period were included in the study. Sociodemographic and clinical data were collected using a structured questionnaire. Blood specimen was analyzed for renal function tests. Descriptive statistics, Mann-Whitney U test and logistic regression analysis were done using SPSS version 16 software. Results A total of 446 HIV positive individuals, 223 HAART naïve and 223 HAART experienced, were recruited. The overall prevalence of renal function impairment was 18.2% [95%CI: 14.6–21.7]. The prevalence of renal impairment in HAART naive and HAART experienced persons was 28.7% [95%CI: 23.1–34.4] and 7.6% [95%CI: 4.6–11.6], respectively. Age ≥ 50 years (AOR = 3.6; 95% CI 1.4, 9.6), advanced WHO stage (AOR = 2.3; 95% CI 1.1, 4.7), and CD4 count <200 (AOR = 6.9; 95% CI 3.3, 14.2) were independent risk factors among HAART naive participants. Female gender (AOR = 6.6; 95 CI % 1.2, 34), age ≥ 50 years (AOR = 12.1; 95% CI 1.7, 84) and CD4 count <200 (AOR = 17; 95% CI 5.2, 58) were independent risk factors among HAART experienced participants. Conclusion The prevalence of renal function impairment was higher among HAART naïve than HAART experienced HIV positive individuals. Renal function impairment was

  10. Coupling Self-Organizing Maps with a Naïve Bayesian classifier: A case study for classifying Vermont streams using geomorphic, habitat and biological assessment data

    NASA Astrophysics Data System (ADS)

    Fytilis, N.; Rizzo, D. M.

    2012-12-01

    Environmental managers are increasingly required to forecast the long-term effects and the resilience or vulnerability of biophysical systems to human-generated stresses. Mitigation strategies for hydrological and environmental systems need to be assessed in the presence of uncertainty. An important aspect of such complex systems is the assessment of variable uncertainty on the model response outputs. We develop a new classification tool that couples a Naïve Bayesian Classifier with a modified Kohonen Self-Organizing Map to tackle this challenge. For proof-of-concept, we use rapid geomorphic and reach-scale habitat assessments data from over 2500 Vermont stream reaches (~1371 stream miles) assessed by the Vermont Agency of Natural Resources (VTANR). In addition, the Vermont Department of Environmental Conservation (VTDEC) estimates stream habitat biodiversity indices (macro-invertebrates and fish) and a variety of water quality data. Our approach fully utilizes the existing VTANR and VTDEC data sets to improve classification of stream-reach habitat and biological integrity. The combined SOM-Naïve Bayesian architecture is sufficiently flexible to allow for continual updates and increased accuracy associated with acquiring new data. The Kohonen Self-Organizing Map (SOM) is an unsupervised artificial neural network that autonomously analyzes properties inherent in a given a set of data. It is typically used to cluster data vectors into similar categories when a priori classes do not exist. The ability of the SOM to convert nonlinear, high dimensional data to some user-defined lower dimension and mine large amounts of data types (i.e., discrete or continuous, biological or geomorphic data) makes it ideal for characterizing the sensitivity of river networks in a variety of contexts. The procedure is data-driven, and therefore does not require the development of site-specific, process-based classification stream models, or sets of if-then-else rules associated with

  11. Decreased Frequencies of Circulating Follicular Helper T Cell Counterparts and Plasmablasts in Ankylosing Spondylitis Patients Naïve for TNF Blockers

    PubMed Central

    Bautista-Caro, María-Belén; Arroyo-Villa, Irene; Castillo-Gallego, Concepción; de Miguel, Eugenio; Peiteado, Diana; Plasencia-Rodríguez, Chamaida; Villalba, Alejandro; Sánchez-Mateos, Paloma; Puig-Kröger, Amaya; Martín-Mola, Emilio; Miranda-Carús, María-Eugenia

    2014-01-01

    Follicular helper T cells (Tfh), localized in lymphoid organs, promote B cell differentiation and function. Circulating CD4 T cells expressing CXCR5, ICOS and/or PD-1 are counterparts of Tfh. Three subpopulations of circulating CD4+CXCR5+ cells have been described: CXCR3+CCR6- (Tfh-Th1), CXCR3-CCR6+ (Tfh-Th17), and CXCR3-CCR6- (Tfh-Th2). Only Tfh-Th17 and Tfh-Th2 function as B cell helpers. Our objective was to study the frequencies of circulating Tfh (cTfh), cTfh subsets and plasmablasts (CD19+CD20-CD27+CD38high cells), and the function of cTfh cells, in patients with Ankylosing Spondylitis (AS). To this end, peripheral blood was drawn from healthy controls (HC) (n = 50), AS patients naïve for TNF blockers (AS/nb) (n = 25) and AS patients treated with TNF blockers (AS/b) (n = 25). The frequencies of cTfh and plasmablasts were determined by flow cytometry. Cocultures of magnetically sorted CD4+CXCR5+ T cells with autologous CD19+CD27- naïve B cells were established from 3 AS/nb patients and 3 HC, and concentrations of IgG, A and M were measured in supernatants. We obseved that AS/nb but not AS/b patients, demonstrated decreased frequencies of circulating CD4+CXCR5+ICOS+PD-1+ cells and plasmablasts, together with a decreased (Tfh-Th17+Tfh-Th2)/Tfh-Th1 ratio. The amounts of IgG and IgA produced in cocultures of CD4+CXCR5+ T cells with CD19+CD27- B cells of AS/nb patients were significantly lower than observed in cocultures established from HC. In summary, AS/nb but not AS/b patients, demonstrate a decreased frequency of cTfh and plasmablasts, and an underrepresentation of cTfh subsets bearing a B helper phenotype. In addition, peripheral blood CD4+CXCR5+ T cells of AS/nb patients showed a decreased capacity to help B cells ex vivo. PMID:25203742

  12. Effects of nateglinide and acarbose on glycemic excursions in standardized carbohydrate and mixed-meal tests in drug-naïve type 2 diabetic patients

    PubMed Central

    LI, HAI; XU, WENMING; LIU, JUAN; CHEN, AILING; LIAO, ZHIHONG; LI, YANBING

    2013-01-01

    The aim of this study was to compare the effects of nateglinide and acarbose on glycemic excursions and postprandial glucose profiles with different types of meals (standardized carbohydrate and mixed meals) in drug-naïve type 2 diabetic patients. A randomized, parallel-group prospective design clinical trial was conducted and a total of 39 drug-naïve patients (16 males and 23 females, aged 56.7±10.2 years) were enrolled. The patients were randomly divided into group A [nateglinide 120 mg three times daily (t.i.d.), n=19] and group B (acarbose 50 mg t.i.d., n=20). The standardized carbohydrate and mixed-meal tests were performed at baseline and at the end of study. Continuous glucose monitoring system (CGMS) data were recorded. Various parameters that measure glucose variability were derived from the CGMS data. In the standardized carbohydrate meal tests, the postprandial glucose excursions (PPGEs) were significantly decreased in the two groups after 12 weeks of treatment (P<0.05), whereas the decrease was more prominent in the acarbose compared to the nateglinide group (P=0.138). In the mixed-meal tests, the mean sensor glucose values [24-h mean blood glucose (MBG)] were significantly decreased in the two groups after 12 weeks of treatment (P<0.05) and the parameters of glucose excursions, including standardized deviation (SD), largest amplitude of glycemic excursion (LAGE), mean of daily differences (MODD) and mean amplitude of glycemic excursion (MAGE), were reduced in the two groups. However, the decreases in SD and LAGE in the nateglinide group were statistically significant, whereas in the acarbose group only the decreases in LAGE were statistically significant. The efficiency of nateglinide or acarbose in lowering postprandial 120-min hyperglycemia were similar in the standardized carbohydrate meal test. However, acarbose was more efficient in lowering postprandial 30- and 60-min hyperglycemia (P<0.05) compared to nateglinide. The fasting and postprandial

