1,474 research outputs found
Electron transport through single donors in silicon
No full text-Kavli Institute of Nanoscience DelftApplied Science
A kinetic model of glucose catabolism in Plasmodium falciparum
No full textThesis (PhD)--Stellenbosch University, 2013.ENGLISH ABSTRACT: Malaria infects over 200 million individuals and leads to the death of over 600
000 people annually. Currently artemisinin combination therapy treatments
are effective in treating the disease, but resistance has started to emerge in
Cambodia and it is suspected in parts of Vietnam. To maintain the drive to
eradicate malaria globally, a great deal of research is aimed at identifying novel
prevention strategies, vaccines and antimalarial compounds.
Plasmodium falciparum, the most deadly of the malaria parasites, is entirely
dependent on glycolysis for ATP. Several of the enzymes within this pathway
have been proposed as drug targets and studied in isolation, but the pathway
as a whole has not been considered. In this study we employ a bottom up
approach for drug target identification in P. falciparum glycolysis. In this thesis we present the biochemical characterisation each of the glycolytic
enzymes in P. falciparum trophozoites. The kinetic rate equations, which described
the kinetic behaviour of the individual enzymes, were incorporated
into a kinetic model. The unfitted model was validated in its ability to predict
experimentally measured steady state metabolite concentrations and fluxes as
well as the experimental inhibition of the glucose transporter.
The validated model provided a tool for drug target identification in P. falciparum
glycolysis. Metabolic control analysis and differential control analysis
identified the glucose transporter, PfHT1, as a drug target based on its high
control of glycolytic flux in the parasite, but low control of flux in the host
erythrocyte. This differential control makes the transporter an attractive drug
target, as even if both the erythrocyte and parasite glucose transporters are
inhibited to the same degree, it is expected that the parasite glycolytic flux
would be inhibited to a much greater degree.
To demonstrate the differential control of the glucose transporter on the flux
and provide further evidence that PfHT1 is an attractive drug target, we investigated
the inhibition of the glucose transporter in isolated trophozoites by
cytochalasin B. We also measured the inhibition of lactate production flux by
cytochalasin B in both isolated P. falciparum trophozoites as well as in erythrocytes.
Our findings demonstrated that differential control analysis can be
used as a tool for drug target identification and that PfHT1 is an attractive
drug target.
In this study the fields of biochemistry and systems biology were merged to
create a detailed kinetic model of asexual P. falciparum glycolysis and identify
several drug targets in the pathway. The model prediction and experimental
evidence of differential flux control of the glucose transporter in the host and
parasite, has highlighted PfHT1 as a drug target and also demonstrates the
strength of differential control analysis in identifying drug targets within a
system. The kinetic model is a valuable tool for furthering our understanding
of P. falciparum glycolysis and it provides a good foundation for expansion to
identify drug targets in the entire central carbon metabolism of P. falciparum.AFRIKAANSE OPSOMMING: Malaria infekteer meer as 200 miljoen mense en veroorsaak jaarliks tot 600 000
sterftes. Tans is die artemisinien-kombinasieterapie effektief in die bestryding
van die siekte, maar weerstandbiedendheid van die parasiet teen die middel
blyk reeds ’n merkbare effek in Kambodja en vermoedelik ook in dele van Viëtnam
te hê. Om ’n wêreldwye bestryding van malaria moontlik te maak, is
’n groot deel van die huidige navorsing gemik op die identifisering van nuwe
voorkomingsstrategieë, entstowwe en malariateenmiddels.
Plasmodium falciparum, die dodelikste van die malaria-parasiete, is geheel
en al afhanklik van glikolise vir ATP vorming. Verskeie van die ensieme in
hierdie metaboliese pad is as teenmiddelteikens voorgestel, en in isolasie bestudeer,
maar die pad as ’n geheel is nie bestudeer nie. In hierdie studie het ons ’n ’bottom-up’ benadering vir teenmiddel teikenidentifisering in P. falciparum
glikolise gebruik.
