TY  - THES
A1  - Winnerlein, Martin
T1  - Molecular Beam Epitaxy and Characterization of the Magnetic Topological Insulator (V,Bi,Sb)\(_2\)Te\(_3\)
T1  - Molekularstrahlepitaxie und Charakterisierung des magnetischen topologischen Isolators (V,Bi,Sb)\(_2\)Te\(_3\)
N2  - The subject of this thesis is the fabrication and characterization of magnetic topological
insulator layers of (V,Bi,Sb)\(_2\)Te\(_3\) exhibiting the quantum anomalous Hall
effect. A major task was the experimental realization of the quantum anomalous
Hall effect, which is only observed in layers with very specific structural,
electronic and magnetic properties. These properties and their influence on the
quantum anomalous Hall effect are analyzed in detail.
First, the optimal conditions for the growth of pure Bi\(_2\)Te\(_3\) and Sb\(_2\)Te\(_3\) crystal
layers and the resulting structural quality are studied. The crystalline quality of
Bi\(_2\)Te\(_3\) improves significantly at higher growth temperatures resulting in a small
mosaicity-tilt and reduced twinning defects. The optimal growth temperature is
determined as 260\(^{\circ}\)C, low enough to avoid desorption while maintaining a high
crystalline quality.
The crystalline quality of Sb\(_2\)Te\(_3\) is less dependent on the growth temperature.
Temperatures below 230\(^{\circ}\)C are necessary to avoid significant material desorption,
though. Especially for the nucleation on Si(111)-H, a low sticking coefficient is
observed preventing the coalescence of islands into a homogeneous layer.
The influence of the substrate type, miscut and annealing sequence on the growth
of Bi\(_2\)Te\(_3\) layers is investigated. The alignment of the layer changes depending on
the miscut angle and annealing sequence: Typically, layer planes align parallel to
the Si(111) planes. This can enhance the twin suppression due to transfer of the
stacking order from the substrate to the layer at step edges, but results in a step
bunched layer morphology. For specific substrate preparations, however, the layer
planes are observed to align parallel to the surface plane. This alignment avoids
displacement at the step edges, which would cause anti-phase domains. This results
in narrow Bragg peaks in XRD rocking curve scans due to long-range order in
the absence of anti-phase domains. Furthermore, the use of rough Fe:InP(111):B
substrates leads to a strong reduction of twinning defects and a significantly reduced
mosaicity-twist due to the smaller lattice mismatch.
Next, the magnetically doped mixed compound V\(_z\)(Bi\(_{1−x}\)Sb\(_x\))\(_{2−z}\)Te\(_3\) is studied in
order to realize the quantum anomalous Hall effect. The addition of V and Bi to
Sb\(_2\)Te\(_3\) leads to efficient nucleation on the Si(111)-H surface and a closed, homogeneous
layer. Magneto-transport measurements of layers reveal a finite anomalous
Hall resistivity significantly below the von Klitzing constant. The observation of
the quantum anomalous Hall effect requires the complete suppression of parasitic
bulklike conduction due to defect induced carriers. This can be achieved by optimizing
the thickness, composition and growth conditions of the layers.
The growth temperature is observed to strongly influence the structural quality.
Elevated temperatures result in bigger islands, improved crystallographic orientation
and reduced twinning. On the other hand, desorption of primarily Sb is
observed, affecting the thickness, composition and reproducibility of the layers.
At 190\(^{\circ}\)C, desorption is avoided enabling precise control of layer thickness and
composition of the quaternary compound while maintaining a high structural
quality.
It is especially important to optimize the Bi/Sb ratio in the (V,Bi,Sb)\(_2\)Te\(_3\) layers,
since by alloying n-type Bi\(_2\)Te\(_3\) and p-type Sb\(_2\)Te\(_3\) charge neutrality is achieved at
a specific mixing ratio. This is necessary to shift the Fermi level into the magnetic
exchange gap and fully suppress the bulk conduction. The Sb content x furthermore
influences the in-plane lattice constant a significantly. This is utilized to
accurately determine x even for thin films below 10 nm thickness required for the
quantum anomalous Hall effect. Furthermore, x strongly influences the surface
morphology: with increasing x the island size decreases and the RMS roughness
increases by up to a factor of 4 between x = 0 and x = 1.
A series of samples with x varied between 0.56-0.95 is grown, while carefully
maintaining a constant thickness of 9 nm and a doping concentration of 2 at.% V.
Magneto-transport measurements reveal the charge neutral point around x = 0.86
at 4.2 K. The maximum of the anomalous Hall resistivity of 0.44 h/e\(^2\) is observed
at x = 0.77 close to charge neutrality. Reducing the measurement temperature
to 50 mK significantly increases the anomalous Hall resistivity. Several samples
in a narrow range of x between 0.76-0.79 show the quantum anomalous Hall effect
with the Hall resistivity reaching the von Klitzing constant and a vanishing
longitudinal resistivity. Having realized the quantum anomalous Hall effect as the
first group in Europe, this breakthrough enabled us to study the electronic and
magnetic properties of the samples in close collaborations with other groups.
In collaboration with the Physikalisch-Technische Bundesanstalt high-precision
measurements were conducted with detailed error analysis yielding a relative de-
viation from the von Klitzing constant of (0.17 \(\pm\) 0.25) * 10\(^{−6}\). This is published
as the smallest, most precise value at that time, proving the high quality of the
provided samples. This result paves the way for the application of magnetic topological
insulators as zero-field resistance standards.
Non-local magneto-transport measurements were conducted at 15 mK in close
collaboration with the transport group in EP3. The results prove that transport
happens through chiral edge channels. The detailed analysis of small anomalies in
transport measurements reveals instabilities in the magnetic phase even at 15 mK.
Their time dependent nature indicates the presence of superparamagnetic contributions
in the nominally ferromagnetic phase.
Next, the influence of the capping layer and the substrate type on structural properties
and the impact on the quantum anomalous Hall effect is investigated. To
this end, a layer was grown on a semi-insulating Fe:InP(111)B substrate using the
previously optimized growth conditions. The crystalline quality is improved significantly
with the mosaicity twist reduced from 5.4\(^{\circ}\) to 1.0\(^{\circ}\). Furthermore, a layer
without protective capping layer was grown on Si and studied after providing sufficient
time for degradation. The uncapped layer on Si shows perfect quantization,
while the layer on InP deviates by about 5%. This may be caused by the higher
crystalline quality, but variations in e.g. Sb content cannot be ruled out as the
cause. Overall, the quantum anomalous Hall effect seems robust against changes
in substrate and capping layer with only little deviations.
Furthermore, the dependence of the quantum anomalous Hall effect on the thickness
of the layers is investigated. Between 5-8 nm thickness the material typically
transitions from a 2D topological insulator with hybridized top and bottom surface
states to a 3D topological insulator. A set of samples with 6 nm, 8 nm, and
9 nm thickness exhibits the quantum anomalous Hall effect, while 5 nm and 15 nm
thick layers show significant bulk contributions. The analysis of the longitudinal
and Hall conductivity during the reversal of magnetization reveals distinct differences
between different thicknesses. The 6 nm thick layer shows scaling consistent
with the integer quantum Hall effect, while the 9 nm thick layer shows scaling expected
for the topological surface states of a 3D topological insulator. The unique
scaling of the 9 nm thick layer is of particular interest as it may be a result of
axion electrodynamics in a 3D topological insulator.
Subsequently, the influence of V doping on the structural and magnetic properties
of the host material is studied systematically. Similarly to Bi alloying, increased
V doping seems to flatten the layer surface significantly. With increasing V content,
Te bonding partners are observed to increase simultaneously in a 2:3 ratio
as expected for V incorporation on group-V sites. The linear contraction of the
in-plane and out-of-plane lattice constants with increasing V doping is quantitatively
consistent with the incorporation of V\(^{3+}\) ions, possibly mixed with V\(^{4+}\)
ions, at the group-V sites. This is consistent with SQUID measurements showing
a magnetization of 1.3 \(\mu_B\) per V ion.
Finally, magnetically doped topological insulator heterostructures are fabricated
and studied in magneto-transport. Trilayer heterostructures with a non-magnetic
(Bi,Sb)\(_2\)Te\(_3\) layer sandwiched between two magnetically doped layers are predicted
to host the axion insulator state if the two magnetic layers are decoupled and in
antiparallel configuration. Magneto-transport measurements of such a trilayer heterostructure
with 7 nm undoped (Bi,Sb)\(_2\)Te\(_3\) between 2 nm thick layers doped with
1.5 at.% V exhibit a zero Hall plateau representing an insulating state. Similar results
in the literature were interpreted as axion insulator state, but in the absence
of a measurement showing the antiparallel magnetic orientation other explanations
for the insulating state cannot be ruled out.
Furthermore, heterostructures including a 2 nm thin, highly V doped layer region
show an anomalous Hall effect of opposite sign compared to previous samples. A
dependency on the thickness and position of the doped layer region is observed,
which indicates that scattering at the interfaces causes contributions to the anomalous
Hall effect of opposite sign compared to bulk scattering effects.
Many interesting phenomena in quantum anomalous Hall insulators as well as axion
insulators are still not unambiguously observed. This includes Majorana bound
states in quantum anomalous Hall insulator/superconductor hybrid systems and
the topological magneto-electric effect in axion insulators. The limited observation
temperature of the quantum anomalous Hall effect of below 1 K could be increased
in 3D topological insulator/magnetic insulator heterostructures which utilize the
magnetic proximity effect.
The main achievement of this thesis is the reproducible growth and characterization
of (V,Bi,Sb)2Te3 layers exhibiting the quantum anomalous Hall effect. The
detailed study of the structural requirements of the quantum anomalous Hall effect
and the observation of the unique axionic scaling behavior in 3D magnetic
topological insulator layers leads to a better understanding of the nature of this
new quantum state. The high-precision measurements of the quantum anomalous
Hall effect reporting the smallest deviation from the von Klitzing constant
are an important step towards the realization of a zero-field quantum resistance
standard.
N2  - Das Thema dieser Arbeit ist die Herstellung und Charakterisierung von Schichten
des magnetischen topologischen Isolators (V,Bi,Sb)\(_2\)Te\(_3\), die den Quanten anomalen
Hall-Effekt zeigen. Die Hauptaufgabe war die experimentelle Realisierung
des Quanten anomalen Hall-Effekts, welcher nur in Schichten mit bestimmten
strukturellen, elektronischen und magnetischen Eigenschaften beobachtet wird.
Diese Eigenschaften wurden ermittelt und ihr Einfluss genau analysiert.
Als Erstes wurden die optimalen Bedingungen für das Wachstum von reinen
Bi\(_2\)Te\(_3\) und Sb\(_2\)Te\(_3\) Kristallschichten und die resultierende strukturelle Qualität
untersucht. Die kristalline Qualität von Bi\(_2\)Te\(_3\) verbessert sich signifikant bei hohen
Wachstumstemperaturen, welche die Neigung der Domänen verringern und
Zwillingsdefekte reduzieren. Als optimale Wachstumstemperatur wurde 260\(^{\circ}\)C
ermittelt, ausreichend niedrig um Desorption zu vermeiden während eine hohe
Kristallqualität erhalten bleibt.
Die Wachstumstemperatur von Sb\(_2\)Te\(_3\) hat einen geringeren Einfluss auf die Kristallqualität.
Temperaturen unter 230\(^{\circ}\)C sind allerdings nötig um erhebliche Desorption
zu vermeiden. Ein geringer Haftkoeffizient wurde besonders bei der Nukleation
auf der Si(111)-H Oberfläche beobachtet und verhindert das Zusammenwachsen
von Inseln zu einer homogenen Schicht.
Der Einfluss des Substrattyps, der Fehlorientierung der Oberfläche und der Ausheizsequenz
auf das Wachstum von Bi\(_2\)Te\(_3\) Schichten wurde untersucht. Die Ausrichtung
der Schicht ändert sich je nach Winkel der Fehlorientierung und der
Ausheilsequenz: Typischerweise orientieren sich die Ebenen der Schicht parallel zu
den Si(111) Ebenen, was aufgrund des Transfers der Stapelfolge vom Substrat zur
Schicht an den Stufenkanten die Unterdrückung von Zwillingsdefekte verbessert.
Andererseits führt diese Orientierung zu Anti-Phasen-Domänen durch die Verschiebung
an den Stufenkanten und zu einer gestuften Oberflächenmorphologie.
Für bestimmte Substratpräparationen richtet sich die Schicht jedoch parallel zur
Oberfläche aus. Diese Orientierung verhindert Verschiebungen an Stufenkanten
und damit Anti-Phasen-Domänen. Dies führt aufgrund der langreichweitigen Ordnung
zu sehr schmalen Bragg-Reflexen in XRD rocking curve Diffraktogrammen.
Weiterhin führen raue Fe:InP(111):B Substrate zu einer starken Unterdrückung
von Zwillingsdefekten und aufgrund der besseren Gitteranpassung zu einer deutlich
verringerten Verdrehung der Domänen.
Als Nächstes wurde das magnetisch dotierte V\(_z\)(Bi\(_{1−x}\)Sb\(_x\))\(_{2−z}\)Te\(_3\) untersucht mit
dem Ziel den Quanten anomalen Hall-Effekt zu realisieren. Die Zugabe von V und
Bi zu Sb\(_2\)Te\(_3\) führt zu einer effizienten Nukleation auf der Si(111)-H Oberfläche
und einer geschlossenen, homogenen Schicht. Magnetotransport Messungen der
Schichten ergeben einen messbaren anomalen Hall-Widerstand deutlich unter der
von-Klitzing-Konstanten. Die Beobachtung des Quanten anomalen Hall-Effekts
setzt eine vollständige Unterdrückung der defekt-induzierten, parasitären Leitfähigkeit
im Inneren der Schicht voraus. Dies kann durch die Optimierung der
Dicke, Zusammensetzung und Wachstumsbedingungen der Schicht erreicht werden.
Beobachtungen zeigen, dass die Wachstumstemperatur die strukturelle Qualität
stark beeinflusst. Erhöhte Temperaturen erzielen größere Inseln, eine verbesserte
kristalline Orientierung und weniger Zwillingsdefekte. Andererseits wird Desorption
von überwiegend Sb beobachtet, was sich auf die Dicke, Zusammensetzung
und Reproduzierbarkeit der Schichten auswirkt. Bei 190\(^{\circ}\)C kann Desorption vermieden
werden, was eine präzise Kontrolle über Schichtdicke und Zusammensetzung
des quaternären Verbunds ermöglicht, während eine hohe strukturelle Qualität
erhalten bleibt.
Es ist besonders wichtig das Bi/Sb Verhältnis zu optimieren, da durch das Legieren
des n-Typ Bi\(_2\)Te\(_3\) mit dem p-Typ Sb\(_2\)Te\(_3\) bei einem bestimmten Verhältnis Ladungsneutralität
erzielt wird. Dies ist nötig um die Leitung im Inneren der Schicht
vollständig zu unterdrücken und die Fermikante in die magnetische Austauschlücke
zu schieben. Der Sb Gehalt x beeinflusst außerdem die Gitterkonstante a in der
Ebene deutlich, im Gegensatz zur Gitterkonstante c in Wachstumsrichtung. Mit
Hilfe dieses Zusammenhangs kann x selbst in dünnen Schichten unter 10 nm Dicke,
wie sie für den Quantum anomalen Hall-Effekt benötigt werden, genau bestimmt
werden. Der Sb Gehalt x beeinflusst weiterhin die Oberflächenmorphologie deutlich:
mit steigenden x verringert sich die Inselgröße und die RMS Rauigkeit wächst
um bis zu einem Faktor 4 zwischen x = 0 und x = 1.
Eine Probenserie mit x zwischen 0,56−0,95 wurde hergestellt, wobei darauf geachtet
wurde eine konstante Dicke von 9 nm und eine Dotierkonzentration von 2 at.%
V beizubehalten. Magnetotransport Messungen bei 4,2K zeigen Ladungsneutra-
lität bei x = 0,86. Der maximale anomale Hall-Widerstand von 0,44 h/e\(^2\) wird
bei x = 0,77 nahe der Ladungsneutralität beobachtet. Wird die Messtemperatur
auf 50 mK reduziert, steigt der anomale Hall-Widerstand signifikant an. Mehrere
Proben mit x in einem schmalen Bereich von 0,76−0,79 zeigen den Quanten
anomalen Hall-Effekt mit einem Hall-Widerstand, der die von-Klitzing-Konstante
erreicht, und verschwindendem longitudinalen Widerstand. Die Realisierung des
Quantum anomalen Hall-Effekts als erste Gruppe in Europa ermöglichte es uns
die elektrischen und magnetischen Eigenschaften der Proben in Zusammenarbeit
mit anderen Gruppen zu untersuchen.
In Kollaboration mit der Physikalisch-Technische Bundesanstalt wurden Hochpräzisionsmessungen
mit detaillierter Fehleranalyse durchgeführt und eine relative
Abweichung von der von-Klitzing-Konstante von (0,17\(\pm\)0,25)*10\(^{−6}\) erzielt. Dieser
Wert wurde als kleinster und genauester Wert publiziert, was die hohe Qualität
der zur Verfügung gestellten Proben zeigt. Dieses Ergebnis ebnet den Weg für die
Anwendung von magnetischen topologischen Isolatoren als Widerstand Standards
ohne Magnetfeld.
In enger Zusammenarbeit mit der Transport Gruppe in der EP3 wurden nichtlokale
Magnetotransport Messungen bei 15mK durchgeführt. Das Ergebnis beweist,
dass Transport durch chirale Randkanäle erfolgt. Die detaillierte Analyse
kleiner Anomalien in Transport Messungen offenbart Instabilitäten in der magnetischen
Phase selbst bei 15 mK. Der zeitabhängige Charakter dieser Anomalien
weist auf superparamagnetische Anteile in der nominell ferromagnetischen Phase
hin.
Als nächstes wurde der Einfluss der Deckschicht und des Substrattyps auf die
strukturellen Eigenschaften und die Auswirkungen auf den Quanten anomalen
Hall-Effekt untersucht. Dazu wurde eine Schicht auf halbisolierendem Fe:InP(111)B
Substrat unter den zuvor optimierten Wachstumsbedingungen gewachsen. Dies
führt zu einer deutlich erhöhten kristallinen Qualität mit einem verringerten Verdrehungswinkel
von 5,4\(^{\circ}\) auf 1,0\(^{\circ}\). Weiterhin wurde eine Schicht ohne schützende
Deckschicht auf Si gewachsen und, nachdem ausreichend Zeit für mögliche Degradation
vergangen war, gemessen. Die Schicht auf Si ohne Deckschicht zeigt perfekte
Quantisierung, während die Schicht auf InP eine Abweichung von etwa 5%
aufweist. Ursache könnte die höhere kristalline Qualität sein, Variationen in z.B.
Sb Gehalt könnten jedoch auch eine Rolle spielen. Insgesamt scheint der Quanten
anomale Hall-Effekt robust gegenüber Änderungen des Substrats und der
Deckschicht zu sein.
Des Weiteren wurde die Abhängigkeit des Quanten anomalen Hall-Effekts von
der Schichtdicke untersucht. Zwischen 5−8 nm Dicke wechselt das Material typischerweise
von einem 2D topologischen Isolator mit hybridisierten oberen und
unteren Oberflächenzustand zu einem 3D topologischen Isolator. Eine Probenreihe
mit 6 nm, 8 nm und 9 nm Schichtdicke zeigt den Quanten anomalen Hall-
Effekt, während 5 nm und 15 nm dicke Schichten deutliche Beiträge aus dem Volumen
haben. Die Analyse der longitudinalen- und Hall-Leitfähigkeit während der
Umkehrung der Magnetisierung offenbart eindeutige Unterschiede. Die 6 nm dicke
Schicht zeigt ein Skalierungsverhalten konsistent mit dem ganzzahligen Quanten-
Hall-Effekt, die 9 nm dicke Schicht dagegen zeigt das erwartete Skalierungsverhalten
für die topologischen Oberflächenzustände eines 3D topologischen Isolators.
Das besondere Skalierungsverhalten der 9 nm dicken Schicht ist von besonderem
Interesse, da es der axionischen Elektrodynamik in einem 3D topologischen Isolator
entspringen könnte.
Anschließend wird der Einfluss von V Dotierung auf die strukturellen und magnetischen
Eigenschaften der Schichten systematisch untersucht. Ähnlich wie das
Legieren mit Bi, scheint V Dotieren die Oberfläche deutlich zu glätten. Mit steigenden
V Gehalt erhöht sich die Zahl der Te Bindungspartner simultan im 2:3 Verhältnis,
wie erwartet für den Einbau von V auf Gruppe-V Plätzen. Die lineare Kontraktion
der Gitterkonstanten in der Ebene und senkrecht dazu mit steigender V
Dotierung ist quantitativ konsistent mit dem Einbau von V\(^{3+}\) Ionen, möglicherweise
gemischt mit V\(^{4+}\) Ionen, auf Gruppe-V Plätzen. Dies ist konsistent mit
SQUID Messungen die eine Magnetisierung von 1,3 \(\mu_B\) pro V Ion zeigen.
Schließlich werden magnetisch dotierte topologische Isolator Heterostrukturen hergestellt
und in Magnetotransport Messungen charakterisiert. Der Axion-Isolator
Zustand wurde in dreischichtigen Heterostrukturen mit einer nichtmagnetischen
(Bi,Sb)\(_2\)Te\(_3\) Lage zwischen zwei magnetischen Schichten vorhergesagt, falls die
beiden magnetischen Lagen entkoppelt sind und in antiparalleler Ausrichtung vorliegen.
Magnetotransport Messungen solcher dreischichtigen Heterostrukturen mit
7 nm undotiertem (Bi,Sb)\(_2\)Te\(_3\) zwischen jeweils 2 nm dicken dotierten Schichten
mit 1,5 at.% V zeigen ein Null Hall-Plateau, das einen isolierenden Zustand repräsentiert.
Ähnliche Ergebnisse in der Literatur wurden als Axion-Isolator Zustand
interpretiert, jedoch können andere Erklärungen ohne eine direkten Messung der
antiparallelen magnetischen Orientierung nicht ausgeschlossen werden.
Weiterhin zeigen Heterostrukturen mit einer 2 nm dünnen, hoch V dotierten Schicht
einen anomalen Hall-Effekt mit entgegengesetzten Vorzeichen im Vergleich zu
vorhergehenden Proben. Die Abhängigkeit von der Dicke und Position dieser
Schicht könnte darauf hindeuten, dass Streuprozesse an den Grenzflächen einen
Beitrag zum anomalen Hall-Effekt entgegengesetzt zu den Volumenstreuprozessen
verursachen.
Viele interessante Phänomene in Quanten anomalen Hall Isolatoren sowie Axion-
Isolatoren sind noch nicht eindeutig beobachtet worden. Dies schließt gebundene
Majorana-Zustände in Quanten anomalen Hall Isolator/Supraleiter Hybridsystemen
und den topologischen magneto-elektrischen Effekt in Axion-Isolatoren ein.
Die limitierte Beobachtungstemperatur des Quanten anomalen Hall-Effekts von
unter 1 K könnte in Heterostrukturen aus 3D topologischen Isolator und magnetischen
Isolator Schichten welche den magnetischen Proximity-Effekt nutzen erhöht
werden.
Das wichtigste Ergebnis dieser Arbeit ist das reproduzierbare Wachstum und
die Charakterisierung von (V,Bi,Sb)\(_2\)Te\(_3\) Schichten die den Quanten anomalen
Hall-Effekt zeigen. Die detaillierte Untersuchung der strukturellen Voraussetzungen
und die Beobachtung des besonderen axionischen Skalierungsverhaltens in
3D magnetischen Isolatorschichten führt zu einem besseren Verständnis dieses
neuen Quantenzustands. Die Hochpräzisionsmessungen des Quanten anomalen
Hall-Effekts mit der geringsten Abweichung von der von-Klitzing-Konstanten sind
ein wichtiger Schritt zur Realisierung eines Widerstand-Standards basierend auf
Quantisierung ohne magnetischem Feld.
KW  - Bismutverbindungen
KW  - Topologischer Isolator
KW  - Molekularstrahlepitaxie
KW  - Quanten anomalen Hall-Effekt
KW  - Quantum anomalous Hall effect
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-211666
ER  - 
TY  - THES
A1  - Kerner, Florian Tobias
T1  - Reactions of rhodium(I) with diynes and studies of the photophysical behavior of the luminescent products
T1  - Reaktionen von Rhodium(I) mit Diinen und Untersuchung der photophysikalischen Eigenschaften der lumineszenten Produkte
N2  - Chapter 1 deals with the reaction of [Rh(acac)(PMe3)2] with para-substituted 1,4-diphenylbuta-1,3-diynes at room temperature, in which a complex containing a bidentate organic fulvene moiety, composed of two diynes, σ-bound to the rhodium center is formed in an all-carbon [3+2] type cyclization reaction. In addition, a complex containing an organic indene moiety, composed of three diynes, attached to the rhodium center in a bis-σ-manner is formed in a [3+2+3] cyclization process. 
Reactions at 100 °C reveal that the third diyne inserts between the rhodium center and the bis-σ-bound organic fulvene moiety. Furthermore, the formation of a 2,5- and a 2,4-bis(arylethynyl)rhodacyclopentadiene is observed. The unique [3+2] cyclization product was used for the synthesis of a highly conjugated organic molecule, which is hard to access or even inaccessible by conventional methods. Thus, at elevated temperatures, reaction of the [3+2] product with para-tolyl isocyanate led to the formation of a purple organic compound containing the organic fulvene structure and one equivalent of para-tolyl isocyanate.
The blue and green [3+2+3] complexes show an unusually broad absorption from 500 – 1000 nm with extinction coefficients ε of up to 11000 M-1 cm-1. The purple organic molecule shows an absorption spectrum similar to those of known diketopyrrolopyrroles.
Additionally, the reaction of [Rh(acac)(PMe3)2] with para-tolyl isocyanate was investigated. A cis-phosphine complex of the form cis-[Rh(acac)(PMe3)2(isocyanate)2] with an isocyanate dimer bound to the rhodium center by one carbon and one oxygen atom was isolated.
Replacing the trimethylphosphine ligands in [Rh(acac)(PMe3)2] with the stronger σ-donating NHC ligand Me2Im (1,3-dimethylimidazolin-2-ylidene), again, drastically alters the reaction. Similar [3+2] and [3+2+3] products to those discussed above could not be unambiguously assigned, but cis- and trans-π-complexes, which are in an equilibrium with the two starting materials, were formed.
Chapters 2 is about the influence of the backbone of the α,ω-diynes on the formation and photophysical properties of 2,5-bis(aryl)rhodacyclopentadienes. Therefore, different α,ω-diynes were reacted with [Rh(acac)(PMe3)2] and [Rh(acac)(P(p-tolyl)3)2] in equimolar amounts. In general, a faster consumption of the rhodium(I) starting material is observed while using preorganized α,ω-diynes with electron withdrawing substituents in the backbone. The isolated PMe3-substituted rhodacyclopentadienes exhibit fluorescence, despite the presence of the heavy atom rhodium, with lifetimes τF of < 1 ns and photoluminescence quantum yields Φ of < 0.01 as in previously reported P(p-tolyl)-substituted 2,5-bis(arylethynyl)rhodacyclopentadienes. However, an isolated P(p-tolyl)-substituted 2,5-bis(aryl)rhodacyclopentadiene shows multiple lifetimes and different absorption and excitation spectra leading to the conclusion that different species may be present.
Reaction of [Rh(acac)(Me2Im)2] with dimethyl 4,4'-(naphthalene-1,8-diylbis(ethyne-2,1-diyl))dibenzoate, results in the formation of a mixture trans- and cis-NHC-substituted 2,5-bis(aryl)rhodacyclopentadienes.
In chapter 3 the reaction of various acac- and diethyldithiocarbamate-substituted rhodium(I) catalysts bearing (chelating)phosphines with α,ω-bis(arylethynyl)alkanes (α,ω-diynes), yielding luminescent dimers and trimers, is described. The photophysical properties of dimers and trimers of the α,ω-diynes were investigated and compared to para-terphenyl, showing a lower quantum yield and a larger apparent Stokes shift.
Furthermore, a bimetallic rhodium(I) complex of the form [Rh2(ox)(P(p-tolyl)3)4] (ox: oxalate) was reacted with a CO2Me-substituted α,ω-tetrayne forming a complex in which only one rhodium(I) center reacts with the α,ω-tetrayne. The photophysical properties of this mixed rhodium(I)/(III) species shows only negligible differences compared to the P(p-tolyl)- and CO2Me-substituted 2,5-bis(arylethynyl)rhodacyclopentadiene, previously synthesized by Marder and co-workers.
N2  - Kapitel 1 beschäftigt sich mit der Umsetzung von [Rh(acac)(PMe3)2] mit zwei Äquivalenten para-substituierten 1,4-Diphenylbuta-1,3-diins bei Raumtemperatur. Dabei bildete sich ein Komplex, welcher eine organische Fulveneinheit, bestehend aus zwei Diinen und verbunden über zwei σ-Bindungen mit dem Rhodiumzentralatom, besitzt. Diese Verbindung bildet sich in einer „all-carbon“ [3+2] ähnlichen Zyklisierungsreaktion. Ebenso konnte aus derselben Reaktion ein Komplex mit einer Indeneinheit, bestehend aus drei Diinen, welche durch zwei σ-Bindungen mit dem Rhodiumzentralatom verbunden sind, isoliert und charakterisiert werden. Diese Verbindung bildet sich in einer „all-carbon“ [3+2+3] ähnlichen Zyklisierungsreaktion. Experimente bei 100 °C zeigen, dass sich das zusätzliche dritte Diin zwischen dem Rhodiumzentralatom und der organischen Fulveneinheit einfügt. Zusätzlich konnte die Bildung von 2,4- und 2,5-Bis(arylethinyl)rhodazyklopentadienen bei 100°C beobachtet werden. Diese seltene [3+2] Zyklisierungsreaktion kann benutzt werden um konjugierte, organische Moleküle darzustellen, welche sonst nur schwer oder gar nicht mit bisher bekannten Synthesemethoden zugänglich sind. In der Umsetzung des [3+2] Komplexes mit para-Tolylisocyanat bei 80 °C konnte ein violetter, rein organischer Feststoff erhalten werden, bestehend aus der organischen Fulveneinheit und einem Äquivalent para-Tolylisocyanat. Die blauen und grünen [3+2+3] Komplexe zeigen unter anderem eine ungewöhnliche breite Absorption von 500 – 1000 nm mit einem Extinktionskoeffizienten von bis zu 11000 M-1 cm-1. Die violette, rein organische Verbindung zeigt ein Absorptionsspektrum ähnlich zu bereits bekannten Diketopyrrolopyrrolen. Auch wurde die Reaktion von [Rh(acac)(PMe3)2] mit para-Tolylisocyanat untersucht. Es konnte ein cis-phosphan Komplex, bei dem ein para-Tolylisocyanat-Dimer über ein Kohlenstoff- und ein Sauerstoffatom an das Rhodiumzentralatom koordiniert, isoliert und charakterisiert werden. Substitution des Trimethylphosphans im Rh(I)-Präkursors durch einen NHC Liganden, nämlich Me2Im (1,3-dimethylimidazolin-2-yliden) führt zu einem unterschiedlichen Reaktionsverlauf. Ähnliche [3+2] und [3+2+3] Komplexe konnten nicht zweifelsfrei bestätigt werden, dafür konnte aber gezeigt werden, dass sich in der Reaktion bildende cis- und trans-Komplexe im Gleichgewicht mit den verwendeten Startmaterialien befinden.
Im zweiten Kapitel dieser Arbeite wurde der Einfluss des Rückgrats von α,ω-bis(arylethynyl)alkanen (α,ω-Diine) auf die Bildung und die photophysikalischen Eigenschaften von 2,5-Bis(aryl)rhodazyklopentadienen untersucht. Dazu wurden mehrere α,ω-Diine mit unterschiedlichem Rückgrat synthetisiert und diese mit [Rh(acac)(PMe3)2] und [Rh(acac)(P(p-tolyl)3)2] in äquimolaren Mengen reagiert. Es konnte ein schnellerer Verbrauch des Rh(I)-Präkursors bei der Verwendung von vororganisierten α,ω-Diinen mit elektronenziehenden Substituenten am Rückgrat festgestellt werden. Die PMe3-substituierten Rhodazyklopentadiene zeigen Fluoreszenz, trotz der Anwesenheit eines Schwermetalls. Lebenszeiten von τF < 1 ns und Quantenausbeuten von Φ < 0.01, ähnlich wie in P(p-tolyl)-substituierten 2,5-Bis(arylethynyl)rhodazyklopentadienen wurden beobachtet. Bei einem isolierten P(p-tolyl)-substituierten 2,5-Bis(aryl)rhodazyklopentadien konnten mehrere Lebenszeiten, wie auch unterschiedliche Absorptions- und Anregungsspektren detektiert werden, was zu der Schlussfolgerung führt, dass in Lösung mehrere Spezies vorhanden sind. Die Reaktion von [Rh(acac)(Me2Im)2] mit Dimethyl 4,4'-(naphthalen-1,8-diylbis(ethyn-2,1-diyl))dibenzoat führt zur Bildung einer Mischung aus trans- und cis-NHC-substituierter 2,5-Bis(aryl)rhodazyklopentadienen.
Im dritten Kapitel, wurde die Bildung lumineszenter Dimere und Trimere aus der Umsetzung von verschiedenen α,ω-Diinen mit katalytischen Mengen verschiedener acac- und diethyldithiocarbamat-substituierter Rhodium(I)-Katalysatoren mit (chelatisierenden) phosphanen untersucht. Anschließend wurden die photophysikalischen Eigenschaften der Dimere und Trimere untersucht und mit para-Terphenyl verglichen. Dabei wurden ähnliche Lebenszeiten, eine geringere Quantenausbeute wie auch größere Stokes-Verschiebungen der Dimere und Trimere im Vergleich zu para-Terphenyl gefunden. Auch wurde die Reaktion zwischen einem bimetallischen Rhodium Komplex [Rh2(ox)(P(p-tolyl)3)4] (ox: oxalat) und einem CO2Me-substituiertem α,ω-bis(arylbutadiynyl)alkan (α,ω-Tetrain) untersucht. In dieser Umsetzung reagierte nur eine der beiden möglichen Rhodium(I)-zentren mit dem α,ω-Tetrain unter Bildung eines 2,5-Bis(arylethynyl)rhodazyklopentadiens. Die photophysikalischen Eigenschaften dieser gemischten Rhodium(I)/(III)-Spezies zeigt nur marginale unterschiede, verglichen mit einem mononuklearen P(p-tolyl)- und CO2Me-substituiertem 2,5-Bis(arylethynyl)rhodazyklopentadiens, welches zuvor im Arbeitskreis Marder schon synthetisiert wurde.
KW  - Übergangsmetallkomplexe
KW  - Rhodium
KW  - Übergangsmetallkomplex
KW  - Zyklisierung
KW  - Transitionmetal
KW  - Cyclization
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-209107
ER  - 
TY  - THES
A1  - Kreß, Luisa Sophia
T1  - Determination of cytokine and axon guidance molecule profiles in patients with small fiber neuropathy
T1  - Bestimmung von Zytokin- und Axon Guidance Molekül-Profilen bei Patienten mit Kleinfaserneuropathie
N2  - The pathophysiological mechanisms of pain in small fiber neuropathy (SFN) are unclear. Based on experimental and clinical studies, sensitized nociceptors in the skin are reported to be involved in pain development. These nociceptors may be sensitized by cutaneous and systemic pain mediators e.g. pro- and anti-inflammatory cytokines. The aim of our study was, to measure the systemic and local gene expression of pro- and anti-inflammatory cytokines in white blood cells (WBC) as well as in primary fibroblasts and keratinocytes obtained from human skin of patients with SFN. Furthermore, gene expression levels of axon guidance molecules and their receptors, as potential regulators of the intraepidermal nerve fiber density (IENFD), were investigated. 55 patients and 31 healthy controls were prospectively recruited. Participants underwent extensive clinical phenotyping and blood sampling, 6-mm skin punch biopsies were taken from the right lateral calf and the upper thigh. Systemic relative gene expression levels (ΔG) of the interleukin (IL)-1β, IL-2, IL-6, IL-8, and tumor necrosis factor (TNF) was measured in WBC. Skin punch biopsies were taken to determine the IENFD and to obtain primary fibroblast and keratinocyte cell cultures. Skin cells were then used for investigation of ΔG in axon guidance molecules netrin 1 (NTN1) and ephrin A4 (EPHA4) as well as their receptors Unc5b receptor, and ephrin A4 (EFNA4) as well as cytokines IL-1β, IL-4, IL-6, IL-8, IL-10, TNF, and transforming growth factor (TGF). Systemically, gene expression of IL-2, IL-8, and TNF was higher in SFN patients compared to healthy controls. In keratinocytes, higher expression levels of NTN1 and TGF were found when comparing the SFN patients to the controls. In fibroblasts higher gene expression was shown in NTN1, Unc5b, IL-6, and IL-8 when comparing patients to healthy controls. The systemically and local elevated levels of pro-inflammatory, algesic cytokines in SFN patients compared to healthy controls, confirms a potential pathophysiological role in the development of neuropathic pain. Data also indicate fibroblasts and keratinocytes to influence subepidermal and intraepidermal nerve fiber growth through the expression of NTN1 and Unc5b. Thus, skin cells may contribute to the development of neuropathic pain through local denervation.
N2  - Der Pathomechanismus von Schmerz bei Small fiber Neuropathie (SFN) ist unklar. Auf Grundlage tierexperimenteller und klinischer Studien wird die Einwirkung kutaner und systemischer Schmerzmediatoren auf sensibilisierte Nozizeptoren in der Haut als mögliche Ursache diskutiert. In diesem Zusammenhang gab es Hinweise auf die Bedeutung von pro- und anti-inflammatorischen Zytokinen in der Pathophysiologie neuropathischer Schmerzen. Ziel der Studie war es, die systemische und lokale Genexpression pro- und anti-inflammatorischer Zytokine in Leukozyten sowie kutanen Fibroblasten und Keratinozyten von Patienten mit SFN zu messen. Ferner wurde untersucht, inwieweit die Expression repellierender Axon Guidance Moleküle und ihrer Rezeptoren in Hautzellen die intraepidermale Nervenfaserdichte (IENFD) regulieren könnte. Insgesamt konnten 55 SFN PatientInnen und 31 gesunde KontrollprobandInnen prospektiv rekrutiert werden. Nach ausführlicher klinischer Phänotypisierung und Blutentnahme wurden bei allen StudienteilnehmerInnen 6-mm Hautstanzbiopsien am lateralen Unter- und Oberschenkel entnommen. Die Messung der systemisch relativen Genexpression (ΔG) der Zytokine Interleukin (IL)-1β, IL-2, IL-6, IL-8 und des tumor necrose factors (TNF) erfolgte aus Leukozyten. Aus den Hautstanzbiopsien, die u.a. zur Bestimmung der IENFD verwendet wurden, wurden außerdem Primärzellkulturen von Keratinozyten und Fibroblasten angelegt, aus denen die lokale ΔG von Axon Guidance Molekülen Netrin 1 (NTN1) und Ephrin A4 (EPHA4), deren Rezeptoren Unc5b, und Ephrin A4 receptor (EFNA4) sowie der Zytokine IL-1β, IL-4, IL-6, IL-8, IL-10, TNF und des transforming growth factors (TGF) erfolgte. Systemisch zeigte sich eine höhere Genexpression für IL-2, IL-8 und TNF bei SFN Patienten im Vergleich zu gesunden Kontrollen. In Keratinozyten konnten höhere Expressionen von NTN1 und TGF-β1 bei Vergleich der Patientengruppe mit der Kontrollgruppe nachgewiesen werden. In Fibroblasten zeigte sich im Gruppenvergleich eine höhere Genexpression für NTN1, Unc5b sowie für IL-6 und IL-8. Die systemisch und lokal bei SFN Patienten nachgewiesene höhere Expression algetischer, pro-inflammatorischer Zytokine verglichen mit Kontrollen unterstützt eine mögliche pathophysiologische Rolle bei der Entstehung von neuropathischen Schmerzen. Ferner weisen die Daten darauf hin, dass Fibroblasten und Keratinozyten durch die Expression von NTN1 und Unc5b Einfluss auf das subepidermale und intraepidermale Nervenfaserwachstum nehmen und durch lokale Denervierung bei der Entstehung neuropathischer Schmerzen mitwirken könnten.
KW  - Neuropathischer Schmerz
KW  - Pathomechanismus
KW  - Cytokine
KW  - small fiber neuropathy
KW  - axon guidance molecules
KW  - pathophysilogical mechanisms
KW  - cytokines
KW  - skin cells
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-209113
ER  - 
TY  - THES
A1  - Koschitzki, Kim Christine Cornelia
T1  - Evaluation of preclinical animal models in bone tissue engineering and their success in clinical translation
T1  - Evaluierung von vorklinischen Tiermodellen für Bone Tissue Engineering und von ihrem Erfolg in der klinischen Umsetzung
N2  - Autologous bone still represents today’s gold standard for the treatment of critical size bone defects and fracture non-unions despite associated disadvantages regarding limitations in availability, donor site morbidity, costs and efficacy. Bone tissue engineered constructs would present a promising alternative to currently available treatments. However, research on preclinical animal studies still fails to provide clinical applicable results able to allow the replacement of currently applied methods. It seems that the idea of bone tissue engineering, which has now been integral part of academic studies for over 30 years, got somehow stuck at an intermediate level, in between intense preclinical research and striven stages of initial clinical trial phases. A clear discrepancy exists between the number of studies with preclinical animal models for bone tissue engineering and the number of clinically approved bone tissue engineered constructs available to patients.
The aim of this thesis was hence to evaluate preclinical animal models for bone tissue engineering as well as the perception of scientists and clinicians towards these models. Moreover, the general role of bone tissue engineering and its clinical need assessed by scientists and surgeons was investigated. A survey was conducted questioning both scientific and clinical opinions on currently available study designs and researchers’ satisfaction with preclinical animal models. Additionally, a literature research was conducted, resulting in 167 papers from the last 10 years that report current designs of preclinical orthotopic animal studies in bone tissue engineering. Thereby, the focus lied on the description of the models regarding animal species, strain, age, gender and defect design. The outcome of the literature search was evaluated and compared to the outcome obtained from the survey.
The survey data revealed that both scientists and surgeons generally remain positive about the future role of bone tissue engineering and its step to clinical translation, at least in the distant future, where it then might replace the current gold standard, autologous bone. Moreover, most of the participants considered preclinical animal models as relevant and well developed but the results as not yet realizable in the clinics. Surgeons thereby demonstrated a slightly more optimistic perception of currently conducted research with animal models compared to scientists. However, a rather inconsistent description of present preclinical study designs could be discerned when evaluating the reported study designs in the survey and the papers of the literature search.
Indeed, defining an appropriate animal species, strain, age, gender, observation time, observation method and surgical design often depends on different indications and research questions and represents a highly challenging task for the establishment of a preclinical animal model. The existing lack of valid guidelines for preclinical testing of bone tissue engineering leads hence to a lack of well standardized preclinical animal models. Moreover, still existing knowledge gaps regarding aspects that affect the process of fracture healing, such as vascularization or immunological aspects, were found to hinder clinical translation of bone tissue engineered constructs. 
Using literature review and survey, this thesis points out critical issues that need to be addressed to allow clinical translation of bone tissue engineered constructs. It can be concluded that currently existing study designs with preclinical animal models cannot live up to the claim of providing suitable results for clinical implementation. The here presented comprehensive summary of currently used preclinical animal models for bone tissue engineering reveals a missing consensus on the usage of models such as an apparent lack of reporting and standardization regarding the study designs described in both papers from the literature review and the survey. It thereby indicates a crucial need to improve preclinical animal models in order to allow clinical translation. Despite the fact that participants of the survey generally revealed a positive perception towards the use of bone tissue engineered constructs and affirmed the clinical need for such novel designs, the missing standardization constitutes a main weak point for the provision of reliable study outcome and the translational success of the models. The optimization of reproducibility and reliability, as well as the further understanding of ongoing mechanisms in bone healing in order to develop effective tissue engineered constructs, need to form the basis of all study designs. The study outcomes might then fulfill the requirements of maybe today's and hopefully tomorrow's aging population.
N2  - Über die letzten 30 Jahre hat die Rolle von Bone Tissue Engineering vielversprechenden Fortschritt gemacht und immer neue Ansätze werden etabliert. Somit stellt Bone Tissue Engineering eine aussichtsvolle Alternative zu dem heutigen Goldstandard (autogene Knochenersatzmaterialien) dar, nachdem diese häufig mit Nachteilen einhergehen: limitierte Verfügbarkeit, Morbidität durch Zweiteingriffe, ungenügend Stabilität und Kosten. Die klinische Umsetzung findet jedoch nicht so schnell statt, wie ursprünglich erhofft und es scheint, als würde die vorklinische Forschung auf der Stelle treten. Das Ausbleiben von reproduzierbaren und standardisierten vorklinischen Studien verhindert dabei eine "bench to bedside" Translation. 
Ziel dieser Doktorarbeit war es, derzeitige präklinische Tiermodelle für Bone Tissue Engineering zu evaluieren und dabei zu untersuchen, woran es liegen könnte, dass die Lücke zwischen vorklinischen Studienergebnissen und klinischer Umsetzung noch immer existiert. Es wurde ein Fragebogen erstellt, anhand dessen die generelle Meinung gegenüber Bone Tissue Engineering und die Effizienz derzeitiger präklinischer Studienmodelle aus sowohl klinischer, als auch wissenschaftlicher Sicht hinterfragt wurde. Hier wurde außerdem auf die Beurteilung der Zufriedenstellung solcher Modelle seitens der Forscher eingegangen. 
Darüber hinaus erfolgte eine systemische Literatursuche auf der Online-Plattform “Pubmed” mit dem Ziel Studien der letzten zehn Jahre über präklinische orthotopische Tiermodelle in Bone Tissue Engineering zusammenzufassen und die verschiedenen Studiendesigns zu evaluieren. Der Fokus lag dabei auf der Beschreibung der Tiermodelle bezüglich Tierart, Geschlecht, Alter und Defektdesign. Ergebnisse der Literatursuche wurden anschließend evaluiert und mit den Antworten aus dem Fragebogen verglichen und diskutiert. 
Es hat sich anhand des Fragebogens gezeigt, dass sowohl Wissenschaftler, als auch Chirurgen positiv gestimmt sind, was die zukünftige Anwendung von Bone Tissue Engineering in den Kliniken betrifft. Jedoch beurteilten die meisten Teilnehmer des Fragebogens die präklinischen Tiermodelle zwar als relevant und gut entwickelt, deren Ergebnisse als klinisch allerdings nicht anwendbar. Dabei fiel die Einschätzung präklinischer Forschung mit Tiermodellen unter den Chirurgen etwas optimistischer aus als unter den Forschern. Die Evaluierung der Studien aus dem Fragebogens und der Literatursuche zeigte jedoch auch, dass die darin beschriebenen Tiermodelle einen eher uneinheitlichen Studienaufbau aufweisen. Tatsächlich stellt die Etablierung eines fundierten Studiendesigns im Anbetracht der zahlreichen Möglichkeiten eine immense Herausforderung dar. Die Festlegung eines Versuchsaufbaus hängt dabei von der Wahl der Tierart, dessen Geschlecht und Alter, des chirurgischen Ablaufs, sowie der technischen und zeitlichen Beobachtungsmöglichkeit ab. Es stellte sich heraus, dass für viele Studien eine diesbezüglich notwendige Standardisierung kaum existiert und dadurch Studienergebnisse entstehen, die schwer reproduzierbar sind und somit den Ansprüchen einer klinischen Umsetzung nicht gerecht werden können. Hinzu kommen außerdem die noch immer bestehenden Wissenslücken in Bezug auf Knochenheilung beeinflussende Faktoren wie Vaskularisation und Abläufe des Immunsystems. 
Abschließend lässt sich sagen, dass die durchgeführte Evaluierung von Studien mit präklinischen Tiermodellen eine fehlende Standardisierung derzeit existierender Studiendesigns darlegt und eine klinische Umsetzung der daraus resultierenden Studienergebnissen somit noch nicht möglich ist. Auch wenn die Teilnehmer des Fragebogens den Bedarf an neuen, klinisch anerkannten Methoden für Knochenaufbauten nahelegten und eine generell positive Einstellung gegenüber dem potentiellen Gebrauch von Bone Tissue Engineering Konstrukte in den Kliniken zeigten, ist die Ablösung von autologem Knochen durch solch neuartige Designs nicht realisierbar, solange die Reproduzierbarkeit der Daten aus präklinischen Tiermodellstudien fehlt. Zusammen mit wegweisenden Richtlinien und fundiertem Wissen über grundliegende Mechanismen im Knochenheilungsprozess, sollte sie die Basis eines jeden Studienaufbaus mit präklinischen Tiermodellen darstellen, um schließlich zu den Ergebnissen zu gelangen, die es für eine klinische Umsetzung von Bone Tissue Engineering bedarf.
KW  - bone
KW  - tissue
KW  - engineering
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-207593
ER  - 
TY  - THES
A1  - Yang, Tao
T1  - Functional insights into the role of a bacterial virulence factor and a host factor in Neisseria gonorrhoeae infection
T1  - Funktionelle Einblicke in die Rolle eines bakteriellen Virulenzfaktors und eines Wirtsfaktors bei der Infektion mit Neisseria gonorrhoeae
N2  - Neisseria gonorrhoeae (GC) is a human specific pathogenic bacterium. Currently, N. gonorrhoeae developed resistance to virtually all the available antibiotics used for treatment. N. gonorrhoeae starts infection by colonizing the cell surface, followed by invasion of the host cell, intracellular persistence, transcytosis and exit into the subepithelial space. Subepithelial bacteria can reach the bloodstream and disseminate to other tissues causing systemic infections, which leads to serious conditions such as arthritis and pneumonia. A number of studies have well established the host-pathogen interactions during the initial adherence and invasion steps. However, the mechanism of intracellular survival and traversal is poorly understood so far. Hence, identification of novel bacterial virulence factors and host factors involved in the host-pathogen interaction is a crucial step in understanding disease development and uncovering novel therapeutic approaches. Besides, most of the previous studies about N. gonorrhoeae were performed in the conventional cell culture. Although they have provided insights into host-pathogen interactions, much information about the native infection microenvironment, such as cell polarization and barrier function, is still missing. 
This work focused on determining the function of novel bacterial virulence factor NGFG_01605 and host factor (FLCN) in gonococcal infection. NGFG_01605 was identified by Tn5 transposon library screening. It is a putative U32 protease. Unlike other proteins in this family, it is not secreted and has no ex vivo protease activity. NGFG_01605 knockout decreases gonococcal survival in the epithelial cell. 3D models based on T84 cell was developed for the bacterial transmigration assay. NGFG_01605 knockout does not affect gonococcal transmigration. 
The novel host factor FLCN was identified by shRNA library screening in search for factors that affected gonococcal adherence and/or internalization. We discovered that FLCN did not affect N. gonorrhoeae adherence and invasion but was essential for bacterial survival. Since programmed cell death is a host defence mechanism against intracellular pathogens, we further explored apoptosis and autophagy upon gonococcal infection and determined that FLCN did not affect apoptosis but inhibited autophagy. Moreover, we found that FLCN inhibited the expression of E-cadherin. Knockdown of E- cadherin decreased the autophagy flux and supported N. gonorrhoeae survival. Both non-polarized and polarized cells are present in the cervix, and additionally, E-cadherin represents different polarization properties on these different cells. Therefore, we established 3-D models to better understand the functions of FLCN. We discovered that FLCN was critical for N. gonorrhoeae survival in the 3-D environment as well, but not through inhibiting autophagy. Furthermore, FLCN inhibits the E-cadherin expression and disturbs its polarization in the 3-D models. Since N. gonorrhoeae can cross the epithelial cell barriers through both cell-cell junctions and transcellular migration, we further explored the roles FLCN and E-cadherin played in transmigration. FLCN delayed N. gonorrhoeae transmigration, whereas the knockdown of E-cadherin increased N. gonorrhoeae transmigration. 
In summary, we revealed roles of the NGFG_01605 and FLCN-E-cadherin axis play in N. gonorrhoeae infection, particularly in relation to intracellular survival and transmigration. This is also the first study that connects FLCN and human-specific pathogen infection.
N2  - Neisseria gonorrhoeae (GC) ist ein humanpathogenes Bakterium. Gegen jedes kommerziell erhältliche Antibiotikum konnten bereits Resistenzen entdeckt werden. Die Infektion von Neisserien startet mit der Kolonisierung der Zelloberfläche, gefolgt von der Invasion in die Zelle, intrazellulärer Persistenz, Transzytose und Verlassen des subepithelen Raums. Subepithele Bakterien können den Blutfluss erreichen und sich somit auf andere Gewebe verbreiten und dadurch schwerwiegende Erkrankungen wie Arthritis und Lungenentzündungen verursachen. Zahlreiche Studien haben die Interaktion zwischen Wirtszelle und Pathogen zwischen Adhärenz und Invasion gut charakterisiert. Allerdings ist der Mechanismus des intrazellulären Überlebens und der Transmigration weitestgehend unbekannt. Um neue therapeutische Ansätze zu definieren ist es deshalb wichtig weitere bakterielle und zelluläre Faktoren verantwortlich für Interaktionen zwischen Wirt und Pathogen zu identifizieren.
Außerdem wurden Studien über N. gonorrhoeae bisher in konventioneller Zellkultur durchgeführt. Auch wenn diese weitere Einsichten in Wirt-Pathogen Interaktionen geben, ist viel Information in der nativen Infektionsumgebung, wie Zellpolarisierung oder Barrierefunktionen, bisher nicht bekannt.