  13. Imaging Characteristics of Driver Mutations in EGFR, KRAS, and ALK among Treatment-Naïve Patients with Advanced Lung Adenocarcinoma

    PubMed Central

    Park, Jangchul; Kobayashi, Yoshihisa; Urayama, Kevin Y.; Yamaura, Hidekazu; Yatabe, Yasushi; Hida, Toyoaki

    2016-01-01

    This study aimed to identify the computed tomography characteristics of treatment-naïve patients with lung adenocarcinoma and known driver mutations in EGFR, KRAS, or ALK. Patients with advanced lung adenocarcinoma (stage IIIB–IV) and known mutations in EGFR, KRAS, or ALK were assessed. The radiological findings for the main tumor and intra-thoracic status were retrospectively analyzed in each group, and the groups’ characteristics were compared. We identified 265 treatment-naïve patients with non-small-cell carcinoma, who had EGFR mutations (n = 159), KRAS mutations (n = 55), or ALK rearrangements (n = 51). Among the three groups, we evaluated only patients with stage IIIB–IV lung adenocarcinoma who had EGFR mutations (n = 126), KRAS mutations (n = 35), or ALK rearrangements (n = 47). We found that ground-glass opacity at the main tumor was significantly more common among EGFR-positive patients, compared to ALK-positive patients (p = 0.009). Lymphadenopathy was significantly more common among ALK-positive patients, compared to EGFR-positive patients (p = 0.003). Extranodal invasion was significantly more common among ALK-positive patients, compared to EGFR-positive patients and KRAS-positive patients (p = 0.001 and p = 0.049, respectively). Lymphangitis was significantly more common among ALK-positive patients, compared to EGFR-positive patients (p = 0.049). Pleural effusion was significantly less common among KRAS-positive patients, compared to EGFR-positive patients and ALK-positive patients (p = 0.046 and p = 0.026, respectively). Lung metastases were significantly more common among EGFR-positive patients, compared to KRAS-positive patients and ALK-positive patients (p = 0.007 and p = 0.04, respectively). In conclusion, EGFR mutations were associated with ground-glass opacity, KRAS-positive tumors were generally solid and less likely to metastasize to the lung and pleura, and ALK-positive tumors tended to present with lymphadenopathy, extranodal

  14. Impact of telephonic interviews on persistence and daily adherence to insulin treatment in insulin-naïve type 2 diabetes patients: dropout study

    PubMed Central

    Yavuz, Dilek Gogas; Bilen, Habip; Sancak, Seda; Garip, Tayfun; Hekimsoy, Zeliha; Sahin, Ibrahim; Yilmaz, Murat; Aydin, Hasan; Atmaca, Aysegul; Sert, Murat; Karakaya, Pinar; Arpaci, Dilek; Oguz, Aytekin; Guvener, Nilgun

    2016-01-01

    Objective The objective of this study is to evaluate the impact of sequential telephonic interviews on treatment persistence and daily adherence to insulin injections among insulin-naïve type 2 diabetes patients initiated on different insulin regimens in a 3-month period. Methods A total of 1,456 insulin-naïve patients with type 2 diabetes (mean [standard deviation, SD] age: 56.0 [12.0] years, 49.1% were females) initiated on insulin therapy and consecutively randomized to sequential (n=733) and single (n=723) telephonic interview groups were included. Data on insulin treatment and self-reported blood glucose values were obtained via telephone interview. Logistic regression analysis was performed for factors predicting increased likelihood of persistence and skipping an injection. Results Overall, 76.8% patients (83.2% in sequential vs 70.3% in single interview group, (P<0.001) remained on insulin treatment at the third month. Significantly higher rate for skipping doses was noted in basal bolus than in other regimens (27.0% vs 15.0% for premixed and 15.8% basal insulin, respectively, P<0.0001). Logistic regression analysis revealed sequential telephonic interview (odds ratio [OR], 1.531; 95% confidence interval [CI], 1.093–2.143; P=0.013), higher hemoglobin A1c levels (OR, 1.090; 95% CI, 0.999–1.189; P=0.049), and less negative appraisal of insulin therapy as significant predictors of higher persistence. Basal bolus regimen (OR, 1.583; 95% CI, 1.011–2.479; P=0.045) and higher hemoglobin A1c levels (OR, 1.114; 95% CI, 1.028–1.207; P=0.008) were the significant predictors of increased likelihood of skipping an injection. Conclusion Our findings revealed positive influence of sequential telephonic interview, although including no intervention in treatment, on achieving better treatment persistence in type 2 diabetes patients initiating insulin. PMID:27274207

  15. Safe and Effective Use of the Once Weekly Dulaglutide Single-Dose Pen in Injection-Naïve Patients With Type 2 Diabetes

    PubMed Central

    Matfin, Glenn; Van Brunt, Kate; Zimmermann, Alan G.; Threlkeld, Rebecca; Ignaut, Debra A.

    2015-01-01

    Background: This 4-week, phase 3b, multicenter, open-label, single-arm, outpatient study demonstrated the safe and effective use of the dulaglutide single-dose pen containing 0.5 mL of placebo for subcutaneous injection in injection-naïve adult patients with type 2 diabetes (T2D), with A1C ≤ 8.5% (69 mmol/mol), BMI ≥ 23 kg/m2 and ≤ 45 kg/m2. Method: Patients completed a modified self-injecting subscale of the Diabetes Fear of Injecting and Self-Testing Questionnaire (mD-FISQ) and were trained to self-inject with the single-dose pen. Patients completed the initial self-injection at the site, injected at home for 2 subsequent weeks, and returned to the site for the final injection. The initial and final self-injections were evaluated for success; the final (initial) self-injection success rate was the primary (secondary) outcome measure, and the primary (secondary) objective was to demonstrate this success rate as being significantly greater than 80%. Patients recorded their level of pain after each injection. After the final injection, patients completed the mD-FISQ and the Medication Delivery Device Assessment Battery (MDDAB) to assess their perceptions of the single-dose pen, including ease of use and experience with the device. Results: Among 211 patients (mean age: 61 years), the primary objective was met, with a final injection success rate of 99.1% (95% CI: 96.6% to 99.7%). Among 214 patients, the initial injection success rate was 97.2% (95% CI: 94.0% to 98.7%), meeting the key secondary objective. Overall, most patients (>96%) found the device easy to use, were satisfied with the device, and would be willing to continue to use the single-dose pen after the study. There was a significant reduction (P < .001) from baseline to study end in patients’ fear of self-injecting, as measured by the mD-FISQ. Conclusions: The dulaglutide single-dose pen was found to be a safe and effective device for use by patients with T2D who were injection-naïve. A

  16. Modified Directly Observed Antiretroviral Therapy Compared with Self-Administered Therapy in Treatment-Naïve HIV-1 Infected Patients: A Randomized Trial

