131,974 research outputs found
Functional analysis of "MEMO / MHO1", an evolutionary conserved gene, in yeast and mammalian cells
No full textThe protein Memo (Mediator of ErbB2 driven cell motility) was identified in a screen for ErbB2 receptor tyrosine kinase (RTK) interacting proteins that have roles in cancer cell motility. A single Memo protein of 297 amino acids is encoded in the human genome. Memo is evolutionarily conserved and homologs are found in all branches of life. The human and the yeast protein share an identity of more than 40% and a similarity of more than 50%. Memo is not homologous to any known signaling proteins and based on its conservation we expect it to have functions in addition to promoting motility in response to RTK activation. In the work described here, we used the model organism S. cerevisiae to characterize Mho1 (Yjr008wp) and to investigate its function in yeast. MHO1 expression is strongly induced in conditions of stress. In stationary phase, one stress condition, a high percentage of Memo is present in the nucleus. In mammalian cells, Memo is also found throughout the cell. Memo has no obvious NLS (nuclear localization sequence), however, an NES (nuclear export sequence) is present in all Memo homologs. In mammalian cells, blocking nuclear export with Leptomycin B led to nuclear Memo accumulation, suggesting that it is actively exported from the nucleus. Since invasive growth in S. cerevisiea can be induced by stress, e.g., nitrogen deprivation, or alcohol induced, we tested the role of Mho1 in this response. Deletion of MHO1 had no effect on the formation of pseudohyphoa or invasion. Growth of mho1Δ cells was not affected by stress inducers including (HU, CoCl2, Heat-shock, Latrunculin, Nocodazol). Interestingly, however, overexpression of Mho1 blocked the ability of the yeast cells to invade. In a synthetic lethal (SL) screen we found MHO1 as a novel SL partner of PLC1. Plc1 is the only phospholipase C in yeast and hydrolyzes phosphatidylinositol 4,5-biphosphate (PIP2) to generate the signaling molecules inositol 1,4,5-triphosphate (IP3) and 1,2-diacylglycerol (DAG). In the absence of MHO1 and PLC1, double deleted spores still germinate but proliferation is impaired after 2 to 10 cell cycles by an unknown mechanism. Introduction of human MEMO into the memoΔplc1Δ strain could rescue the SL phenotype showing that the specific function of Mho1/Memo needed to overcome the synthetic lethal phenotype is conserved
Divine action, Christ and the doctrine of God : the trinitarian grammar of Adolf Schlatter's theology
No full textThis dissertation constitutes an examination of the inner-theological basis of Adolf
Schlatter's theology which, as recent research has established, needs to be understood in
terms of a theology of God's works. The foundation of Schlatter's theology is recon-
structed by means of a critical outline and assessment of three dogmatic concepts,
namely: a) the relation between God and the world; b) the ground and mode of God's
agency in, and towards, the world; c) the structure of God's agency and works.
I argue that the doctrine of the Trinity constitutes the ontological basis for Schlat-
ter's concept of divine action. It is seen that Schlatter relates God's triune being ad intra
and God's triune economy ad extra, through the notion of love. This analogia caritatis
assumes the form of an analogia operationis which gives rise to an analogia relationis.
Special attention is devoted in this context, first, to the role which Schlatter ascribes to
the Holy Spirit and, second, to the Christocentricity of Schlatter's approach. At decisive
points in this study, attention is drawn to parallels between Schlatter's thought and the
contemporary trinitarian theology of Wolfhart Pannenberg, Colin Gunton, Christoph
Schwebel and others.
In the light of the trinitarian depth-structures of Schlatter's theology of divine ac-
tion, an effort is made to explicate his theology of God's works as an attempt to model a
theology in methodological obedience to God's triune economy. Fundamental aspects of
Schlatter's approach are briefly reconsidered from a trinitarian perspective. What the
present study has found itself obliged to offer constitutes, in essence, a new reading of
Schlatter's dogmatics, conceived, in effect, as an applied trinitarian theology
Dose adaptation of drugs in patients with liver disease
No full textA detailed introduction into the topic was obtained by developing a German-language
online course named “Dose adjustment in Patients with Liver Disease” for the “Swiss
Virtual Campus” in collaboration with PNN AG, a spin-off company of the ETH Zurich.
This was followed by the German-language publication “Dosage Adaptation in
Patients with Liver Disease” in “Grundlagen der Arzneimitteltherapie”, Documed,
2005, and an additional German-language online course for pharmacists named
“Dose Adaptation of Drugs in Patients with Liver Insufficiency” published by PNN AG.
The documents of these online courses and german publications can be found in the
electronic appendix on CD-ROM.
This extensive introduction into the topic was followed by the actual investigational
thesis.
The aim of the thesis was to define strategies for dose adaptation of drugs in patients
with liver disease. The main focus was to compare the prediction of the kinetic
behaviour as estimated using hepatic extraction with kinetic studies performed in
patients with liver cirrhosis. For this purpose, the antineoplastic drugs and the central
nervous agents on the market in Switzerland were studied.
In chapter 2 and 3, a general introduction and recommendation of dosing in liver
disease is given.
Chapter 4 contains a more detailed description of the online course about dose
adaptation in liver disease for the Swiss Virtual Campus.