Diese Arbeit fokussiert sich auf die Bestimmung eines neuen bakteriellen Virulenzfaktors, NGFG_01605, und Wirtsfaktoren (FLCN) in der Infektion von Gonokokken. NGFG_01605 wurde über Screening einer Transposonsammlung identifiziert und ist eine vermeintliche U32 Protease. Im Gegensatz zu anderen Proteinen dieser Familie, wird diese Protease nicht sekretiert und hat keine ex vivo Proteaseaktivität. Der Knockout von NGFG_01605 vermindert die Überlebensrate von Gonokokken in Epithelzellen. 3D-Modelle basierend auf T84-Zellen wurden für die Analyse der bakteriellen Transmigration entwickelt. Der Knockout von NGFG_01605 hat keinen Einfluss auf die Transmigration.

Bei der Suche neuer Wirtsfaktoren, die für die Adhärenz und/oder Internalisierung wichtig sind, wurde FLCN durch ein Screening einer shRNA Sammlung entdeckt. Wir konnten zeigen, dass dieser Faktor zwar nicht für die Adhärenz oder Invasion von N. gonorrhoeae, aber für das Überleben der Bakterien in der Wirtszelle essenziell ist. Da der programmierte Zelltod ein typischer Abwehrmechanismus gegen intrazelluläre Bakterien ist, haben wir Apoptose und Autophagie weiter untersucht und konnten zeigen, dass FLCN zwar keinen Effekt auf Apoptose hat, aber Autophagie inhibiert.
Außerdem konnten wir zeigen, dass FLCN die Expression von E-cadherin inhibiert. Auch der Knockdown von E-cadherin verringerte Autophagie und erhöhte das Überleben von N. gonorrhoeae. Im Gebärmutterhals sind sowohl polarisierte als auch nicht-polarisierte Zellen präsent. E-cadherin hat zudem unterschiedliche Einflüsse auf diese unterschiedlichen Zellen. Aus diesem Grund haben wir ein 3D-Modell entwickelt, um die Funktionen von FLCN besser zu verstehen. Wir entdeckten, dass FLCN zwar auch im 3D Modell wichtig für das Überleben ist, aber nicht durch Inhibition von Autophagie. Außerdem inhibiert FLCN die Expression und Verteilung von E-cadherin in 3D-Modellen. Da N. gonorrhoeae die Epithelzellbarierre durch sowohl Zell-Zell-Kontakte als auch transzelluläre Migration überwinden kann, untersuchten wir daraufhin die Rollen von FLCN und E-cadherin in der transzellulären Migration. Diese wird durch FLCN verspätet und durch Knockdown von E-cadherin erhöht.