    PubMed Central

    Gross, Robert; Tierney, Camlin; Andrade, Adriana; Lalama, Christina; Rosenkranz, Susan; Eshleman, Susan H.; Flanigan, Timothy; Santana, Jorge; Salomon, Nadim; Reisler, Ronald; Wiggins, Ilene; Hogg, Evelyn; Flexner, Charles; Mildvan, Donna

    2009-01-01

    Context Success of antiretroviral therapy depends on high rates of adherence, but few interventions are effective. Objective Determine if modified directly observed therapy (mDOT) improves initial antiretroviral success. Design Open-label randomized trial comparing mDOT and self-administered therapy with lopinavir/ritonavir soft gel capsules 800 mg/200 mg, emtricitabine 200 mg, and either extended release stavudine 100 mg or tenofovir 300 mg, all once daily. Setting 23 U.S. AIDS Clinical Trials Group (ACTG) sites and one in South Africa between October 2002 and January 2006. Participants Plasma HIV RNA ≥2000 copies/ml and antiretroviral-naïve. 82 participants received mDOT and 161 self-administration. Participants were predominantly male (79%), median age 38 years, with 84 Latinos (35%), 74 non-Latino blacks (30%), and 79 non-Latino whites (33%). Intervention mDOT Monday through Friday for 24 weeks. Main Outcome Measure(s) Primary outcome was week 24 virologic success and secondary outcomes were week 48 virologic success, clinical progression, and adherence. Results mDOT had greater virologic success over 24 weeks [0.91 (95% CI: 0.81, 0.95)] than self-administered therapy [0.84 (95% CI: 0.77, 0.89)], but the difference [0.07 (lower bound 95% CI: −0.01)] did not reach the pre-specified threshold of 0.075. Over 48 weeks, virologic success was not significantly different between mDOT [0.72 (95% CI: 0.61, 0.81)] and self-administered therapy [0.78 (95% CI: 0.70, 0.84)], [−0.06 (95% CI: −0.18, 0.07); p=0.19)]. Conclusions The potential benefit of mDOT was marginal and not sustained after mDOT was discontinued. mDOT should not be incorporated routinely for care of treatment naïve HIV-1 infected patients. PMID:19597072

  17. Causal connectivity alterations of cortical-subcortical circuit anchored on reduced hemodynamic response brain regions in first-episode drug-naïve major depressive disorder

    PubMed Central

    Gao, Qing; Zou, Ke; He, Zongling; Sun, Xueli; Chen, Huafu

    2016-01-01

    Some efforts were done to investigate the disruption of brain causal connectivity networks involved in major depressive disorder (MDD) using Granger causality (GC) analysis. However, the homogenous hemodynamic response function (HRF) assumption over the brain may disturb the inference of temporal precedence. Here we applied a blind deconvolution approach to examine the altered HRF shape in first-episode, drug-naïve MDD patients. The regions with abnormal HRF shape in patients were chosen as seeds to detect the GC alterations in MDD. The results demonstrated significantly decreased magnitude of spontaneous hemodynamic response of the orbital frontal cortex (OFC) and the caudate nucleus (CAU) in MDD comparing to healthy controls, suggesting MDD patients likely had alterations in neurovascular coupling and cerebrovascular physiology in these two regions. GC mapping showed increased/decreased GC in OFC-/CAU centered networks in MDD. The outgoing GC values from OFC to anterior cingulate cortex and occipital regions were positively correlated with Hamilton Depression Scale (HAMD) scores, while the incoming GC from insula, middle and superior temporal gyrus to CAU were negatively correlated with HAMD scores of MDD. The abnormalities of directional connections in the cortico-subcortico-cerebellar network may lead to unbalanced integrating the emotional-related information for MDD, and further exacerbating depressive symptoms. PMID:26911651

  18. Alterations of naïve and memory B-cell subsets are associated with risk of rejection and infection in heart recipients.

    PubMed

    Lanio, Nallibe; Sarmiento, Elizabeth; Gallego, Antonio; Calahorra, Leticia; Jaramillo, María; Navarro, Joaquin; Palomo, Jesus; Fernandez-Yañez, Juan; Ruiz, Manuel; Fernandez-Cruz, Eduardo; Carbone, Javier

    2013-08-01

    Rejection and infection are relevant causes of mortality in heart recipients. We evaluated the kinetics of the maturation status of B lymphocytes and its relationship with acute cellular rejection and severe infection in heart recipients. We analyzed B-cell subsets using 4-color flow cytometry in a prospective follow-up study of 46 heart recipients. Lymphocyte subsets were evaluated at specific times before and up to 1 year after transplantation. Higher percentages of pretransplant class-switched memory B cells (CD19+CD27+IgM-IgD- >14%) were associated with a 74% decrease in the risk of severe infection [Cox regression relative hazard (RH) 0.26, 95% confidence interval (CI), 0.07-0.86; P = 0.027]. Patients with higher percentages of naïve B cells at day 7 after transplantation (CD19+CD27-IgM+IgD+ >58%) had a 91% decrease in the risk of developing acute cellular rejection (RH 0.09; 95% CI, 0.01-0.80; P = 0.02). Patients with infections showed a strong negative correlation between baseline serum B-cell-activating factor (BAFF) concentration and absolute counts of memory class-switched B cells (R = -0.81, P = 0.01). The evaluation of the immunophenotypic maturation status of B lymphocytes could prove to be a useful marker for identifying patients at risk of developing rejection or infection after heart transplantation. PMID:23746145

  19. Pirate stealth or inattentional blindness? The effects of target relevance and sustained attention on security monitoring for experienced and naïve operators.

    PubMed

    Näsholm, Erika; Rohlfing, Sarah; Sauer, James D

    2014-01-01

    Closed Circuit Television (CCTV) operators are responsible for maintaining security in various applied settings. However, research has largely ignored human factors that may contribute to CCTV operator error. One important source of error is inattentional blindness--the failure to detect unexpected but clearly visible stimuli when attending to a scene. We compared inattentional blindness rates for experienced (84 infantry personnel) and naïve (87 civilians) operators in a CCTV monitoring task. The task-relevance of the unexpected stimulus and the length of the monitoring period were manipulated between participants. Inattentional blindness rates were measured using typical post-event questionnaires, and participants' real-time descriptions of the monitored event. Based on the post-event measure, 66% of the participants failed to detect salient, ongoing stimuli appearing in the spatial field of their attentional focus. The unexpected task-irrelevant stimulus was significantly more likely to go undetected (79%) than the unexpected task-relevant stimulus (55%). Prior task experience did not inoculate operators against inattentional blindness effects. Participants' real-time descriptions revealed similar patterns, ruling out inattentional amnesia accounts. PMID:24465932

  20. Altered resting state functional connectivity of anterior cingulate cortex in drug naïve adolescents at the earliest stages of anorexia nervosa

    PubMed Central

    Gaudio, Santino; Piervincenzi, Claudia; Beomonte Zobel, Bruno; Romana Montecchi, Francesca; Riva, Giuseppe; Carducci, Filippo; Cosimo Quattrocchi, Carlo

