190,262 research outputs found
Targeted delivery of advanced functionality by nanomaterials : focus on nucleic acids delivery by novel block copolymers
No full textAbstract: Smart drug delivery systems are versatile examples of successful nanomedicine with
potential in diagnostics and medical therapy. The thesis presents selected
approaches in current drug delivery systems in the (pre-)clinical trials, and deals with
potential side effects, including complement activation and hypersensitivity reactions
as well as the design requirements of the delivery systems. Furthermore, it presents
approaches of cationic block copolymers, which are capable to condense negatively
charged nucleic acid molecules such as plasmid deoxyribonucleic acid (pDNA) and
small interfering ribonucleic acid (siRNA) with the aim of efficient cell gene delivery
and specific gene suppression, respectively.
The first part addresses the transfection efficiency of circular versus linearized
plasmid DNA using a green fluorescent protein expressing vector with Lipofectamine
2000 and linear 25 kDA polyethylenimine (PEI). These results show a considerably
improved transfection efficiency with the circular compared to the linearized DNA for
the two transfection reagents. The electron microscopy images with Lipofectamine or
PEI demonstrate that the circular DNA gives rise to random coil appearance of
compact, spherical shape, while linearized DNA appear as worm-like strands.
Particle size and shape are important in the cell biology of endocytosis and
phagocytosis. The findings indicate that the shape of the transfection particle is vital
for successful gene transfer.
To develop a delivery system for gene therapy, two cationic diblock copolymers
consisting of primary and tertiary amines were synthesized and analyzed with
respect to DNA condensation properties, morphology of the condensed plasmid DNA
and transfection efficiency using two cell lines. This study revealed proof-of-concept
showing an order of magnitude lower transfection efficiency of primary amine diblock
copolymers compared to PEI after 48 h with increasing plasmid DNA concentration.
Furthermore, primary amines compared to tertiary ones show much stronger binding
to DNA and improved transfection efficiency. Transmission electron and atomic force
microscopy data revealed morphologies of primary and tertiary amines regarding the
condensation of the plasmid DNA, in agreement with the transfection efficiency.
In a second part the design and characterization of pentablock-based polyplexes
based on the combination of cationic pentablock copolymers with folic acid
functionalized copolymers for targeted specific siRNA delivery is described. The
achieved 31 % knockdown efficiency shows its potential regarding cancer gene
therapy. The pentablock architecture allows the formation of highly stable
micelleplexes of (21 ± 3) nm in 10 mM PBS buffer solution with a neutral surface
charge, excellent siRNA condensation properties, outstanding colloidal stability in
10 % serum over 24 h and biocompatibility deduced from the absence of
considerable cytotoxicity even after 48 h incubation. Furthermore, selective delivery
of the siRNA could be proven by the introduction of a ligand-linked block copolymer,
resulting in 31 % compared to 8 % gene suppression for targeted a non-targeted
micelleplexes. This pentablock-based delivery system might yield impact to future
delivery systems as well as being a potential platform to be applied in vivo for cancer
gene therapy. ---------- Zusammenfassung
Innerhalb des Bereichs der Nanomedizin weisen intelligente Wirkstoffabgabesysteme
ein großes Potenzial auf, sowohl hinsichtlich der Diagnostik wie auch der
medizinischen Therapie. Die vorliegende Arbeit stellt im Rahmen einer
Literaturrecherche ausgewählte Wirkstoffabgabesysteme vor, welche sich in (vor-)
klinischen Studien befinden, den Nebenwirkungen welche durch diese entstehen
können, im speziellen der Komplementaktivierung und Überempfindlichkeitsreaktionen,
sowie deren Konstruktionsanforderungen. Des weiteren werden in einem
experimentellen Teil kationische Block-Kopolymere präsentiert, welche in der Lage
sind, negativ geladene Nukleinsäuremoleküle zu binden - wie etwa Plasmid
Desoxyribonukleinsäure (pDNA) und kleine interferierende Ribonukleinsäuren
(siRNA) - mit dem Ziel der Transfektion von fremder DNA in die Wirtszellen und
damit der spezifischen Unterdrückung der Genexpression.
Der erste Teil der experimentellen Arbeit untersucht die Transfektionseffizienz von
zirkulärer gegenüber linearisierter Plasmid-DNA mittels eines Vektors, welcher ein
grün fluoreszierendes Protein exprimiert. Transfiziert wurde einerseits mit
Lipofectamine 2000 und andererseits mit linearem 25 kDa Polyethylenimin (PEI),
zwei etablierten Transfektionsreagenzien. Die Ergebnisse zeigen eine wesentlich
verbesserte Transfektionseffizienz der zirkulären, verglichen mit der linearisierten
DNA für beide Transfektionsreagenzien. Die elektronenmikroskopischen Bilder von
Lipofectamine sowie PEI komplexiert mit DNA zeigen, dass die zirkuläre DNA
zufällige, kompakte Kugelformen bildet, während die linearisierte DNA wurmartige
Stränge aufweist. Partikelgröße und -form spielen in der Zellbiologie eine wichtige
Rolle bei der Endozytose und Phagozytose. Die Ergebnisse legen die Vermutung
nahe dass die Form der zu transfizierenden DNA-Transfektions-Komplexen eine
wichtige Rolle einnimmt für einen erfolgreichen Gentransfer.