Chapter 6 contains the results of the literature research for kinetic studies in liver
disease subdivided into the class of antineoplastic drugs (chapter 6.1) and
psychotropic drugs (chapter 6.2). For each drug, the pharmacokinetic information
was collected and drugs were classified according to their bioavailability / hepatic
extraction in order to predict their kinetic behaviour in patients with decreased liver
function as illustrated in chapter 3. These predictions were compared with kinetic
studies in patients with liver disease. Furthermore, both the dose dependent and liver
specific adverse reactions were listed, the identified kinetic studies in liver disease
summarized for each drug and specific dosing recommendations given. In conclusion, there are currently not enough data for the safe use of cyctostatics and
psychotropic drugs in patients with liver disease. There are obvious gaps about the
kinetic behaviour of drugs in patients with liver disease, in particular concerning data
about hepatic extraction and kinetic studies of drugs with biliary elimination in
patients with cholestasis.
Pharmaceutical companies should be urged to provide kinetic data (especially
hepatic extraction) needed for the classification of such drugs. Kinetic studies should
be conducted in patients with impaired liver function for drugs with primarily hepatic
metabolism, allowing to give quantitative advise for dose adaptation
A vorticity stretching diagnostic for turbulent and transitional flows
No full textVorticity stretching in wall-bounded turbulent and transitional flows has been investigated by meansof a new diagnostic measure, denoted by ?, designed to pick up regions with large amounts of vorticitystretching. It is based on the maximum vorticity stretching component in every spatial point, thus yielding athree-dimensional scalar field. The measure was applied in four different flows with increasing complexity: (a)the near-wall cycle in an asymptotic suction boundary layer (ASBL), (b) K-type transition in a plane channelflow, (c) fully turbulent channel flow at Re? = 180 and (d) a complex turbulent three-dimensional separatedflow. Instantaneous data show that the coherent structures associated with intense vorticity stretching in all fourcases have the shape of flat ‘pancake’ structures in the vicinity of high-speed streaks, here denoted ‘h-type’events. The other event found is of ‘l-type’, present on top of an unstable low-speed streak. These events (l-type)are further thought to be associated with the exponential growth of streamwise vorticity in the turbulent nearwallcycle. It was found that the largest occurrence of vorticity stretching in the fully turbulent wall-boundedflows is present at a wall-normal distance of y+ = 6.5, i.e. in the transition between the viscous sublayer andbuffer layer. The associated structures have a streamwise length of ?200–300 wall units. In K-type transition,the ?-measure accurately locates the regions of interest, in particular the formation of high-speed streaks nearthewall (h-type) and the appearance of the hairpin vortex (l-type). In the turbulent separated flow, the structurescontaining large amounts of vorticity stretching increase in size and magnitude in the shear layer upstreamof the separation bubble but vanish in the backflow region itself. Overall, the measure proved to be useful inshowing growing instabilities before they develop into structures, highlighting the mechanisms creating highshear region on a wall and showing turbulence creation associated with instantaneous separations
Direct numerical simulation of the flow around a wing section at moderate Reynolds numbers
No full textA three dimensional direct numerical simulation has been performed to study the flow around the asymmetric NACA-4412 wing at a moderate chord Reynolds number (Rec = 400, 000) with an angle of attack of 5◦ . The flow case under investigation poses numerous challenges for a numerical method due to the wide range of scales and complicated flow physics induced by the geometry. The mesh is optimized and well resolved to account for such varying scales in the flow. An unsteady volume force is used to trip the flow to turbulence on both sides of the wing at 10% chord. Full turbulent statistics are computed on the fly to further investigate the complicated flow features around the wing. The present simulation shows the potential of high-order methods in simulating complex external flows at moderately high Reynolds numbers
Searching for Higgs : From LEP towards LHC
No full textAfter a brief introduction to the theoretical basis of the Higgs mechanism for generating
the masses of elementary particles, the experimental searches for Higgs particles will be
summarized, from bounds at LEP to inferences for LHC. The report will focus on the
Standard Model, though some central results on extended Higgs systems, as conjectured for
example in supersymmetric theories, will also be recapitulated. Alternative scenarios
based on spontaneous symmetry breaking by novel strong interactions are adumbrated at the
theoretical level
MeSH term explosion and author rank improve expert recommendations
No full textInformation overload is an often-cited phenomenon that reduces the productivity, efficiency and efficacy of scientists. One challenge for scientists is to find appropriate collaborators in their research. The literature describes various solutions to the problem of expertise location, but most current approaches do not appear to be very suitable for expert recommendations in biomedical research. In this study, we present the development and initial evaluation of a vector space model-based algorithm to calculate researcher similarity using four inputs: 1) MeSH terms of publications; 2) MeSH terms and author rank; 3) exploded MeSH terms; and 4) exploded MeSH terms and author rank. We developed and evaluated the algorithm using a data set of 17,525 authors and their 22,542 papers. On average, our algorithms correctly predicted 2.5 of the top 5/10 coauthors of individual scientists. Exploded MeSH and author rank outperformed all other algorithms in accuracy, followed closely by MeSH and author rank. Our results show that the accuracy of MeSH term-based matching can be enhanced with other metadata such as author rank
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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