    2015-01-01

    Previous Resting-State Functional Connectivity (RSFC) studies have shown several functional alterations in adults with or recovered from long Anorexia Nervosa (AN). The aim of this paper was to investigate whole brain RSFC in adolescents with AN in the earliest stages, less than 6 months, of the disorder. Sixteen drug-naïve outpatient female adolescents with AN-restrictive type (AN-r) (mean age: 15,8; SD 1,7) were compared to 16 age-matched healthy female (mean age: 16,3; SD 1,4). Relevant resting state networks (RSNs) were identified using independent component analysis (ICA) from functional magnetic resonance imaging data; a dual regression technique was used to detect between-group differences in the RSNs. Between-group differences of the functional connectivity maps were found in the executive control network (ECN). Particularly, decreased temporal correlation was observed in AN-r patients relative to healthy controls between the ECN functional connectivity maps and the anterior cingulate cortex (p < 0.05 corrected). Our results in AN adolescents may represent an early trait-related biomarker of the disease. Considering that the above mentioned network and its area are mainly involved in cognitive control and emotional processing, our findings could explain the impaired cognitive flexibility in relation to body image and appetite in AN patients. PMID:26043139

  1. Application of Karhunen-Loève Expansions for the Dynamic Analysis of a Natural Convection Loop for Known Heat Flux

    NASA Astrophysics Data System (ADS)

    Hummel, Tobias; Pacheco-Vega, Arturo

    2012-11-01

    In the present study we use Karhunen-Loève (KL) expansions to model the dynamic behavior of a single-phase natural convection loop. The loop is filled with an incompressible fluid that exchanges heat through the walls of its toroidal shape. Influx and efflux of energy take place at different parts of the loop. The focus here is a sinusoidal variation of the heat flux exchanged with the environment for three different scenarios; i.e., stable, limit cycles and chaos. For the analysis, one-dimensional models, in which the tilt angle and the amplitude of the heat flux are used as parameters, were first developed under suitable assumptions and then solved numerically to generate the data from which the KL-based models could be constructed. The method of snapshots, along with a Galerkin projection, was then used to find the basis functions and corresponding constants of each expansion, thus producing the optimal representation of the system. Results from this study indicate that the dimension of the KL-based dynamical system depends on the linear stability of the steady states; the number of basis functions necessary to describe the system increases with increased complexity of the system operation. When compared to typical dynamical systems based on Fourier expansions the KL-based models are, in general, more compact and equally accurate in the dynamic description of the natural convection loop.

  2. Monitoring of local CD8β-expressing cell populations during Eimeria tenella infection of naïve and immune chickens.

    PubMed

    Wattrang, E; Thebo, P; Lundén, A; Dalgaard, T S

    2016-08-01

    The purpose of this study was to monitor abundance and activation of local CD8β-expressing T-cell populations during Eimeria tenella infections of naïve chickens and chickens immune by previous infections. Chickens were infected with E. tenella up to three times. Caecal T-cell receptor (TCR) γ/δ-CD8β+ cells (cytotoxic T lymphocytes; CTL) and TCRγ/δ+CD8β+ cells were characterized with respect to activation markers (blast transformation, CD25 and cell surface CD107a). Cells were also induced to degranulate in vitro as a measure of activation potential. Major findings included a prominent long-lasting, up to 6 weeks, increase in the proportion of CTL among caecal CD45+ cells in the later stages after primary E. tenella infection. These CTL also showed clear signs of activation, that is blast transformation and increased in vitro induced degranulation. At second and third E. tenella infection, chickens showed strong protective immunity but discrete signs of cellular activation were observed, for example increased in vitro induced degranulation of CTL. Thus, primary E. tenella infection induced clear recruitment and activation of local CTL. Upon subsequent infections of strongly immune chickens cellular changes were less prominent, possibly due to lower overall numbers of cells being activated because of the severe restriction of parasite replication. PMID:27138684

  3. Distribution of sulphuric acid aerosols in the clouds and upper haze of Venus using Venus Express VAST and VeRa temperature profiles

    NASA Astrophysics Data System (ADS)

    Parkinson, Christopher D.; Gao, Peter; Schulte, Rick; Bougher, Stephen W.; Yung, Yuk L.; Bardeen, Charles G.; Wilquet, Valérie; Vandaele, Ann Carine; Mahieux, Arnaud; Tellmann, Silvia; Pätzold, Martin

    2015-08-01

    Observations from Pioneer Venus and from SPICAV/SOIR aboard Venus Express (VEx) have shown the upper haze (UH) of Venus to be highly spatially and temporally variable, and populated by multiple particle size modes. Previous models of this system (e.g., Gao et al., 2014. Icarus 231, 83-98), using a typical temperature profile representative of the atmosphere (viz., equatorial VIRA profile), did not investigate the effect of temperature on the UH particle distributions. We show that the inclusion of latitude-dependent temperature profiles for both the morning and evening terminators of Venus helps to explain how the atmospheric aerosol distributions vary spatially. In this work we use temperature profiles obtained by two instruments onboard VEx, VeRa and SPICAV/SOIR, to represent the latitudinal temperature dependence. We find that there are no significant differences between results for the morning and evening terminators at any latitude and that the cloud base moves downwards as the latitude increases due to decreasing temperatures. The UH is not affected much by varying the temperature profiles; however, the haze does show some periodic differences, and is slightly thicker at the poles than at the equator. We also find that the sulphuric acid "rain" seen in previous models may be restricted to the equatorial regions of Venus, such that the particle size distribution is relatively stable at higher latitudes and at the poles.

  4. Relationship between clinical and patient-reported outcomes in a phase 3 trial of tofacitinib or MTX in MTX-naïve patients with rheumatoid arthritis

    PubMed Central

    Fleischmann, Roy; Strand, Vibeke; Wilkinson, Bethanie; Kwok, Kenneth; Bananis, Eustratios

    2016-01-01

    Objective To compare the relationship between clinical measures and patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA) treated with tofacitinib or methotrexate (MTX). Methods In a phase 3 randomised controlled trial, patients (N=956) who were MTX-naïve or had received ≤3 doses were randomised and received tofacitinib 5 or 10 mg twice daily or MTX titrated to 20 mg/week. Outcomes included: per cent of patients achieving American College of Rheumatology 70% responses (ACR70), ACR50, low disease activity (LDA) by Simplified Disease Activity Index (SDAI ≤11) and Clinical Disease Activity Index (CDAI ≤10), remission by SDAI (≤3.3) and CDAI (≤2.8), patient-reported Health Assessment Questionnaire-Disability Index (HAQ-DI scores <0.5), pain and global assessment of disease activity. Results At month 6, most patients who achieved LDA/remission by one definition achieved LDA/remission with others; however, discordance between measures was greater with MTX than with tofacitinib. As expected, concordance between CDAI and SDAI responses was high. Overall, patients achieving LDA or ACR50 responses reported less improvement in PROs (HAQ-DI, pain and patient global assessment) compared with clinical measures (tender and swollen joint counts). Conclusions Variability in levels of responses between clinical outcomes and PROs should be considered when setting treat-to-target goals in patients with RA. Trial registration number NCT01039688; Post-results. PMID:27175296

  5. Selfie and the city: a world-wide, large, and ecologically valid database reveals a two-pronged side bias in naïve self-portraits.

