Role of genetic polymorphisms of drug metabolising enzymes in idiosyncratic drug reactions In vitro to in vivo translation

Vermeulen, N.P.E. [Promotor]Commandeur, J.N.M. [Copromotor

Contact complete integrability

Complete integrability in a symplectic setting means the existence of a Lagrangian foliation leaf-wise preserved by the dynamics. In the paper we describe complete integrability in a contact set-up as a more subtle structure: a flag of two foliations, Legendrian and co-Legendrian, and a holonomy-invariant transverse measure of the former in the latter. This turns out to be equivalent to the existence of a canonical $\R\ltimes \R^{n-1}$ structure on the leaves of the co-Legendrian foliation. Further, the above structure implies the existence of $n$ contact fields preserving a special contact 1-form, thus providing the geometric framework and establishing equivalence with previously known definitions of contact integrability. We also show that contact completely integrable systems are solvable in quadratures. We present an example of contact complete integrability: the billiard system inside an ellipsoid in pseudo-Euclidean space, restricted to the space of oriented null geodesics. We describe a surprising acceleration mechanism for closed light-like billiard trajectories

A research-informed, school-based professional development workshop programme to promote dialogic teaching with interactive technologies

The study reported in this article investigated the influence of a researchinformed, school-based, professional development workshop programme on the quality of classroom dialogue using the interactive whiteboard (IWB). The programme aimed to develop a dialogic approach to teaching and learning mediated through more interactive uses of the IWB, through a model of active participation of students, collaborative knowledgebuilding, learning through inquiry and evaluating ideas. Ten professional development workshops based on video-stimulated discussions of practices were co-developed and conducted with an ‘ambassador’ within each of five school clusters. In total, 80 teachers from 15 schools, ranging from infant to secondary schools, participated. Data were collected through surveys, semi-structured interviews with teachers and ambassadors, teachers’ posters created during workshop activities, lesson observations and a portfolio of dialogic classroom practices, mediated by the IWB. Findings strongly support the potential of this ambassador-led workshop model to involve teachers in developing their understandings of classroom dialogue and devising new approaches to support it. The research additionally confirms the potential of the IWB as a tool to support dialogic teaching.This work was supported by the UK Economic and Social Research Council (ESRC) Impact Acceleration Pilot Programme from February-August 2014. It built on previous work carried out as part of a personal Research Fellowship programme of work by Sara Hennessy in 2007-2010 under ESRC Grant RES063270081; the 'IWBs and Dialogic Teaching' project (http://dialogueiwb.educ.cam.ac.uk/) was conducted in collaboration with Neil Mercer and Paul Warwick

Molecular basis of oocyte-paracrine signalling that promotes granulosa cell proliferation

Copyright © 2006 Company of BiologistsOocytes regulate follicle growth by secreting paracrine growth factors that act on neighbouring granulosa cells (GCs). Those factors identified to date are mainly members of the transforming growth factor-ß (TGFß) superfamily, but little is known about which specific receptor/signalling system(s) they employ. This study was conducted to determine the requisite pathways utilised by oocytes to promote GC proliferation. We used an established oocyte-secreted mitogen bioassay, where denuded mouse oocytes are co-cultured with mural GCs. Oocytes, growth differentiation factor-9 (GDF9), TGFß1 and activin-A all promoted GC DNA synthesis, but bone-morphogenetic protein 6 (BMP6) did not. Subsequently, we tested the capacity of various TGFß superfamily receptor ectodomains (ECD) to neutralise oocyte- or specific growth factor-stimulated GC proliferation. The BMP type-II receptor (BMPR-II) ECD antagonised oocyte and GDF9 bioactivity dose-dependently, but had no or minimal effect on TGFß1 and activin-A bioactivity, demonstrating its specificity. The TGFßR-II, activinR-IIA and activinR-IIB ECDs all failed to neutralise oocyte- or GDF9-stimulated GC DNA synthesis, whereas they did antagonise the activity of their respective native ligands. An activin receptor-like kinase (ALK) 4/5/7 inhibitor, SB431542, also antagonised both oocyte and GDF9 bioactivity in a dose-dependent manner. Consistent with these findings, oocytes, GDF9 and TGFß1 all activated SMAD2/3 reporter constructs in transfected GC, and led to phosphorylation of SMAD2 proteins in treated cells. Surprisingly, oocytes did not activate the SMAD1/5/8 pathway in transfected GCs although exogenous BMP6 did. This study indicates that oocyte paracrine factors primarily utilise a similar signalling pathway first identified for GDF9 that employs an unusual combination of TGFß superfamily receptors, the BMPR-II and a SMAD2/3 stimulatory ALK (4, 5 or 7), for transmitting their mitogenic actions in GC. This cell-signalling pathway may also have relevance in the hypothalamic-pituitary axis and in germ-somatic cell interactions in the testis.Robert B. Gilchrist, Lesley J. Ritter, Samu Myllymaa, Noora Kaivo-Oja, Rebecca A. Dragovic, Theresa E. Hickey, Olli Ritvos and David G. Mottershea