Für die Entwicklung eines intelligenten Wirkstoffabgabe-Systems für die Gentherapie
wurden zwei kationische Diblock-Kopolymere, die aus primären und tertiären Aminen
bestehen synthetisiert und im Hinblick auf deren DNA-Kondensationseigenschaften,
Morphologie der kondensierten Plasmid-DNA sowie Transfektionseffizienz unter
Verwendung von zwei Zelllinien analysiert. Die Studie bestätigt trotz einer um den
Faktor 10 schwächeren Transfektionseffizienz der primären Amin-DiblockKopolymeren
im Vergleich zu PEI nach 48 h mit zunehmender pDNA Konzentration
eine Bestätigung des Konzepts. Außerdem weisen die primären Amin-Block-
Kopolymere im Vergleich zu den tertiären eine viel stärkere Komplexbildung der DNA
auf - wie transmissions-elektronen- und rasterkraft-mikroskopische Daten ergaben -
als auch eine verbesserte Transfektionseffizienz. Diese physikalischmorphologischem
Erkenntnisse über die Kondensation der primären und tertiären
Amine mit Plasmid-DNA konnten mittels der biologischen Transfektionseffizienzdaten
validiert werden.
Der zweite Teil der experimentellen Arbeit befasst sich mit dem Design sowie der
Charakterisierung von pentablock-basierten Polyplexen für einen gezielten siRNA
Transport. Diese Polyplexe beruhen auf einer Kombination von kationischen
Pentablock-Kopolymeren mit folsäure-funktionalisierten Kopolymeren. Die erreichten
31% Gen-Suppression in einem Krebszellkulturmodell, zeigen das Potenzial des
Wirkstoffabgabesystems in Bezug auf eine Krebstherapie auf. Die Architektur
ermöglicht die Bildung von sehr stabilen Mizellen mit einer Grösse von (21 ± 3) nm in
10 mM PBS Pufferlösung, eine neutrale Oberflächenladung, ausgezeichneten siRNAKondensationseigenschaften,
hervorragender kolloidaler Stabilität in
Zellkulturmedium supplementiert mit 10 % Serum über 24 h, sowie guter
Biokompatibilität aufgrund fehlender erheblicher Zytotoxizität auch nach 48 h
Inkubation in einem Zellkulturmodell. Ferner konnte durch die Einführung eines
liganden-gebundenen Block-Kopolymers der selektive Transport der siRNA
nachgewiesen werden, was zu einer Gen Suppression von 31% gegenüber 8% nicht
funktionalisierter Polyplexen führte. Das in dieser Arbeit eingeführte und
charakterisierte pentablock-basierte Wirkstoffabgabesystem könnte Auswirkungen
auf das Design zukünftiger Wirkstoffabgabesystem haben als auch als eine
potentielle Plattform für in vivo-Krebsgentherapien angewendet werden
The group structure of the normalizer of Γ0(N) after Atkin-Lehner
No full textWe determine the group structure of the normalizer of Γ0 (N) in SL2(R) modulo Γ0 (N). These results correct the Atkin-Lehner statement (Atkin and Lehner, 1970, Theorem 8)
A complete map of specificity encoding for a partially fuzzy protein interaction
No full text<p>All data required to run analyses for "A complete map of specificity encoding for a partially fuzzy protein interaction". Please see <a href="https://github.com/lehner-lab/fuzzy_specificity">https://github.com/lehner-lab/fuzzy_specificity</a> for instructions. </p>
Downscaling WaterGAP streamflow from 0.5 arc-deg to 15 arc-sec
No full text<h3>1. Overview: </h3><p>Our approach for downscaling the LR output of a global hydrological model to HR streamflow is based on the conceptual framework developed by Lehner and Grill (2013) which was globally applied, for example, in Linke et al. (2019). </p><h3>2. Reference</h3><p>Lehner, B., & Grill, G. (2013). Global river hydrography and network routing: baseline data and new approaches to study the world's large river systems. <i>Hydrological Processes</i>, <i>27</i>(15), 2171–2186. https://doi.org/10.1002/hyp.9740</p><p>Linke, S., Lehner, B., Ouellet Dallaire, C., Ariwi, J., Grill, G., & Anand, M., et al. (2019). Global hydro-environmental sub-basin and river reach characteristics at high spatial resolution. <i>Scientific Data</i>, <i>6</i>(1), 283. https://doi.org/10.1038/s41597-019-0300-6</p><p> </p>
lehner-lab/DiMSum: Wonton
No full text<p>Major updates:</p>
<ul>
<li>New 'vsearchMaxQual' option to support maximum base qualities >41 e.g. as provided by the Element AVITI sequencer</li>
</ul>
Modular symbols over number fields
No full textLet K be a number field, R its ring of integers. For some classes of fields, spaces of cusp forms of weight 2 for GL(2;K) have been computed using methods based on modular symbols. J.E. Cremona [9] began the programme of extending the classical methods over Q to the case of imaginary quadratic fields. This work was continued by some of his Ph.D. students [35, 6, 22], and results have been obtained for some imaginary quadratic fields with small class number. More recently, P. Gunnells and D. Yasaki [18] have developed related algorithms for real quadratic fields.