    PubMed

    Bruno, Nicola; Bertamini, Marco; Protti, Federica

    2015-01-01

    Self-portraits are more likely to show the artist's right than left cheek. This phenomenon may have a psychobiological basis: Self-portraitists often copy their subject from mirrors and, if they prefer to present their left cheek (more expressive due to right-lateralization of emotions) to the mirror, this would result in a right-cheek bias in the painting. We tested this hypothesis using SelfieCity (3200 selfies posted on Instagram from December 4 through 12, 2013 from New York, Sao Paulo, Berlin, Moskow, and Bangkok), which includes two selfie-taking styles: a "standard" (photograph of selfie-taker) and a "mirror" (photograph of mirror reflection of selfie-taker) style. We show that the first style reveals a left cheek bias, whereas the second reveals a right cheek bias. Thus side biases observed in a world-wide, large, and ecologically valid database of naïve self-portraits provide strong support for a role of psychobiological factors in the artistic composition of self-portraits. PMID:25915767

  6. Causal connectivity alterations of cortical-subcortical circuit anchored on reduced hemodynamic response brain regions in first-episode drug-naïve major depressive disorder.

    PubMed

    Gao, Qing; Zou, Ke; He, Zongling; Sun, Xueli; Chen, Huafu

    2016-01-01

    Some efforts were done to investigate the disruption of brain causal connectivity networks involved in major depressive disorder (MDD) using Granger causality (GC) analysis. However, the homogenous hemodynamic response function (HRF) assumption over the brain may disturb the inference of temporal precedence. Here we applied a blind deconvolution approach to examine the altered HRF shape in first-episode, drug-naïve MDD patients. The regions with abnormal HRF shape in patients were chosen as seeds to detect the GC alterations in MDD. The results demonstrated significantly decreased magnitude of spontaneous hemodynamic response of the orbital frontal cortex (OFC) and the caudate nucleus (CAU) in MDD comparing to healthy controls, suggesting MDD patients likely had alterations in neurovascular coupling and cerebrovascular physiology in these two regions. GC mapping showed increased/decreased GC in OFC-/CAU centered networks in MDD. The outgoing GC values from OFC to anterior cingulate cortex and occipital regions were positively correlated with Hamilton Depression Scale (HAMD) scores, while the incoming GC from insula, middle and superior temporal gyrus to CAU were negatively correlated with HAMD scores of MDD. The abnormalities of directional connections in the cortico-subcortico-cerebellar network may lead to unbalanced integrating the emotional-related information for MDD, and further exacerbating depressive symptoms. PMID:26911651

  7. Altered resting state functional connectivity of anterior cingulate cortex in drug naïve adolescents at the earliest stages of anorexia nervosa.

    PubMed

    Gaudio, Santino; Piervincenzi, Claudia; Beomonte Zobel, Bruno; Romana Montecchi, Francesca; Riva, Giuseppe; Carducci, Filippo; Quattrocchi, Carlo Cosimo

    2015-01-01

    Previous Resting-State Functional Connectivity (RSFC) studies have shown several functional alterations in adults with or recovered from long Anorexia Nervosa (AN). The aim of this paper was to investigate whole brain RSFC in adolescents with AN in the earliest stages, less than 6 months, of the disorder. Sixteen drug-naïve outpatient female adolescents with AN-restrictive type (AN-r) (mean age: 15,8; SD 1,7) were compared to 16 age-matched healthy female (mean age: 16,3; SD 1,4). Relevant resting state networks (RSNs) were identified using independent component analysis (ICA) from functional magnetic resonance imaging data; a dual regression technique was used to detect between-group differences in the RSNs. Between-group differences of the functional connectivity maps were found in the executive control network (ECN). Particularly, decreased temporal correlation was observed in AN-r patients relative to healthy controls between the ECN functional connectivity maps and the anterior cingulate cortex (p < 0.05 corrected). Our results in AN adolescents may represent an early trait-related biomarker of the disease. Considering that the above mentioned network and its area are mainly involved in cognitive control and emotional processing, our findings could explain the impaired cognitive flexibility in relation to body image and appetite in AN patients. PMID:26043139

  8. Detection of Natural Resistance-Associated Substitutions by Ion Semiconductor Technology in HCV1b Positive, Direct-Acting Antiviral Agents-Naïve Patients.

    PubMed

    Marascio, Nadia; Pavia, Grazia; Strazzulla, Alessio; Dierckx, Tim; Cuypers, Lize; Vrancken, Bram; Barreca, Giorgio Settimo; Mirante, Teresa; Malanga, Donatella; Oliveira, Duarte Mendes; Vandamme, Anne-Mieke; Torti, Carlo; Liberto, Maria Carla; Focà, Alfredo; The Sinergie-Umg Study Group

    2016-01-01

    Naturally occurring resistance-associated substitutions (RASs) can negatively impact the response to direct-acting antivirals (DAAs) agents-based therapies for hepatitis C virus (HCV) infection. Herein, we set out to characterize the RASs in the HCV1b genome from serum samples of DAA-naïve patients in the context of the SINERGIE (South Italian Network for Rational Guidelines and International Epidemiology, 2014) project. We deep-sequenced the NS3/4A protease region of the viral population using the Ion Torrent Personal Genome Machine, and patient-specific majority rule consensus sequence summaries were constructed with a combination of freely available next generation sequencing data analysis software. We detected NS3/4A protease major and minor variants associated with resistance to boceprevir (V36L), telaprevir (V36L, I132V), simeprevir (V36L), and grazoprevir (V36L, V170I). Furthermore, we sequenced part of HCV NS5B polymerase using Sanger-sequencing and detected a natural RAS for dasabuvir (C316N). This mutation could be important for treatment strategies in cases of previous therapy failure. PMID:27618896

  9. Associations of hippocampal metabolism and regional brain grey matter in neuroleptic-naïve ultra-high-risk subjects and first-episode schizophrenia.

    PubMed

    Nenadic, Igor; Maitra, Raka; Basu, Soumyajit; Dietzek, Maren; Schönfeld, Nils; Lorenz, Carsten; Gussew, Alexander; Amminger, G Paul; McGorry, Patrick; Reichenbach, Jürgen R; Sauer, Heinrich; Gaser, Christian; Smesny, Stefan

    2015-10-01

    Hippocampal pathology has been shown to be central to the pathophysiology of schizophrenia and a putative risk marker for developing psychosis. We applied both (1)H MRS (proton magnetic resonance spectroscopy) at 3Tesla and voxel-based morphometry (VBM) of high-resolution brain structural images in order to study the association of the metabolites glutamate (Glu) and N-acetyl-aspartate (NAA) in the hippocampus with whole-brain morphometry in 31 persons at ultra-high-risk for psychosis (UHR), 18 first-episode schizophrenia patients (Sz), and 42 healthy controls (all subjects being neuroleptic-naïve). Significantly diverging associations emerged for UHR subjects hippocampal glutamate showed positive correlation with the left superior frontal cortex, not seen in Sz or controls, while in first-episode schizophrenia patients a negative correlation was significant between glutamate and a left prefrontal area. For NAA, we observed different associations for left prefrontal and caudate clusters bilaterally for both high-risk and first-episode schizophrenia subjects, diverging from the pattern seen in healthy subjects. Our results suggest that associations of hippocampal metabolites in key areas of schizophrenia might vary due to liability to or onset of the disorder. PMID:26088723

  10. A retrospective database analysis of insulin use patterns in insulin-naïve patients with type 2 diabetes initiating basal insulin or mixtures

    PubMed Central

    Bonafede, Machaon MK; Kalsekar, Anupama; Pawaskar, Manjiri; Ruiz, Kimberly M; Torres, Amelito M; Kelly, Karen R; Curkendall, Suellen M