Selenium isotope evidence for pulsed flow of oxidative slab fluids

Isotope systematics of the redox sensitive and chalcophile element selenium (Se) were investigated on exhumed parts of subducted oceanic lithosphere to provide new constraints on slab dehydration conditions during subduction. The samples c,, show increasing delta(82/76)Se(NIST3149 )with higher abundances of fluid mobile elements, comprising a larger range (-1.89 to +0.48 parts per thousand) than that of mantle (-0.13 +/- 0.12 parts per thousand) and altered ocean crust (-0.35 to -0.07 parts per thousand). Our data point to pronounced, local scale redox variations within the subducting crust, wherein oxidative fluids dissolve sulfides and mobilise oxidised Se species. Subsequently recrystallising sulfides preferentially incorporate isotopically lighter, reduced Se, which shifts evolving fluids and late stage sulfides to higher delta Se-82/76(NIST3149). Redistribution of Se by repeated cydes of sulfide reworking within the subducted crust can be reconciled with episodes of oxidised fluid pulses from underlying slab mantle in modem subduction zones

REMOVAL OF THE FALSE TARGETS IN THE ISSUESOF SPATIAL TRIANGULATION BY PROJECTIVE GEOMETRY METHODS

This paper deals with an issue of determination of the spatial coordinates within confined area in general terms. Mobile air space control stations were set and related to the system of spa- tial triangulation. As a result of the air space "scanning", targets appear in adequate representa- tion, representing identified aircrafts and other flying objects (FOs). The main objective is inter- pretation of collected data processing, in order to determine the reliable coordinates of an air- craft. The problem of false target identification occurs when data are analyzed from only two sta- tions. Descriptive Geometry method, for the construction of the planes containing rays targeted from the station towards the flying objects, in both classic-orthogonal projections and 3D model, as well, offers the solution of a problem. Dynamic 3D model consists of two flying objects, moni- tored from two stations in predefined time periods. The constructive 3D solutions represent geo- metrical locus of false targets trajectories, for several settings of flaying objects and monitoring stations. The analyses have shown geometrical positioning of the third station impact to the exact FO's coordinates determination. The geometrical solution could be the key for the development of numerical method, which will lead to applied software solutio

Language intermediaries and local agency: peacebuilding, translation/interpreting and political disempowerment in 'mature' post-Dayton Bosnia-Herzegovina

The peace negotiations that ended the 1992–95 war in Bosnia-Herzegovina established a constitutional system of ethnic power-sharing that satisfied its signatories (the presidents of Serbia, Croatia and Bosnia) enough for war to cease and provided for international military and civilian peacebuilding to play a significant role in post-conflict Bosnia’s governance and economy. This indefinite peacebuilding mission, still ongoing in a downsized form, depended – like any other form of intervention where foreigners work across linguistic boundaries – on interlinguistic mediation by locally-recruited translators/interpreters, an aspect of knowledge production that even current peace and conflict research into peacebuilding’s micropolitics often neglects. On an individual level, locally-recruited interpreters’ frequently-overlooked agency was integral to peacebuilding practice. Yet theorising their agency must also acknowledge the macrosocial level, where the post-war constitutional system has often been argued to have stripped Bosnians of political agency, since it foreclosed political participation as anything but an ethnic subject corresponding to the three institutionalised ethnic identities (Bosniak, Croat or Serb). The entrenched and growing disconnect between political elites and the public, expressed through social protest in 2014, foregrounds the problem of agency and dis/empowerment in Bosnian society more sharply than research on the politics of translation/interpreting and peacebuilding in Bosnia before 2014 took into account, yet reveals further articulations of how international peacebuilding and domestic political contestation were intertwined