Zusammengefasst, haben wir die Rolle von NGFG_01605 und den Zusammenhang von FLCN und E-cadherin während der Infektion von N. gonorrhoeae untersucht. Unser Fokus war hierbei das intrazelluläre Überleben sowie zelluläre Transmigration. Diese Arbeit ist die Erste, die FLCN und humanpathogenspezifische Infektion miteinander in Verbindung bringt.
KW  - Folliculin
KW  - autophagy
KW  - polarized epithelium
KW  - protease
KW  - Gonococcal invasion
KW  - autophagocytose
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-208959
ER  - 
TY  - INPR
A1  - Wohlgemuth, Matthias
A1  - Mitric, Roland
T1  - Excitation energy transport in DNA modelled by multi-chromophoric field-induced surface hopping
T2  - Physical Chemistry Chemical Physics
N2  - Absorption of ultraviolet light is known as a major source of carcinogenic mutations of DNA. The underlying processes of excitation energy dissipation are yet not fully understood. In this work we provide a new and generally applicable route for studying the excitation energy transport in multi-chromophoric complexes at an atomistic level. The surface-hopping approach in the frame of the extended Frenkel exciton model combined with QM/MM techniques allowed us to simulate the photodynamics of the alternating (dAdT)10 : (dAdT)10 double-stranded DNA. In accordance with recent experiments, we find that the excited state decay is multiexponential, involving a long and a short component which are due to two distinct mechanisms: formation of long-lived delocalized excitonic and charge transfer states vs. ultrafast decaying localized states resembling those of the bare nucleobases. Our simulations explain all stages of the ultrafast photodynamics including initial photoexcitation, dynamical evolution out of the Franck-Condon region, excimer formation and nonradiative relaxation to the ground state.
KW  - Photodynamics
KW  - DNA
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-209467
ET  - submitted version
ER  - 
TY  - THES
A1  - Klein, Thomas
T1  - Establishing an in vitro disease model for Fabry Disease using patient specific induced pluripotent stem cell-derived sensory neurons
T1  - Etablierung eines in vitro Krankheitsmodells für M. Fabry mittels patienteneigener sensibler Neurone, generiert über induzierte pluripotente Stammzellen
N2  - Fabry disease (FD) is an X-linked lysosomal storage disorder caused by deficiency of the α-galactosidase A (GLA), leading to intracellular accumulations of globotriaosylceramide (Gb3). Acral burning pain, which can be triggered by heat, fever or physical activity is an early hallmark of FD and greatly reduces patients’ quality of life. The pathophysiology of FD pain is unknown and research is hindered by the limited in vivo availability of suitable human biomaterial. To overcome this obstacle, we generated induced pluripotent stem cells (iPSC) from one female and two male patients with a differing pain phenotype, and developed a refined differentiation protocol for sensory neurons to increase reliability and survival of these neurons, serving as an in vitro disease model. Neurons were characterized for the correct neuronal subtype using immunocytochemistry, gene expression analysis, and for their functionality using electrophysiological measurements. 
iPSC and sensory neurons from the male patients showed Gb3 accumulations mimicking the disease phenotype, whereas no Gb3 depositions were detected in sensory neurons derived from the female cell line, likely caused by a skewed X-chromosomal inactivation in favor of healthy GLA. Using super-resolution imaging techniques we showed that Gb3 is localized in neuronal lysosomes of male patients and in a first experiment using dSTORM microscopy we were able to visualize the neuronal membrane in great detail. To test our disease model, we treated the neurons with enzyme replacement therapy (ERT) and analyzed its effect on the cellular Gb3 load, which was reduced in the male FD-lines, compared to non-treated cells. We also identified time-dependent differences of Gb3 accumulations, of which some seemed to be resistant to ERT. We also used confocal Ca2+ imaging to investigate spontaneous neuronal network activity, but analysis of the dataset proofed to be difficult, nonetheless showing a high potential for further investigations. We revealed that neurons from a patient with pain pain are more easily excitable, compared to cells from a patient without pain and a healthy control. 
We provide evidence for the potential of patient-specific iPSC to generate a neuronal in vitro disease model, showing the typical molecular FD phenotype, responding to treatment, and pointing towards underlying electrophysiological mechanisms causing different pain phenotypes. Our sensory neurons are suitable for state-of-the-art microscopy techniques, opening new possibilities for an in-depth analysis of cellular changes, caused by pathological Gb3 accumulations. Taken together, our system can easily be used to investigate the effect of the different mutations of GLA on a functional and a molecular level in affected neurons.
N2  - Morbus Fabry (M. Fabry) ist eine X-chromosomal vererbte lysosomale Speichererkrankung, die durch die Defizienz von α-Galaktosidase A (GLA) verursacht wird. Diese führt zu pathologischen Ablagerungen von Globotriaosylceramid (Gb3) in Zellen. Akraler, brennender Schmerz, der durch Hitze, Fieber oder Sport ausgelöst werden kann, ist ein frühes Krankheitsmerkmal und reduziert die Lebensqualität der Patienten deutlich. Die Pathophysiologie von M. Fabry ist unklar und die Forschung ist durch die limitierte Verfügbarkeit von humanem Biomaterial nur eingeschränkt möglich. Um dieses Problem zu bewältigen haben wir induzierte pluripotente Stammzellen (iPSC) von einer weiblichen Patientin und zwei männlichen Patienten mit unterschiedlichen Schmerzphänotypen generiert. Mit diesen Zellen konnten wir ein verbessertes Protokoll zur Herstellung sensibler Neurone etablieren um diese als in vitro Krankheitsmodell zu nutzen. Die Neurone wurden mittels Immunozytochemie, Genexpressionsanalyse und elektrophysiologischer Messungen auf die korrekte Zellidentität und deren Funktionalität getestet.
Gb3 Ablagerungen konnten als Krankheitsmerkmal in iPSC und sensiblen Neuronen der männlichen Patienten, nicht aber in Zellen der weiblichen Patientin und der Kontrollperson nachgewiesen werden. Das Fehlen von pathologischen Ablagerungen in Zellen der weiblichen Betroffenen ist vermutlich auf eine verschobene X-Inaktivierung zu Gunsten des gesunden GLA zurückzuführen. Nichtsdestotrotz ist es uns durch die Nutzung hochauflösender Mikroskopietechniken gelungen, bei männlichen Patienten Gb3 in neuronalen Lysosomen nachzuweisen und die Membran in großem Detail abzubilden. Die Behandlung der Neurone mit der Enzymersatztherapie (ERT) als Nachweis für die Funktionalität des Krankheitsmodells führte zu einer Reduktion der Gb3 Ablagerungen bei männlichen Zellen, im Vergleich zu unbehandelten Zellen. Zudem konnten wir unterschiedliche Arten von Gb3 Akkumulationen identifizieren, von denen einige scheinbar behandlungsresistent sind. Erste Versuche mit Ca2+ Imaging zeigten spontane, neuronale Netzwerkaktivität, die noch weitergehend analysiert werden müssen. Mittels Patch-Clamp Analysen konnten wir zeigen, dass Neurone des Patienten mit Schmerzen leichter erregbar sind als Zellen des Patienten ohne Schmerzen, was einen Hinweis auf die mögliche Beteiligung gestörter Ionenkanäle gibt.
Wir konnten zeigen, dass patientenspezifische iPSC geeignet sind um ein neuronales in vitro Krankheitsmodell zu erstellen. Dieses Modell zeigt den typischen molekularen Phänotypen des M. Fabry, spricht auf ERT an und liefert erste Hinweise auf pathologische elektrophysiologische Krankheitsursachen, die zu unterschiedlichen Schmerzphänotypen führen können. Zelluläre Veränderungen durch Gb3 Ablagerungen können nun mittels neuester Mikroskopietechniken anhand der von uns generierten Neurone untersucht werden um ein besseres Verständnis der zugrundeliegenden Pathophysiologie zu bekommen. Zusammenfassend bietet unser System eine neue Möglichkeit den neuronalen Einfluss verschiedener GLA Mutationen auf einer funktionellen und molekularen Ebene zu untersuchen und die Diversität von M. Fabry aufzuschlüsseln.
KW  - Induzierte pluripotente Stammzelle
KW  - iPSC
KW  - disease model
KW  - fabry disease
KW  - pain
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199705
ER  - 
TY  - THES
A1  - Klepsch, Maximilian Andreas
T1  - Small RNA-binding complexes in Chlamydia trachomatis identified by Next-Generation Sequencing techniques
T1  - Identifizierung von kleinen RNA-bindenden Komplexen in Chlamydia trachomatis mittels Hochdurchsatz- Sequenziertechniken
N2  - Chlamydia infect millions worldwide and cause infertility and blinding trachoma. Chlamydia trachomatis (C. trachomatis) is an obligate intracellular gram-negative pathogen with a significantly reduced genome. This bacterium shares a unique biphasic lifecycle in which it alternates between the infectious, metabolically inert elementary bodies (EB) and the non-infections, metabolically active replicative reticular bodies (RB).
One of the challenges of working with Chlamydia is its difficult genetic accessibility. In the present work, the high-throughput method TagRNA-seq was used to differentially label transcriptional start sites (TSS) and processing sites (PSS) to gain new insights into the transcriptional landscape of C. trachomatis in a coverage that has never been achieved before. Altogether, 679 TSSs and 1067 PSSs were detected indicating its high transcriptional activity and the need for transcriptional regulation. Furthermore, the analysis of the data revealed potentially new non-coding ribonucleic acids (ncRNA) and a map of transcriptional processing events. Using the upstream sequences, the previously identified σ66 binding motif was detected.
In addition, Grad-seq for C. trachomatis was established to obtain a global interactome of the RNAs and proteins of this intracellular organism. The Grad-Seq data suggest that many of the newly annotated RNAs from the TagRNA-seq approach are present in complexes. Although Chlamydia lack the known RNA-binding proteins (RBPs), e.g. Hfq and ProQ, observations in this work reveal the presence of a previously unknown RBP. 
Interestingly, in the gradient analysis it was found that the σ66 factor forms a complex with the RNA polymerase (RNAP). On the other hand, the σ28 factor is unbound. This is in line with results from previous studies showing that most of the genes are under control of σ66. The ncRNA IhtA is known to function via direct base pairing to its target RNA of HctB, and by doing so is influencing the chromatin condensation in Chlamydia. This study confirmed that lhtA is in no complex. On the other hand, the ncRNA ctrR0332 was found to interact with the SNF2 protein ctl0077, a putative helicase. Both molecules co-sedimented in the gradient and were intact after an aptamer-based RNA pull-down. The SWI2/SNF2 class of proteins are nucleosome remodeling complexes. The prokaryotic RapA from E. coli functions as transcription regulator by stimulating the RNAP recycling. This view might imply that the small ncRNA (sRNA) ctrR0332 is part of the global regulation network in C. trachomatis controlling the transition between EBs and RBs via interaction with the SNF2 protein ctl0077.
The present work is the first study describing a global interactome of RNAs and proteins in C. trachomatis providing the basis for future interaction studies in the field of this pathogen.
N2  - Chlamydien verursachen jährlich Millionen Neuinfektionen weltweit und können zu Spätschäden wie Unfruchtbarkeit und Erblindung führen. Chlamydien sind obligat intrazelluläre, gram-negative Pathogene mit einem stark reduzierten Genom. Sie besitzen einen einzigartigen biphasischen Lebenszyklus, bei dem der Erreger zwischen den metabolisch inaktiven, infektiösen Elementarkörperchen (EBs) und den nicht infektiösen, metabolisch aktiven und replikativen Retikularkörperchen (RBs) alterniert.
Eine Problemantik beim Arbeiten mit Chlamydien ist die Schwierigkeit der gezielten genetischen Manipulation des Pathogens. 
In der vorliegenden Arbeit wurde die Hochdurchsatz-Sequenziermethode TagRNA-Seq genutzt, um die transkriptionelle Organisation von Chlamydia trachomatis (C. trachomatis) zu analysieren und besser zu verstehen. Transkriptionelle Start Stellen (TSS) und Prozessierungsstellen (PSS) werden dabei unterschiedlich markiert, sodass eine zuverlässigere und genauere Auflösung erreicht wird als bisher durch in anderen Studien verwendete Methoden. Insgesamt konnten so 679 TSSs und 1067 PSSs detektiert werden. Es konnte gezeigt werden, dass das Transkriptom von C. trachomatis weitaus aktiver ist als bisher angenommen und eine Regulation auf transkriptioneller Ebene bedarf. Die Methode erlaubte zudem die Identifizierung von potenziell neuen nicht-kodierende RNAs sowie die Kartierung von transkriptionellen Prozessierungsereignissen. Unter Verwendung der 5’-upstreamliegenden Sequenzen konnte außerdem das in anderen Bakterien bereits bekannte σ66-Bindemotiv detektiert werden.
In der vorliegenden Arbeit wurde zudem die Methode Grad-Seq in C. trachomatis etabliert, um ein globales Interaktom für RNAs (engl. ribonucleic acid) und Proteine des intrazellulären Organismus zu erstellen. 
Für viele der im TagRNA-Seq Ansatz identifizierten und neu annotierten RNAs konnte so eine Komplexbildung beobachtet werden. Dies deutet auf das Vorhandensein eines bislang unbekanntes RNA-Bindeprotein (RBP) hin, da Chlamydien keines der bekannten RBPs, z.B. Hfq oder ProQ, besitzen.
Die Gradienten-Analyse ergab, dass der σ66-Faktor in einem Komplex mit der RNA-Polymerase (RNAP) vorliegt und dass der σ28-Faktor ungebunden ist. Diese Beobachtung entspricht den Ergebnissen vorheriger Studien, die zeigten das die meisten Gene durch σ66 kontrolliert werden. Die Daten bestätigen außerdem, dass IhtA, eine ncRNA (engl. non-coding ribonucleic acid), die über direkte Basenpaarbindung mit ihrem Ziel-RNA von hctB interagiert, nicht in einem Komplex vorliegt. Für die ncRNA ctrR0332 hingegen konnte das SNF2-Protein ctl0077 als Interaktionspartner identifiziert werden. Beide Moleküle co-sedimentieren im Gradienten und konnten mittels eines Aptamer-basierenden RNA Pull-Downs in intakter Form isoliert werden. Die Klasse der SWI2/SNF2-Proteine gehört zu den Nukleosomen-Remodeling-Komplexen. In Prokaryoten konnte für das in E. coli vorkommende RapA, welches ebenfalls zu den SWI2/SNF2-Proteinen zählt, die Funktion eines Transkriptionsregulators nachgewiesen werden, indem die RNAP-Wiederverwertung stimuliert wird. Dies könnte bedeuten, dass die ncRNA ctrR0332 ebenfalls Teil eines globalen Regulationsnetzwerks ist, welches durch Interaktion mit dem SNF2-Protein ctl0077 die Transition zwischen dem RB- und EB-Stadium reguliert. 
In der vorliegenden Arbeit konnte erstmals ein globales Interaktom von RNAs und Proteinen in C. trachomatis erstellt werden, welches als Grundlage für zukünftige Interaktionsstudien des Pathogens genutzt werden kann.
KW  - High throughput screening
KW  - Small RNA
KW  - Chlamydia trachomatis
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199741
ER  - 
TY  - INPR
A1  - Humeniuk, Alexander
A1  - Bužančić, Margarita
A1  - Hoche, Joscha
A1  - Cerezo, Javier
A1  - Mitric, Roland
A1  - Santoro, Fabrizio
A1  - Bonačić-Koutecky, Vlasta
T1  - Predicting fluorescence quantum yields for molecules in solution: A critical assessment of the harmonic approximation and the choice of the lineshape function
T2  - The Journal of Chemical Physics
N2  - For the rational design of new fluorophores, reliable predictions of fluorescence quantum yields from first principles would be of great help. However, efficient computational approaches for predicting transition rates usually assume that the vibrational structure is harmonic. While the harmonic approximation has been used successfully to predict vibrationally resolved spectra and radiative rates, its reliability for non-radiative rates is much more questionable. Since non-adiabatic transitions convert large amounts of electronic energy into vibrational energy, the highly excited final vibrational states deviate greatly from harmonic oscillator eigenfunctions. We employ a time-dependent formalism to compute radiative and non-radiative rates for transitions and study the dependence on model parameters. For several coumarin dyes we compare different adiabatic and vertical harmonic models (AS, ASF, AH, VG, VGF, VH), in order to dissect the
importance of displacements, frequency changes and Duschinsky rotations. In addition we analyze the effect of different broadening functions (Gaussian, Lorentzian or Voigt). Moreover, to assess the qualitative influence of anharmonicity on the internal conversion rate, we develop a simplified anharmonic model. We adress the reliability of these models considering the potential errors introduced by the harmonic approximation and the phenomenological width of the broadening function.
KW  - fluorescence quantum yield
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199305
UR  - https://doi.org/10.1063/1.5143212
N1  - Accepted Manuscript.
N1  - This article may be downloaded for personal use only. Any other use requires prior permission of the author and AIP Publishing. This article appeared in A. Humeniuk et al. J. Chem. Phys. 152, 054107 (2020); https://doi.org/10.1063/1.5143212 and may be found at https://doi.org/10.1063/1.5143212.
ER  - 
TY  - THES
A1  - Maimari, Theopisti
T1  - The influence of N-terminal peptides of G-protein coupled receptor kinase (GRK) 2, 3 and 5 on β-adrenergic signaling
T1  - Der Einfluss von N-terminalen Peptiden der G-Protein gekoppelten Rezeptorkinasen (GRK) 2, 3 und 5 in der β-adrenergen Signaltransduktion
N2  - G protein coupled receptor kinases (GRK) phosphorylate and thereby desensitize G protein coupled receptors (GPCR) including β-adrenergic receptors (βAR), which are critical regulators of cardiac function. We identified the Raf kinase inhibitor protein (RKIP) as an endogenous inhibitor of GRK2 that leads to increased cardiac contractility via βAR activation. RKIP binds to the N-terminus (aa1-185) of GRK2, which is important for the GRK2/receptor interaction. Thereby it interferes with the GRK2/receptor interaction without interference with cytosolic GRK2 target activation. In this project, the RKIP/GRK interface was investigated to develop strategies that simulate the effects of RKIP on βAR. 
RKIP binding to different isoforms of GRK expressed in the heart was analyzed by protein interaction assays using full-length and N-termini of GRK2, GRK3 and GRK5: 1-53, 54-185 and 1-185. Co-immunoprecipitation (Co-IPs) and pull-down assays revealed that RKIP binds to the peptides of GRK2 and GRK3 but not to the ones of GRK5, which suggests the existence of several binding sites of RKIP within the N-termini of GRK2 and GRK3. To analyze whether the peptides of GRK2 and GRK3 are able to simulate the RKIP mediated interference of the GRK2/receptor interaction, we analyzed the β2-AR phosphorylation in the absence and presence of the peptides. Interestingly, N-termini (aa1-185) of GRK2 and GRK3 reduced β2AR phosphorylation to a comparable extent as RKIP. In line with reduced receptor phosphorylation, the peptides also reduced isoproterenol-stimulated receptor internalization as shown by [3H] CGP-12177 radioligand binding assay and fluorescence microscopy compared to control cells. Subsequently, these peptides increased downstream signaling of β2AR, i.e. the phosphorylation of the PKA substrate phosducin. In an attempt to elucidate the mechanism behind the observed effects, Co-IPs were performed in order to investigate whether the peptides bind directly to the β2-AR and block its phosphorylation by GRK2. Indeed, GRK2 1-185 and GRK3 1-185 could bind the receptor, suggesting that this way GRK2 is prevented from inhibiting the receptor. To investigate the physiological effect of GRK2 1-185, GRK3 1-185 and GRK5 1-185, their effect on neonatal mouse cardiomyocyte contractility and hypertrophy was analyzed. After long-term isoproterenol stimulation, in the presence of GRK2 1 185 and GRK3 1-185 the cross-sectional area of the cardiomyocytes showed no significant increase in comparison to the unstimulated control cells. In addition, upon isoproterenol stimulation, GRK2 1-185 and GRK3 1-185 increased the beat rate in cardiomyocytes, mimicking RKIP while the base impedance, an indicator of viability, remained stable.
The N-termini (1-185) of GRK2 and GRK3 simulated RKIP’s function and had a significant influence on β2AR phosphorylation, on its downstream signaling and internalization, could bind β2-AR, increased beat rate and did not significantly induce hypertrophy, suggesting that they may serve as a model for the generation of new and more specific targeting strategies for GRK mediated receptor regulation.
N2  - G-Protein gekoppelte Rezeptorkinasen (GRK) phosphorylieren und desensitisieren G-Protein gekoppelte Rezeptoren (GPCR), einschließlich β-adrenerge Rezeptoren (βAR), welche wichtige Regulatoren der Herzfunktion sind. Raf Kinase Inhibitor Protein (RKIP) ist ein endogener Inhibitor von GRK2, der zur Aktivierung von βAR führt und dadurch zur Steigerung der Herzkontraktilität. RKIP bindet N-terminal (1-185) an GRK2; der GRK2 N-Terminus ist wichtig für die GRK2/Rezeptor Interaktion. Durch diese Bindung wird GRK2 inhibiert und derer Interaktion mit den Rezeptor gestört, allerdings bleiben die zytosolische GRK2 Substrate unbeeinflusst. In diesem Projekt wurde die Interaktion zwischen RKIP und GRK untersucht, um neue Targeting Strategien zu entwickeln, die die positiven Effekte von RKIP auf βAR Signalwege simulieren.
Die Bindung von RKIP an verschiedene, im Herzen lokalisierte GRK-Isoformen wurde über protein interaction assays untersucht:  mit GRK2, GRK3 und GRK5 und mit deren N-terminalen Peptiden  1-53, 54-185, 1-185. Die Co-Immunopräzipitationen (Co-IPs) und die pull-down Versuche haben gezeigt, dass RKIP sowohl GRK2 und GRK3 als auch deren N-Termini bindet, GRK5 und dessen N-termini hingegen nicht. Daraus lässt sich schlussfolgern, dass sich mehrere RKIP Bindungsstellen an dem GRK2 N-Terminus befinden. Um zu analysieren, ob die GRK2- und GRK3-Peptide eine ähnliche Wirkung wie RKIP auf die Interaktion von GRK2 und Rezeptor aufweisen, wurde die Rezeptorphosphorylierung ermittelt. Es konnte gezeigt werden, dass GRK2 1-185 und GRK3 1-185 die Phosphorylierung des βAR reduzieren können. Radioligandbindungsassays mit [3H] CGP-12177 und Fluoreszenzmikroskopie zeigten zudem, dass GRK2 1-185 und GRK3 1-185 auch die Internalisierungsrate des βAR senken können. Anschließend hatten GRK2 1-185 und GRK3 1-185 einen positiven Effekt auf einem βAR downstream Signalmolekül. Hierbei handelte es sich um die Phosphorylierung von Phosducin, was ein PKA-Substrat ist. Um die Wirkungsweise der N-termini zu erläutern, wurde untersucht, ob diese direkt den β2AR binden und somit die GRK2 vermittelte Phosphorylierung hindern. Interessanterweise konnte gezeigt werden, dass GRK2 1-185 und GRK3  1- 185 den β2AR binden und dementsprechend einen Einfluss auf die Phosphorylierung haben. Des Weiteren, wurden die Effekte der Peptide auf  Kontraktilität und Hypertrophie in neonatalen Mauskardiomyozyten analysiert. In Anwesenheit von GRK2 1-185 und GRK3 1-185 war die Querschnittsfläche der Mauskardiomyozyten nicht signifikant größer im Vergleich zu den unstimulierten Kontrollzellen.  Außerdem wurde eine signifikante Erhöhung der Kontraktilität in den Mauskardiomyozyten mit GRK2 1-185 und GRK3 1-185 beobachtet.  
Insgesamt, konnten GRK2 1-185 und GRK3 1-185 RKIPs Funktion simulieren: sie hatten einen signifikanten Effekt auf β2AR-Phosphorylierung, Internalisierung und downstream Signaling. Zudem konnten sie die Kontraktilität erhöhen und hatten keinen Einfluss auf Hypertrophie. Somit könnten sie als Prototyp für die Entwicklung neuer Targeting Strategien für die GRK-vermittelte Rezeptor Regulation, genutzt werden.
KW  - G protein-coupled receptor kinase
KW  - Raf kinase inhibitor protein
KW  - Inhibition
KW  - Heart failure
KW  - Peptides
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199322
ER  - 
TY  - THES
A1  - Kurz, Andreas
T1  - Correlative live and fixed cell superresolution microscopy
T1  - Korrelative hochauflösende Mikroskopie an lebenden und fixierten Zellen
N2  - Over the last decade life sciences have made an enormous leap forward. The development of complex analytical instruments, in particular in fluorescence microscopy, has played a decisive role in this. Scientist can now rely on a wide range of imaging techniques that offer different advantages in terms of optical resolution, recording speed or living cell compatibility. With the help of these modern microscopy techniques, multi-protein complexes can be resolved, membrane receptors can be counted, cellular pathways analysed or the internalisation of receptors can be tracked. However, there is currently no universal technique for comprehensive experiment execution that includes dynamic process capture and super resolution imaging on the same target object. In this work, I built a microscope that combines two complementary imaging techniques and enables correlative experiments in living and fixed cells. With an image scanning based laser spot confocal microscope, fast dynamics in several colors with low photodamage of the cells can be recorded. This novel system also has an improved resolution of 170 nm and was thoroughly characterized in this work. The complementary technique is based on single molecule localization microscopy, which can achieve a structural resolution down to 20-30 nm. Furthermore I implemented a microfluidic pump that allows direct interaction with the sample placed on the microscope. Numerous processes such as living cell staining, living cell fixation, immunostaining and buffer exchange can be observed and performed directly on the same cell. Thus, dynamic processes of a cell can be frozen and the structures of interest can be stained and analysed with high-resolution microscopy. Furthermore, I have equipped the detection path of the single molecule technique with an adaptive optical element. With the help of a deformable mirror, imaging functions can be shaped and information on the 3D position of the individual molecules can be extracted.
N2  - Im letzten Jahrzehnt hat der Bereich der Lebenswissenschaften einen enormen Sprung nach vorne gemacht. Maßgeblich dafür waren die Entwicklung von komplexen Analysegeräten insbesondere in der Fluoreszenz Mikroskopie. Die Anwender können nun auf eine Vielzahl von Bildgebungstechniken zurückgreifen die unterschiedliche Vorzüge hinsichtlich optischer Auflösung, Aufnahmegeschwindigkeit oder Lebend Zell Kompatibilität bieten. Mithilfe dieser modernen Mikroskopietechniken lassen sich beispielsweise Multiproteinkomplexe auflösen, Membranrezeptoren zählen, zelluläre Signalwege analysieren oder die Internalisierung von Rezeptoren verfolgen. Für eine umfassende Experimentdurchführung, die Erfassung dynamischer Prozesse sowie superhochauflösende Bildgebung an ein und demselben Zielobjekt beinhalten, gibt es derzeit keine einheitliche Technik. In dieser Arbeit habe ich ein Mikroskop aufgebaut, das zwei komplementäre Bildgebungstechniken vereint und korrelative Experimente von lebend zu fixierten Zellen ermöglicht. Mit einem Image Scanning basierten Konfokal Mikroskop können schnelle Dynamiken in mehreren Farben mit geringer Photoschädigung der Zellen aufgenommen werden. Dieses neuartige System weist zudem eine Auflösungsverbesserung von 170 nm auf und wurde im Rahmen der Arbeit ausführlich charakterisiert. Die komplementäre Technik basiert auf der Einzel-Molekül Lokalisations Mikroskopie, mit der sich eine strukturelle Auflösung von bis zu 20 nm erreichen lässt. Desweiteren habe ich eine Mikrofluidpumpe implementiert, die eine direkte Interaktion mit der auf dem Mikroskop platzierten Probe erlaubt. Zahlreiche Prozesse wie Lebend-Zell Färbung, Lebend-Zell Fixierung, Immuno-Färbung und Puffertausch können damit direkt an der gleichen Zelle beobachtet und durchgeführt werden. So können dynamische Prozesse einer Zelle sozusagen eingefroren werden und die Strukturen von Interesse gefärbt und mit höchstauflösender Mikroskopie analysiert werden. Desweiteren habe ich den Detektionspfad der Einzel-Molekül Technik mit einem adaptiven optischen Element ausgestattet. Mithilfe eines deformierbaren Spiegels lässt sich so Abbildungsfunktion formen und Information zur 3D Position der einzelnen Moleküle gewinnen.
KW  - Einzelmolekülmikroskopie
KW  - Adaptive Optik
KW  - Image-Scanning Microscope
KW  - Correlative microscopy
KW  - Adaptive Optics
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199455
ER  - 
TY  - THES
A1  - Hagmann, Hanns Antony
T1  - The impact of the CRISPR/Cas system on the interaction of Neisseria meningitidis with human host cells
T1  - Der Einfluss des CRISPR/Cas-Systems auf die Interaktion von Neisseria meningitidis mit menschlichen Wirtszellen
N2  - Neisseria meningitidis, a commensal β-proteobacterium residing exclusively in the human nasopharynx, is a leading cause of sepsis and epidemic meningitis worldwide. While comparative genome analysis was able to define hyperinvasive lineages that are responsible for most of the cases of invasive meningococcal disease (IMD), the genetic basis of their virulence remains unclear. Recent studies demonstrate that the type II C CRISPR/Cas system of meningococci is associated with carriage and less invasive lineages. CRISPR/Cas, an adaptive defence system against foreign DNA, was shown to be involved in gene regulation in Francisella novicida. This study shows that knockout strains of N. meningitidis lacking the Cas9 protein are impaired in the adhesion to human nasopharyngeal cells in a strain-dependant manner, which constitutes a central step in the pathogenesis of IMD. Consequently, this study indicates that the meningococcal CRISPR/Cas system fulfils functions beyond the defence of foreign DNA and is involved in the regulation of meningococcal virulence.
N2  - Neisseria meningitidis, ein ß-Proteobakterium, welches als Kommensale ausschließlich den humanen Nasopharynx besiedelt, ist ein weltweit führender Verursacher von Sepsis und epidemischer Meningitis. Auch wenn mittels vergleichender Genomanalysen hyperinvasive Stämme definiert werden konnten, welche für die meisten Fälle von invasiven Meningokokkenerkrankungen verantwortlich sind, bleibt die genetische Grundlage ihrer Virulenz ungeklärt. In vorangegangenen Studien konnte gezeigt werden, dass das Typ II-C CRISPR/Cas-System der Meningokokken assoziiert ist mit Trägerstämmen. CRISPR/Cas ist ein adaptives Verteidigungssystem der Bakterien gegen fremde DNA, das darüber hinaus Aufgaben in der Genregulation von Francisella novicida erfüllt. Diese Arbeit zeigt, dass knockout Stämme von N. meningitidis, denen das Cas9-Protein fehlt, in Abhängigkeit von ihrem genetischen Hintergrund die Fähigkeit verlieren an Zellen des menschlichen Nasopharynx zu adhärieren. Die Adhäsion an den Wirtszellen stellt einen zentralen
Schritt in der Pathogenese der invasiven Meningokokkenerkrankungen dar. Die Ergebnisse dieser Arbeit deuten darauf hin, dass das CRISPR/Cas-System in Meningokokken neben seiner Funktion als bakterielles Immunsystem an der Regulation der bakteriellen Virulenz beteiligt sein könnte.
KW  - CRISPR/Cas-Methode
KW  - Neisseria meningitidis
KW  - Bacteria-Host Cell Interaction
KW  - Regulation of Gene Expression
KW  - Cas9
KW  - Type II-C CRISPR/Cas
KW  - Adhesion and Invasion
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199490
ER  - 
TY  - THES
A1  - Reichenbach, Juliane Renate
T1  - Paternal age effects on sperm DNA methylation and its impact on the next generation
T1  - Der väterliche Alterseffekt auf das Spermienmethylom und seine Auswirkungen auf die nächste Generation
N2  - The effect of late parenthood on the offspring´s physical and mental health status has recently become an increasingly important topic of discussion. Studies on neurodevelopmental disorders in children of older parents (Naserbakht et al., 2011) outline the negative consequences of aging fathers as unpredictable compared to the better-understood unfavorable maternal influences (Cedars  et al. 2015). This may be due to the fact that lifelong production of male gametes becomes more susceptible to error, not only for somatic mutations. Non-genomic mechanisms such as epigenetic methylation also alter DNA dynamically throughout life (Jones et al., 2015) and influence the aging human sperm DNA (Jenkins et al., 2014). These methylation changes may be transmitted to the next generation via epigenetic inheritance mechanisms (Milekic et al., 2015), which may negatively impact the sensitive epigenetic regulation of cell differentiation in the embryonic period (Curley et al., 2011; Spiers et al., 2015). Accordingly, Nardone et al. (2014) reported several hypomethylated regions in autistic patients, illustrating potential epigenetic influences on the multifactorial pathogenesis of neuropsychiatric disorders. In the present study, the methylation status of five gene regions in the sperm DNA of males of different ages was analyzed by two techniques - pyrosequencing and deep bisulfite sequencing. Two gene regions, FOXK1 and DMPK, showed a highly significant age-related methylation loss and FOXK1 a reduced methylation variation at the level of single alleles. In addition, the examined gene region of FOXK1 showed significant methylation changes in the fetal cord blood DNA of the respective offspring of the sperm donor. This fact suggests a transfer of age-related methylation loss to the next generation. Interestingly, a methylation analysis at the level of single alleles showed that the methylation loss was inherited exclusively by the father. FOXK1 is a transcription factor that plays an important role in the epigenetic regulation of the cell cycle during embryonic neuronal development (Huang et al., 2004; Wijchers et al., 2006). For this reason, the methylation status of FOXK1 in the blood of autistic patients and an age- and sex-matched control group was investigated. While both groups showed age-associated FOXK1 methylation loss, a faster dynamics of methylation change was observed in the autistic group. Although further studies are needed to uncover inheritance mechanisms of epigenetic information, the present results show an evident influence of age-related methylation changes on offspring. When advising future fathers, it is important to consider how the paternal epigenome is altered by aging and can have a negative impact on the developing embryo.
N2  - Die Auswirkungen einer späten Elternschaft auf die körperliche und geistige Gesundheit der Nachkommen wurde in letzter Zeit zunehmend diskutiert. Studien zu neurologischen Entwicklungsstörungen bei Kindern älterer Eltern (Naserbakht et al. 2011) skizzieren insbesondere die negativen Folgen alternder Väter (Cedars et al. 2015). Dies ist möglicherweise darauf zurückzuführen, dass die lebenslange Produktion männlicher Gameten im Laufe des Lebens nicht nur für somatische Mutationen fehleranfälliger wird. Auch nicht-genomische Mechanismen wie die epigenetische Methylierung verändert die DNA im Laufe des Lebens dynamisch (Jones et al. 2015) und beeinflussen die alternde menschliche Spermien-DNA (Jenkins et al. 2014). Möglicherweise werden diese Methylierungsveränderungen über epigenetische Vererbungsmechanismen an die nächste Generation übertragen (Milekic et al. 2015), was sich negativ auf die empfindliche epigenetische Regulation der Zelldifferenzierung in der Embryonalperiode auswirken kann (Curley et al. 2011; Spiers et al. 2015). Mögliche epigenetische Einflüsse auf die multifaktorielle Pathogenese neuropsychiatrischer Erkrankungen veranschaulichend, zeigten Nardone et al. (2014) mehrere hypomethylierte Regionen bei autistischen Patienten auf. In der vorliegenden Arbeit wurde der Methylierungsstatus von fünf Genregionen in der Spermien-DNA von Männern unterschiedlichen Alters durch zwei Techniken analysiert – das Pyrosequencing und das Deep Bisulfite Sequencing. Zwei Genregionen, FOXK1 und DMPK, zeigten einen hochgradig signifikanten altersbedingten Methylierungsverlust und FOXK1 auf der Ebene einzelner Allele eine verringerte Methylierungsvariation. Darüber hinaus zeigte die untersuchte Genregion von FOXK1 signifikante Methylierungsveränderungen in der Nabelschnurblut-DNA der jeweiligen Nachkommen der Samenspender. Diese Tatsache spricht für eine Übertragung des altersbedingten Methylierungsverlustes auf die nächste Generation.
Anhand einer Methylierungsanalyse auf der Ebene einzelner Allele konnte interessanterweise gezeigt werden, dass der Methylierungsverlust ausschließlich durch den Vater vererbt wurde. FOXK1 ist ein Transkriptionsfaktor, der eine wichtige Rolle bei der epigenetischen Regulation des Zellzyklus während der embryonalen neuronalen Entwicklung spielt (Huang et al. 2004; Wijchers et al. 2006). Aus diesem Grund wurde der Methylierungsstatus von FOXK1 im Blut autistischer Patienten und einer alters- und geschlechtsentsprechenden Kontrollgruppe untersucht. Während beide Gruppen einen altersassoziierten FOXK1-Methylierungverlust zeigten, wurde in der autistischen Gruppe eine schnellere Dynamik der Methylierungsänderung beobachtet. Obwohl weitere Studien erforderlich sind, um Vererbungsmechanismen epigenetischer Information aufzudecken, zeigen die vorliegenden Ergebnisse einen offensichtlichen Einfluss altersbedingter Methylierungsveränderungen auf die Nachkommen. Bei der Beratung zukünftiger Väter ist es wichtig zu berücksichtigen, wie das väterliche Epigenom durch das Altern verändert wird und negative Auswirkungen auf den sich entwickelnden Embryo haben kann.
KW  - Epigenetik
KW  - Vater
KW  - Spermium
KW  - Autismus
KW  - Methylierung
KW  - paternal age
KW  - epigenetics
KW  - sperm
KW  - methylation
KW  - reproduction
KW  - autism
KW  - Väterliches Alter
KW  - Epigenetik
KW  - Spermien
KW  - Methylierung
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199805
ER  - 
TY  - JOUR
A1  - Blättner, Sebastian
A1  - Das, Sudip
A1  - Paprotka, Kerstin
A1  - Eilers, Ursula
A1  - Krischke, Markus
A1  - Kretschmer, Dorothee
A1  - Remmele, Christian W.
A1  - Dittrich, Marcus
A1  - Müller, Tobias
A1  - Schuelein-Voelk, Christina
A1  - Hertlein, Tobias
A1  - Mueller, Martin J.
A1  - Huettel, Bruno
A1  - Reinhardt, Richard
A1  - Ohlsen, Knut
A1  - Rudel, Thomas
A1  - Fraunholz, Martin J.
T1  - Staphylococcus aureus Exploits a Non-ribosomal Cyclic Dipeptide to Modulate Survival within Epithelial Cells and Phagocytes
JF  - PLoS Pathogens
N2  - Community-acquired (CA) Staphylococcus aureus cause various diseases even in healthy individuals. Enhanced virulence of CA-strains is partly attributed to increased production of toxins such as phenol-soluble modulins (PSM). The pathogen is internalized efficiently by mammalian host cells and intracellular S. aureus has recently been shown to contribute to disease. Upon internalization, cytotoxic S. aureus strains can disrupt phagosomal membranes and kill host cells in a PSM-dependent manner. However, PSM are not sufficient for these processes. Here we screened for factors required for intracellular S. aureus virulence. We infected escape reporter host cells with strains from an established transposon mutant library and detected phagosomal escape rates using automated microscopy. We thereby, among other factors, identified a non-ribosomal peptide synthetase (NRPS) to be required for efficient phagosomal escape and intracellular survival of S. aureus as well as induction of host cell death. By genetic complementation as well as supplementation with the synthetic NRPS product, the cyclic dipeptide phevalin, wild-type phenotypes were restored. We further demonstrate that the NRPS is contributing to virulence in a mouse pneumonia model. Together, our data illustrate a hitherto unrecognized function of the S. aureus NRPS and its dipeptide product during S. aureus infection.
KW  - cell death
KW  - cytotoxicity
KW  - Staphylococcus aureus
KW  - host cells
KW  - neutrophils
KW  - macrophages
KW  - transposable elements
KW  - epithelial cells
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-180380
VL  - 12
IS  - 9
ER  - 
TY  - INPR
A1  - Titov, Evgenii
A1  - Humeniuk, Alexander
A1  - Mitric, Roland
T1  - Comparison of moving and fixed basis sets for nonadiabatic quantum dynamics at conical intersections
T2  - Chemical Physics
N2  - We assess the performance of two different types of basis sets for nonadiabatic quantum dynamics at conical intersections. The basis sets of both types are generated using Ehrenfest trajectories of nuclear coherent states. These trajectories can either serve as a moving (time-dependent) basis or be employed to sample a fixed (time-independent) basis. We demonstrate on the example of two-state two-dimensional and three-state five-dimensional models that both basis set types can yield highly accurate results for population transfer at intersections, as compared with reference quantum dynamics. The details of wave packet evolutions are discussed for the case of the two-dimensional model. The fixed basis is found to be superior to the moving one in reproducing nonlocal spreading and maintaining correct shape of the wave packet upon time evolution. Moreover, for the models considered, the fixed basis set outperforms the moving one in terms of computational efficiency.
KW  - Nonadiabatic quantum dynamics
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199225
UR  - https://doi.org/10.1016/j.chemphys.2019.110526
N1  - Submitted version
ER  - 
TY  - INPR
A1  - Lindner, Joachim O.
A1  - Sultangaleeva, Karina
A1  - Röhr, Merle I. S.
A1  - Mitric, Roland
T1  - metaFALCON: A program package for automatic sampling of conical intersection seams using multistate metadynamics
T2  - Journal of Chemical Theory and Computation
N2  - The multistate metadynamics for automatic exploration of conical intersection seams and systematic location of minimum energy crossing points in molecular systems and its implementation into the software package metaFALCON is presented. Based on a locally modified energy gap between two Born–Oppenheimer electronic states as a collective variable, multistate metadynamics trajectories are driven toward an intersection point starting from an arbitrary ground state geometry and are subsequently forced to explore the conical intersection seam landscape. For this purpose, an additional collective variable capable of distinguishing structures within the seam needs to be defined and an additional bias is introduced into the off-diagonal elements of an extended (multistate) electronic Hamiltonian. We demonstrate the performance of the algorithm on the examples of the 1,3-butadiene, benzene, and 9H-adenine molecules, where multiple minimum energy crossing points could be systematically located using the Wiener number or Cremer–Pople parameters as collective variables. Finally, with the example of 9H-adenine, we show that the multistate metadynamics potential can be used to obtain a global picture of a conical intersection seam. Our method can be straightforwardly connected with any ab initio or semiempirical electronic structure theory that provides energies and gradients of the respective electronic states and can serve for systematic elucidation of the role of conical intersections in the photophysics and photochemistry of complex molecular systems, thus complementing nonadiabatic dynamics simulations.
KW  - Computational Chemistry
KW  - Metadynamics
KW  - Hydrogen
KW  - Hydrocarbons
KW  - Chemical Structure
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199258
UR  - https://doi.org/10.1021/acs.jctc.9b00029
N1  - This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Chemical Theory and Computation, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see Journal of Chemical Theory and Computation 2019, 15, 6, 3450-3460. https://doi.org/10.1021/acs.jctc.9b00029.
ER  - 
TY  - JOUR
A1  - Hansmann, T.
A1  - Heinzmann, J.
A1  - Wrenzycki, C.
A1  - Zechner, U.
A1  - Niemann, H.
A1  - Haaf, T.
T1  - Characterization of Differentially Methylated Regions in 3 Bovine Imprinted Genes: A Model for Studying Human Germ-Cell and Embryo Development
JF  - Cytogenetic and Genome Research
N2  - Correct imprinting is crucial for normal fetal and placental development in mammals. Experimental evidence in animal models and epidemiological studies in humans suggest that assisted reproductive technologies (ARTs) can interfere with imprinted gene regulation in gametogenesis and early embryogenesis. Bos taurus is an agriculturally important species in which ARTs are commonly employed. Because this species exhibits a similar preimplantation development and gestation length as humans, it is increasingly being used as a model for human germ-cell and embryo development. However, in contrast to humans and mice, there is relatively little information on bovine imprinted genes. Here, we characterized the bovine intergenic IGF2-H19 imprinting control region (ICR) spanning approximately 3 kb. We identified a 300-bp differentially methylated region (DMR) approximately 6 kb upstream of the H19 promoter, containing a CpG island with CTCF-binding site and high sequence similarity with the human intergenic ICR. Additional differentially methylated CpG islands lie –6 kb to –3 kb upstream of the promoter, however these are less conserved. Both classical bisulfite sequencing and bisulfite pyrosequencing demonstrated complete methylation of the IGF2-H19 ICR in sperm, complete demethylation in parthenogenetic embryos having only the female genome, and differential methylation in placental and somatic tissues. In addition, we established pyrosequencing assays for the previously reported bovine SNRPN and PEG3 DMRs. The observed methylation patterns were consistent with genomic imprinting in all analyzed tissues/cell types. The identified IGF2-H19 ICR and the developed quantitative methylation assays may prove useful for further studies on the relationship between ARTs and imprinting defects in the bovine model.
KW  - bovine
KW  - differentially methylated region
KW  - IGF2-H19
KW  - imprinting control region
Y1  - 2010
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199051
SN  - 1424-8581
SN  - 1424-859X
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 132
IS  - 4
ER  - 
TY  - JOUR
A1  - Kraft, Peter
A1  - Drechsler, Christiane
A1  - Gunreben, Ignaz
A1  - Heuschmann, Peter Ulrich
A1  - Kleinschnitz, Christoph
T1  - Regulation of Blood Coagulation Factors XI and XII in Patients with Acute and Chronic Cerebrovascular Disease: A Case-Control Study
JF  - Cerebrovascular Diseases
N2  - Background: Animal models have implicated an integral role for coagulation factors XI (FXI) and XII (FXII) in thrombus formation and propagation of ischemic stroke (IS). However, it is unknown if these molecules contribute to IS pathophysiology in humans, and might be of use as biomarkers for IS risk and severity. This study aimed to identify predictors of altered FXI and FXII levels and to determine whether there are differences in the levels of these coagulation factors between acute cerebrovascular events and chronic cerebrovascular disease (CCD). Methods: In this case-control study, 116 patients with acute ischemic stroke (AIS) or transitory ischemic attack (TIA), 117 patients with CCD, and 104 healthy volunteers (HVs) were enrolled between 2010 and 2013 at our University hospital. Blood sampling was undertaken once in the CCD and HV groups and on days 0, 1, and 3 after stroke onset in patients with AIS or TIA. Correlations between serum FXI and FXII levels and demographic and clinical parameters were tested by linear regression and analysis of variance. Results: The mean age of AIS/TIA patients was 70 ± 12. Baseline clinical severity measured with NIHSS and Barthel Index was 4.8 ± 6.0 and 74 ± 30, respectively. More than half of the patients had an AIS (58%). FXI levels were significantly correlated with different leukocyte subsets (p < 0.05). In contrast, FXII serum levels showed no significant correlation (p > 0.1). Neither FXI nor FXII levels correlated with CRP (p > 0.2). FXII levels were significantly higher in patients with CCD compared with those with AIS/TIA (mean ± SD 106 ± 26% vs. 97 ± 24%; univariate analysis: p < 0.05); these differences did not reach significance in multivariate analysis adjusted for sex and age. FXI levels did not differ significantly between study groups. Sex and age were significantly associated with FXI and/or FXII levels in patients with AIS/TIA (p < 0.05). In contrast, no statistical significant influence was found for treatment modality (thrombolysis or not), pre-treatment with platelet inhibitors, and severity of stroke. Conclusions: In this study, there was no differential regulation of FXI and FXII levels between disease subtypes but biomarker levels were associated with patient and clinical characteristics. FXI and FXII levels might be no valid biomarker for predicting stroke risk.
KW  - biomarker
KW  - factor XI
KW  - factor XII
KW  - ischemic stroke
KW  - chronic cerebrovascular disease
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199076
SN  - 1015-9770
SN  - 1421-9786
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 38
IS  - 5
ER  - 
TY  - JOUR
A1  - Zahnert, Thomas
A1  - Löwenheim, Hubert
A1  - Beutner, Dirk
A1  - Hagen, Rudolf
A1  - Ernst, Arneborg
A1  - Pau, Hans-Wilhelm
A1  - Zehlicke, Thorsten
A1  - Kühne, Hilke
A1  - Friese, Natascha
A1  - Tropitzsch, Anke
A1  - Lüers, Jan-Christoffer
A1  - Mlynski, Robert
A1  - Todt, Ingo
A1  - Hüttenbrink, Karl-Bernd
T1  - Multicenter Clinical Trial of Vibroplasty Couplers to Treat Mixed/Conductive Hearing Loss: First Results
JF  - Audiology and Neurotology
N2  - Objective: To evaluate the safety and effectiveness of round window (RW), oval window (OW), CliP and Bell couplers for use with an active middle ear implant. Methods: This is a multicenter, long-term, prospective trial with consecutive enrollment, involving 6 university hospitals in Germany. Bone conduction, air conduction, implant-aided warble-tone thresholds and Freiburger monosyllable word recognition scores were compared with unaided preimplantation results in 28 moderate-to-profound hearing-impaired patients after 12 months of follow-up. All patients had previously undergone failed reconstruction surgeries (up to 5 or more). In a subset of patients, additional speech tests at 12 months postoperatively were used to compare the aided with the unaided condition after implantation with the processor switched off. An established quality-of-life questionnaire for hearing aids was used to determine patient satisfaction. Results: Postoperative bone conduction remained stable. Mean functional gain for all couplers was 37 dB HL (RW = 42 dB, OW = 35 dB, Bell = 38 dB, CliP = 27 dB). The mean postoperative Freiburger monosyllable score was 71% at 65 dB SPL. The postimplantation mean SRT<sub>50</sub> (speech reception in quiet for 50% understanding of words in sentences) improved on average by 23 dB over unaided testing and signal-to-noise ratios also improved in all patients. The International Outcome Inventory for Hearing Aids (IOI-HA)quality-of-life questionnaire was scored very positively by all patients. Conclusion: A significant improvement was seen with all couplers, and patients were satisfied with the device at 12 months postoperatively. These results demonstrate that an active implant is an advantage in achieving good hearing benefit in patients with prior failed reconstruction surgery.
KW  - conductive hearing loss
KW  - mixed hearing loss
KW  - vibroplasty
KW  - couplers
KW  - middle ear implant
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199129
SN  - 1420-3030
SN  - 1421-9700
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 21
IS  - 4
ER  - 
TY  - JOUR
A1  - Schwarzmeier, Hanna
A1  - Leehr, Elisabeth Johanna
A1  - Böhnlein, Joscha
A1  - Seeger, Fabian Reinhard
A1  - Roesmann, Kati
A1  - Gathmann, Bettina
A1  - Herrmann, Martin J.
A1  - Siminski, Niklas
A1  - Junghöfer, Markus
A1  - Straube, Thomas
A1  - Grotegerd, Dominik
A1  - Dannlowski, Udo
T1  - Theranostic markers for personalized therapy of spider phobia: Methods of a bicentric external cross‐validation machine learning approach
JF  - International Journal of Methods in Psychiatric Research
N2  - Objectives
Embedded in the Collaborative Research Center “Fear, Anxiety, Anxiety Disorders” (CRC‐TRR58), this bicentric clinical study aims at identifying biobehavioral markers of treatment (non‐)response by applying machine learning methodology with an external cross‐validation protocol. We hypothesize that a priori prediction of treatment (non‐)response is possible in a second, independent sample based on multimodal markers.