In hierdie tesis bied ons die biochemiese karakterisering van elk van die glikolitiese
ensieme in P. falciparum trofozoïete aan. Die kinetiese vergelykings
wat die kinetiese gedrag van die individuele ensieme beskryf, is geintegreer in
’n enkele kinetiese model. Die model waarop geen datapassing toegepas is nie,
is gevalideer om eksperimenteel bepaalde bestendige-toestand metabolietkonsentrasies
en fluksiewaardes, asook die eksperimentele inhibisie van die glukose
transporter, te voorspel.
Die gevalideerde model verskaf ’n bykomende hulpmiddel om teenmiddelteikens
te identifiseer in P. falciparum glikolise. Metaboliese kontrole-analise en
differensiële kontrole-analise het die glukose transporter, PfHT1, as ’n teenmiddelteiken
geïdentifiseer, gebaseer op sy hoë kontrole van glikolitiese fluksie
in die parasiet, tesame met ’n lae beheer van die glukose transporter op die
fluksie in die gasheer eritrosiet. Dié differensiële kontrole maak die glukose
transporter ’n aantreklike teenmiddelteiken, want selfs as beide die eritrosiet
en die parasiet glukose transporters tot dieselfde mate geïnhibeer word, sal dit
steeds ’n hoër glikolietiese fluksieinhibisie van die parasiet tot gevolg hê.
Om die differensiële kontrole van die glukose transporter op die fluks te demonstreer
en verdere bewyse te lewer dat PfHT1 ’n teenmiddelteiken kan wees,
het ons die inhibisie van die glukosetransporter in geïsoleerde trofozoïete deur
sitokalasien B ondersoek. Ons het ook die inhibisie van die laktaatproduksiefluksie
deur sitokalasien B in beide geïsoleerde P. falciparum trofozoïete sowel
as in eritrosiete ondersoek. Ons bevindings bewys dat differensiële kontroleanalise
as ’n hulpmiddel vir teenmiddelteikenidentifikasie gebruik kan word en
dat PfHT1 ’n aantreklike teenmiddelteiken is.
In hierdie studie is die velde van biochemie en sisteembiologie gekombineer om
’n gedetaileerde kinetiese model van ongeslagtelike P. falciparum glikolise te
konstueer en verskeie teenmiddelteikens in die metaboliese pad te identifiseer.
Die modelvoorspelling sowel as eksperimentele bewyse van die differensiële
flukskontrole van die glukose transporter in die gasheer en parasiet het PfHT1 uitgelig as ’n teenmiddelteiken en demonstreer ook die krag van differensiële
kontrole analise in die identifisering van teenmiddelteikens binne ’n biologiese
stelsel. Die kinetiese model is ’n waardevolle hulpmiddel vir die bevordering
van ons begrip van P. falciparum glikolise en dit bied ’n goeie basis vir uitbreiding
om teenmiddelteikens in die hele sentrale koolstofmetabolisme van P.
falciparum te identifiseer.Doctora
New (Probabilistic) Derivation of Diaz-Metcalf and Pólya-Szegő Inequalities and Consequences
No full textClassical inequalities of Diaz - Metcalf and Pólya - Szegő are generalized to
probabilistic setting which covers the initial deterministic (both discrete and integral) variants.