Cardiac and Pulmonary Dosimetric Parameters in Lung Cancer Patients Undergoing Post-Operative Radiation Therapy in the Real-World Setting

Purpose/Objective(s): The recently published Lung ART trial reported increased rates of cardiac and pulmonary toxicity in the post-operative radiation therapy arm. It remains unknown whether the dosimetric parameters reported in Lung ART are representative of real-world practice. The purpose of this study is to examine heart and lung dose exposure in patients receiving post-operative radiation therapy for non-small cell lung cancer (NSCLC) across a statewide consortium. Materials/Methods: From 2012 to 2020, 377 patients at 27 academic and community centers within the Michigan Radiation Oncology Quality Consortium (MROQC) underwent surgical resection followed by post-operative radiation therapy for non-metastatic NSCLC. Demographic and dosimetric data were prospectively collected for these patients. Rates of 3D-CRT and IMRT use were analyzed. Mean heart dose (MHD), heart V5, heart V35, mean lung dose (MLD), lung V20, target volume and minimum dose to 95% PTV were calculated for these patients and the reported dosimetric parameters were stratified by treatment modality. Results: 51% of patients in this cohort had N2 disease at the time of surgery, 18% had a positive margin. 65.8% of patients were treated with IMRT compared to 32.1% treated with 3D-CRT. Average MHD for all patients was 10.3 Gy, mean Heart V5 was 40.3% and mean heart V35 was 12.6%. Average MLD was 11.2 Gy and mean lung V20 was 18.9%. These dosimetric parameters did not significantly differ based on treatment modality, with MHD and MLD 9.9 Gy and 10.1 Gy, respectively, for patients treated with 3D-CRT compared to 10.6 Gy and 11.8 Gy for patients treated with IMRT. Conclusion: Cardiac and lung dosimetric parameters for patients receiving post-operative radiation therapy for NSCLC are similar to the dosimetric characteristics reported in Lung ART. The mean heart and mean lung doses observed are slightly lower (MHD 10.3 Gy, MLD 11.2 Gy) compared to Lung ART (MHD 13 Gy, MLD 13 Gy), possibly owing to increased use of IMRT. These data support application of Lung ART\u27s findings outside of the clinical trial setting

Color Confinement, Quark Pair Creation and Dynamical Chiral-Symmetry Breaking in the Dual Ginzburg-Landau Theory

We study the color confinement, the $q$-$\bar q$ pair creation and the dynamical chiral-symmetry breaking of nonperturbative QCD by using the dual Ginzburg-Landau theory, where QCD-monopole condensation plays an essential role on the nonperturbative dynamics in the infrared region. As a result of the dual Meissner effect, the linear static quark potential, which characterizes the quark confinement, is obtained in the long distance within the quenched approximation. We obtain a simple expression for the string tension similar to the energy per unit length of a vortex in the superconductivity physics. The dynamical effect of light quarks on the quark confining potential is investigated in terms of the infrared screening effect due to the $q$-$\bar q$ pair creation or the cut of the hadronic string. The screening length of the potential is estimated by using the Schwinger formula for the $q$-$\bar q$ pair creation. We introduce the corresponding infrared cutoff to the strong long-range correlation factor in the gluon propagator as a dynamical effect of light quarks, and obtain a compact formula of the quark potential including the screening effect in the infrared region. We investigate the dynamical chiral-symmetry breaking by using the Schwinger-Dyson equation, where the gluon propagator includes the nonperturbative effect related toComment: 37 pages, plain TeX (using `phyzzx' macro), (( 8 figures - available on request from [email protected] )