    2010-01-01

    Objective: To describe insulin persistence among patients with type 2 diabetes initiating insulin therapy with basal insulin or insulin mixtures and determine factors associated with nonpersistence. Research design and methods: The Thomson Reuters MarketScan® databases were used to retrospectively analyze insulin-naïve patients with type 2 diabetes by initiating insulin therapy. Insulin use was described using a variety of measures. The persistence to insulin was described using both a gap-based measure and the number of claims measure. Results: Patients in the basal insulin cohort (N = 15,255) primarily used insulin analogs (88.1%) and vial and syringe (97%). Patients in the mixture cohort (N = 2,732) were more likely to initiate on human insulin mixtures (62.5%) and vial and syringe (68.1%). Average time between insulin refills was 80 and 71 days for basal and mixture initiators, respectively. Nearly, 75% of basal insulin initiators and 65% of insulin mixture initiators had a 90-day gap in insulin prescriptions. More than half of all the patients had at least one insulin prescription per quarter. Patients initiating with insulin analogs were more likely to be persistent compared with those initiating with human insulin across both cohorts and measures of persistence (P < 0.001). Conclusion: Persistence to insulin therapy is poorer than one would anticipate, but appears to be higher in users of insulin analogs and insulin mixtures. PMID:20622915

  11. Effector lymphocyte-induced lymph node-like vasculature enables naïve T-cell entry into tumors and enhanced anti-tumor immunity

    PubMed Central

    Peske, J. David; Thompson, Elizabeth D.; Gemta, Lelisa; Baylis, Richard A.; Fu, Yang-Xin; Engelhard, Victor H.

    2015-01-01

    The presence of lymph node (LN)-like vasculature in tumors, characterized by expression of peripheral node addressin and chemokine CCL21, is correlated with T-cell infiltration and positive prognosis in breast cancer and melanoma patients. However, mechanisms controlling the development of LN-like vasculature and how it might contribute to a beneficial outcome for cancer patients are unknown. Here we demonstrate that LN-like vasculature is present in murine models of melanoma and lung carcinoma. It enables infiltration by naïve T-cells that significantly delay tumor outgrowth after intratumoral activation. Development of this vasculature is controlled by a mechanism involving effector CD8 T-cells and NK cells that secrete LTα3 and IFNγ. LN-like vasculature is also associated with organized aggregates of B-lymphocytes and gp38+ fibroblasts that resemble tertiary lymphoid organs that develop in models of chronic inflammation. These results establish LN-like vasculature as both a consequence of and key contributor to anti-tumor immunity. PMID:25968334

  12. Prognostic value of EEG asymmetries for development of drug-resistance in drug-naïve patients with genetic generalized epilepsies

    PubMed Central

    Karakis, Ioannis; Pathmanathan, Jay S.; Chang, Richard; Cook, E. Francis; Cash, Sydney S.; Cole, Andrew J.

    2014-01-01

    Objective Previous studies based solely on visual EEG analysis reported equivocal results regarding an association of pharmaco-resistance with EEG asymmetries in genetic generalized epilepsies (GGE). We addressed this issue by applying both visual and quantitative methods to the pretreatment EEG of GGE patients. Methods Socio-demographic/disease characteristics and response to treatment/discontinuation trial for these patients were recorded at 6 months and at last follow up. The first EEG was retrospectively, blindly, and visually assessed for focal slowing, focal discharges and also quantitatively analyzed for amplitude or latency asymmetries of generalized discharges. Association between these variables and development of drug-resistance was evaluated. Results Out of 51 subjects, 40% had some type of EEG asymmetry by visual, 37% by quantitative and 54% by combined analysis. Drug-resistance was identified in 52% of patients after 6 months and in 24% at the end of the follow up period (~4.2 years). 27% of patients underwent a discontinuation trial; 43% unsuccessfully. There was no association between baseline EEG asymmetries of any type and refractoriness to medical therapy, regardless of analytical method used. Conclusions In a carefully selected cohort of medication-naïve GGE patients, visual and quantitative asymmetries in the first EEG were not associated with the development of pharmaco-resistance. Significance These findings do not provide support for utilization of EEG asymmetries as a prognostic tool in GGE. PMID:24095154

  13. Pirate Stealth or Inattentional Blindness? The Effects of Target Relevance and Sustained Attention on Security Monitoring for Experienced and Naïve Operators

    PubMed Central

    Näsholm, Erika; Rohlfing, Sarah; Sauer, James D.

    2014-01-01

    Closed Circuit Television (CCTV) operators are responsible for maintaining security in various applied settings. However, research has largely ignored human factors that may contribute to CCTV operator error. One important source of error is inattentional blindness – the failure to detect unexpected but clearly visible stimuli when attending to a scene. We compared inattentional blindness rates for experienced (84 infantry personnel) and naïve (87 civilians) operators in a CCTV monitoring task. The task-relevance of the unexpected stimulus and the length of the monitoring period were manipulated between participants. Inattentional blindness rates were measured using typical post-event questionnaires, and participants' real-time descriptions of the monitored event. Based on the post-event measure, 66% of the participants failed to detect salient, ongoing stimuli appearing in the spatial field of their attentional focus. The unexpected task-irrelevant stimulus was significantly more likely to go undetected (79%) than the unexpected task-relevant stimulus (55%). Prior task experience did not inoculate operators against inattentional blindness effects. Participants' real-time descriptions revealed similar patterns, ruling out inattentional amnesia accounts. PMID:24465932

  14. Getting ready for invasions: can background level of risk predict the ability of naïve prey to survive novel predators?

    PubMed Central

    Ferrari, Maud C. O.; Crane, Adam L.; Brown, Grant E.; Chivers, Douglas P.

    2015-01-01

    Factors predicting the outcome of predator invasions on native prey communities are critical to our understanding of invasion ecology. Here, we tested whether background level of risk affected the survival of prey to novel predators, both native and invasive, predicting that high-risk environments would better prepare prey for invasions. We used naïve woodfrog as our prey and exposed them to a high or low risk regime either as embryos (prenatal exposure) or as larvae (recent exposure). Tadpoles were then tested for their survival in the presence of 4 novel predators: two dytiscid beetles, crayfish and trout. Survival was affected by both risk level and predator type. High risk was beneficial to prey exposed to the dytiscids larvae (ambush predators), but detrimental to prey exposed to crayfish or trout (pursuit predators). No effect of ontogeny of risk was found. We further documented that high-risk tadpoles were overall more active than their low-risk counterparts, explaining the patterns found with survival. Our results provide insights into the relationship between risk and resilience to predator invasions. PMID:25655436

  15. Responses of dopaminergic, serotonergic and noradrenergic networks to acute levo-tetrahydropalmatine administration in naïve rats detected at 9.4 T

    PubMed Central

    Liu, Xiping; Yang, Zheng; Li, Rupeng; Xie, Jun; Yin, Qian; Bloom, Alan S.; Li, Shi-Jiang

    2012-01-01

    Aim The aim of this study was to understand the neuropharmacological characteristics of levo-tetrahydropalmatine (l-THP), a recently found potential treatment for drug addiction, and discover its neural correlates and sites of action. Methods High-field pharmacological magnetic resonance imaging (phMRI) was used to detect activation induced by acute l-THP administration in the naïve rat brain at dose levels of 5, 10, 20 and 40 mg/kg. Results Interestingly, the pharmacological profile of l-THP selectively binds to the receptors of the dopaminergic, serotonergic and noradrenergic systems. Using the phMRI method, it was demonstrated that l-THP selectively activated the key brain regions of the dopaminergic, serotonergic and noradrenergic systems in a dose-dependent manner. Conclusion Numerous studies suggest a critical role of monoamines in the behavioral, pharmacological and addictive properties of psychostimulants. It is suggested that l-THP holds great potential to be a therapeutic medication for drug addiction. PMID:22079072

  16. Characteristics and genotype profiles of antiretroviral-naïve patients entering a Southern US HIV outpatient clinic 2009-2012.