Methods
One‐session virtual reality exposure treatment (VRET) with patients with spider phobia was conducted on two sites. Clinical, neuroimaging, and genetic data were assessed at baseline, post‐treatment and after 6 months. The primary and secondary outcomes defining treatment response are as follows: 30% reduction regarding the individual score in the Spider Phobia Questionnaire and 50% reduction regarding the individual distance in the behavioral avoidance test.

Results
N = 204 patients have been included (n = 100 in Würzburg, n = 104 in Münster). Sample characteristics for both sites are comparable.

Discussion
This study will offer cross‐validated theranostic markers for predicting the individual success of exposure‐based therapy. Findings will support clinical decision‐making on personalized therapy, bridge the gap between basic and clinical research, and bring stratified therapy into reach. The study is registered at ClinicalTrials.gov (ID: NCT03208400).
KW  - machine learning
KW  - spider phobia
KW  - theranostic markers
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-213430
VL  - 29
IS  - 2
ER  - 
TY  - THES
A1  - Brandt, Gregor A.
T1  - Gait Initiation in Parkinson's Disease: The Interplay of Dopamine and Postural Control
T1  - Der erste Schritt bei M. Parkinson: Der Zusammenhang zwischen Dopamin und posturaler Kontrolle
N2  - Deterioration of gait and alterations of physiological gait initiation contribute significantly to the burden of disease in Parkinson's disease. This paper systematically investigates disease-specific alterations during the postural phases of gait initiation and demonstrates the influence of dopaminergic networks by assessing levodopa mediated improvements in motor performance and correlation of motor behavior with loss of striatal and cortical dopaminergic neurons. Particular attention is given to known confounders such as initial stance and anthropometrics.
N2  - Störungen des Gangbildes und Veränderungen der physiologischen Bewegungsabläufe während des ersten Schrittes tragen einen signifikanten Teil zur Krankheitslast der Parkinsonerkrankung bei. Diese Veröffentlichung untersucht systematisch die krankheitsspezifischen Veränderungen der posturalen Phase des ersten Schrittes und demonstriert den Einfluss dopaminerger Netzwerke durch Untersuchungen Levodopa-induzierter Verbesserungen des Bewegungsablaufs und Korrelationen des Bewegungsverhaltens mit dem Verlust striataler und kortikaler dopaminerger Neuronen. Besondere Sorgfalt wurde bekannten modifizierenden Faktoren wie initaler Standbreite und anthropometrischen Größen zu Teil.
KW  - Parkinson-Krankheit
KW  - Parkinson's Disease
KW  - Gait initiation
KW  - Motor Control
KW  - Dopamine
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-214636
ER  - 
TY  - THES
A1  - Vollmuth, Nadine
T1  - Role of the proto-oncogene c-Myc in the development of Chlamydia trachomatis
T1  - Die Rolle des proto-onkogenes c-Myc in der Entwicklung von Chlamydia trachomatis
N2  - Chlamydia trachomatis, an obligate intracellular human pathogen, is the world’s leading cause of infection related blindness and the most common, bacterial sexually transmitted disease. In order to establish an optimal replicative niche, the pathogen extensively interferes with the physiology of the host cell. Chlamydia switches in its complex developmental cycle between the infectious non-replicative elementary bodies (EBs) and the non-infectious replicative reticulate bodies (RBs). The transformation to RBs, shortly after entering a host cell, is a crucial process in infection to start chlamydial replication. Currently it is unknown how the transition from EBs to RBs is initiated. In this thesis, we could show that, in an axenic media approach, L glutamine uptake by the pathogen is crucial to initiate the EB to RB transition. L-glutamine is converted to amino acids which are used by the bacteria to synthesize peptidoglycan. Peptidoglycan inturn is believed to function in separating dividing Chlamydia. The glutamine metabolism is reprogrammed in infected cells in a c-Myc-dependent manner, in order to accomplish the increased requirement for L-glutamine. Upon a chlamydial infection, the proto-oncogene c-Myc gets upregulated to promote host cell glutaminolysis via glutaminase GLS1 and the L-glutamine transporter SLC1A5/ASCT2. Interference with this metabolic reprogramming leads to limited growth of C. trachomatis. Besides the active infection, Chlamydia can persist over a long period of time within the host cell whereby chronic and recurrent infections establish. C. trachomatis acquire a persistent state during an immune attack in response to elevated interferon-γ (IFN-γ) levels. It has been shown that IFN-γ activates the catabolic depletion of L-tryptophan via indoleamine 2,3-dioxygenase (IDO), resulting in the formation of non-infectious atypical chlamydial forms. In this thesis, we could show that IFN-γ depletes the key metabolic regulator c-Myc, which has been demonstrated to be a prerequisite for chlamydial development and growth, in a STAT1-dependent manner. Moreover, metabolic analyses revealed that the pathogen de routs the host cell TCA cycle to enrich pyrimidine biosynthesis. Supplementing pyrimidines or a-ketoglutarate helps the bacteria to partially overcome the persistent state. Together, the results indicate a central role of c-Myc induced host glutamine metabolism reprogramming and L-glutamine for the development of C. trachomatis, which may provide a basis for anti-infectious strategies. Furthermore, they challenge the longstanding hypothesis of L-tryptophan shortage as the sole reason for IFN-γ induced persistence and suggest a pivotal role of c-Myc in the control of the C. trachomatis dormancy.
N2  - Chlamydia trachomatis, ein obligat intrazellul¨ares humanes Pathogen, ist weltweit fu¨hrende Ursache fu¨r infektionsbedingte Erblindung und die h¨aufigste, bakterielle sexuell u¨bertragbare Krankheit. Um eine optimale Replikationsnische zu etablieren, interagiert das Pathogen in tensiv mit der Physiologie der Wirtszelle. Chlamydien wechseln in ihrem komplexen Entwick lungszyklus zwischen den infekti¨osen nicht replizierenden Elementark¨orperchen (EBs) und den nicht infekti¨osen replizierenden Retikulark¨orperchen (RBs), und diese Umwandlung in RBs kurz nach dem Eintritt in die Wirtszelle ist ein entscheidender Prozess in der Infektion, um die Replikation des Bakteriums einzuleiten. Derzeit ist noch nicht bekannt, wodurch diese Transformation von EBs zu RBs eingeleitet wird. In dieser Arbeit konnte gezeigt werden, dass bei einer zellfreien Kultivierung des Pathogens die Aufnahme von Glutamin durch den Erreger entscheidend ist, um den ¨Ubergang von EB zu RB zu initiieren. Vor kurzem wurde Peptidoglykan in den Septen von sich replizierenden Chlamydien nachgewiesen. Fu¨r die Syn these des Peptidoglykans nutzen die Bakterien das aufgenommene Glutamin. Der Glutamin metabolismus wird in infizierten Zellen c-Myc abh¨angig umprogrammiert, um den erh¨ohten Bedarf an Glutamin zu bew¨altigen. Bei einer Chlamydieninfektion wird das Proto-Onkogen c-Myc zur F¨orderung der Glutaminolyse der Wirtszelle u¨ber die Glutaminase GLS1 und den Glutamin Transporter SLC1A5/ASCT2 hochreguliert. Ein Eingreifen in diese metabolische Neuprogrammierung fu¨hrt zu einem reduzierten Wachstum von C. trachomatis. Neben der aktiven Infektion k¨onnen Chlamydien u¨ber einen sehr langen Zeitraum in der Wirtszelle persistieren, wodurch es zur Etablierung von chronischen und wiederkehrenden Infektionen kommt. C. trachomatis verf¨allt bei einem Immunangriff in Persistenz, wenn sie auf das freigesetzte Interferon-γ treffen. Es ist bekannt, dass Interferon-γ den Katabolismus von Tryptophan mittels indoleamine 2,3-dioxygenase (IDO) aktiviert, was zur Bildung von nicht infekti¨osen atypischen Chlamydienformen fu¨hrt. In dieser Arbeit konnte gezeigt werden, dass Interferon-γ den zentralen Stoffwechselregulator c-Myc, der sich fu¨r die Entwicklung und das Wachstum von Chlamydien als essentiell erwiesen hat, in Abh¨angigkeit von STAT1 herunter reguliert. Daru¨ber hinaus zeigte die Analyse des Metabolismus, dass das Pathogen den TCA Zyklus der Wirtszelle umleitet, um die Pyrimidinbiosynthese zu unterstu¨tzen. Die Zugabe von Pyrimidinen oder α-Ketoglutarat hilft den Bakterien den Status der Persistenz teilweise zu u¨berwinden. Zusammengenommen deuten die Ergebnisse auf eine zentrale Rolle der c-Myc induzierten Umprogrammierung des Glutaminmetabolismus und des Glutamins selbst fu¨r die Entwicklung von C. trachomatis hin. Diese Befunde k¨onnten eine Basis fu¨r Strategien gegen eine Infektion darstellen. Weiterhin stellen sie die seit langem bestehende Hypothese des Trypotphanmangels als alleiniger Grund fu¨r die von Interferon-γ induzierte Persistenz in Frage und legen eine zentrale Rolle von c-Myc bei der Kontrolle der C. trachomatis Dormanz nahe.
KW  - Chlamydia trachomatis
KW  - Persistence
KW  - trachomatis
KW  - chlamydia
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-203655
ER  - 
TY  - JOUR
A1  - Kotseva, Kornelia
A1  - De Backer, Guy
A1  - De Bacquer, Dirk
A1  - Rydén, Lars
A1  - Hoes, Arno
A1  - Grobbee, Diederick
A1  - Maggioni, Aldo
A1  - Marques-Vidal, Pedro
A1  - Jennings, Catriona
A1  - Abreu, Ana
A1  - Aguiar, Carlos
A1  - Badariene, Jolita
A1  - Bruthans, Jan
A1  - Castro Conde, Almudena
A1  - Cifkova, Renata
A1  - Crowley, Jim
A1  - Davletov, Kairat
A1  - Deckers, Jaap
A1  - De Smedt, Delphine
A1  - De Sutter, Johan
A1  - Dilic, Mirza
A1  - Dolzhenko, Marina
A1  - Dzerve, Vilnis
A1  - Erglis, Andrejs
A1  - Fras, Zlatko
A1  - Gaita, Dan
A1  - Gotcheva, Nina
A1  - Heuschmann, Peter
A1  - Hasan-Ali, Hosam
A1  - Jankowski, Piotr
A1  - Lalic, Nebojsa
A1  - Lehto, Seppo
A1  - Lovic, Dragan
A1  - Mancas, Silvia
A1  - Mellbin, Linda
A1  - Milicic, Davor
A1  - Mirrakhimov, Erkin
A1  - Oganov, Rafael
A1  - Pogosova, Nana
A1  - Reiner, Zeljko
A1  - Stöerk, Stefan
A1  - Tokgözoğlu, Lâle
A1  - Tsioufis, Costas
A1  - Vulic, Dusko
A1  - Wood, David
T1  - Lifestyle and impact on cardiovascular risk factor control in coronary patients across 27 countries: Results from the European Society of Cardiology ESC-EORP EUROASPIRE V registry
JF  - European Journal of Preventive Cardiology
N2  - Aims
The aim of this study was to determine whether the Joint European Societies guidelines on secondary cardiovascular prevention are followed in everyday practice.
	
Design
A cross-sectional ESC-EORP survey (EUROASPIRE V) at 131 centres in 81 regions in 27 countries.
	
Methods
Patients (<80 years old) with verified coronary artery events or interventions were interviewed and examined ≥6 months later.
	
Results
A total of 8261 patients (females 26%) were interviewed. Nineteen per cent smoked and 55% of them were persistent smokers, 38% were obese (body mass index ≥30 kg/m2), 59% were centrally obese (waist circumference: men ≥102 cm; women ≥88 cm) while 66% were physically active <30 min 5 times/week. Forty-two per cent had a blood pressure ≥140/90 mmHg (≥140/85 if diabetic), 71% had low-density lipoprotein cholesterol ≥1.8 mmol/L (≥70 mg/dL) and 29% reported having diabetes. Cardioprotective medication was: anti-platelets 93%, beta-blockers 81%, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers 75% and statins 80%.
	