From these two inequalities, by the probabilistic derivation method further well -
known inequalities are obtained (that ones by Kantorovich, Rennie and Schweitzer)
The electrons are waves: impossible interview to C.J. Davisson (1881-1958) and G.P. Thomson (1892-1975)
No full textThe author imagines to interview the Nobel Laureates in Physics of the year 1937, who turned upside-down modern physics, demonstrating the wave nature of matter. The answers of C. Davisson and G.P. Thomson are based on
the Nobel Lectures they delivered during the Nobel Prize Award Ceremony
Evaluatierapport “Powered by you”: Ontwikkeling Sustainable Energy Floor- energieopwekkende vloer
No full textOp weg naar rendabele energieopwekking door lopen. Er was een voorsprong in kennis en ervaring aangaande de techniek die nodig was een energie genererende loopvloer (de Sustainable Energy Floor – SEF) te realiseren. Specifieke aanpassingen moesten echter ontwikkeld worden in verband met de andere bewegingsvorm, de schaal die vele malen groter is en de andere installatie- en logistieke eisen. Het doel was om een pilot te doen op één of meer aansprekende locaties. Het project moest een belangrijke stap zijn op weg naar rendabele energieopwekking door lopen. Samen met de TU Delft, faculteit Industrieel Ontwerpen en Rinnic Vaude is onderzoek gedaan naar de haalbaarheid van het ontwikkelen van SEF, zijn prototypes en een pilotvloer gerealiseerd, tests gedaan en presentaties en demonstraties gegeven aan vele partijen en een breed publiek in Delft en Rotterdam. Vanwege technische knelpunten gedurende het project en de praktische haalbaarheid is er niet één grote pilot voor een langere periode gedaan, maar zijn er meerdere kortdurende pilots en tests gedaan. Het voordeel hiervan was dat we op basis van de analyses, tests en de feedback van gebruikers op verschillende versies prototypes, het ontwerp steeds verder konden verbeteren. Tenslotte heeft dit geresulteerd in het bouwen van de pilotvloer, waarmee de eindtest in De Kuip is uitgevoerd naar tevredenheid van alle betrokken partijen. Het project is succesvol afgerond en de doelstellingen zijn gehaald binnen het gestelde budget. Het project is uitgevoerd met steun van het programma Kansen voor West, wat valt onder het Europese Fonds voor Regionale Ontwikkeling.Industrial Design Engineerin
Decay of turbulence at high Reynolds numbers
No full textUsing the unique capabilities of the Variable Density Turbulence Tunnel at the Max Planck Institute for Dynamics and Self-Organization, we investigated virtually homogeneous and isotropic grid turbulence over a wide range of Reynolds numbers, , between and . The choice of pressurizable Sulfur Hexafluoride as a working gas makes it possible to reach extremely high Reynolds numbers without changing boundary conditions. Indeed, the Reynolds number we reached were higher than any previous classical grid wind-tunnel experiment. In this talk, we focus on the fundamental question of how fast turbulent energy decays once it has been created, and show that the Reynolds number plays no important role in setting the decay rate if it is high enough
Wall to wall optimal transport
No full textThe calculus of variations is employed to find steady divergence-free velocity fields that maximize transport of a tracer between two parallel walls held at fixed concentration for one of two constraints on flow strength: a fixed value of the kinetic energy or a fixed value of the enstrophy (the mean square rate of strain in this situation). The optimizing flows realize upper limits on convective transport in this scenario. We interpret the results in the context of buoyancy-driven Rayleigh–Bénard convection problems that satisfy the flow intensity constraints, enabling us to investigate how optimal transport scalings compare with upper bounds on Nu expressed as a function of the Rayleigh number Ra
Experiments and DNS of a round jet with turbulent inlet
No full textExperimental and Direct Numerical Simulation data of a turbulent round jet fed by a turbulent pipe are compared in the near field. The Reynolds number achieved in both the experiment and the simulation, Re = 16000, allows a direct comparison of both the average and the fluctuating velocity statistics. In the experiments the jet is fed with olive oil droplets with a Stokes number St ' 1 whose dynamics is compared against the corresponding DNS simulation to asses the ability of particles to reproduce high order turbulence statistics and to asses the accumulation properties of inertial particles in the near field
Rapport naar aanleiding van de werking eener proefinrichting tot verlaging van de waterspiegel door middel van bronbemaling en de daarmede verkregen uitkomsten, opgemaakt dor den ingenieur van den Rijkswaterstaat G.P. Nijhoff
No full textPrototype proef voor de bronbemaling bij de sluis van Linne
Are all paper citations equal?
No full textGreen Open Access added to TU Delft Institutional Repository ‘You share, we take care!’ – Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Transport and Logistic
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