    PubMed

    Seal, Paula S; Frontini, Maria; Jhita, Preya K; Deichmann, Paige C; Clark, Rebecca A

    2016-06-01

    The US city of New Orleans was ranked second in the nation for estimated HIV case rates in 2011. Opt-out testing was established at the Interim Louisiana Hospital in New Orleans in 2013. The majority of new diagnoses were referred to the HIV outpatient program. We conducted a retrospective chart review of newly referred antiretroviral-naïve patients establishing HIV care between January 2009 and June 2013 to characterise demographic and genotype profiles to assist in clinical management and needed services. Of the eligible 226 patients, 68% were men, and 88% were African American. Nearly half of the study patients were younger than 35 years of age. Forty-six percent had an initial CD4 count <200 cells/mm(3), and 39% had a HIV viral load >100,000 copies/mL. The antiretroviral class with the most common major mutation was the non-nucleoside reverse transcriptase inhibitors (NNRTIs) where K103N was the most common major NNRTI mutation at presentation. We observed that male patients showed more advanced disease with later presentation to care, confirming the need for earlier HIV diagnosis. When considering initial antiretroviral therapy, baseline genotype information is encouraged, particularly if considering a NNRTI-based regimen. PMID:26016726

  17. Engineering Human Peripheral Blood Stem Cell Grafts That Are Depleted of Naïve T Cells and Retain Functional Pathogen-Specific Memory T cells

    PubMed Central

    Bleakley, Marie; Heimfeld, Shelly; Jones, Lori A.; Turtle, Cameron; Riddell, Stanley R.; Shlomchik, Warren

    2014-01-01

    Graft-versus-host disease (GVHD) is a frequent major complication of allogeneic hematopoietic cell transplantation (HCT). The development of approaches that selectively deplete T cells that cause GVHD from allogeneic stem cell grafts and preserve T cells specific for pathogens may improve HCT outcomes. It has been hypothesized that the majority of T cells that can cause GVHD reside within the naïve T cell (TN) subset, and previous studies performed in mouse models and with human cells in vitro support this hypothesis. As a prelude to translating these findings to the clinic, we developed and evaluated a novel, two-step, clinically compliant procedure for manipulating peripheral blood stem cells (PBSC) to remove TN, preserve CD34+ hematopoietic stem cells, and provide for a fixed dose of memory T cells (TM) that includes T cells with specificity for common opportunistic pathogens encountered after HCT. Our studies demonstrate effective and reproducible performance of the immunomagnetic cell selection procedure for depleting TN. Moreover, after cell processing the CD45RA-depleted PBSC products are enriched for CD4+ and CD8+ TM with a central memory phenotype and contain TM cells that are capable of proliferating and producing effector cytokines in response to opportunistic pathogens. PMID:24525279

  18. Loss of thalamic serotonin transporters in early drug-naïve Parkinson's disease patients is associated with tremor: an [(123)I]beta-CIT SPECT study.

    PubMed

    Caretti, V; Stoffers, D; Winogrodzka, A; Isaias, I-U; Costantino, G; Pezzoli, G; Ferrarese, C; Antonini, A; Wolters, E-Ch; Booij, J

    2008-05-01

    In vitro studies revealed serotonin transporter (5-HTT) decline in Parkinson's disease (PD). Yet, few studies investigated thalamic 5-HTT in vivo and its effect on PD heterogeneity. We analyzed thalamic [(123)I]beta-CIT binding (mainly reflecting 5-HTT binding) in 32 drug-naïve PD patients and 13 controls with SPECT. Twenty-six patients were examined twice (17 months apart). Based on UPDRS scores, we identified subgroups of patients with moderate/severe tremor (PD(T)) and without tremor (PD(WT)) at the time of clinical diagnosis. Additionally, depressive symptoms were evaluated using the Beck Depression Inventory (BDI) at baseline. Mean thalamic specific to non-specific [(123)I]beta-CIT binding ratio was lower in patients when compared to controls, and further decreased during follow-up. At baseline, average thalamic ratio was significantly lower in the PD(T) than in the PD(WT) subgroup. No correlation was found between BDI scores and thalamic binding ratios. Our findings show decline of [(123)I]beta-CIT binding to thalamic 5-HTT in PD and its possible contribution to tremor onset. PMID:18335163

  19. White matter alterations in first episode treatment-naïve patients with deficit schizophrenia: a combined VBM and DTI study.

    PubMed

    Lei, Wei; Li, Na; Deng, Wei; Li, Mingli; Huang, Chaohua; Ma, Xiaohong; Wang, Qiang; Guo, Wanjun; Li, Yinfei; Jiang, Lijun; Zhou, Yi; Hu, Xun; McAlonan, Grainne Mary; Li, Tao

    2015-01-01

    Categorizing 'deficit schizophrenia' (DS) as distinct from 'non-deficit' schizophrenia (NDS) may help reduce heterogeneity within schizophrenia. However, it is unknown if DS has a discrete white matter signature. Here we used MRI to compare white matter volume (voxel-based morphometry) and microstructural integrity (fractional anisotropy, FA) in first-episode treatment-naïve patients with DS and NDS and their unaffected relatives to control groups of similar age. We found that white matter disruption was prominent in DS compared to controls; the DS group had lower volumes in the cerebellum, bilateral extra-nuclear and bilateral frontoparietal regions, and lower FA in the body of corpus callosum, posterior superior longitudinal fasciculus and uncinate fasciculus. The DS group also had lower volume in bilateral extra-nuclear regions compared to NDS, and the volume of these clusters was negatively correlated with deficit symptom ratings. NDS patients however, had no significant volume alterations and limited disruption of microstructural integrity compared to controls. Finally, first-degree relatives of those with DS shared volume abnormalities in right extra-nuclear white matter. Thus, white matter pathology in schizophrenia is most evident in the deficit condition, and lower extra-nuclear white matter volumes in both DS patients and their relatives may represent a brain structural 'endophenotype' for DS. PMID:26257373

  20. Therapeutic outcome of 6198 interferon-naïve Egyptian patients with chronic hepatitis C: a real-life experience and lessons to be learned in DAAs' era.