Conclusion
A large majority of coronary patients have unhealthy lifestyles in terms of smoking, diet and sedentary behaviour, which adversely impacts major cardiovascular risk factors. A majority did not achieve their blood pressure, low-density lipoprotein cholesterol and glucose targets. Cardiovascular prevention requires modern preventive cardiology programmes delivered by interdisciplinary teams of healthcare professionals addressing all aspects of lifestyle and risk factor management, in order to reduce the risk of recurrent cardiovascular events.
KW  - EUROASPIRE
KW  - lifestyle
KW  - cardiovascular risk factors
KW  - secondary prevention
KW  - guidelines
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-205526
SN  - 2047-4873
SN  - 2047-4881
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 26
IS  - 8
ER  - 
TY  - CHAP
A1  - Schmitz, Barbara
T1  - King and God : conceptions of rule and God in 3 Maccabees
T2  - Figures who shape scriptures, scriptures that shape figures
N2  - In 3 Maccabees, kingship as a form of rule is addressed on two levels: On the political level the question about a good king is addressed against the background of Hellenistic understandings of kingship, using the example of Ptolemy IV Philopator. This king is portrayed at the beginning of 3 Maccabees as a successful, positive, Hellenistic ruler, but one whose good rule goes off the rails. This analysis of the ideal of Hellenistic rule (cf. 3 Macc. 3:12-29; 6:24-28; 7:1-9) is then taken to a theological level: the God of Israel is portrayed as the true good king, the Soter who saves his people in their time of greatest trial (6:29, 32; 7:16). By these means the many divine epithets that are a striking feature of 3 Maccabees are incorporated into the narrative (cf. 2:2-3). Thereby 3 Maccabees not only thematises the conflict with a Hellenistic king who exploits his power in diverse ways but also focuses in a concentrated way the notion of a good (Hellenistic) king into the notion of God as king and ruler.
KW  - Maccabees
KW  - Hellenistic kingship
KW  - Xenophon
KW  - Cyropaidia
KW  - Isocrates
KW  - God in 3 Macc
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-205149
ER  - 
TY  - CHAP
A1  - Schmitz, Barbara
T1  - Aspects of Worship in the Letter of Aristeas
T2  - Various Aspects of Worship in Deuterocanonical and Cognate Literature
N2  - Although the Letter of Aristeas mentions the translation of the Jewish nomos into Greek, it is striking that worship is not a fundamental theme of this writing. Nevertheless, six passages present acts of worship, which recount worship from different perspectives: Aristeas prays to God and explains his “Greek” idea of worship (Let. Aris. 17), whereas in Let. Aris. 132-140 the high priest explains the Jewish concept of worship. Sacrifices and prayers at the temple in Jerusalem for the Ptolemaic royal house are told in Let. Aris. 45, while at the Ptolemaic court in Alexandria one of the Jewish scholars prays at the beginning of the symposium (Let. Aris. 184-186). Then the daily prayer of the Jewish scholars are recounted in Let. Aris. 305-306 and finally the Ptolemaic king performs a proskynesis before the law at the end of the letter and thereby accepts the translation (Let. Aris. 317).
KW  - Aristeas
KW  - Letter of Aristeas
KW  - worship
KW  - proskynesis
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-205150
VL  - 2016/2017
ER  - 
TY  - JOUR
A1  - Figueiredo, Ludmilla
A1  - Krauss, Jochen
A1  - Steffan-Dewenter, Ingolf
A1  - Cabral, Juliano Sarmento
T1  - Understanding extinction debts: spatio-temporal scales, mechanisms and a roadmap for future research
JF  - Ecography
N2  - Extinction debt refers to delayed species extinctions expected as a consequence of ecosystem perturbation. Quantifying such extinctions and investigating long‐term consequences of perturbations has proven challenging, because perturbations are not isolated and occur across various spatial and temporal scales, from local habitat losses to global warming. Additionally, the relative importance of eco‐evolutionary processes varies across scales, because levels of ecological organization, i.e. individuals, (meta)populations and (meta)communities, respond hierarchically to perturbations. To summarize our current knowledge of the scales and mechanisms influencing extinction debts, we reviewed recent empirical, theoretical and methodological studies addressing either the spatio–temporal scales of extinction debts or the eco‐evolutionary mechanisms delaying extinctions. Extinction debts were detected across a range of ecosystems and taxonomic groups, with estimates ranging from 9 to 90% of current species richness. The duration over which debts have been sustained varies from 5 to 570 yr, and projections of the total period required to settle a debt can extend to 1000 yr. Reported causes of delayed extinctions are 1) life‐history traits that prolong individual survival, and 2) population and metapopulation dynamics that maintain populations under deteriorated conditions. Other potential factors that may extend survival time such as microevolutionary dynamics, or delayed extinctions of interaction partners, have rarely been analyzed. Therefore, we propose a roadmap for future research with three key avenues: 1) the microevolutionary dynamics of extinction processes, 2) the disjunctive loss of interacting species and 3) the impact of multiple regimes of perturbation on the payment of debts. For their ability to integrate processes occurring at different levels of ecological organization, we highlight mechanistic simulation models as tools to address these knowledge gaps and to deepen our understanding of extinction dynamics.
KW  - Anthropocene
KW  - biotic interaction
KW  - extinction dynamics
KW  - mechanistic modelling
KW  - time lag
KW  - transient dynamics
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204859
VL  - 42
IS  - 12
ER  - 
TY  - JOUR
A1  - Ataee, Mohammad Sadegh
A1  - Maghsoudi, Yasser
A1  - Latifi, Hooman
A1  - Fadaie, Farhad
T1  - Improving estimation accuracy of growing stock by multi-frequency SAR and multi-spectral data over Iran's heterogeneously-structured broadleaf Hyrcanian forests
JF  - Forests
N2  - Via providing various ecosystem services, the old-growth Hyrcanian forests play a crucial role in the environment and anthropogenic aspects of Iran and beyond. The amount of growing stock volume (GSV) is a forest biophysical parameter with great importance in issues like economy, environmental protection, and adaptation to climate change. Thus, accurate and unbiased estimation of GSV is also crucial to be pursued across the Hyrcanian. Our goal was to investigate the potential of ALOS-2 and Sentinel-1's polarimetric features in combination with Sentinel-2 multi-spectral features for the GSV estimation in a portion of heterogeneously-structured and mountainous Hyrcanian forests. We used five different kernels by the support vector regression (nu-SVR) for the GSV estimation. Because each kernel differently models the parameters, we separately selected features for each kernel by a binary genetic algorithm (GA). We simultaneously optimized R\(^2\) and RMSE in a suggested GA fitness function. We calculated R\(^2\), RMSE to evaluate the models. We additionally calculated the standard deviation of validation metrics to estimate the model's stability. Also for models over-fitting or under-fitting analysis, we used mean difference (MD) index. The results suggested the use of polynomial kernel as the final model. Despite multiple methodical challenges raised from the composition and structure of the study site, we conclude that the combined use of polarimetric features (both dual and full) with spectral bands and indices can improve the GSV estimation over mixed broadleaf forests. This was partially supported by the use of proposed evaluation criterion within the GA, which helped to avoid the curse of dimensionality for the applied SVR and lowest over estimation or under estimation.
KW  - GSV
KW  - nu SVR
KW  - uneven-aged mountainous
KW  - polarimetery
KW  - multi-spectral
KW  - optimization
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197212
SN  - 1999-4907
VL  - 10
IS  - 8
ER  - 
TY  - INPR
A1  - Lisinetskaya, Polina G.
A1  - Mitric, Roland
T1  - Collective Response in DNA-Stabilized Silver Cluster Assemblies from First-Principles Simulations
T2  - The Journal of Physical Chemistry Letters
N2  - We investigate fluorescence resonant energy transfer and concurrent electron dynamics in a pair of DNA-stabilized silver clusters. For this purpose we introduce a methodology for the simulation of collective optoelectronic properties of coupled molecular aggregates starting from first-principles quantum chemistry, which can be further applied to a broad range of coupled molecular systems to study their electro-optical response. Our simulations reveal the existence of low-energy coupled excitonic states, which enable ultrafast energy transport between subunits, and give insight into the origin of the fluorescence signal in coupled DNA-stabilized silver clusters, which have been recently experimentally detected. Hence, we demonstrate the possibility of constructing ultrasmall energy transmission lines and optical converters based on these hybrid molecular systems.
KW  - Metal clusters
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-198729
UR  - https://doi.org/10.1021/acs.jpclett.9b03136
N1  - This document is the unedited Author’s version of a  Submitted Work that was subsequently accepted for  publication in Journal of Physical Chemistry A, copyright © American Chemical Society after peer review. To access the final edited and published work see The Journal of Physical Chemistry Letters 2019, 10, 24, 7884-7889. https://doi.org/10.1021/acs.jpclett.9b03136.
ER  - 
TY  - INPR
A1  - Röder, Anja
A1  - Petersen, Jens
A1  - Issler, Kevin
A1  - Fischer, Ingo
A1  - Mitric, Roland
A1  - Poisson, Lionel
T1  - Exploring the Excited-State Dynamics of Hydrocarbon Radicals, Biradicals and Carbenes using Time-Resolved Photoelectron Spectroscopy and Field-Induced Surface Hopping Simulations
T2  - The Journal of Physical Chemistry A
N2  - Reactive hydrocarbon molecules like radicals, biradicals and carbenes are not only key players in combustion processes and interstellar and atmospheric chemistry, but some of them are also important intermediates in organic synthesis. These systems typically possess many low-lying, strongly coupled electronic states. After light absorption, this leads to rich photodynamics characterized by a complex interplay of nuclear and electronic motion, which is still not comprehensively understood and not easy to investigate both experimentally and theoretically. In order to elucidate trends and contribute to a more general understanding, we here review our recent work on excited-state dynamics of open-shell hydrocarbon species using time-resolved photoelectron spectroscopy and field-induced surface hopping simulations, and report new results on the excited-state dynamics of the tropyl and the 1-methylallyl radical. The different dynamics are compared, and the difficulties and future directions of time-resolved photoelectron spectroscopy and excited state dynamics simulations of open-shell hydrocarbon molecules are discussed.
KW  - Excited state dynamics
KW  - Hydrocarbon radicals
KW  - time-resolved photoelectron spectroscopy
KW  - field-induced surface hopping
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-198734
UR  - https://doi.org/10.1021/acs.jpca.9b06346
N1  - This document is the unedited Author’s version of a  Submitted Work that was subsequently accepted for  publication in Journal of Physical Chemistry A, copyright © American Chemical Society after peer review. To access the final edited and published work see Journal of Physical Chemistry A 2019, 123, 50, 10643-10662. https://doi.org/10.1021/acs.jpca.9b06346.
ER  - 
TY  - INPR
A1  - Titov, Evgenii
A1  - Humeniuk, Alexander
A1  - Mitric, Roland
T1  - Exciton localization in excited-state dynamics of a tetracene trimer: A surface hopping LC-TDDFTB study
T2  - Physical Chemistry Chemical Physics
N2  - Excitons in the molecular aggregates of chromophores are key participants in important processes such as photosynthesis or the functioning of organic photovoltaic devices. Therefore, the exploration of exciton dynamics is crucial. Here we report on exciton localization during excited-state dynamics of the recently synthesized tetracene trimer [Liu et al., Org. Lett., 2017, 19, 580]. We employ the surface hopping approach to nonadiabatic molecular dynamics in conjunction with the long-range corrected time-dependent density functional tight binding (LC-TDDFTB) method [Humeniuk and Mitrić, Comput. Phys. Commun., 2017, 221, 174]. Utilizing a set of descriptors based on the transition density matrix, we perform comprehensive analysis of exciton dynamics. The obtained results reveal an ultrafast exciton localization to a single tetracene unit of the trimer during excited-state dynamics, along with exciton transfer between units.
KW  - Exciton dynamics
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-198680
UR  - https://doi.org/10.1039/C8CP05240A
N1  - Accepted Manuscript
ER  - 
TY  - INPR
A1  - Auerhammer, Nina
A1  - Schulz, Alexander
A1  - Schmiedel, Alexander
A1  - Holzapfel, Marco
A1  - Hoche, Joscha
A1  - Röhr, Merle I. S.
A1  - Mitric, Roland
A1  - Lambert, Christoph
T1  - Dynamic exciton localisation in a pyrene-BODIPY-pyrene dye conjugate
T2  - Physical Chemistry Chemical Physics
N2  - The photophysics of a molecular triad consisting of a BODIPY dye and two pyrene chromophores attached in 2-position are investigated by steady state and fs-time resolved transient absorption spectroscopy as well as by field induced surface hopping (FISH) simulations. While the steady state measurements indicate moderate chromophore interactions within the triad, the time resolved measurements show upon pyrene excitation a delocalised excited state which localises onto the BODIPY chromophore with a time constant of 0.12 ps. This could either be interpreted as an internal conversion process within the excitonically coupled chromophores or as an energy transfer from the pyrenes to the BODIPY dye. The analysis of FISH-trajectories reveals an oscillatory behaviour where the excitation hops between the pyrene units and the BODIPY dye several times until finally they become localised on the BODIPY chromophore within 100 fs. This is accompanied by an ultrafast nonradiative relaxation within the excitonic manifold mediated by the nonadiabatic coupling. Averaging over an ensemble of trajectories allowed us to simulate the electronic state population dynamics and determine the time constants for the nonradiative transitions that mediate the ultrafast energy transfer and exciton localisation on BODIPY.
KW  - Exciton localization dynamics
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-198718
UR  - https://doi.org/10.1039/C9CP00908F
N1  - Accepted manuscript
ER  - 
TY  - JOUR
A1  - Bauer, Boris
A1  - Goebeler, Matthias
A1  - Weissbrich, Benedikt
A1  - Kerstan, Andreas
T1  - Kerinokeratosis papulosa of childhood
JF  - Dermatology
N2  - Background: Kerinokeratosis papulosa (KP) is considered an extremely rare genodermatosis presenting usually as waxy papules on the trunk in childhood. 
Objective: To describe and analyze the clinical, histological and potential etiopathological aspects of KP. 
Methods: The dermatoscopic features of a new case of KP of childhood are investigated. The presence of human papillomavirus (HPV) DNA in lesional skin was studied by polymerase chain reaction. Furthermore, all cases of KP of childhood reported so far were reviewed. 
Results: As a diagnostic tool, we describe for the first time a dermatoscopic feature, namely a cribriform pattern of KP, in an 11-year-old boy. In addition, we detected HPV (type 57) in his KP lesions. 
Conclusions: Dermatoscopic examination might be a useful tool to distinguish KP from other skin lesions, e.g. common warts. The detection of HPV type 57 might hint to an etiological role of HPV for KP.
KW  - Waxy papulosis of childhood
KW  - Human papillomavirus
KW  - EVER1
KW  - EVER2
KW  - Kerinokeratosis papulosa
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-198997
SN  - 1018-8665
SN  - 1421-9832
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 231
IS  - 1
SP  - 1
EP  - 4
ER  - 
TY  - JOUR
A1  - Schmid, Michael
A1  - Steinlein, Claus
A1  - Winking, Heinz
T1  - Multicolor Spectral Analyses of Mitotic and Meiotic Mouse Chromosomes Involved in Multiple Robertsonian Translocations. I. The CD/Cremona Hybrid Strain
JF  - Cytogenetic and Genome Research
N2  - Multicolor spectral analysis (spectral karyotyping) was applied to mitotic and male diakinetic chromosomes of hybrid mice carrying a unique system of 18 autosomal Robertsonian translocation chromosomes with alternating arm homologies. Only the autosomes 19 and the XY sex chromosomes are excluded from these Robertsonian translocations. The translocations, previously identified by conventional banding analyses, could be verified by spectral karyotyping. Besides the Robertsonian translocations, no other interchromosomal rearrangements were detected. In diakineses of male meiosis, the 18 metacentric Robertsonian translocation chromosomes form a very large meiotic ‘superring'. The predictable, specific order of the chromosomes along this ‘superring' was completely confirmed by multicolor spectral analysis. In the majority of diakineses analyzed, the free autosomal bivalent 19 and the XY sex bivalent form a conspicuous complex which tightly associates with the 12;14 Robertsonian translocation chromosome in the ‘superring'.
KW  - meiotic ‘superring’
KW  - mouse
KW  - Robertsonian translocation chromosomes
KW  - spectral karyotyping
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199013
SN  - 1424-8581
SN  - 1424-859X
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 147
IS  - 4
ER  - 
TY  - JOUR
A1  - Schmid, Michael
A1  - Steinlein, Claus
T1  - Chromosome Banding in Amphibia. XXXIII. Demonstration of 5-Methylcytosine-Rich Heterochromatin in Anura
JF  - Cytogenetic and Genome Research
N2  - An experimental approach using monoclonal anti-5-methylcytosine (5-MeC) antibodies and indirect immunofluorescence was elaborated for detecting 5-MeC-rich chromosome regions in anuran chromosomes. This technique was applied to mitotic metaphases of 6 neotropical frog species belonging to 6 genera and 4 families. The hypermethylation patterns were compared with a variety of banding patterns obtained by conventional banding techniques. The hypermethylated DNA sequences are species-specific and located exclusively in constitutive heterochromatin. They are found in centromeric, pericentromeric, telomeric, and interstitial positions of the chromosomes and adjacent to nucleolus organizer regions. 5-MeC-rich DNA sequences can be embedded both in AT- and GC-rich repetitive DNA. The experimental parameters that have major influence on the reproducibility and quality of the anti-5-MeC antibody labeling are discussed.
KW  - Anura
KW  - heterochromatin
KW  - hypermethylated DNA
KW  - immunofluorescence
KW  - 5-Methylcytosine
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199022
SN  - 1424-8581
SN  - 1424-859X
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 148
IS  - 1
ER  - 
TY  - JOUR
A1  - Schneider, Eberhard
A1  - El Hajj, Nady
A1  - Müller, Fabian
A1  - Navarro, Bianca
A1  - Haaf, Thomas
T1  - Epigenetic Dysregulation in the Prefrontal Cortex of Suicide Completers
JF  - Cytogenetic and Genome Research
N2  - The epigenome is thought to mediate between genes and the environment, particularly in response to adverse life experiences. Similar to other psychiatric diseases, the suicide liability of an individual appears to be influenced by many genetic factors of small effect size as well as by environmental stressors. To identify epigenetic marks associated with suicide, which is considered the endpoint of complex gene-environment interactions, we compared the cortex DNA methylation patterns of 6 suicide completers versus 6 non-psychiatric sudden-death controls, using Illumina 450K methylation arrays. Consistent with a multifactorial disease model, we found DNA methylation changes in a large number of genes, but no changes with large effects reaching genome-wide significance. Global methylation of all analyzed CpG sites was significantly (0.25 percentage point) lower in suicide than in control brains, whereas the vast majority (97%) of the top 1,000 differentially methylated regions (DMRs) were higher methylated (0.6 percentage point) in suicide brains. Annotation analysis of the top 1,000 DMRs revealed an enrichment of differentially methylated promoters in functional categories associated with transcription and expression in the brain. In addition, we performed a comprehensive literature research to identify suicide genes that have been replicated in independent genetic association, brain methylation and/or expression studies. Although, in general, there was no significant overlap between different published data sets or between our top 1,000 DMRs and published data sets, our methylation screen strengthens a number of candidate genes (APLP2, BDNF, HTR1A, NUAK1, PHACTR3, MSMP, SLC6A4, SYN2, and SYNE2) and supports a role for epigenetics in the pathophysiology of suicide.
KW  - Cortex
KW  - DNA methylation
KW  - Suicidal behavior
KW  - Transcription regulation
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199032
SN  - 1424-8581
SN  - 1424-859X
VL  - 146
IS  - 1
ER  - 
TY  - JOUR
A1  - Schmid, Michael
A1  - Steinlein, Claus
A1  - Haaf, Thomas
A1  - Mijares-Urrutia, Abraham
T1  - Nascent ZW Sex Chromosomes in Thecadactylus rapicauda (Reptilia, Squamata, Phyllodactylidae)
JF  - Cytogenetic and Genome Research
N2  - The chromosomes of the turnip-tailed gecko Thecadactylus rapicauda from the Falcón State in northern Venezuela were examined by means of conventional staining, a variety of banding techniques and in situ hybridization with an 18S + 28S rDNA probe. In female specimens, C-banding analyses detected a cryptic W sex chromosome-associated interstitial heterochromatic segment which is absent in the Z sex chromosome. These ZW sex chromosomes are considered to be in a nascent stage of morphological differentiation and are absent in T. rapicauda collected in Guatemala. The amount, location and fluorochrome affinities of constitutive heterochromatin, the position of the nucleolus organizer region, and the genome sizes of female and male individuals were determined. The previously published cytogenetic data on T. rapicauda are discussed.
KW  - ZW sex chromosomes
KW  - Gecko
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199041
SN  - 1424-8581
SN  - 1424-859X
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 143
IS  - 4
ER  - 
TY  - JOUR
A1  - Bura, Thomas
A1  - Beaupré, Serge
A1  - Légaré, Marc-André
A1  - Ibraikulov, Olzhas A.
A1  - Leclerc, Nicolas
A1  - Leclerc, Mario
T1  - Theoretical calculations for highly selective Direct Heteroarylation Polymerization: new nitrile-substituted Dithienyl-Diketopyrrolopyrrole-based polymers
JF  - Molecules
N2  - Direct Heteroarylation Polymerization (DHAP) is becoming a valuable alternative to classical polymerization methods being used to synthesize π-conjugated polymers for organic electronics applications. In previous work, we showed that theoretical calculations on activation energy (Ea) of the C–H bonds were helpful to rationalize and predict the selectivity of the DHAP. For readers’ convenience, we have gathered in this work all our previous theoretical calculations on Ea and performed new ones. Those theoretical calculations cover now most of the widely utilized electron-rich and electron-poor moieties studied in organic electronics like dithienyl-diketopyrrolopyrrole (DT-DPP) derivatives. Theoretical calculations reported herein show strong modulation of the Ea of C–H bond on DT-DPP when a bromine atom or strong electron withdrawing groups (such as fluorine or nitrile) are added to the thienyl moiety. Based on those theoretical calculations, new cyanated dithienyl-diketopyrrolopyrrole (CNDT-DPP) monomers and copolymers were prepared by DHAP and their electro-optical properties were compared with their non-fluorinated and fluorinated analogues.
KW  - DHAP
KW  - selectivity
KW  - theoretical calculations
KW  - conjugated polymers
KW  - organic electronics
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197648
SN  - 1420-3049
VL  - 23
IS  - 9
ER  - 
TY  - JOUR
A1  - Papenfort, Kai
A1  - Vogel, Jörg
T1  - Small RNA functions in carbon metabolism and virulence of enteric pathogens
JF  - Frontiers in Cellular and Infection Microbiology
N2  - Enteric pathogens often cycle between virulent and saprophytic lifestyles. To endure these frequent changes in nutrient availability and composition bacteria possess an arsenal of regulatory and metabolic genes allowing rapid adaptation and high flexibility. While numerous proteins have been characterized with regard to metabolic control in pathogenic bacteria, small non-coding RNAs have emerged as additional regulators of metabolism. Recent advances in sequencing technology have vastly increased the number of candidate regulatory RNAs and several of them have been found to act at the interface of bacterial metabolism and virulence factor expression. Importantly, studying these riboregulators has not only provided insight into their metabolic control functions but also revealed new mechanisms of post-transcriptional gene control. This review will focus on the recent advances in this area of host-microbe interaction and discuss how regulatory small RNAs may help coordinate metabolism and virulence of enteric pathogens.
KW  - sRNA
KW  - carbon metabolism
KW  - Hfq
KW  - CsrA
KW  - virulence
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197520
SN  - 2235-2988
VL  - 4
IS  - 91
ER  - 
TY  - JOUR
A1  - Jungwirth, Gerhard
A1  - Yu, Tao
A1  - Moustafa, Mahmoud
A1  - Rapp, Carmen
A1  - Warta, Rolf
A1  - Jungk, Christine
A1  - Sahm, Felix
A1  - Dettling, Steffen
A1  - Zweckberger, Klaus
A1  - Lamszus, Katrin
A1  - Senft, Christian
A1  - Loehr, Mario
A1  - Keßler, Almuth F.
A1  - Ketter, Ralf
A1  - Westphal, Manfred
A1  - Debus, Juergen
A1  - von Deimling, Andreas
A1  - Simon, Matthias
A1  - Unterberg, Andreas
A1  - Abdollahi, Amir
A1  - Herold-Mende, Christel
T1  - Identification of KIF11 as a Novel Target in Meningioma
JF  - Cancers
N2  - Kinesins play an important role in many physiological functions including intracellular vesicle transport and mitosis. The emerging role of kinesins in different cancers led us to investigate the expression and functional role of kinesins in meningioma. Therefore, we re-analyzed our previous microarray dataset of benign, atypical, and anaplastic meningiomas (n = 62) and got evidence for differential expression of five kinesins (KIFC1, KIF4A, KIF11, KIF14 and KIF20A). Further validation in an extended study sample (n = 208) revealed a significant upregulation of these genes in WHO°I to °III meningiomas (WHO°I n = 61, WHO°II n = 88, and WHO°III n = 59), which was most pronounced in clinically more aggressive tumors of the same WHO grade. Immunohistochemical staining confirmed a WHO grade-associated upregulated protein expression in meningioma tissues. Furthermore, high mRNA expression levels of KIFC1, KIF11, KIF14 and KIF20A were associated with shorter progression-free survival. On a functional level, knockdown of kinesins in Ben-Men-1 cells and in the newly established anaplastic meningioma cell line NCH93 resulted in a significantly inhibited tumor cell proliferation upon siRNA-mediated downregulation of KIF11 in both cell lines by up to 95% and 71%, respectively. Taken together, in this study we were able to identify the prognostic and functional role of several kinesin family members of which KIF11 exhibits the most promising properties as a novel prognostic marker and therapeutic target, which may offer new treatment options for aggressive meningiomas.
KW  - meningioma
KW  - KIF
KW  - kinesin
KW  - KIF11
KW  - NCH93
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197402
SN  - 2072-6694
VL  - 11
IS  - 4
ER  - 
TY  - JOUR
A1  - Lamatsch, D. K.
A1  - Trifonov, V.
A1  - Schories, S.
A1  - Epplen, J. T.
A1  - Schmid, M.
A1  - Schartl, M.
T1  - Isolation of a Cancer-Associated Microchromosome in the Sperm-Dependent Parthenogen Poecilia formosa
JF  - Cytogenetic and Genome Research
N2  - In the asexual all-female fish species Poecilia formosa, the Amazon molly, supernumerary chromosomes have frequently been found in both laboratory-reared and wild-caught individuals. While wild-caught individuals with B chromosomes are phenotypically indifferent from conspecifics, individuals carrying B chromosomes from recent introgression events in the laboratory show phenotypic changes. Former analyses showed that the expression of a pigment cell locus is associated with the presence of these B chromosomes. In addition, they contain a so far unidentified locus that confers a higher susceptibility to tumor formation in the presence of pigmentation pattern. Isolation by microdissection and hybridization to metaphase chromosomes revealed that they contain one or several sequences with similarity to a highly repetitive pericentromeric and subtelomeric sequence in A chromosomes. Isolation of one particular sequence by AFLP showed that the B chromosomes contain at least 1 copy of an A-chromosomal region which is highly conserved in the whole genus Poecilia, i.e. more than 5 million years old. We propose it to be a single copy sequence.
KW  - paternal introgression
KW  - AFLP
KW  - asexual reproduction
KW  - B chromosomes
KW  - gynogenesis
KW  - microdissection
KW  - telomeres
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196785
SN  - 1424-8581
SN  - 1424-859X
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 135
IS  - 2
ER  - 
TY  - JOUR
A1  - Dengler, Julius
A1  - Maldaner, Nicolai
A1  - Gläsker, Sven
A1  - Endres, Matthias
A1  - Wagner, Martin
A1  - Malzahn, Uwe
A1  - Heuschmann, Peter U.
A1  - Vajkoczy, Peter
T1  - Outcome of Surgical or Endovascular Treatment of Giant Intracranial Aneurysms, with Emphasis on Age, Aneurysm Location, and Unruptured Aneuryms - A Systematic Review and Meta-Analysis
JF  - Cerebrovascular Diseases
N2  - Background: Designing treatment strategies for unruptured giant intracranial aneurysms (GIA) is difficult as evidence of large clinical trials is lacking. We examined the outcome following surgical or endovascular GIA treatment focusing on patient age, GIA location and unruptured GIA. Methods: Medline and Embase were searched for studies reporting on GIA treatment outcome published after January 2000. We calculated the proportion of good outcome (PGO) for all included GIA and for unruptured GIA by meta-analysis using a random effects model. Results: We included 54 studies containing 64 study populations with 1,269 GIA at a median follow-up time (FU-T) of 26.4 months (95% CI 10.8-42.0). PGO was 80.9% (77.4-84.4) in the analysis of all GIA compared to 81.2% (75.3-86.1) in the separate analysis of unruptured GIA. For each year added to patient age, PGO decreased by 0.8%, both for all GIA and unruptured GIA. For all GIA, surgical treatment resulted in a PGO of 80.3% (95% CI 76.0-84.6) compared to 84.2% (78.5-89.8, p = 0.27) after endovascular treatment. In unruptured GIA, PGO was 79.7% (95% CI 71.5-87.8) after surgical treatment and 84.9% (79.1-90.7, p = 0.54) after endovascular treatment. PGO was lower in high quality studies and in studies presenting aggregate instead of individual patient data. In unruptured GIA, the OR for good treatment outcome was 5.2 (95% CI 2.0-13.0) at the internal carotid artery compared to 0.1 (0.1-0.3, p < 0.1) in the posterior circulation. Patient sex, FU-T and prevalence of ruptured GIA were not associated with PGO. Conclusions: We found that the chances of good outcome after surgical or endovascular GIA treatment mainly depend on patient age and aneurysm location rather than on the type of treatment conducted. Our analysis may inform future research on GIA.
KW  - surgical aneurysm treatment
KW  - giant intracranial aneurysm
KW  - endovascular treatment
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196792
SN  - 1015-9770
SN  - 1421-9786
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 41
IS  - 3-4
ER  - 
TY  - JOUR
A1  - Schneider, Eberhard
A1  - El Hajj, Nady
A1  - Haaf, Thomas
T1  - Epigenetic Information from Ancient DNA Provides New Insights into Human Evolution
BT  - Commentary on Gokhman D et al. (2014): Reconstructing the DNA 
Methylation Maps of the Neanderthal and the Denisovan. Science 344:523–527
JF  - Brain, Behavior and Evolution
N2  - No abstract available.
KW  - human evolution
KW  - Neanderthal
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196800
SN  - 0006-8977
SN  - 1421-9743
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 84
IS  - 3
ER  - 
TY  - JOUR
A1  - Stieb, Sara Mae
A1  - Kelber, Christina
A1  - Wehner, Rüdiger
A1  - Rössler, Wolfgang
T1  - Antennal-Lobe Organization in Desert Ants of the Genus Cataglyphis
JF  - Brain, Behavior and Evolution
N2  - Desert ants of the genus Cataglyphis possess remarkable visual navigation capabilities. Although Cataglyphis species lack a trail pheromone system, Cataglyphis fortis employs olfactory cues for detecting nest and food sites. To investigate potential adaptations in primary olfactory centers of the brain of C. fortis, we analyzed olfactory glomeruli (odor processing units) in their antennal lobes and compared them to glomeruli in different Cataglyphis species. Using confocal imaging and 3D reconstruction, we analyzed the number, size and spatial arrangement of olfactory glomeruli in C. fortis, C.albicans, C.bicolor, C.rubra, and C.noda. Workers of all Cataglyphis species have smaller numbers of glomeruli (198–249) compared to those previously found in olfactory-guided ants. Analyses in 2 species of Formica – a genus closely related to Cataglyphis – revealed substantially higher numbers of olfactory glomeruli (c. 370), which is likely to reflect the importance of olfaction in these wood ant species. Comparisons between Cataglyphis species revealed 2 special features in C. fortis. First, with c. 198 C. fortis has the lowest number of glomeruli compared to all other species. Second, a conspicuously enlarged glomerulus is located close to the antennal nerve entrance. Males of C. fortis possess a significantly smaller number of glomeruli (c. 150) compared to female workers and queens. A prominent male-specific macroglomerulus likely to be involved in sex pheromone communication occupies a position different from that of the enlarged glomerulus in females. The behavioral significance of the enlarged glomerulus in female workers remains elusive. The fact that C. fortis inhabits microhabitats (salt pans) that are avoided by all other Cataglyphis species suggests that extreme ecological conditions may not only have resulted in adaptations of visual capabilities, but also in specializations of the olfactory system.
KW  - olfactory glomeruli
KW  - plasticity
KW  - ant
KW  - antennal lobe
KW  - glomerulus
KW  - insects
KW  - interspecific comparison
KW  - macroglomerulus
KW  - olfaction
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196815
SN  - 0006-8977
SN  - 1421-9743
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 77
IS  - 3
ER  - 
TY  - JOUR
A1  - Schraven, Sebastian P.
A1  - Dalhoff, Ernst
A1  - Wildenstein, Daniela
A1  - Hagen, Rudolf
A1  - Gummer, Anthony W.
A1  - Mlynski, Robert
T1  - Alternative Fixation of an Active Middle Ear Implant at the Short Incus Process
JF  - Audiology and Neurotology
N2  - Introduction: Since 1996, the preferred approach for positioning the active middle-ear implant Vibrant Soundbridge© is a mastoidectomy and a posterior tympanotomy. With this device, placement of the floating mass transducer (FMT) on the long incus process is the standard method for treatment of mild-to-severe sensorineural hearing loss in the case of normal middle-ear anatomy. The aim of this study was to determine the vibrational effectiveness of FMT placement at the short incus process. Materials and Methods: An extended antrotomy and a posterior tympanotomy were performed in 5 fresh human temporal bones. As a control for normal middle-ear function, the tympanic membrane was stimulated acoustically and the vibration of the stapes footplate and the round-window (RW) membrane were (sequentially) measured by laser Doppler vibrometry. Vibration responses for coupling of an FMT to the long incus process (standard coupling) were compared to those for coupling to the short incus process. Results: Apart from narrow frequency bands near 3 and 9 kHz for the stapes footplate and RW membrane, respectively, the velocity responses presented no significant differences between standard coupling of the FMT and coupling to the short incus process. Conclusion: Coupling the FMT to the short incus process may be a viable alternative in cases where the surgical approach is limited to an extended antrotomy. A reliable technique for attachment to the short incus process has yet to be developed.
KW  - middle-ear surgery
KW  - active middle-ear implant
KW  - floating mass transducer
KW  - incus
KW  - Laser Doppler vibrometer
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196823
SN  - 1420-3030
SN  - 1421-9700
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 19
IS  - 1
ER  - 
TY  - JOUR
A1  - de Zeeuw, Dick
A1  - Akizawa, Tadao
A1  - Agarwal, Rajiv
A1  - Audhya, Paul
A1  - Bakris, George L.
A1  - Chin, Melanie
A1  - Krauth, Melissa
A1  - Lambers Heerspink, Hiddo J.
A1  - Meyer, Colin J.
A1  - McMurray, John J.
A1  - Parving, Hans-Henrik
A1  - Pergola, Pablo E.
A1  - Remuzzi, Giuseppe
A1  - Toto, Robert D.
A1  - Vaziri, Nosratola D.
A1  - Wanner, Christoph
A1  - Warnock, David G.
A1  - Wittes, Janet
A1  - Chertow, Glenn M.
T1  - Rationale and Trial Design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: The Occurrence of Renal Events (BEACON)
JF  - American Journal of Nephrology
N2  - Background: Chronic kidney disease (CKD) associated with type 2 diabetes mellitus constitutes a global epidemic complicated by considerable renal and cardiovascular morbidity and mortality, despite the provision of inhibitors of the renin-angiotensin-aldosterone system (RAAS). Bardoxolone methyl, a synthetic triterpenoid that reduces oxidative stress and inflammation through Nrf2 activation and inhibition of NF-κB was previously shown to increase estimated glomerular filtration rate (eGFR) in patients with CKD associated with type 2 diabetes mellitus. To date, no antioxidant or anti-inflammatory therapy has proved successful at slowing the progression of CKD. Methods: Herein, we describe the design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: the Occurrence of Renal Events (BEACON) trial, a multinational, multicenter, double-blind, randomized, placebo-controlled Phase 3 trial designed to determine whether long-term administration of bardoxolone methyl (on a background of standard therapy, including RAAS inhibitors) safely reduces renal and cardiac morbidity and mortality. Results: The primary composite endpoint is time-to-first occurrence of either end-stage renal disease or cardiovascular death. Secondary endpoints include the change in eGFR and time to occurrence of cardiovascular events. Conclusion: BEACON will be the first event-driven trial to evaluate the effect of an oral antioxidant and anti-inflammatory drug in advanced CKD.
KW  - clinical trial
KW  - diabetes mellitus
KW  - glomerular filtration rate
KW  - trial design
KW  - bardoxolone methyl
KW  - Nrf2
KW  - end-stage renal disease
KW  - cardiovascular death
KW  - chronic kidney disease
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196832
SN  - 0250-8095
SN  - 1421-9670
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 37
IS  - 3
ER  - 
TY  - JOUR
A1  - Mayr, Stefan
A1  - Kuenzer, Claudia
A1  - Gessner, Ursula
A1  - Klein, Igor
A1  - Rutzinger, Martin
T1  - Validation of earth observation time-series: a review for large-area and temporally dense land surface products
JF  - Remote Sensing
N2  - Large-area remote sensing time-series offer unique features for the extensive investigation of our environment. Since various error sources in the acquisition chain of datasets exist, only properly validated results can be of value for research and downstream decision processes. This review presents an overview of validation approaches concerning temporally dense time-series of land surface geo-information products that cover the continental to global scale. Categorization according to utilized validation data revealed that product intercomparisons and comparison to reference data are the conventional validation methods. The reviewed studies are mainly based on optical sensors and orientated towards global coverage, with vegetation-related variables as the focus. Trends indicate an increase in remote sensing-based studies that feature long-term datasets of land surface variables. The hereby corresponding validation efforts show only minor methodological diversification in the past two decades. To sustain comprehensive and standardized validation efforts, the provision of spatiotemporally dense validation data in order to estimate actual differences between measurement and the true state has to be maintained. The promotion of novel approaches can, on the other hand, prove beneficial for various downstream applications, although typically only theoretical uncertainties are provided.
KW  - accuracy
KW  - error estimation
KW  - global
KW  - intercomparison
KW  - remote sensing
KW  - uncertainty
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193202
SN  - 2072-4292
VL  - 11
IS  - 22
ER  - 
TY  - JOUR
A1  - Grebinyk, Anna
A1  - Prylutska, Svitlana
A1  - Buchelnikov, Anatoliy
A1  - Tverdokhleb, Nina
A1  - Grebinyk, Sergii
A1  - Evstigneev, Maxim
A1  - Matyshevska, Olga
A1  - Cherepanov, Vsevolod
A1  - Prylutskyy, Yuriy
A1  - Yashchuk, Valeriy
A1  - Naumovets, Anton
A1  - Ritter, Uwe
A1  - Dandekar, Thomas
A1  - Frohme, Marcus
T1  - C60 fullerene as an effective nanoplatform of alkaloid Berberine delivery into leukemic cells
JF  - Pharmaceutics
N2  - A herbal alkaloid Berberine (Ber), used for centuries in Ayurvedic, Chinese, Middle-Eastern, and native American folk medicines, is nowadays proved to function as a safe anticancer agent. Yet, its poor water solubility, stability, and bioavailability hinder clinical application. In this study, we have explored a nanosized carbon nanoparticle—C60 fullerene (C60)—for optimized Ber delivery into leukemic cells. Water dispersions of noncovalent C60-Ber nanocomplexes in the 1:2, 1:1, and 2:1 molar ratios were prepared. UV–Vis spectroscopy, dynamic light scattering (DLS), and atomic force microscopy (AFM) evidenced a complexation of the Ber cation with the negatively charged C60 molecule. The computer simulation showed that π-stacking dominates in Ber and C\(_{60}\) binding in an aqueous solution. Complexation with C\(_{60}\) was found to promote Ber intracellular uptake. By increasing C\(_{60}\) concentration, the C\(_{60}\)-Ber nanocomplexes exhibited higher antiproliferative potential towards CCRF-CEM cells, in accordance with the following order: free Ber < 1:2 < 1:1 < 2:1 (the most toxic). The activation of caspase 3/7 and accumulation in the sub-G1 phase of CCRF-CEM cells treated with C\(_{60}\)-Ber nanocomplexes evidenced apoptosis induction. Thus, this study indicates that the fast and easy noncovalent complexation of alkaloid Ber with C\(_{60}\) improved its in vitro efficiency against cancer cells.
KW  - C60 fullerene
KW  - Berberine
KW  - noncovalent nanocomplex
KW  - UV–Vis
KW  - DLS and AFM measurements
KW  - drug release
KW  - leukemic cells
KW  - uptake
KW  - cytotoxicity
KW  - apoptosis
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193216
SN  - 1999-4923
VL  - 11
IS  - 11
ER  - 
TY  - JOUR
A1  - Teichmann, Christoph
T1  - Corporate Groups within the Legal Framework of the European Union: The Group-Related Aspects of the SUP Proposal and the EU Freedom of Establishment
JF  - European Company and Financial Law Review
N2  - No abstract available.
KW  - EU
KW  - corporate groups
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-194513
SN  - 1613-2556
SN  - 1613-2548
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 12
IS  - 2
SP  - 202
EP  - 229
ER  - 
TY  - JOUR
A1  - Li, Shan
A1  - Li, Xin
A1  - Link, Roman
A1  - Li, Ren
A1  - Deng, Liping
A1  - Schuldt, Bernhard
A1  - Jiang, Xiaomei
A1  - Zhao, Rongjun
A1  - Zheng, Jingming
A1  - Li, Shuang
A1  - Yin, Yafang
T1  - Influence of cambial age and axial height on the spatial patterns of xylem traits in Catalpa bungei, a ring-porous tree species native to China
JF  - Forests
N2  - Studying how cambial age and axial height affects wood anatomical traits may improve our understanding of xylem hydraulics, heartwood formation and axial growth. Radial strips were collected from six different heights (0–11.3 m) along the main trunk of three Manchurian catalpa (Catalpa bungei) trees, yielding 88 samples. In total, thirteen wood anatomical vessel and fiber traits were observed usinglight microscopy (LM) and scanning electron microscopy (SEM), and linear models were used to analyse the combined effect of axial height, cambial age and their interaction. Vessel diameter differed by about one order of magnitude between early- and latewood, and increased significantly with both cambial age and axial height in latewood, while it was positively affected by cambial age and independent of height in earlywood. Vertical position further had a positive effect on earlywood vessel density, and negative effects on fibre wall thickness, wall thickness to diameter ratio and length. Cambial age had positive effects on the pit membrane diameter and vessel element length, while the annual diameter growth decreased with both cambial age and axial position. In contrast, early- and latewood fiber diameter were unaffected by both cambial age and axial height. We further observed an increasing amount of tyloses from sapwood to heartwood, accompanied by an increase of warty layers and amorphous deposits on cell walls, bordered pit membranes and pit apertures. This study highlights the significant effects of cambial age and vertical position on xylem anatomical traits, and confirms earlier work that cautions to take into account xylem spatial position when interpreting wood anatomical structures, and thus, xylem hydraulic functioning.
KW  - wood anatomy
KW  - vertical and radial variation
KW  - earlywood
KW  - latewood
KW  - growth ring width
KW  - tyloses
KW  - pit membrane diameter
KW  - vessel lumen diameter
KW  - fibre length
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196297
SN  - 1999-4907
VL  - 10
IS  - 8
ER  - 
TY  - JOUR
A1  - Camacho, J.P.M.
A1  - Schmid, M.
A1  - Cabrero, J.
T1  - B Chromosomes and Sex in Animals
JF  - Sexual Development
N2  - Supernumerary (B) chromosomes are dispensable elements found in many eukaryote genomes in addition to standard (A) chromosomes. In many respects, B chromosomes resemble sex chromosomes, so that a common ancestry for them has frequently been suggested. For instance, B chromosomes in grasshoppers, and other insects, show a pycnotic cycle of condensation-decondensation during meiosis remarkably similar to that of the X chromosome. In some cases, B chromosome size is even very similar to that of the X chromosome. These resemblances have led to suggest the X as the B ancestor in many cases. In addition, sex chromosome origin from B chromosomes has also been suggested. In this article, we review the existing evidence for both evolutionary pathways, as well as sex differences for B frequency at adult and embryo progeny levels, B chromosome effects or B chromosome transmission. In addition, we review cases found in the literature showing sex-ratio distortion associated with B chromosome presence, the most extreme case being the paternal sex ratio (PSR) chromosomes in some Hymenoptera. We finally analyse the possibility of B chromosome regularisation within the host genome and, as a consequence of it, whether B chromosomes can become regular members of the host genome.
KW  - A chromosomes
KW  - B chromosomes
KW  - sex ratio
KW  - X chromosome
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196321
SN  - 1661-5425
SN  - 1661-5433
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 5
IS  - 3
ER  - 
TY  - JOUR
A1  - Kühn, Heike
A1  - Schön, Franz
A1  - Edelmann, Karola
A1  - Brill, Stefan
A1  - Müller, Joachim
T1  - The Development of Lateralization Abilities in Children with Bilateral Cochlear Implants
JF  - ORL
N2  - Objectives: The purpose of this study was to investigate the development of lateralization skills in children who received bilateral cochlear implants (CIs) in sequential operations. Methods: The lateralization skills of 9 children with a mean age of 4.1 years at the first surgery and 5.5 years at the second surgery were assessed at 3 time intervals. Children were assessed with a 3-loudspeaker setup (front, left and right) at 0.9 years (interval I) and 1.6 years (interval II) after the second implantation, and after 5.3 years of bilateral implant use (interval III) with a 9-loudspeaker setup in the frontal horizontal plane between -90° and 90° azimuth. Results: With bilateral implants, a significant decrease in lateralization error was noted between test interval I (45.0°) and II (23.3°), with a subsequent significant decrease at test interval III (4.7°). Unilateral performance with the CI did not improve significantly between the first 2 intervals; however, there was a bias of responses towards the unilateral side by test interval III. Conclusions: The lateralization abilities of children with bilateral CIs develop in a relatively short period of time (1-2 years) after the second implant. Children appear to be able to acquire binaural skills after bilateral cochlear implantation.
KW  - localization
KW  - bilateral cochlear implant
KW  - children
KW  - MED-EL cochlear implant
KW  - lateralization
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196375
SN  - 0301-1569
SN  - 1423-0275
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 75
IS  - 2
ER  - 
TY  - JOUR
A1  - Kolominsky-Rabas, Peter L.
A1  - Wiedmann, Silke
A1  - Weingärtner, Michael
A1  - Liman, Thomas G.
A1  - Endres, Matthias
A1  - Schwab, Stefan
A1  - Buchfelder, Michael
A1  - Heuschmann, Peter U.
T1  - Time Trends in Incidence of Pathological and Etiological Stroke Subtypes during 16 Years: The Erlangen Stroke Project
JF  - Neuroepidemiology