The aim of this thesis is to contribute to the extension of the modular symbols method, when possible developing algorithms and implementations for effective computations. Some parts of the theory are purely algebraic and can be extended to all number fields. We generalise the theory for cusps and Manin symbols; we also describe a generalisation of Atkin-Lehner involutions and study other normaliser elements. On the other hand, all previous explicit computations for the imaginary quadratic field case were done only for specific fields. In the last part of this thesis we begin work towards a general implementation of the techniques used in this case. In particular, we are able to compute a fundamental domain of the hyperbolic 3-space for any imaginary quadratic field.
Implementations of the algorithms described in this thesis have been written by the author in the open-source mathematics software Sage [31]
Professor Thomas Lehner
No full textProfessor Thomas Lehner is one of the most distinguished oral and dental researchers to have come out of the UK. Over the past 40 years, he has made an astonishing number of discoveries which have had an impact on our understanding of the pathogenesis of a variety of mucosal diseases. He has consistently practiced both basic and clinical research and built an integrated group of clinical and non-clinical researchers, which allowed him easy transition from the laboratory to the clinic. Tom Lehner was among the early scientists studying mucosal immunology, initially exploring oral diseases, with special emphasis on the immunobiology of Streptococcus mutans, leading to active and passive vaccination against dental caries. He was the first to demonstrate cellular immunity as the immunopathological basis of periodontal diseases, recurrent aphthous stomatitis, and candidiasis. Over the past 20 years, his expertise in mucosal immunobiology has been applied to the immunology of HIV/SIV infections. His seminal contributions include regional innate mucosal immunity, prevention of SIV infection in macaques by secretory IgA antibodies, up-regulation of CC chemokines, and the first demonstration of protective CCR5 antibodies. Arguably, his leadership, his students, and the establishment of immunology applied to oral mucosal diseases will be his greatest legacy. His contributions continue unabated.</p
The allosteric landscape of the Src kinase
No full text<p>Fitness scores, MoCHI weights and miscellaneous files required to reproduce the analyses and figures in The allosteric landscape of Src (https://github.com/lehner-lab/src_allostery/blob/main/README.md) - Beltran A et al., 2023.</p>
Broue-Enguehard maps and Atkin-Lehner involutions
No full textLet a be one of the ten integers such that the sum of their divisors divide 24. For each such e, (except 15) we give a map from an algebra of polynomial invariants of some finite group to the algebra of modular forms invariant under the Atkin-Lehner group of level e. These maps are motivated and inspired by constructions of modular lattices from self-dual codes over rings. This work generalizes Broue-Enguehard work in level one and three obtained from binary and ternary codes. (c) 2007 Elsevier Ltd. All rights reserved.X113sciescopu
Eichler cohomology for generalized modular forms
No full textBy using Stokes's theorem, we prove an Eichler cohomology theorem for generalized modular forms with some restrictions on the relevant multiplier systems. © 2009 World Scientific Publishing Company.Bol G., 1949, ABH MATH SEM HAMBURG, V16, P1; Eichler M., 1957, MATH Z, V67, P267, DOI 10.1007-BF01258863; Eichler M., 1965, ACTA ARITH, V11, P169; Ford L. R., 1929, AUTOMORPHIC FUNCTION; Gunning R., 1961, T AM MATH SOC, V100, P44, DOI 10.2307-1993353; HUSSEINI SY, 1971, ILLINOIS J MATH, V15, P565; Knopp M, 2003, ACTA ARITH, V110, P117, DOI 10.4064-aa110-2-2; KNOPP M, INT J NUMBER THEORY; Knopp M, 2003, J NUMBER THEORY, V99, P1, DOI 10.1016-S0022-314X(02)00065-3; Knopp M., 1962, T AM MATH SOC, V103, P168, DOI 10.2307-1993746; KNOPP M, 1965, DUKE MATH J, V32, P452; KNOPP M, 1974, B AM MATH SOC, V50, P607; Knopp M. I., 1993, MODULAR FUNCTIONS AN; KRA I, 1969, ANN MATH, V90, P576, DOI 10.2307-1970749; LEHNER J, 1971, P SCI RES COUNC ATL, P49; LEHNER J, 1969, J RES NBS B MATH SCI, VB 73, P153, DOI 10.6028-jres.073B.016; PETERSSON H, 1937, MATH ANN, V115, P175; RAJI W, EICHLER COHOMO UNPUB; Raji W, 2009, INT J NUMBER THEORY, V5, P153; Shimura G., 1959, J MATH SOC JAPAN, V11, P29155
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