    PubMed

    Zayed, N; Gamal Eldeen, H; Elmakhzangy, H; Seif, M; El-Akel, W; Awad, T; Esmat, G; Mabrouk, M

    2016-07-01

    Antiviral therapy for HCV infection has been validated in randomized controlled clinical trials, but its value in the real world is less well studied. There is relatively little data on real-world responses to interferon-based therapies for patients with genotype 4 infection. We aimed to examine experience with large-scale access to antiviral therapy in chronic HCV in a real-life clinical setting in Egypt. Detailed pretreatment data of 6198 IFN-naïve chronic HCV patients who had received PEG-IFN/RBV therapy at Cairo-Fatemic Hospital, Egypt, between 2009 and 2012 were obtained from the HCV database. At week 12, 95.7% of patients had undetectable HCV RNA, and by week 24 and 48, breakthrough was 6% and 4%, respectively. However, 43.7% of patients discontinued treatment prematurely, and intent to treat end of treatment response was 44.6% (79.3% per protocol). Sustai-ned response data were available from only 1281 patients and was 84.9%. Haematological abnormalities were comparable in patients who did or did not comply with therapy. This is the first real-world, large-scale experience of antiviral therapy in chronic HCV in Egypt. Suboptimal response in HCV predominantly genotype 4 was mainly driven by noncompliance as well as gaps in the healthcare system leading to treatment discontinuation. These results need to be considered in the era of all oral antiviral regimes. PMID:26936687

  1. Altered functional connectivity links in neuroleptic-naïve and neuroleptic-treated patients with schizophrenia, and their relation to symptoms including volition

    PubMed Central

    Pu, Weidan; Rolls, Edmund T.; Guo, Shuixia; Liu, Haihong; Yu, Yun; Xue, Zhimin; Feng, Jianfeng; Liu, Zhening

    2014-01-01

    In order to analyze functional connectivity in untreated and treated patients with schizophrenia, resting-state fMRI data were obtained for whole-brain functional connectivity analysis from 22 first-episode neuroleptic-naïve schizophrenia (NNS), 61 first-episode neuroleptic-treated schizophrenia (NTS) patients, and 60 healthy controls (HC). Reductions were found in untreated and treated patients in the functional connectivity between the posterior cingulate gyrus and precuneus, and this was correlated with the reduction in volition from the Positive and Negative Symptoms Scale (PANSS), that is in the willful initiation, sustenance, and control of thoughts, behavior, movements, and speech, and with the general and negative symptoms. In addition in both patient groups interhemispheric functional connectivity was weaker between the orbitofrontal cortex, amygdala and temporal pole. These functional connectivity changes and the related symptoms were not treated by the neuroleptics. Differences between the patient groups were that there were more strong functional connectivity links in the NNS patients (including in hippocampal, frontal, and striatal circuits) than in the NTS patients. These findings with a whole brain analysis in untreated and treated patients with schizophrenia provide evidence on some of the brain regions implicated in the volitional, other general, and negative symptoms, of schizophrenia that are not treated by neuroleptics so have implications for the development of other treatments; and provide evidence on some brain systems in which neuroleptics do alter the functional connectivity. PMID:25389520

  2. Selfie and the City: A World-Wide, Large, and Ecologically Valid Database Reveals a Two-Pronged Side Bias in Naïve Self-Portraits

    PubMed Central

    Bruno, Nicola; Bertamini, Marco; Protti, Federica

    2015-01-01

    Self-portraits are more likely to show the artist’s right than left cheek. This phenomenon may have a psychobiological basis: Self-portraitists often copy their subject from mirrors and, if they prefer to present their left cheek (more expressive due to right-lateralization of emotions) to the mirror, this would result in a right-cheek bias in the painting. We tested this hypothesis using SelfieCity (3200 selfies posted on Instagram from December 4 through 12, 2013 from New York, Sao Paulo, Berlin, Moskow, and Bangkok), which includes two selfie-taking styles: a “standard” (photograph of selfie-taker) and a “mirror” (photograph of mirror reflection of selfie-taker) style. We show that the first style reveals a left cheek bias, whereas the second reveals a right cheek bias. Thus side biases observed in a world-wide, large, and ecologically valid database of naïve self-portraits provide strong support for a role of psychobiological factors in the artistic composition of self-portraits. PMID:25915767

  3. White matter alterations in first episode treatment-naïve patients with deficit schizophrenia: a combined VBM and DTI study

    PubMed Central

    Lei, Wei; Li, Na; Deng, Wei; Li, Mingli; Huang, Chaohua; Ma, Xiaohong; Wang, Qiang; Guo, Wanjun; Li, Yinfei; Jiang, Lijun; Zhou, Yi; Hu, Xun; Mary McAlonan, Grainne; Li, Tao

    2015-01-01

    Categorizing ‘deficit schizophrenia’ (DS) as distinct from ‘non-deficit’ schizophrenia (NDS) may help reduce heterogeneity within schizophrenia. However, it is unknown if DS has a discrete white matter signature. Here we used MRI to compare white matter volume (voxel-based morphometry) and microstructural integrity (fractional anisotropy, FA) in first-episode treatment-naïve patients with DS and NDS and their unaffected relatives to control groups of similar age. We found that white matter disruption was prominent in DS compared to controls; the DS group had lower volumes in the cerebellum, bilateral extra-nuclear and bilateral frontoparietal regions, and lower FA in the body of corpus callosum, posterior superior longitudinal fasciculus and uncinate fasciculus. The DS group also had lower volume in bilateral extra-nuclear regions compared to NDS, and the volume of these clusters was negatively correlated with deficit symptom ratings. NDS patients however, had no significant volume alterations and limited disruption of microstructural integrity compared to controls. Finally, first-degree relatives of those with DS shared volume abnormalities in right extra-nuclear white matter. Thus, white matter pathology in schizophrenia is most evident in the deficit condition, and lower extra-nuclear white matter volumes in both DS patients and their relatives may represent a brain structural ‘endophenotype’ for DS. PMID:26257373

  4. Evaluation of dry powder inhalers with a focus on ease of use and user preference in inhaler-naïve individuals.

    PubMed

    von Schantz, Sofia; Katajavuori, Nina; Antikainen, Osmo; Juppo, Anne

    2016-07-25

    Inhaler errors are common amongst inhaler users. Therefore, in the development work of new inhalation devices, it is important to characterize the ease of use of the inhalers. In this study four dry powder inhalers, Diskus, Easyhaler, Ellipta and Turbuhaler, were evaluated, focusing on ease of use and patient preference. The study used a triangular methodology. The sample consisted of 31 inhaler naïve individuals. Educational videos for all inhalers were watched, and afterwards, the use of all four inhalers was demonstrated in a random order. The demonstrations were videotaped. Thereafter they were checked against a predefined checklist and all mistakes were recorded. Only 33% of inhaler demonstrations were completed without the participants making any mistakes. The proportions of subjects who used the devices correctly were as follows: Diskus 48%, Easyhaler 19%, Ellipta 55% and Turbuhaler 16%. When comparing correct and incorrect inhaler technique for each inhaler pair the following differences were statistically significant: Diskus vs. Easyhaler (p<0.05), Ellipta vs. Easyhaler (p<0.01), Diskus vs. Turbuhaler (p<0.01), Ellipta vs. Turbuhaler (p<0.01). In the participants' ranking, the inhalers Ellipta, followed by Turbuhaler, were most often ranked as most preferred. Participants' preference of Ellipta over Easyhaler (p<0.01) and over Diskus (p<0.001) were statistically significant. PMID:27208655

  5. MRI-Targeted Biopsies versus Systematic Transrectal Ultrasound Guided Biopsies for the Diagnosis of Localized Prostate Cancer in Biopsy Naïve Men

    PubMed Central

    Peltier, Alexandre; Aoun, Fouad; Lemort, Marc; Kwizera, Félix; Paesmans, Marianne; Van Velthoven, Roland

    2015-01-01

    Introduction. To compare,