N2  - Background: Population-based data, which continuously monitors time trends in stroke epidemiology are limited. We investigated the incidence of pathological and etiological stroke subtypes over a 16 year time period. Methods: Data were collected within the Erlangen Stroke Project (ESPro), a prospective, population-based stroke register in Germany covering a total study population of 105,164 inhabitants (2010). Etiology of ischemic stroke was classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. Results: Between January 1995 and December 2010, 3,243 patients with first-ever stroke were documented. The median age was 75 and 55% were females. The total stroke incidence decreased over the 16 year study period in men (Incidence Rate Ratio 1995-1996 vs. 2009-2010 (IRR) 0.78; 95% CI 0.58-0.90) but not in women. Among stroke subtypes, a decrease in ischemic stroke incidence (IRR 0.73; 95% CI 0.57-0.93) and of large artery atherosclerotic stroke (IRR 0.27; 95% CI 0.12-0.59) was found in men and an increase of stroke due to small artery occlusion in women (IRR 2.33; 95% CI 1.39-3.90). Conclusions: Variations in time trends of pathological and etiological stroke subtypes were found between men and women that might be linked to gender differences in the development of major vascular risk factors in the study population.
KW  - stroke
KW  - epidemiology
KW  - incidence
KW  - time trends
KW  - register
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196503
SN  - 0251-5350
SN  - 1423-0208
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 44
IS  - 1
ER  - 
TY  - JOUR
A1  - Schneider, Andreas
A1  - Gutjahr-Lengsfeld, Lena
A1  - Ritz, Eberhard
A1  - Scharnagl, Hubert
A1  - Gelbrich, Götz
A1  - Pilz, Stefan
A1  - Macdougall, Iain C.
A1  - Wanner, Christoph
A1  - Drechsler, Christiane
T1  - Longitudinal Assessments of Erythropoietin-Stimulating Agent Responsiveness and the Association with Specific Clinical Outcomes in Dialysis Patients
JF  - Nephron Clinical Practice
N2  - Background: Dose requirements of erythropoietin-stimulating agents (ESAs) can vary considerably over time and may be associated with cardiovascular outcomes. We aimed to longitudinally assess ESA responsiveness over time and to investigate its association with specific clinical end points in a time-dependent approach. Methods: The German Diabetes and Dialysis study (4D study) included 1,255 diabetic dialysis patients, of whom 1,161 were receiving ESA treatment. In those patients, the erythropoietin resistance index (ERI) was assessed every 6 months during a median follow-up of 4 years. The association between the ERI and cardiovascular end points was analyzed by time-dependent Cox regression analyses with repeated ERI measures. Results: Patients had a mean age of 66 ± 8.2 years; 53% were male. During follow-up, a total of 495 patients died, of whom 136 died of sudden death and 102 of infectious death. The adjusted and time-dependent risk for sudden death was increased by 19% per 5-unit increase in the ERI (hazard ratio, HR = 1.19, 95% confidence interval, CI = 1.07-1.33). Similarly, mortality increased by 25% (HR = 1.25, 95% CI = 1.18-1.32) and infectious death increased by 27% (HR = 1.27, 95% CI = 1.13-1.42). Further analysis revealed that lower 25-hydroxyvitamin D levels were associated with lower ESA responsiveness (p = 0.046). Conclusions: In diabetic dialysis patients, we observed that time-varying erythropoietin resistance is associated with sudden death, infectious complications and all-cause mortality. Low 25-hydroxyvitamin D levels may contribute to a lower ESA responsiveness.
KW  - dialysis
KW  - erythropoietin
KW  - diabetes
KW  - epidemiology
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196511
SN  - 1660-2110
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 128
IS  - 1-2
ER  - 
TY  - JOUR
A1  - Poot, Martin
A1  - Haaf, Thomas
T1  - Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements
JF  - Molecular Syndromology
N2  - Complex chromosome rearrangements (CCRs) are currently defined as structural genome variations that involve more than 2 chromosome breaks and result in exchanges of chromosomal segments. They are thought to be extremely rare, but their detection rate is rising because of improvements in molecular cytogenetic technology. Their population frequency is also underestimated, since many CCRs may not elicit a phenotypic effect. CCRs may be the result of fork stalling and template switching, microhomology-mediated break-induced repair, breakage-fusion-bridge cycles, or chromothripsis. Patients with chromosomal instability syndromes show elevated rates of CCRs due to impaired DNA double-strand break responses during meiosis. Therefore, the putative functions of the proteins encoded by ATM, BLM, WRN, ATR, MRE11, NBS1, and RAD51 in preventing CCRs are discussed. CCRs may exert a pathogenic effect by either (1) gene dosage-dependent mechanisms, e.g. haploinsufficiency, (2) mechanisms based on disruption of the genomic architecture, such that genes, parts of genes or regulatory elements are truncated, fused or relocated and thus their interactions disturbed - these mechanisms will predominantly affect gene expression - or (3) mixed mutation mechanisms in which a CCR on one chromosome is combined with a different type of mutation on the other chromosome. Such inferred mechanisms of pathogenicity need corroboration by mRNA sequencing. Also, future studies with in vitro models, such as inducible pluripotent stem cells from patients with CCRs, and transgenic model organisms should substantiate current inferences regarding putative pathogenic effects of CCRs. The ramifications of the growing body of information on CCRs for clinical and experimental genetics and future treatment modalities are briefly illustrated with 2 cases, one of which suggests KDM4C(JMJD2C) as a novel candidate gene for mental retardation.
KW  - triplosufficiency
KW  - complex chromosome rearrangements
KW  - DNA double-strand break
KW  - haploinsufficiency
KW  - mixed mutation mechanisms
KW  - structural genome variations
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196524
SN  - 1661-8769
SN  - 1661-8777
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 6
IS  - 3
ER  - 
TY  - JOUR
A1  - Heinrich, T.
A1  - Nanda, I.
A1  - Rehn, M.
A1  - Zollner, U.
A1  - Frieauff, E.
A1  - Wirbelauer, J.
A1  - Grimm, T.
A1  - Schmid, M.
T1  - Live-Born Trisomy 22: Patient Report and Review
JF  - Molecular Syndromology
N2  - Trisomy 22 is a common trisomy in spontaneous abortions. In contrast, live-born trisomy 22 is rarely seen due to severe organ malformations associated with this condition. Here, we report on a male infant with complete, non-mosaic trisomy 22 born at 35 + 5 weeks via caesarean section. Peripheral blood lymphocytes and fibroblasts showed an additional chromosome 22 in all metaphases analyzed (47,XY,+22). In addition, array CGH confirmed complete trisomy 22. The patient’s clinical features included dolichocephalus, hypertelorism, flattened nasal bridge, dysplastic ears with preauricular sinuses and tags, medial cleft palate, anal atresia, and coronary hypospadias with scrotum bipartitum. Essential treatment was implemented in close coordination with the parents. The child died 29 days after birth due to respiratory insufficiency and deterioration of renal function. Our patient’s history complements other reports illustrating that children with complete trisomy 22 may survive until birth and beyond.
KW  - chromosomal abnormality
KW  - live-born
KW  - non-mosaic
KW  - trisomy 22
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196535
SN  - 1661-8769
SN  - 1661-8777
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 3
IS  - 6
ER  - 
TY  - JOUR
A1  - Almanzar, Giovanni
A1  - Klein, Matthias
A1  - Schmalzing, Marc
A1  - Hilligardt, Deborah
A1  - El Hajj, Nady
A1  - Kneitz, Hermann
A1  - Wild, Vanessa
A1  - Rosenwald, Andreas
A1  - Benoit, Sandrine
A1  - Hamm, Henning
A1  - Tony, Hans-Peter
A1  - Haaf, Thomas
A1  - Goebeler, Matthias
A1  - Prelog, Martina
T1  - Disease Manifestation and Inflammatory Activity as Modulators of Th17/Treg Balance and RORC/FoxP3 Methylation in Systemic Sclerosis
JF  - International Archives of Allergy and Immunology
N2  - Background: There is much evidence that T cells are strongly involved in the pathogenesis of localized and systemic forms of scleroderma (SSc). A dysbalance between FoxP3+ regulatory CD4+ T cells (Tregs) and inflammatory T-helper (Th) 17 cells has been suggested. Methods: The study aimed (1) to investigate the phenotypical and functional characteristics of Th17 and Tregs in SSc patients depending on disease manifestation (limited vs. diffuse cutaneous SSc, dcSSc) and activity, and (2) the transcriptional level and methylation status of Th17- and Treg-specific transcription factors. Results: There was a concurrent accumulation of circulating peripheral IL-17-producing CCR6+ Th cells and FoxP3+ Tregs in patients with dcSSc. At the transcriptional level, Th17- and Treg-associated transcription factors were elevated in SSc. A strong association with high circulating Th17 and Tregs was seen with early, active, and severe disease presentation. However, a diminished suppressive function on autologous lymphocytes was found in SSc-derived Tregs. Significant relative hypermethylation was seen at the gene level for RORC1 and RORC2 in SSc, particularly in patients with high inflammatory activity. Conclusions: Besides the high transcriptional activity of T cells, attributed to Treg or Th17 phenotype, in active SSc disease, Tregs may be insufficient to produce high amounts of IL-10 or to control proliferative activity of effector T cells in SSc. Our results suggest a high plasticity of Tregs strongly associated with the Th17 phenotype. Future directions may focus on enhancing Treg functions and stabilization of the Treg phenotype.
KW  - methylation
KW  - systemic sclerosis
KW  - suppression
KW  - Tregs
KW  - Th17
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196577
SN  - 1018-2438
SN  - 1423-0097
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 171
IS  - 2
ER  - 
TY  - JOUR
A1  - Matthies, Cordula
A1  - Brill, Stefan
A1  - Kaga, Kimitaka
A1  - Morita, Akio
A1  - Kumakawa, Kozo
A1  - Skarzynski, Henryk
A1  - Claassen, Andre
A1  - Hui, Yau
A1  - Chiong, Charlotte
A1  - Müller, Joachim
A1  - Behr, Robert
T1  - Auditory Brainstem Implantation Improves Speech Recognition in Neurofibromatosis Type II Patients
JF  - ORL
N2  - This prospective study aimed to determine speech understanding in neurofibromatosis type II (NF2) patients following implantation of a MED-EL COMBI 40+ auditory brainstem implant (ABI). Patients (n = 32) were enrolled postsurgically. Nonauditory side effects were evaluated at fitting and audiological performance was determined using the Sound Effects Recognition Test (SERT), Monosyllable-Trochee-Polysyllable (MTP) test and open-set sentence tests. Subjective benefits were determined by questionnaire. ABI activation was documented in 27 patients, 2 patients were too ill for testing and 3 patients were without any auditory perception. SERT and MTP outcomes under auditory-only conditions improved significantly between first fitting and 12-month follow-up. Open-set sentence recognition improved from 5% at first fitting to 37% after 12 months. The number of active electrodes had no significant effect on performance. All questionnaire respondents were ‘satisfied' to ‘very satisfied' with their ABI. An ABI is an effective treatment option in NF2 patients with the potential to provide open-set speech recognition and subjective benefits. To our knowledge, the data presented herein is exceptional in terms of the open-set speech perception achieved in NF2 patients.
KW  - acoustic neuroma
KW  - auditory brainstem implant
KW  - nonauditory side effects
KW  - open-set sentence recognition
KW  - subjective benefits
KW  - vestibular schwannoma
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196383
SN  - 0301-1569
SN  - 1423-0275
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 75
IS  - 5
ER  - 
TY  - JOUR
A1  - Müller, Joachim
A1  - Brill, Stefan
A1  - Hagen, Rudolf
A1  - Moeltner, Alexander
A1  - Brockmeier, Steffi-Johanna
A1  - Stark, Thomas
A1  - Helbig, Silke
A1  - Maurer, Jan
A1  - Zahnert, Thomas
A1  - Zierhofer, Clemens
A1  - Nopp, Peter
A1  - Anderson, Ilona
T1  - Clinical Trial Results with the MED-EL Fine Structure Processing Coding Strategy in Experienced Cochlear Implant Users
JF  - ORL
N2  - Objectives: To assess the subjective and objective performance of the new fine structure processing strategy (FSP) compared to the previous generation coding strategies CIS+ and HDCIS. Methods: Forty-six adults with a minimum of 6 months of cochlear implant experience were included. CIS+, HDCIS and FSP were compared in speech perception tests in noise, pitch scaling and questionnaires. The randomized tests were performed acutely (interval 1) and again after 3 months of FSP experience (interval 3). The subjective evaluation included questionnaire 1 at intervals 1 and 3, and questionnaire 2 at interval 2, 1 month after interval 1. Results: Comparison between FSP and CIS+ showed that FSP performed at least as well as CIS+ in all speech perception tests, and outperformed CIS+ in vowel and monosyllabic word discrimination. Comparison between FSP and HDCIS showed that both performed equally well in all speech perception tests. Pitch scaling showed that FSP performed at least as well as HDCIS. With FSP, sound quality was at least as good and often better than with HDCIS. Conclusions: Results indicate that FSP performs better than CIS+ in vowel and monosyllabic word understanding. Subjective evaluation demonstrates strong user preferences for FSP when listening to speech and music.
KW  - pitch
KW  - CIS+
KW  - OPUS
KW  - fine structure processing
KW  - cochlear implant
KW  - coding strategy
KW  - speech perception
KW  - music
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196396
SN  - 0301-1569
SN  - 1423-0275
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 74
IS  - 4
ER  - 
TY  - JOUR
A1  - Ono, Mitsuaki
A1  - Sonoyama, Wataru
A1  - Nema, Kazuki
A1  - Hara, Emilio Satoshi
A1  - Oida, Yasutaka
A1  - Pham, Hai Thanh
A1  - Yamamoto, Katushi
A1  - Hirota, Kazuo
A1  - Sugama, Kazushige
A1  - Sebald, Walter
A1  - Kuboki, Takuo
T1  - Regeneration of calvarial defects with Escherichia coli-derived rhBMP-2 adsorbed in PLGA membrane
JF  - Cells Tissues Organs
N2  - Objective: Escherichia coli-derived recombinant human bone morphogenetic protein-2 (E-BMP-2) has been shown to be as effective as mammalian cell-derived BMP-2. However, several in vitro and in vivo experiments are still necessary to validate the effectiveness of E-BMP-2 due to the difference in synthesis process, mainly related to protein nonglycosylation. The objective of this study was to investigate whether biodegradable polylactide-co-glycolide (PLGA) membrane is a suitable carrier for E-BMP-2 delivery for bone regeneration of critical-sized defects in rat calvaria. Materials and Methods: First, the osteoinductive effect of E-BMP-2 was confirmed in vitro in mouse bone marrow stromal cells by analysis of osteocalcin mRNA levels, and calcium deposition was detected by alizarin red staining. Before in vivo experiments, the release profile of E-BMP-2 from PLGA membranes was determined by ELISA. E-BMP-2 (0, 1, 5 and 10 μg/μl) was applied for ectopic and orthotopic bone formation and was analyzed by X-ray, micro-CT and histology. Results: Release-profile testing showed that PLGA membrane could retain 94% of the initially applied E-BMP-2. Ectopic bone formation assay revealed that combination of E-BMP-2/PLGA membrane strongly induced bone formation. Stronger osteoinductivity with complete repair of critical-sized defects was observed only with PLGA membranes adsorbed with 5 and 10 μg/μl of E-BMP-2, whereas no bone formation was observed in the groups that received no membrane or 0-μg/μl dose of E-BMP-2. Conclusion: PLGA membrane was shown to be a suitable carrier for sustained release of E-BMP-2, and the E-BMP-2/PLGA membrane combination was demonstrated to be efficient in bone regeneration in a model of critical-sized defects.
KW  - Escherichia coli-derived recombinant human bone morphogenetic protein-2
KW  - Bone regeneration
KW  - Polylactide-co-glycolide
KW  - Ectopic bone formation
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196680
SN  - 1422-6405
SN  - 1422-6421
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 198
IS  - 5
SP  - 367
EP  - 376
ER  - 
TY  - JOUR
A1  - Schmid, Michael
A1  - Steinlein, Claus
T1  - Chromosome Banding in Amphibia. XXXIV. Intrachromosomal Telomeric DNA Sequences in Anura
JF  - Cytogenetic and Genome Research
N2  - The mitotic chromosomes of 4 anuran species were examined by various classical banding techniques and by fluorescence in situ hybridization using a (TTAGGG)\(_n\) repeat. Large intrachromosomal telomeric sequences (ITSs) were demonstrated in differing numbers and chromosome locations. A detailed comparison of the present results with numerous published and unpublished data allowed a consistent classification of the various categories of large ITSs present in the genomes of anurans and other vertebrates. The classification takes into consideration the total numbers of large ITSs in the karyotypes, their chromosomal locations and their specific distribution patterns. A new category of large ITSs was recognized to exist in anuran species. It consists of large clusters of ITSs located in euchromatic chromosome segments, which is in clear contrast to the large ITSs in heterochromatic chromosome regions known in vertebrates. The origin of the different categories of large ITSs in heterochromatic and euchromatic chromosome regions, their mode of distribution in the karyotypes and evolutionary fixation in the genomes, as well as their cytological detection are discussed.
KW  - heterochromatin
KW  - intrachromosomal telomeric sequences
KW  - Anura
KW  - euchromatin
KW  - evolutionary fixation
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196693
SN  - 1424-8581
SN  - 1424-859X
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 148
IS  - 2-3
ER  - 
TY  - JOUR
A1  - Schmid, Michael
A1  - Steinlein, Claus
A1  - Lomb, Christian
A1  - Sperling, Karl
A1  - Neitzel, Heidemarie
T1  - 5-Methylcytosine-Rich Heterochromatin in the Indian Muntjac
JF  - Cytogenetic and Genome Research
N2  - Two 5-methylcytosine (5-MeC)-rich heterochromatic regions were demonstrated in metaphase chromosomes of the Indian muntjac by indirect immunofluorescence using a monoclonal anti-5-MeC antibody. The metaphases were obtained from diploid and triploid cell lines. A major region is located in the ‘neck' of the 3;X fusion chromosome and can be detected after denaturation of the chromosomal DNA with UV-light irradiation for 1 h. It is located exactly at the border of the X chromosome and the translocated autosome 3. A minor region is found in the centromeric region of the free autosome 3 after denaturing the chromosomal DNA for 3 h or longer. The structure and possible function of the major hypermethylated region as barrier against spreading of the X-inactivation process into the autosome 3 is discussed.
KW  - heterochromatin
KW  - immunofluorescence
KW  - Indian muntjac
KW  - 5-Methylcytosine
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196701
SN  - 1424-8581
SN  - 1424-859X
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 147
IS  - 4
ER  - 
TY  - JOUR
A1  - Schmid, Michael
A1  - Steinlein, Claus
A1  - Yano, Cassia F.
A1  - Cioffi, Marcelo B.
T1  - Hypermethylated Chromosome Regions in Nine Fish Species with Heteromorphic Sex Chromosomes
JF  - Cytogenetic and Genome Research
N2  - Sites and amounts of 5-methylcytosine (5-MeC)-rich chromosome regions were detected in the karyotypes of 9 Brazilian species of Characiformes fishes by indirect immunofluorescence using a monoclonal anti-5-MeC antibody. These species, belonging to the genera Leporinus, Triportheus and Hoplias, are characterized by highly differentiated and heteromorphic ZW and XY sex chromosomes. In all species, the hypermethylated regions are confined to constitutive heterochromatin. The number and chromosome locations of hypermethylated heterochromatic regions in the karyotypes are constant and species-specific. Generally, heterochromatic regions that are darkly stained by the C-banding technique are distinctly hypermethylated, but several of the brightly fluorescing hypermethylated regions merely exhibit moderate or faint C-banding. The ZW and XY sex chromosomes of all 9 analyzed species also show species-specific heterochromatin hypermethylation patterns. The analysis of 5-MeC-rich chromosome regions contributes valuable data for comparative cytogenetics of closely related species and highlights the dynamic process of differentiation operating in the repetitive DNA fraction of sex chromosomes.
KW  - heterochromatin
KW  - heteromorphic sex chromosomes
KW  - hypermethylation
KW  - immunofluorescence
KW  - 5-Methylcytosine
KW  - fish
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196710
SN  - 1424-8581
SN  - 1424-859X
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 147
IS  - 2-3
ER  - 
TY  - JOUR
A1  - Schmid, Michael
A1  - Steinlein, Claus
T1  - Chromosome Banding in Amphibia. XXXII. The Genus Xenopus (Anura, Pipidae)
JF  - Cytogenetic and Genome Research
N2  - Mitotic chromosomes of 16 species of the frog genus Xenopus were prepared from kidney and lung cell cultures. In the chromosomes of 7 species, high-resolution replication banding patterns could be induced by treating the cultures with 5-bromodeoxyuridine (BrdU) and deoxythymidine (dT) in succession, and in 6 of these species the BrdU/dT-banded chromosomes could be arranged into karyotypes. In the 3 species of the clade with 2n = 20 and 4n = 40 chromosomes (X. tropicalis, X. epitropicalis, X. new tetraploid 1), as well as in the 3 species with 4n = 36 chromosomes (X. laevis, X. borealis, X. muelleri), the BrdU/dT-banded karyotypes show a high degree of homoeology, though differences were detected between these groups. Translocations, inversions, insertions or sex-specific replication bands were not observed. Minor replication asynchronies found between chromosomes probably involve heterochromatic regions. BrdU/dT replication banding of Xenopus chromosomes provides the landmarks necessary for the exact physical mapping of genes and repetitive sequences. FISH with an X. laevis 5S rDNA probe detected multiple hybridization sites at or near the long-arm telomeric regions in most chromosomes of X. laevis and X. borealis, whereas in X. muelleri, the 5S rDNA sequences are located exclusively at the long-arm telomeres of a single chromosome pair. Staining with the AT base pair-specific fluorochrome quinacrine mustard revealed brightly fluorescing heterochromatic regions in the majority of X. borealis chromosomes which are absent in other Xenopus species.
KW  - X. laevis-type karyotype
KW  - X. tropicalis-type karyotype
KW  - BrdU/dT replication banding
KW  - chromosome staining
KW  - FISH
KW  - polyploidy
KW  - Xenopus
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196727
SN  - 1424-8581
SN  - 1424-859X
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 145
IS  - 3-4
ER  - 
TY  - JOUR
A1  - Schmid, Michael
A1  - Evans, Ben J.
A1  - Bogart, James P.
T1  - Polyploidy in Amphibia
JF  - Cytogenetic and Genome Research
N2  - This review summarizes the current status of the known extant genuine polyploid anuran and urodelan species, as well as spontaneously originated and/or experimentally produced amphibian polyploids. The mechanisms by which polyploids can originate, the meiotic pairing configurations, the diploidization processes operating in polyploid genomes, the phenomenon of hybridogenesis, and the relationship between polyploidization and sex chromosome evolution are discussed. The polyploid systems in some important amphibian taxa are described in more detail.
KW  - allopolyploidy
KW  - Anura
KW  - autopolyploidy
KW  - diploidization
KW  - hybridogenesis
KW  - polyploidization
KW  - sex chromosome evolution
KW  - Urodela
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196730
SN  - 1424-8581
SN  - 1424-859X
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 145
IS  - 3-4
ER  - 
TY  - JOUR
A1  - Matsuda, Yoichi
A1  - Uno, Yoshinobu
A1  - Kondo, Mariko
A1  - Gilchrist, Michael J.
A1  - Zorn, Aaron M.
A1  - Rokhsar, Daniel S.
A1  - Schmid, Michael
A1  - Taira, Masanori
T1  - A New Nomenclature of Xenopus laevis Chromosomes Based on the Phylogenetic Relationship to Silurana/Xenopus tropicalis
JF  - Cytogenetic and Genome Research
N2  - Xenopus laevis (XLA) is an allotetraploid species which appears to have undergone whole-genome duplication after the interspecific hybridization of 2 diploid species closely related to Silurana/Xenopus tropicalis (XTR). Previous cDNA fluorescence in situ hybridization (FISH) experiments have identified 9 sets of homoeologous chromosomes in X. laevis, in which 8 sets correspond to chromosomes 1-8 of X. tropicalis (XTR1-XTR8), and the last set corresponds to a fusion of XTR9 and XTR10. In addition, recent X. laevis genome sequencing and BAC-FISH experiments support this physiological relationship and show no gross chromosome translocation in the X. laevis karyotype. Therefore, for the benefit of both comparative cytogenetics and genome research, we here propose a new chromosome nomenclature for X. laevis based on the phylogenetic relationship and chromosome length, i.e. XLA1L, XLA1S, XLA2L, XLA2S, and so on, in which the numbering of XLA chromosomes corresponds to that in X. tropicalis and the postfixes ‘L' and ‘S' stand for ‘long' and ‘short' chromosomes in the homoeologous pairs, which can be distinguished cytologically by their relative size. The last chromosome set is named XLA9L and XLA9S, in which XLA9 corresponds to both XTR9 and XTR10, and hence, to emphasize the phylogenetic relationship to X. tropicalis, XLA9_10L and XLA9_10S are also used as synonyms.
KW  - BrdU replication banding pattern
KW  - homoeologous chromosomes
KW  - nomenclature
KW  - Xenopus laevis
KW  - Xenopus tropicalis
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196748
SN  - 1424-8581
SN  - 1424-859X
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 145
IS  - 3-4
ER  - 
TY  - JOUR
A1  - Schmid, Michael
A1  - Steinlein, Claus
A1  - Feichtinger, Wolfgang
A1  - Haaf, Thomas
A1  - Mijares-Urrutia, Abraham
A1  - Schargel, Walter E.
A1  - Hedges, S. Blair
T1  - Cytogenetic Studies on Gonatodes (Reptilia, Squamata, Sphaerodactylidae)
JF  - Cytogenetic and Genome Research
N2  - Mitotic and meiotic chromosomes of 5 species of the reptile genus Gonatodes are described by means of conventional staining, banding analyses and in situ hybridization using a synthetic telomeric DNA probe. The amount, location and fluorochrome affinities of constitutive heterochromatin, the number and positions of nucleolus organizer regions, and the patterns of telomeric DNA sequences were determined for most of the species. The karyotypes of G. falconensis and G. taniae from northern Venezuela are distinguished by their extraordinarily reduced diploid chromosome number of 2n = 16, which is the lowest value found so far in reptiles. In contrast to most other reptiles, both species have exclusively large biarmed (meta- and submetacentric) chromosomes. Comparison of the karyotypes of G. falconensis and G. taniae with those of other Gonatodes species indicates that the exceptional 2n = 16 karyotype originated by a series of 8 centric fusions. The karyotypes of G. falconensis and G. taniae are further characterized by the presence of considerable amounts of (TTAGGG)<sub>n</sub> telomeric sequences in the centromeric regions of all chromosomes. These are probably not only relics of the centric fusion events, but a component of the highly repetitive DNA in the constitutive heterochromatin of the chromosomes. The genome sizes of 4 Gonatodes species were determined using flow cytometry. For comparative purposes, all previously published cytogenetic data on Gonatodes and other sphaerodactylids are included and discussed.
KW  - banding analyses
KW  - FISH
KW  - geckos
KW  - karyotype evolution
KW  - meiotic chromosomes
KW  - mitotic chromosomes
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196753
SN  - 1424-8581
SN  - 1424-859X
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 144
IS  - 1
ER  - 
TY  - JOUR
A1  - Schmid, Michael
A1  - Steinlein, Claus
A1  - Feichtinger, Wolfgang
A1  - Bogart, James P.
T1  - Chromosome Banding in Amphibia. XXXI. The Neotropical Anuran Families Centrolenidae and Allophrynidae
JF  - Cytogenetic and Genome Research
N2  - The mitotic chromosomes of 11 species from the anuran families Centrolenidae and Allophrynidae were analyzed by means of conventional staining, banding techniques, and in situ hybridization. The amount, location, and fluorochrome affinities of constitutive heterochromatin, the number and positions of nucleolus organizer regions, and the patterns of telomeric DNA sequences were determined for most of the species. The karyotypes were found to be highly conserved with a low diploid chromosome number of 2n = 20 and morphologically similar chromosomes. The sister group relationship between the Centrolenidae and Allophrynidae (unranked taxon Allocentroleniae) is clearly corroborated by the cytogenetic data. The existence of heteromorphic XY♂/XX♀ sex chromosomes in an initial stage of morphological differentiation was confirmed in Vitreorana antisthenesi. The genome sizes of 4 centrolenid species were determined using flow cytometry. For completeness and for comparative purposes, all previously published cytogenetic data on centrolenids are included.
KW  - Allophrynidae
KW  - Anura
KW  - chromosome evolution
KW  - sex chromosomes
KW  - Centrolenidae
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196763
SN  - 1424-8581
SN  - 1424-859X
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 142
IS  - 4
ER  - 
TY  - JOUR
A1  - Focken, T.
A1  - Steinemann, D.
A1  - Skawran, B.
A1  - Hofmann, W.
A1  - Ahrens, P.
A1  - Arnold, N.
A1  - Kroll, P.
A1  - Kreipe, H.
A1  - Schlegelberger, B.
A1  - Gadzicki, D.
T1  - Human BRCA1-associated breast cancer: No increase in numerical chromosomal instability compared to sporadic tumors
JF  - Cytogenetic and Genome Research
N2  - BRCA1 is a major gatekeeper of genomic stability. Acting in multiple central processes like double-strand break repair, centrosome replication, and checkpoint control, BRCA1 participates in maintaining genomic integrity and protects the cell against genomic instability. Chromosomal instability (CIN) as part of genomic instability is an inherent characteristic of most solid tumors and is also involved in breast cancer development. In this study, we determined the extent of CIN in 32 breast cancer tumors of women with a BRCA1 germline mutation compared to 62 unselected breast cancers. We applied fluorescence in situ hybridization (FISH) with centromere-specific probes for the chromosomes 1, 7, 8, 10, 17, and X and locus-specific probes for 3q27 (BCL6), 5p15.2 (D5S23), 5q31 (EGR1), 10q23.3 (PTEN), and 14q32 (IGH@) on formalin-fixed paraffin-embedded tissue microarray sections. Our hypothesis of an increased level of CIN in BRCA1-associated breast cancer could not be confirmed by this approach. Surprisingly, we detected no significant difference in the extent of CIN in BRCA1-mutated versus sporadic tumors. The only exception was the CIN value for chromosome 1. Here, the extent of CIN was slightly higher in the group of sporadic tumors.
KW  - Hereditary breast cancer
KW  - BRCA1
KW  - Chromosomal instability
KW  - CIN
KW  - Fluorescence in situ hybridization
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196770
SN  - 1424-8581
SN  - 1424-859X
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 135
IS  - 2
SP  - 84
EP  - 92
ER  - 
TY  - JOUR
A1  - Hohmann, Cynthia
A1  - Pinart, Mariona
A1  - Tischer, Christina
A1  - Gehring, Ulrike
A1  - Heinrich, Joachim
A1  - Kull, Inger
A1  - Melén, Eric
A1  - Smit, Henriette A.
A1  - Torrent, Maties
A1  - Wijga, Alet H.
A1  - Wickman, Magnus
A1  - Bachert, Claus
A1  - Lødrup Carlsen, Karin C.
A1  - Carlsen, Kai-Håkon
A1  - Bindslev-Jensen, Carsten
A1  - Eller, Esben
A1  - Esplugues, Ana
A1  - Fantini, Maria Pia
A1  - Annesi-Maesano, Isabella
A1  - Momas, Isabelle
A1  - Porta, Daniela
A1  - Vassilaki, Maria
A1  - Waiblinger, Dagmar
A1  - Sunyer, Jordi
A1  - Antó, Josep M.
A1  - Bousquet, Jean
A1  - Keil, Thomas
T1  - The Development of the MeDALL Core Questionnaires for a Harmonized Follow-Up Assessment of Eleven European Birth Cohorts on Asthma and Allergies
JF  - International Archives of Allergy and Immunology
N2  - Background: Numerous birth cohorts have been initiated in the world over the past 30 years using heterogeneous methods to assess the incidence, course and risk factors of asthma and allergies. The aim of the present work is to provide the stepwise proceedings of the development and current version of the harmonized MeDALL-Core Questionnaire (MeDALL-CQ) used prospectively in 11 European birth cohorts. Methods: The harmonization of questions was accomplished in 4 steps: (i) collection of variables from 14 birth cohorts, (ii) consensus on questionnaire items, (iii) translation and back-translation of the harmonized English MeDALL-CQ into 8 other languages and (iv) implementation of the harmonized follow-up. Results: Three harmonized MeDALL-CQs (2 for parents of children aged 4-9 and 14-18, 1 for adolescents aged 14-18) were developed and used for a harmonized follow-up assessment of 11 European birth cohorts on asthma and allergies with over 13,000 children. Conclusions: The harmonized MeDALL follow-up produced more comparable data across different cohorts and countries in Europe and will offer the possibility to verify results of former cohort analyses. Thus, MeDALL can become the starting point to stringently plan, conduct and support future common asthma and allergy research initiatives in Europe.
KW  - harmonization
KW  - MeDALL
KW  - european birth cohorts
KW  - asthma
KW  - allergy
KW  - questionnaire assessment
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196594
SN  - 1018-2438
SN  - 1423-0097
VL  - 163
IS  - 3
ER  - 
TY  - JOUR
A1  - Prelog, Martina
T1  - Differential Approaches for Vaccination from Childhood to Old Age
JF  - Gerontology
N2  - Primary prevention strategies, such as vaccinations at the age extremes, in neonates and elderly individuals, demonstrate a challenge to health professionals and public health specialists. The aspects of the differentiation and maturation of the adaptive immune system, the functional implications of immunological immaturity or immunosenescence and its impact on vaccine immunogenicity and efficacy will be highlighted in this review. Several approaches have been undertaken to promote Th1 responses in neonates and to enhance immune functions in elderly, such as conjugation to carrier proteins, addition of adjuvants, concomitant vaccination with other vaccines, change in antigen concentrations or dose intervals or use of different administration routes. Also, early protection by maternal vaccination seems to be beneficial in neonates. However, it also appears necessary to think of other end points than antibody concentrations to assess vaccine efficacy in neonates or elderly, as also the cellular immune response may be impaired by the mechanisms of immaturity, underlying health conditions, immunosuppressive treatments or immunosenescence. Thus, lifespan vaccine programs should be implemented to all individuals on a population level not only to improve herd protection and to maintain protective antibody levels and immune memory, but also to cover all age groups, to protect unvaccinated elderly persons and to provide indirect protection for neonates and small infants.
KW  - immunosenescence
KW  - aging
KW  - T cells
KW  - B cells
KW  - immunization
KW  - vaccination
KW  - thymus
KW  - influenza
KW  - neonates
KW  - antibody
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196602
SN  - 0304-324X
SN  - 1423-0003
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 59
IS  - 3
ER  - 
TY  - JOUR
A1  - Vaiopoulos, Aristeidis G.
A1  - Kanakis, Meletios A.
A1  - Kapsimali, Violetta
A1  - Vaiopoulos, Georgios
A1  - Kaklamanis, Phedon G.
A1  - Zouboulis, Christos C.
T1  - Juvenile Adamantiades-Behçet disease
JF  - Dermatology
N2  - Adamantiades-Behçet disease (ABD) is a chronic, multisystemic, recurrent, inflammatory vascular disorder of unknown etiology. Patients with symptoms initially appearing at the age of 16 or less are considered as cases of juvenile-onset ABD (JABD). JABD is relatively rare compared to ABD of adults, and only case reports and case studies have been published regarding this subtype of the disease. Epidemiology, clinical features, diagnosis and treatment of JABD are discussed in this review.
KW  - Aphthae
KW  - Childhood
KW  - Epidemiological study
KW  - Genitoanal region
KW  - Adamantiades-Behçet disease
KW  - Behçet’s disease
KW  - Uveitis
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196616
SN  - 1018-8665
SN  - 1421-9832
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 232
IS  - 2
SP  - 129
EP  - 136
ER  - 
TY  - JOUR
A1  - Müller, P.A.
A1  - Bröcker, E.B.
A1  - Klinker, E.
A1  - Stoevesandt, J.
A1  - Benoit, S.
T1  - Adjuvant treatment of recalcitrant Bullous pemphigoid with immunoadsorption
JF  - Dermatology
N2  - Elimination of pathogenic autoantibodies by immunoadsorption (IA) has been described as an effective adjuvant treatment in severe bullous autoimmune diseases, especially in pemphigus. There is much less experience in the treatment of bullous pemphigoid (BP). BP was diagnosed in a 62-year-old Caucasian woman presenting a pruritic rash with multiple tense blisters. Standard treatments with topical and oral corticosteroids, steroid-sparing agents including dapsone, azathioprine, mycophenolate mofetil (MMF) and intravenous immunoglobulins were ineffective or had to be discontinued due to adverse events. An immediate clinical response could be achieved by two treatment cycles of adjuvant protein A immunoadsorption (PA-IA) in addition to continued treatment with MMF (2 g/day) and prednisolone (1 mg/kg/day). Tolerance was excellent. Clinical improvement remained stable after discontinuation of IA and went along with sustained reduction of circulating autoantibodies. Our data demonstrate that PA-IA might be a safe and effective adjuvant treatment in severe and recalcitrant BP.
KW  - Bullous pemphigoid
KW  - Immunoadsorption
KW  - Immunoapheresis
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196620
SN  - 1018-8665
SN  - 1421-9832
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 224
IS  - 3
SP  - 224
EP  - 227
ER  - 
TY  - JOUR
A1  - Grundmeier, Natalie
A1  - Hamm, Henning
A1  - Weissbrich, Benedikt
A1  - Lang, Sabrina Christine
A1  - Bröcker, Eva-Bettina
A1  - Kerstan, Andreas
T1  - High-risk human papillomavirus infection in Bowen’s disease of the nail unit: report of three cases and review of the literature
JF  - Dermatology
N2  - Background: Bowen’s disease (BD) of the nail unit is associated with human papillomavirus (HPV) infection. Objective: This study aimed to investigate the frequency of high-risk HPV infection, gender, age and digital distribution in this condition. 
Methods: Biopsy specimens of 3 consecutive cases with periungual BD were investigated for the presence of HPV DNA by in situ hybridization and by polymerase chain reaction (PCR). Furthermore, 74 cases of ungual BD conducted with HPV genotyping as reported in the literature were reviewed. 
Results: PCR of biopsy specimens revealed in 2 cases infection with HPV-16 and in 1 case with HPV-73. Additionally, in 1 HPV-16-positive case HPV-31/33 was detected by in situ hybridization. In line, review of the literature demonstrated a clear association of HPV-positive BD with high-risk HPV types. Interestingly, age at diagnosis was significantly lower in women. Whereas in both genders the second to fourth fingers on both hands were commonly diseased, only in men the thumbs were also prominently affected. 
Conclusions: Infection with high-risk HPV types is common in BD of the nail unit suggesting the aetiological cause. Therefore, patients and partners should be closely followed up for digital and genital HPV-associated lesions.
KW  - Nail unit
KW  - Human papillomavirus
KW  - Bowen’s disease, periungual
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196638
SN  - 1018-8665
SN  - 1421-9832
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 223
IS  - 4
SP  - 293
EP  - 300
ER  - 
TY  - JOUR
A1  - Abdullahi, Sahra
A1  - Wessel, Birgit
A1  - Huber, Martin
A1  - Wendleder, Anna
A1  - Roth, Achim
A1  - Kuenzer, Claudia
T1  - Estimating penetration-related X-band InSAR elevation bias: a study over the Greenland ice sheet
JF  - Remote Sensing
N2  - Accelerating melt on the Greenland ice sheet leads to dramatic changes at a global scale. Especially in the last decades, not only the monitoring, but also the quantification of these changes has gained considerably in importance. In this context, Interferometric Synthetic Aperture Radar (InSAR) systems complement existing data sources by their capability to acquire 3D information at high spatial resolution over large areas independent of weather conditions and illumination. However, penetration of the SAR signals into the snow and ice surface leads to a bias in measured height, which has to be corrected to obtain accurate elevation data. Therefore, this study purposes an easy transferable pixel-based approach for X-band penetration-related elevation bias estimation based on single-pass interferometric coherence and backscatter intensity which was performed at two test sites on the Northern Greenland ice sheet. In particular, the penetration bias was estimated using a multiple linear regression model based on TanDEM-X InSAR data and IceBridge laser-altimeter measurements to correct TanDEM-X Digital Elevation Model (DEM) scenes. Validation efforts yielded good agreement between observations and estimations with a coefficient of determination of R\(^2\) = 68% and an RMSE of 0.68 m. Furthermore, the study demonstrates the benefits of X-band penetration bias estimation within the application context of ice sheet elevation change detection.
KW  - InSAR height
KW  - penetration bias
KW  - cryosphere
KW  - TanDEM-X
KW  - Greenland ice sheet
KW  - DEM
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193902
SN  - 2072-4292
VL  - 11
IS  - 24
ER  - 
TY  - JOUR
A1  - Weber, Christoph
A1  - Gräf, Stephan
T1  - Eine halb so schlimme Täuschung
JF  - JURA - Juristische Ausbildung
N2  - Kein Abstract verfügbar.
KW  - Examensklausur
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-195484
SN  - 1612-7021
SN  - 0170-1452
N1  - Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
VL  - 36
IS  - 1
ER  - 
TY  - JOUR
A1  - Kiesler, Reinhard
T1  - Anja Overbeck / Wolfgang Schweickard / Harald Völker (edd.), Lexikon, Varietät, Philologie: Romanistische Studien. Günter Holtus zum 65. Geburtstag, Berlin, De Gruyter, 2011, XLIV + 824 p.
JF  - Zeitschrift für romanische Philologie
N2  - Kein Abstract verfügbar.
KW  - Rezension
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-195505
SN  - 1865-9063
SN  - 0049-8661
N1  - Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
VL  - 130
IS  - 4
SP  - 1165
EP  - 1170
ER  - 
TY  - JOUR
A1  - Reber, Elisabeth
T1  - Constructing evidence at Prime Minister's Question Time: An analysis of the grammar, semantics and pragmatics of the verb see
JF  - Intercultural Pragmatics
N2  - Abstract
Constructing evidence constitutes a practice to establish the speaker's authority at Prime Minister's Question Time (PMQT), a weekly half-hour session in the British House of Commons. Here the verb see constitutes a resource for both the questioning Leader of the Opposition (LO) and Members of Parliament (MP) as well as for the responding Prime Minister (PM) to claim first-hand perceptual experience. This paper takes an integrated approach, offering a combined analysis of the grammatical formatting, semantics and pragmatics of the verb see in the context of evidential moves at PMQT. It shows how the verb see is functional in referring to the perceptual basis of a claim made and how its grammatical formatting is reflective of the contingencies of the local interactional context. The analysis is grounded in 32 sessions of PMQT (ca. 16 hrs of video-recordings). The results can be summarised as follows: 1) The evidential function of the verb is achieved through its context-specific grammatical formatting and semantics. 2) The reference to the perceptual basis of a claim evoked by see may co-occur with epistemic qualification and evaluative expressions. 3) The formatting of the verb may be indexical of the political relationship between the questioner and the responding PM.
KW  - parliamentary interaction
KW  - perception
KW  - evidentiality
KW  - epistemic modality
KW  - see
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-195549
SN  - 1613-365X
SN  - 1612-295X
N1  - Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
VL  - 11
IS  - 3
SP  - 357
EP  - 387
ER  - 
TY  - JOUR
A1  - Karremann, Isabel
T1  - April London.The Cambridge Introduction to the Eighteenth-Century Novel. Cambridge Introductions to Literature. Cambridge: Cambridge University Press, 2012, 260 pp., $ 26.99 pb.
JF  - Anglia
N2  - No abstract available.
KW  - novel
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-195307
SN  - 1865-8938
SN  - 0340-5222
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 132
IS  - 3
ER  - 
TY  - JOUR
A1  - Gwosdek, Hedwig
T1  - Nicholas Orme. English School Exercises, 1420–1530. Studies and Texts 181. Toronto: Pontifical Institute of Mediaeval Studies, 2013, xi + 441 pp., $ 95.00.
JF  - Anglia
N2  - No abstract available.
KW  - exercise
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-195318
SN  - 1865-8938
SN  - 0340-5222
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 132
IS  - 3
ER  - 
TY  - THES
A1  - John, Vini
T1  - Interaction of mycobacteria with myeloid-derived suppressor cells
T1  - Wechselwirkung von Mykobakterien mit myeloiden Suppressorzellen
N2  - Myeloid-derived suppressor cells (MDSCs) constitute of monocytic (M-MDSCs) and granulocytic cell subsets (G-MDSCs)and were initially described as suppressors of T-cell function in tumor microenvironments. Recent studies have shown the involvement of MDSCs in a number of infectious diseases including Mycobacterium tuberculosis (Mtb) infection. MDSCs are tremendously accumulated in patients with Mtb infection and exert a suppressive effect on T cell responses against mycobacteria. Mycobacterium bovis BCG, the only available vaccine against Mtb fails to protect against the adult pulmonary tuberculosis (TB). Understanding the mechanisms of MDSC suppression for immunity against mycobacterial infection will provide a rational basis to improve anti- TB vaccination and host-directed therapies against TB. In this study, we investigated the role of three lipid-rich components of the plasma membrane, Caveolin-1(Cav-1), Acid Sphingomyelinase (ASM) and asialo-GM1 on BCG-activated MDSCs.
Cav-1 is one of the vital components of caveolae (plasma membrane invaginations) which regulates apoptosis and lipid metabolism. In this work, we found that MDSCs upregulated Cav-1, TLR4 and TLR2 expression after BCG infection on the cell surface. However, Cav-1 deficiency resulted in a selective defect in the intracellular TLR2 accumulation in the M-MDSC, but not G-MDSC subset. Further analysis indicated no difference in the phagocytosis of BCG by M-MDSCs from WT and Cav1-/- mice but a reduced capacity to up-regulate surface markers, to secrete various cytokines, induce iNOS and NO production. These defects correlated with deficits of Cav1-/- MDSCs in the suppression of T cell proliferation. Among the signaling pathways that were affected by Cav-1 deficiency, we found lower phosphorylation of NF-kB and p38 mitogen-activated protein kinase (MAPK) in BCG - activated MDSCs.
ASM is an enzyme present in lysosomes and is translocated to the cell surface where it hydrolyzes sphingomyelin into ceramide. Flow cytometric studies revealed that MDSCs phagocytosed BCG independent of inhibiting ASMase using pharmacological inhibitors (amitryptiline or desipramine) or MDSCs from WT and ASM-/-. Suppression of ASMase or using ASM-/- MDSCs resulted in reduced NO production and decreased cytokine secretion by MDSCs in response to BCG. Furthermore, MDSCs inhibited by amitryptiline had impaired AKT phosphorylation upon BCG infection.
Asialo-GM1 is a ganglioside expressed on the cell surface of MDSCs reported to cooperate with TLR2 for activating ERK signaling. Here, in this study, we found that asialo-GM1 expression was upregulated specifically upon mycobacterial infection and not upon any other stimulus. We noted that the soluble form of asialo-GM1 bound to BCG. Flow cytometric studies revealed that blocking
81
asialo-GM1 did not affect the phagocytosis of BCG into MDSCs. Furthermore, blocking of asialo- GM1 had no effect on the cytokine and NO secretion or AKT signaling.
Collectively, the data presented in this work implicated that Cav-1, ASM, asialo-GM1 are dispensable for the internalization of BCG. Rather, Cav-1 and ASM are required for the functional activation of MDSCs. Although asialo-GM1 binds to BCG, we did not find any difference in the functional activation of MDSCs after blocking asialo-GM1. This study provides insights into the role of lipid raft components of the MDSC cell membrane during mycobacterial infection.
N2  - Myeloide Suppressorzellen (engl, myeloid-derived suppressor cells MDSCs) bestehen aus monozytischen (M-MDSCs) und granulozytären Subtypen (G-MDSCs)  und wurden anfangs als Suppressoren der T-Zellfunktion in Tumormikroumgebungen beschrieben. Kürzlich durchgeführte Studien haben gezeigt, dass MDSCs an einer Reihe von Infektionskrankheiten beteiligt sind, einschließlich einer Infektion mit Mycobacterium tuberculosis (Mtb). MDSCs sind bei der Patienten Mtb-Infektion enorm akkumuliert und üben eine supprimierende Wirkung auf die T-Zell-Antworten gegen Mykobakterien aus. Mycobacterium bovis BCG, der einzige verfügbare Impfstoff gegen Mtb, schützt nicht gegen die Lungentuberkulose bei Erwachsenen (TB). Das Verständnis der Mechanismen über welche MDSCs eine der Immunsuppression bei mykobakteriellen Infektionen vermitteln, bilden eine rationale Grundlage für die Verbesserung der Anti-TB-Impfung und Therapien gegen TB. In dieser Studie wurden die Rolle der drei lipidreichen Komponenten der Plasmamembran, Caveolin-1 (Cav-1), Saure Sphingomyelinase (ASM) und Asialo-GM1 bei BCGaktivierten MDSCs untersucht. 
 
       Cav-1 ist eine der Komponenten von Caveolae (Plasmamembran-Invagination), die die Apoptose und den Fettstoffwechsel regulieren. Diese Arbeit zeigte, dass MDSCs die Expression von Cav-1, TLR4 und TLR2 nach BCG-Infektion auf der Zelloberfläche hochregulierten. Eine Cav-1 Defizienz führte jedoch zu einem selektiven Defekt in der intrazellulären TLR2-Akkumulation bei MMDSCs, jedoch nicht bei G-MDSCs. Weitere Analysen zeigten keinen Unterschied in der Phagozytose von BCG durch M-MDSCs von WT- und Cav1-/- Mäusen, jedoch eine verringerte Fähigkeit, Oberflächenmarker hoch zu regulieren, verschiedene Zytokine zu sekretieren und die Produktion von iNOS und NO zu induzieren. Diese Defekte korrelierten mit Defiziten von Cav1-/- MDSCs bei der Unterdrückung der T-Zell-Proliferation. Unter den von Cav-1-Mangel betroffenen Signalwegen fanden wir eine geringere Phosphorylierung der NF-KB- und p38- Mitogen-aktivierten Proteinkinase (MAPK) in BCG-aktivierten MDSCs. 
 
      ASM ist ein in Lysosomen vorhandenes Enzym, das an die Zelloberfläche transloziert wird, wo es Sphingomyelin zu Ceramid hydrolysiert. Durchflusszytometrische Studien ergaben, dass MDSCs BCG unabhängig von der Hemmung von ASMase mit pharmakologischen Inhibitoren (Amitryptilin oder Desipramin) oder MDSCs von ASM-/- Mäusen BCG phagozytierten. Die Suppression von ASMase oder die Verwendung von ASM-/- MDSCs führte zu einer verringerten NO Produktion und einer verringerten Zytokinsekretion durch MDSCs als Antwort auf BCG. Darüber hinaus hatten MDSCs, die durch Amitryptilin inhibiert wurden, die AKT-Phosphorylierung bei einer BCG-Infektion beeinträchtigt. 
  
      Asialo-GM1 ist ein Gangliosid, das auf der Zelloberfläche von MDSCs exprimiert wird, von dem berichtet wurde, dass es mit TLR2 kooperiert, um ERK-Signale zu aktivieren. Hier in dieser Studie haben wir festgestellt, dass die Expression von Asialo-GM1 spezifisch bei mycobakterieller Infektion und nicht bei einem anderen Stimulus hochreguliert wurde. Wir haben festgestellt, dass die lösliche Form von Asialo-GM1 an BCG binden kann. Durchflusszytometrische Studien ergaben, dass die Blockade von Asialo-GM1 die Phagozytose von BCG in MDSCs nicht beeinflusst. Darüber hinaus hatte die Blockierung von Asialo-GM1 keinen Einfluss auf die Zytokin- und NO-Sekretion oder das AKT-Signal. 
 
      Zusammenfassend ergaben die in dieser Arbeit präsentierten Daten, dass Cav-1, ASM, asialoGM1 für die Internalisierung von BCG entbehrlich sind. Dagegen sind Cav-1 und ASM für die funktionale Aktivierung von MDSCs erforderlich. Obwohl Asialo-GM1 an BCG bindet, konnten wir nach der Blockierung von Asialo-GM1 keinen Unterschied in der funktionellen Aktivierung von MDSCs feststellen. Diese Studie liefert Einblicke in die Rolle einiger Komponenten der lipid-reicher Areale der MDSC-Zellmembran bei mykobakteriellen Infektionen.
KW  - MDSCs
KW  - BCG
KW  - Caveolin-1
KW  - ASM
KW  - asialoGM1
KW  - BCG
KW  - nitric oxide
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-183501
ER  - 
TY  - INPR
A1  - Dandekar, Thomas
T1  - Biological heuristics applied to cosmology suggests a condensation nucleus as start of our universe and inflation cosmology replaced by a period of rapid Weiss domain-like crystal growth
N2  - Cosmology often uses intricate formulas and mathematics to derive new theories and concepts. We do something different in this paper: We look at biological processes and derive from these heuristics so that the revised cosmology agrees with astronomical observations but does also agree with standard biological observations. We show that we then have to replace any type of singularity at the start of the universe by a condensation nucleus and that the very early period of the universe usually assumed to be inflation has to be replaced by a period of rapid crystal growth as in Weiss magnetization domains.
Impressively, these minor modifications agree well with astronomical observations including removing the strong inflation perturbations which were never observed in the recent BICEP2 experiments. Furthermore, looking at biological principles suggests that such a new theory with a condensation nucleus at start and a first rapid phase of magnetization-like growth of the ordered, physical laws obeying lattice we live in is in fact the only convincing theory of the early phases of our universe that also is compatible with current observations.
We show in detail in the following that such a process of crystal creation, breaking of new crystal seeds and ultimate evaporation of the present crystal readily leads over several generations to an evolution and selection of better, more stable and more self-organizing crystals. Moreover, this explains the “fine-tuning” question why our universe is fine-tuned to favor life: Our Universe is so self-organizing to have enough offspring and the detailed physics involved is at the same time highly favorable for all self-organizing processes including life.
This biological theory contrasts with current standard inflation cosmologies. The latter do not perform well in explaining any phenomena of sophisticated structure creation or self-organization. As proteins can only thermodynamically fold by increasing the entropy in the solution around them we suggest for cosmology a condensation nucleus for a universe can form only in a “chaotic ocean” of string-soup or quantum foam if the entropy outside of the nucleus rapidly increases. We derive an interaction potential for 1 to n-dimensional strings or quantum-foams and show that they allow only 1D, 2D, 4D or octonion interactions. The latter is the richest structure and agrees to the E8 symmetry fundamental to particle physics and also compatible with the ten dimensional string theory E8 which is part of the M-theory. Interestingly, any other interactions of other dimensionality can be ruled out using Hurwitz compositional theorem. Crystallization explains also extremely well why we have only one macroscopic reality and where the worldlines of alternative trajectories exist: They are in other planes of the crystal and for energy reasons they crystallize mostly at the same time, yielding a beautiful and stable crystal. This explains decoherence and allows to determine the size of Planck´s quantum h (very small as separation of crystal layers by energy is extremely strong).
Ultimate dissolution of real crystals suggests an explanation for dark energy agreeing with estimates for the “big rip”. The halo distribution of dark matter favoring galaxy formation is readily explained by a crystal seed starting with unit cells made of normal and dark matter.
That we have only matter and not antimatter can be explained as there may be right handed mattercrystals and left-handed antimatter crystals. Similarly, real crystals are never perfect and we argue that exactly such irregularities allow formation of galaxies, clusters and superclusters. Finally, heuristics from genetics suggest to look for a systems perspective to derive correct vacuum and Higgs Boson energies.
KW  - heuristics
KW  - inflation
KW  - cosmology
KW  - crystallization
KW  - crystal growth
KW  - E8 symmetry
KW  - Hurwitz theorem
KW  - evolution
KW  - Lee Smolin
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-183945
ER  - 
TY  - THES
A1  - Irmisch, Linda
T1  - The role of septins and other regulatory proteins in abscission and midbody fate in C. elegans embryos
T1  - Die Rolle von Septinen und anderen regulatorischen Proteinen in Abszission und Schicksal des Midbodys in C. elegans Embryonen
N2  - Abscission marks the last step of cytokinesis and gives rise to two physically separated daughter cells and a midbody remnant. This work studies abscission by examining the extent of the abscission failure in C. elegans septin and ESCRT mutants with the help of the ZF1-degradation technique. The ZF1 technique is also applied to discern a possible role for PI3K during abscission. Lastly, we test the role of proteins required for macroautophagy but not for LC3-associated phagocytosis (LAP) and show that after release into the extracellular space, the midbody is resolved via LAP.
N2  - Durch Abszission, den letzten Schritt der Zytokinese, entstehen zwei physisch voneinander getrennte Tochterzellen und ein Mittelkörper, auch Flemming-Körper oder Midbody genannt. In dieser Arbeit wird mittels ZF1-vermittelter Abbautechnik in C. elegans Septin- und ESCRT-Mutanten das Ausmaß eines Abszissionsdefekts untersucht. Die ZF1-Technik wird ebenso eingesetzt, um eine mögliche Rolle von PI3K in Abszission festzustellen. Schließlich wird die Rolle von Proteinen erforderlich für Makroautophagie aber nicht für LC3-assoziierte Phagozytose (LAP) getestet und gezeigt, dass der Midbody nach Freilassung in den extrazellulären Raum mittels LAP verarbeitet wird.
KW  - Zellteilung
KW  - Caenorhabditis elegans
KW  - Abszision
KW  - Septine
KW  - Phagozytose
KW  - midbody remnant
KW  - LC3-associated phagocytosis
KW  - ZF1 degradation assay
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-183244
ER  - 
TY  - THES
A1  - Martens, Johannes
T1  - Development of an In-Silico Model of the Arterial Epicardial Vasculature
T1  - Entwicklung eines in-silico Modells der arteriellen epikardialen Vaskulatur
N2  - In dynamic CE MR perfusion imaging the passage of an intravenously injected CA bolus through tissue is monitored to assess the myocardial pefusion state.
To enable this, knowledge of the shape of CA wash-in through upstream epicardial vessels is required, the so-called AIF.
For technical reasons this cannot be quantified directly in the supplying vessels and is thus measured in the left ventricle, which introduces the risk of systematic errors in quantification of MBF due to bolus dispersion in coronary vessels. 
This means occuring CA dispersion must be accounted in the quantification process in order to produce reliable and reproducible results.
In order to do this, CFD simulations are performed to analyze and approximate these errors and deepen insights and knowledge gained from previous CFD analyses on both idealized as well as realistic and pathologically altered 3D geometries.

In a first step, several different procedures and approaches are undertaken in order to accelerate the performed workflow, however, maintaining a sufficient degree of numerical accuracy.
In the end, the implementation of these steps makes the analysis of the cardiovascular 3D model of unprecedented detail including vessels at pre-arteriolar level feasible at all.
The findings of the Navier-Stokes simulations are thus validated with regard to different aspects of cardiac blood flow.
These include the distribution of VBF into the different myocardial regions, the areals, which can be associated to the large coronary arteries as well as the fragmentation of VBF into vessels of different diameters.

The subsequently performed CA transport simulations yield results on the one hand confirming previous studies.
On the other hand, interesting additional knowledge about the behavior of CA dispersion in coronary arteries is obtained both regarding travelled distance as well as vessel diameters.
The relative dispersion of the so-called vascular transport function, a characterizing feature of vascular networks, shows a linear decrease with vessel diameter.
This results in asymptotically decreased additional dispersion of the CA time curve towards smaller and more distal vessels.
Nonetheless, perfusion quantification errors are subject to strong regional variability and reach an average value of $(-28\pm16)$ \% at rest across the whole myocardium.
Depending on the distance from the inlet and the considered coronary tree, MBF errors up to 62 \% are observed.
N2  - Bei der Messung der myokardialen Perfusion mittels Kontrastmittel (KM)-gestützter Magnet Resonanz Tomographie (MRT) wird die zeitliche Entwicklung der Anströmung eines intravenös injizierten Kontrastmittel-Bolus im Herzmuskelgewebe gemessen und hinsichtlich des Myokardialen Blutflusses (MBF) ausgewertet.
Zusätzlich zum Signal des KM im Gewebe ist für eine Quantifizierung des MBF außerdem aber die sogenannte arterielle Eingangsfunktion (AEF) notwendig.
Diese Funktion beschreibt, wie das KM durch das versorgende koronare Blutgefäß ins Gewebe einströmt.
Aus technischen Gründen ist die AEF nicht direkt messbar, weshalb sie in der Regel im großen Blutvolumen des linken Ventrikels bestimmt wird.
Da der KM-Bolus auf dem Weg vom linken Ventrikel aufgrund der Strömungsverhältnisse in den Herzkranzgefäßen einer zeitlichen und räumlichen Veränderung, sogenannter Dispersion unterliegt, birgt die Verwendent der AEF aus dem linken Ventrikel das Risiko systematischer Fehler bei der MBF-Quantifizierung mit dieser Methode.
Für eine reproduzierbare und verlässliche Perfusionsmessung mittels KM-gestützter MRT ist daher die Berücksichtigung der Bolus-Dispersion zwingend erforderlich.
Um diese Effekte zu untersuchen und eine Fehlerabschätzung zu ermöglichen, werden in dieser Arbeit fluid-mechanische Berechnungen (Computational Fluid Dynamics, CFD) des Blutflusses und KM-Transports in 3D Geometrien von Herzkranzgefäßen durchgeführt.

CFD Simulationen auf realistischen Gefäßgeometrien, wie sie hier präsentiert werden, gehen mit speziellen Anforderungen einher.
Dies betrifft sowohl die technische Durchführbarkeit als auch die Wahl der Randbedingungen um physiologisch korrekte Ergebnisse zu erhalten.
In dieser Arbeit werden daher verschiedene Ansätze angewendet und validiert, um die zeitlich effiziente aber dennoch numerisch akkurate Berechnung des Blutflusses und KM-Transports in hochdetaillierten 3D Geometrien der kardialen Vaskulatur unter Verwendung realistischer Randbedingungen überhaupt erst zu ermöglichen.
Anschließend werden die Ergebnisse der Blutfluss-Simulationen hinsichtlich verschiedener Aspekte validiert.
Dies beinhaltet sowohl die Verteilung des gesamten Blutvolumens in die verschiedenen Regionen des Myokards, die Zuordnung dieser Regionen zu den großen epikardialen Gefäßen (die rechte und die Hauptadern der linken Koronarie) sowie das Verhältnis des Volumen-Blut-Flusses zur Größe des betrachteten Gefäßes.

Anschließend werden die Ergebnisse der Blutfluss-Simulationen verwendet, um die CFD-Analyse des KM-Transports in den kleinen koronaren Gefäßen durchzuführen.
Diese Analysen bestätigen zum Einen die Erkenntnisse aus vorherigen Arbeiten, liefern jedoch wichtige neue Erkenntnisse über auftretende KM-Dispersion in Abhängigkeit sowohl des Gefäßdurch\-messers als auch des zurückgelegten Wegs des KM.
Hierfür wird die sogenannte vaskuläre Transportfunktion (VTF) verwendet.
Sie beschreibt die Veränderung der AEF auf dem Weg vom linken Ventrikel durch die Herzkranzgefäße aufgrund der Gefäßbeschaffenheit.
Die relative Dispersion (RD) der VTF kann als charakteristische Größe eines vaskulären Netzwerks betrachtet werden und die Ergebnisse dieser Arbeit zeigen eine lineare Abnahme der RD mit dem Gefäßdurchmesser.
Dies hat zur Folge, dass die zeitliche Verbreiterung der AEF selbst eine asmptotische Sättigung in kleineren distalen Gefäßen aufweist.
Nichtsdestotrotz zeigen die Untersuchungen dieser Arbeit, dass die Fehler der Perfusionsquantifizierung mit Bolus-basierten MRT-Messungen starker regionaler Variabilität unterliegen.
Im Ruhezustand beträgt dieser Fehler $(-28\pm16)$ \% im Durchschnitt über den gesamten Herzmuskel.
In Abhängigkeit vom Abstand zum Inlet des Gefäßmodells und des betrachteten Koronarbaums wird eine maximale Unterschätzung von bis zu 62 \% beobachtet.
KW  - Computerunterstütztes Verfahren
KW  - Magnetische Resonanz
KW  - Kardiologie
KW  - Computational Fluid Dynamics
KW  - Contrast Agent Bolus Based Perfusion Magnetic Resonance Imaging
KW  - Numerische Fluidmechanik
KW  - Kontrastmittel-gestützte MRT-Perfusionsmessung
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-182478
ER  - 
TY  - JOUR
A1  - Verma, Pramod Kumar
A1  - Steinbacher, Andreas
A1  - Schmiedel, Alexander
A1  - Nuernberger, Patrick
A1  - Brixner, Tobias
T1  - Excited-state intramolecular proton transfer of 2-acetylindan-1,3-dione studied by ultrafast absorption and fluorescence spectroscopy
JF  - Structural Dynamics
N2  - We employ transient absorption from the deep-UV to the visible region and fluorescence upconversion to investigate the photoinduced excited-state intramolecular proton-transfer dynamics in a biologically relevant drug molecule, 2-acetylindan-1,3-dione. The molecule is a ß-diketone which in the electronic ground state exists as exocyclic enol with an intramolecular H-bond. Upon electronic excitation at 300 nm, the first excited state of the exocyclic enol is initially populated, followed by ultrafast proton transfer (≈160 fs) to form the vibrationally hot endocyclic enol. Subsequently, solvent-induced vibrational relaxation takes place (≈10 ps) followed by decay (≈390 ps) to the corresponding ground state.
KW  - time resolved spectroscopy
KW  - ground states
KW  - fluorescence spectra
KW  - absorption spectra
KW  - ultraviolet light
KW  - hydrogen bonding
KW  - excited states
KW  - reaction mechanisms
KW  - fluorescence
KW  - solvents
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181301
VL  - 3
ER  - 
TY  - THES
A1  - Halbig, Benedikt
T1  - Surface Raman Spectroscopy on Ordered Metal Adsorbates on Semiconductor Substrates and Thin Intermetallic Films
T1  - Oberflächen-Raman-Spektroskopie an geordneten Metalladsorbaten auf Halbleitersubstraten und dünnen intermetallischen Filmen
N2  - Surface systems attract great scientific attention due to novel and exotic properties. The atomically structured surfaces lead to a reduced dimensionality which alters electronic correlations, vibrational properties, and their impact on each other. The emerging physical phenomena are not observed for related bulk materials. In this thesis, ordered (sub)monolayers of metal atoms (Au and Sn) on semiconductor substrates (Si(111) and Ge(111)) and ultrathin intermetallic films (CePt5 and LaPt5) on metal substrate (Pt(111)) are investigated by polarized in situ surface Raman spectroscopy. The surface Raman spectra exhibit features of specific elementary excitations like surface phonons and electronic excitations, which are suitable to gain fundamental insights into the surface systems.
The Au-induced surface reconstructions (5x2) and (r3xr3) constitute quasi-one- and two-dimensional Au structures on the Si(111) substrate, respectively. The new reconstruction-related Raman peaks are analyzed with respect to their polarization and temperature behavior. The Raman results are combined with firstprinciples calculations to decide between different proposed structural models. The Au-(5x2)/Si(111) reconstruction is best described by the model of Kwon and Kang, while for Au-(r3xr3)/Si(111) the conjugate honeycomb-chained-trimer model is favored. The Sn-induced reconstructions with 1/3 monolayer on Ge(111) and Si(111) are investigated to reveal their extraordinary temperature behavior. Specific surface phonon modes are identified that are predicted within the dynamical fluctuation model. Contrary to Sn/Si(111), the corresponding vibrational mode of Sn/Ge(111) exhibits a nearly harmonic character. The reversible structural phase transition of Sn/Ge(111) from (r3xr3) to (3x3) is observed, while no phase transition is apparent for Sn/Si(111). Moreover, Raman spectra of the closely related systems Sn-(2r3x2r3)/Si(111) and thin films of a-Sn as well as the clean semiconductor surfaces Si(111)-(7x7) and Ge(111)-c(2x8) are evaluated and compared.
The CePt5/Pt(111) system hosts 4f electrons whose energy levels are modified by the crystal field and are relevant for a description of the observed Kondo physics. In contrast, isostructural LaPt5/Pt(111) has no 4f electrons. For CePt5/Pt(111), distinct Raman features due to electronic Raman scattering can be unambiguously related to transitions between the crystal-field states which are depth-dependent. This assignment is supported by comparison to LaPt5/Pt(111) and group theoretical considerations. Furthermore, the vibrational properties of CePt5 and LaPt5 reveal interesting similarities but also striking differences like an unusual temperature shift of a vibration mode of CePt5, which is related to the influence of 4f electrons.
N2  - Oberflächensysteme sind durch ihre neuartigen Eigenschaften von großem wissenschaftlichen Interesse. Die reduzierten Dimensionen atomar-strukturierter Oberflächen ändern elektronische Korrelationen, vibronische Eigenschaften und deren gegenseitige Beeinflussung. Entsprechende physikalische Phänomene sind für Volumensysteme unbekannt. In dieser Arbeit werden geordnete Monolagen von Metallatomen (Au und Sn) auf Halbleitersubstraten (Si(111) und Ge(111)) und dünne intermetallische Filme (CePt5 und LaPt5) auf metallischem Substrat (Pt(111)) durch polarisierte in situ Oberflächen-Raman-Spektroskopie untersucht. Die OberflächenRaman-Spektren zeigen spezielle elementare Anregungen, wie Oberflächenphononen und elektronische Anregungen, die fundamentale Einsichten gewähren.
Die Au-induzierten Oberflächenrekonstruktionen (5x2) und (w3xw3) bilden jeweils quasi-ein- und zwei-dimensionale Au-Strukturen auf Si(111). Die entstehenden rekonstruktionsbedingten Raman-Peaks werden hinsichtlich ihres Polarisations- und Temperaturverhaltens untersucht. Die Kombination der Raman-Ergebnisse mit firstprinciples-Berechnungen ermöglicht die Unterscheidung zwischen vorgeschlagenen Strukturmodellen. Au-(5x2)/Si(111) wird am besten durch das Modell von Kwon und Kang beschrieben, während für Au-(w3xw3)/Si(111) das conjugate honeycombchained-trimer-Modell bevorzugt wird. Die Sn-induzierten Rekonstruktionen mit 1/3 Monolage auf Ge(111) und Si(111) werden aufgrund ihres außergewöhnlichen Temperaturverhaltens untersucht. Die durch das dynamical fluctuation-Modell vorhergesagten spezifischen Oberflächenphononen werden identifiziert, wobei die entsprechende Vibrationsmode von Sn/Ge(111), im Gegensatz zu Sn/Si(111), nahezu harmonischen Charakter zeigt. Der umkehrbare strukturelle Phasenübergang von (w3xw3) zu (3x3) wird für Sn/Ge(111), jedoch nicht für Sn/Si(111), beobachtet. Außerdem werden Sn-(2w3x2w3)/Si(111) und dünne a-Sn-Filme sowie Si(111)-(7x7) und Ge(111)-c(2x8) untersucht und verglichen.
CePt5/Pt(111) enthält 4f-Elektronen, deren Energieniveaus sich durch das Kristallfeld ändern und die zur Beschreibung der Kondo-Physik nötig sind. Strukturgleiches LaPt5/Pt(111) hat hingegen keine 4f-Elektronen. Für CePt5/Pt(111) werden spezifische Raman-Signaturen durch elektronische Raman-Streuung eindeutig identifiziert und Übergängen zwischen tiefenabhängigen Kristallfeldzuständen zugeordnet. Der Vergleich mit LaPt5/Pt(111) und Gruppentheorie stützt die Zuordnung. Die vibronischen Eigenschaften von CePt5 and LaPt5 zeigen neben Gemeinsamkeiten auch Unterschiede wie anormale Temperaturverschiebungen einer CePt5-Vibrationsmode, die auf Wechselwirkungen mit 4f-Elektronen zurückgehen.
KW  - Raman-Spektroskopie
KW  - Oberflächenphysik
KW  - Oberflächenphonon
KW  - Kristallfeld
KW  - Surface Raman spectroscopy
KW  - Ordered metal adsorbates on semiconductor surfaces
KW  - Thin intermetallic films
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181385
ER  - 
TY  - THES
A1  - Mayer, Alexander E.
T1  - Protein kinase D3 signaling in the regulation of liver metabolism
T1  - Proteinkinase D3 Signalwirkung in der Regulation des Leberstoffwechsels
N2  - The liver plays a pivotal role in maintaining energy homeostasis. Hepatic carbohydrate and lipid metabolism are tightly regulated in order to adapt quickly to changes in nutrient availability. Postprandially, the liver lowers the blood glucose levels and stores nutrients in form of glycogen and triglycerides (TG). In contrast, upon fasting, the liver provides glucose, TG, and ketone bodies. However, obesity resulting from a discrepancy in food intake and energy expenditure leads to abnormal fat accumulation in the liver, which is associated with the development of hepatic insulin resistance, non-alcoholic fatty liver disease, and diabetes. In this context, hepatic insulin resistance is directly linked to the accumulation of diacylglycerol (DAG) in the liver. Besides being an intermediate product of TG synthesis, DAG serves as second messenger in response to G-protein coupled receptor signaling. Protein kinase D (PKD) family members are DAG effectors that integrate multiple metabolic inputs. However, the impact of PKD signaling on liver physiology has not been studied so far. In this thesis, PKD3 was identified as the predominantly expressed isoform in liver. Stimulation of primary hepatocytes with DAG as well as high-fat diet (HFD) feeding of mice led to an activation of PKD3, indicating its relevance during obesity. HFD-fed mice lacking PKD3 specifically in hepatocytes displayed significantly improved glucose tolerance and insulin sensitivity. However, at the same time, hepatic deletion of PKD3 in mice resulted in elevated liver weight as a consequence of increased hepatic lipid accumulation. Lack of PKD3 in hepatocytes promoted sterol regulatory element-binding protein (SREBP)-mediated de novo lipogenesis in vitro and in vivo, and thus increased hepatic triglyceride and cholesterol content. Furthermore, PKD3 suppressed the activation of SREBP by impairing the activity of the insulin effectors protein kinase B (AKT) and mechanistic target of rapamycin complexes (mTORC) 1 and 2. In contrast, liver-specific overexpression of constitutive active PKD3 promoted glucose intolerance and insulin resistance. Taken together, lack of PKD3 improves hepatic insulin sensitivity but promotes hepatic lipid accumulation. For this reason, manipulating PKD3 signaling might be a valid strategy to improve hepatic lipid content or insulin sensitivity. However, the exact molecular mechanism by which PKD3 regulates hepatocytes metabolism remains unclear. 
Unbiased proteomic approaches were performed in order to identify PKD3 phosphorylation targets. In this process, numerous potential targets of PKD3 were detected, which are implicated in different aspects of cellular metabolism. Among other hits, phenylalanine hydroxylase (PAH) was identified as a target of PKD3 in hepatocytes. PAH is the enzyme that is responsible for the conversion of phenylalanine to tyrosine. In fact, manipulation of PKD3 activity using genetic tools confirmed that PKD3 promotes PAH-dependent conversion of phenylalanine to tyrosine. Therefore, the data in this thesis suggests that PKD3 coordinates lipid and amino acid metabolism in the liver and contributes to the development of hepatic dysfunction.
N2  - Die Leber spielt eine zentrale Rolle bei der Aufrechterhaltung der Energiehomöostase. Der hepatische Kohlenhydrat- und Fettstoffwechsel ist stark reguliert, um sich schnell an Veränderungen in der Nährstoffverfügbarkeit anzupassen. Die Leber senkt postprandial den Blutzuckerspiegel und speichert Nährstoffe in Form von Glykogen und Triglyzeriden (TG). Im Gegensatz dazu stellt die Leber beim Fasten Glukose, TG und Ketonkörper bereit. Fettleibigkeit, welche aus einer Diskrepanz zwischen Nahrungsaufnahme und Energieaufwand resultiert, führt allerdings zu einer abnormalen Fettansammlung in der Leber, die mit der Entwicklung von Leberinsulinresistenz, nicht-alkoholischen Fettlebererkrankungen und Diabetes einhergeht. Hepatische Insulinresistenz steht dabei in direktem Zusammenhang mit der Akkumulation von Diacylglycerol (DAG) in der Leber. DAG ist nicht nur ein Zwischenprodukt der TG-Synthese, sondern dient auch als sekundärer Messenger im G-Protein-gekoppelten Rezeptor-Signalweg. Die Mitglieder der Proteinkinase D (PKD)-Familie sind DAG-Effektoren, die vielfache metabolische Inputs integrieren. Jedoch wurden die Auswirkungen der PKD-Signalwirkung auf die Leberphysiologie bisher nicht untersucht. Im Rahmen dieser Thesis wurde PKD3 als die in der Leber überwiegend exprimierte Isoform identifiziert. Die Stimulation von primären Hepatozyten mit DAG sowie die Fütterung von Mäusen mit fettreicher Nahrung (HFD) führte zu einer Aktivierung von PKD3, was auf eine Relevanz von PKD3 bei Fettleibigkeit hinweist. Mäusen, welchen PKD3 spezifisch in Hepatozyten fehlte und mit HFD gefüttert wurden, zeigten eine deutlich verbesserte Glukosetoleranz und Insulinsensitivität. Gleichzeitig führte jedoch die hepatische Deletion von PKD3 bei Mäusen zu einem erhöhten Lebergewicht in Folge einer erhöhten Lipidakkumulation in der Leber. Das Fehlen von PKD3 in Hepatozyten förderte die Sterol Regulatory Element-Binding Protein (SREBP)-vermittelte de novo Lipogenese in vitro und in vivo und erhöhte damit den Gehalt an Triglyceriden und Cholesterol in der Leber. Darüber hinaus supprimierte PKD3 die Aktivierung von SREBP, indem es die Aktivität der Insulin-Effektoren Proteinkinase B (AKT) und mechanistisches Ziel von Rapamycin- Komplexen (mTORC) 1 und 2 verminderte. Im Gegensatz dazu förderte die leberspezifische Überexpression von konstitutiv aktiver PKD3 die Glukoseintoleranz und Insulinresistenz. Zusammenfassend verbessert der Mangel an PKD3 die hepatische Insulinempfindlichkeit, aber fördert gleichzeitig die Akkumulation von Lipiden in der Leber. Aus diesem Grund könnte das Eingreifen in den PKD3-Signalweg eine gute Strategie zur Verbesserung des hepatischen Lipidgehalts oder der Insulinempfindlichkeit sein. Allerdings bleibt der genaue molekulare Mechanismus, mit dem PKD3 den Stoffwechsel von Hepatozyten reguliert, unklar.
Es wurden unvoreingenommene proteomische Ansätze durchgeführt, um PKD3- Phosphorylierungsziele zu identifizieren. In diesem Prozess wurden zahlreiche potenzielle Ziele von PKD3 entdeckt, welche in den verschiedensten Aspekten des Zellstoffwechsels involviert sind. Unter anderem wurde Phenylalaninhydroxylase (PAH) als Ziel von PKD3 in Hepatozyten identifiziert. PAH ist das Enzym, welches für die Umwandlung von Phenylalanin in Tyrosin verantwortlich ist. Tatsächlich bestätigte die Manipulation der PKD3-Aktivität mit Hilfe von genetischen Werkzeugen, dass PKD3 die PAH-abhängige Umwandlung von Phenylalanin in Tyrosin fördert. Deswegen legen die Daten in dieser Arbeit nahe, dass PKD3 den Lipid- und Aminosäurestoffwechsel in der Leber koordiniert und zur Entwicklung von Leber- Dysfunktion beiträgt.
KW  - Metabolismus
KW  - Proteinkinase D
KW  - Leber-Metabolismus
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-207978
ER  - 
TY  - THES
A1  - Eidel, Matthias T. A. M.
T1  - Training Effects of a Tactile Brain-Computer Interface System During Prolonged Use by Healthy And Motor-Impaired People
T1  - Trainingseffekte eines Taktilen Brain-Computer Interface Systems bei längerer Nutzung von gesunden sowie motorisch eingeschränkten Personen
N2  - Background 
- Brain-Computer Interfaces (BCI) enable their users to interact and communicate with the environment without requiring intact muscle control. To this end, brain activity is directly measured, digitized and interpreted by the computer. Thus, BCIs may be a valuable tool to assist severely or even completely paralysed patients. Many BCIs, however, rely on neurophysiological potentials evoked by visual stimulation, which can result in usability issues among patients with impaired vision or gaze control. Because of this, several non-visual BCI paradigms have been developed. Most notably, a recent study revealed promising results from a tactile BCI for wheelchair control. In this multi-session approach, healthy participants used the BCI to navigate a simulated wheelchair through a virtual apartment, which revealed not only that the BCI could be operated highly efficiently, but also that it could be trained over five sessions. The present thesis continues the research on this paradigm in order to - confirm its previously reported high performance levels and trainability - reveal the underlying factors responsible for observed performance increases - establish its feasibility among potential impaired end-users 

Methods 
- To approach these goals, three studies were conducted with both healthy participants and patients with amyotrophic lateral sclerosis (ALS). Brain activity during BCI operation was recorded via electroencephalography (EEG) and interpreted using a machine learning-based linear classifier. Wheelchair navigation was executed according to the classification results and visualized on a monitor. For offline statistical analysis, neurophysiological features were extracted from EEG data. Subjective data on usability were collected from all participants. Two specialized experiments were conducted to identify factors for training. 

Results and Discussion 
- Healthy participants: Results revealed positive effects of training on BCI performances and their underlying neurophysiological potentials. The paradigm was confirmed to be feasible and (for a non-visual BCI) highly efficient for most participants. However, some had to be excluded from analysis of the training effects because they could not achieve meaningful BCI control. Increased somatosensory sensitivity was identified as a possible mediator for training-related performance improvements. Participants with ALS: Out of seven patients with various stages of ALS, five could operate the BCI with accuracies significantly above chance level. Another ALS patient in a state of near-complete paralysis trained with the BCI for several months. Although no effects of training were observed, he was consistently able to operate the system above chance level. Subjective data regarding workload, satisfaction and other parameters were reported. 

Significance 
- The tactile BCI was evaluated on the example of wheelchair control. In the future, it could help impaired patients to regain some lost mobility and self-sufficiency. Further, it has the potential to be adapted to other purposes, including communication. Once visual BCIs and other assistive technologies fail for patients with (progressive) motor impairments, vision-independent paradigms such as the tactile BCI may be among the last remaining alternatives to interact with the environment. The present thesis has strongly confirmed the general feasibility of the tactile paradigm for healthy participants and provides first clues about the underlying factors of training. More importantly, the BCI was established among potential end-users with ALS, providing essential external validity.
N2  - Hintergrund 
- Brain-Computer Interfaces (BCI) ermöglichen ihren Benutzern die Interaktion und Kommunikation mit der Außenwelt, ohne dabei die Funktionstüchtigkeit der Muskeln voraus zu setzen. Zu diesem Zweck wird die Gehirnaktivität vom Computer direkt gemessen, digitalisiert und schließlich interpretiert. BCIs könnten daher eine wertvolle Methode sein, schwer körperlich beeinträchtigten oder sogar vollständig gelähmten Patienten zu assistieren. Viele BCI Ansätze basieren allerdings auf neurophysiologischen Potentialen, welche mittels visueller Stimulation evoziert werden. Dies kann zur Folge haben, dass das BCI von Patienten mit Sehbehinderung oder fehlender Kontrolle über die eigene Blickrichtung nicht erfolgreich benutzt werden kann. Deshalb wurden bereits einige nicht-visuelle BCI Paradigmen entwickelt. Insbesondere eine aktuelle Studie über ein taktiles BCI zur Rollstuhlkontrolle lieferte vielversprechende Ergebnisse: In fünf Trainingssitzungen navigierten gesunde Studienteilnehmer per BCI einen simulierten Rollstuhl durch eine virtuelle Wohnung. Hierbei konnte gezeigt werden, dass das BCI System nicht nur sehr effizient genutzt werden konnte, sondern auch, dass sich die Kontrolle durch das Training über mehrere Sitzungen verbesserte. Die vorliegende Dissertation befasst sich mit der weiterführenden Erforschung eben dieses Paradigmas, insbesondere mit den Zielen: . die zuvor berichtete hohe Performanz und Trainierbarkeit zu bestätigen . aufzuklären, welche Faktoren der Steigerung der BCI-Leistung zugrunde liegen . die Anwendbarkeit des Paradigmas bei beeinträchtigten Endnutzern zu etablieren Methoden - Um diese Ziele zu erreichen wurden drei Studien sowohl mit gesunden als auch mit Teilnehmern mit amyotropher Lateralsklerose (ALS) durchgeführt. Während der BCI-Nutzung wurde die Gehirnaktivität per Elektroenzephalographie (EEG) aufgezeichnet und von einem linearen Klassifikator (basierend auf Maschinenlernverfahren) interpretiert. Die Navigation des Rollstuhls wurde entsprechend der Ergebnisse des Klassifikators umgesetzt und auf einem Bildschirm visualisiert. Zur späteren statistischen Analyse wurden aus den EEG Daten neurophysiologische Merkmale extrahiert. Zudem wurden Fragebogendaten zur Nutzbarkeit des Systems von allen Teilnehmern erhoben. Zwei Experimente zur Identifizierung von Trainingsfaktoren wurden durchgeführt. 

Ergebnisse und Diskussion 
- Gesunde Teilnehmer: Die Ergebnisse zeigten positive Effekte des Trainings auf die BCI Performanz und deren zugrundeliegenden neurophysiologischen Potentiale. Es konnte bestätigt werden, dass das Paradigma anwendbar und für die meisten Teilnehmer hocheffizient nutzbar war (im Vergleich zu anderen nicht-visuellen Ansätzen). Einige Teilnehmer mussten jedoch von der Analyse der Trainingseffekte ausgeschlossen werden, da sie keine ausreichende Kontrolle über das BCI ausüben konnten. Eine Steigerung der somatosensorischen Empfindlichkeitsschwelle wurde als ein möglicher Faktor für die Trainierbarkeit und Verbesserung der Performanz identifiziert. Teilnehmer mit ALS: Fünf von sieben Teilnehmern in verschiedenen ALS-Stadien konnten das BCI signifikant überzufällig benutzen. Ein weiterer ALS Patient mit nahezu vollständiger Lähmung trainierte den Umgang mit dem BCI über mehrere Monate hinweg. Er war beständig in der Lage, das System mit Genauigkeiten über dem Zufallsniveau zu steuern, jedoch konnten keine Trainingseffekte gezeigt werden. Fragebogendaten zur subjektiven Arbeitsbelastung, Zufriedenheit und einigen weiteren Parametern wurden ausführlich berichtet. 

Bedeutung 
- Das taktile BCI wurde am Beispiel der Rollstuhlkontrolle evaluiert. In naher Zukunft könnte es beeinträchtigten Patienten helfen, ihre verlorene Mobilität und Selbstständigkeit zurück zu erlangen. Zudem kann es für viele weitere Zwecke adaptiert werden, insbesondere zur Kommunikation. Sobald visuelle BCIs oder andere technische Hilfsmittel bei Patienten mit (progressiver) motorischer Lähmung scheitern, könnten nicht-visuelle Paradigmen wie das taktile BCI zu den letzten verbleibenden Alternativen gehören, die eine Interaktion mit der Außenwelt noch erlauben. Die vorliegende Arbeit hat die grundsätzliche Anwendbarkeit des taktilen Paradigmas für gesunde Benutzer klar bestätigt. Zudem liefert sie erste Hinweise darauf, welche Faktoren den beobachteten Trainingseffekten zugrunde liegen könnten. Das BCI hat sich zudem bei potentiellen End-Nutzern mit ALS bewährt, was der externen Validität der Studienergebnisse enorm zuträgt.
KW  - Myatrophische Lateralsklerose
KW  - Gehirn-Computer-Schnittstelle
KW  - Elektroencephalographie
KW  - Rollstuhl
KW  - Brain-Computer Interface
KW  - Amyotrophic Lateral Sclerosis
KW  - Wheelchair Navigation
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-208511
ER  - 
TY  - JOUR
A1  - Gallo, Lorenzo
T1  - Nomenclatural adjustments and typifications in the genus Phedimus (Crassulaceae)
JF  - Forum Geobotanicum
N2  - This paper deals with the taxonomical position and the nomenclature of two taxa belonging to the genus Sedum (Crassulaceae), today treated as Phedimus, namely Sedum middendorffianum Maxim var. diffusum Praeger and Sedum oppositifolium Sims. The correct taxonomical application of names is based on the nomenclatural types designated here.
KW  - lectotype
KW  - neotype
KW  - Phedimus middendorffianus, var. diffusus
KW  - Phedimus spurius subsp. oppositifolius
KW  - Sedum oppositifolium
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-206347
UR  - http://www.forum-geobotanicum.net/articles/vol_9-2020/gallo-phedimus/gallo-phedimus.pdf
SN  - 1867-9315
VL  - 9
ER  - 
TY  - THES
A1  - Höfner, Christiane
T1  - Human Adipose-derived Mesenchymal Stem Cells in a 3D Spheroid Culture System - Extracellular Matrix Development, Adipogenic Differentiation, and Secretory Properties
T1  - Humane mesenchymale Stammzellen aus dem Fettgewebe in einem 3D Sphäroid Kultursystem - Entwicklung der Extrazellulärmatrix, adipogene Differenzierung und sekretorische Eigenschaften
N2  - The ability to differentiate into mesenchymal lineages, as well as immunomodulatory, anti-inflammatory, anti-apoptotic, and angiogenic properties give ASCs great therapeutic potential. Through their culture as multicellular, three-dimensional spheroids this potential can even be enhanced. Accordingly, 3D spheroids are not only promising candidates for the application in regenerative medicine and inflammatory disease therapy, but also for the use as building blocks in tissue engineering approaches. Due to the resemblance to physiological cell-cell and cell-matrix interactions, 3D spheroids gain higher similarity to real tissues, what makes them a valuable tool in the development of bioactive constructs equivalent to native tissues in terms of its cellular and extracellular structure. Especially, to overcome the still tremendous clinical need for adequate implants to repair soft tissue defects, 3D spheroids consisting of ASCs are a promising approach in adipose tissue engineering. Nevertheless, studies on the use of ASC-based spheroids as building blocks for fat tissue reconstruction have so far been very rare. In order to optimally exploit their therapeutic potential to further their use in regenerative medicine, including adipose tissue engineering approaches, a 3D spheroid model consisting of ASCs was characterized extensively in this work. This included not only the elucidation of the structural features, but also the differentiation capacity, gene expression, and secretory properties. In addition, the elucidation of underlying mechanisms contributing to the improved therapeutic efficiency was addressed.
N2  - Humane mesenchymale Stammzellen aus dem Fettgewebe (ASCs) verfügen über ein großes therapeutisches Potenzial. Dieses reicht von ihrer Fähigkeit zur Differenzierung entlang der mesenchymalen Linien bis hin zu entzündungshemmenden und immunmodulatorischen Eigenschaften, was sie zu vielversprechenden Kandidaten im Einsatz für die regenerative Zelltherapie macht. Die Routinekultur dieser Zellen unter herkömmlichen 2D-Kulturbedingungen führt durch den Verlust der Umgebung in einem dreidimensionalen Gewebeverbund zur Beeinträchtigung ihrer regenerativen Fähigkeiten. Die Kultivierung in dreidimensionalen Zellaggregaten (Sphäroiden), in denen die Zellen in einem mehr physiologischen 3D Verbund innerhalb ihrer sekretierten Matrix interagieren können, erscheint somit als geeignete Möglichkeit das therapeutische Potential von ASCs zu steigern. Dies macht ASC-basierte Sphäroide nicht nur zu einem vielversprechenden Ansatz in der regenerativen Medizin im Allgemeinen, sondern auch zu einem innovativen Tool in ihrer Verwendung als „Bausteine“ für das Konzept des Tissue Engineerings. Insbesondere im Bereich des Fettgewebe-Engineerings besteht ein immenser klinischer Bedarf an der Entwicklung geeigneter Implantate für die Rekonstruktion von Weichteildefekten. Hierfür erscheinen Sphäroide aus den leicht und in ausreichender Menge zu isolierenden ASCs besonders attraktiv. Der effektive Einsatz solcher Sphäroide in der regenerativen Medizin, sowie im Fettgewebe-Engineering, erfordert jedoch zunächst ihre umfassende Charakterisierung in Bezug auf Strukturmerkmale, Differenzierungsfähigkeit und sekretorische Eigenschaften. Dazu wurden im ersten Teil dieser Arbeit der Prozess der Sphäroidbildung sowie die daran beteiligten Zell-Zell- und Zell-ECM-Interaktionen untersucht. Mit Hilfe der sogenannten Liquid-Overlay Technik gelang die reproduzierbare und kontrollierte Zusammenlagerung der ASCs in dreidimensionale Sphäroide innerhalb von 24 h. Hinsichtlich der Entwicklung von Extrazellulärmatrix-Komponenten während der Sphäroidbildung zeigte sich Fibronektin als die Matrix-Komponente, welche als Erste während des Prozesses zu detektieren war. Durch das Blockieren des Fibronektin-spezifischen β1-Integrins mittels eines spezifischen Antikörpers konnte ein Einfluss dieser frühen Fibronektin-Expression auf den Verlauf der Zellaggregation gezeigt werden. Bei dem hier blockierten β1-Integrin handelt es sich um einen zellulären Rezeptor, welcher maßgeblich an der Fibronektinbindung beteiligt ist. Eine Abhängigkeit der Sphäroidbildung von der Zell-Zell Interaktion mittels Cadherine konnte hingegen für die ASCs nicht nachgewiesen werden. Somit konnten im ersten Abschnitt neben einer detaillierten Beschreibung der ASC-Sphäroidbildung zusätzlich erste Erkenntnisse über die dem Prozess zugrundeliegenden Mechanismen gewonnen werden.
Der effektive Einsatz von ASC-basierten Sphäroiden als Bausteine für das Fettgewebe-Engineering erfordert Kenntnisse sowohl über die Entwicklung der ECM als wichtigen gewebe-inhärenten Faktor, als auch über eine effiziente adipogene Induktion. Somit lag der Fokus im zweiten Teil dieser Arbeit auf der Charakterisierung der Extrazellulärmatrix in den ASC-Sphäroiden, sowie auf deren Fähigkeit zur adipogenen Differenzierung im Vergleich zur konventionellen 2D-Kultur unter der Verwendung verschiedener Induktionsprotokolle. Differenzierte Sphäroide weisen mit Laminin, Kollagen Typ I, IV und VI als nachgewiesenen Hauptbestandteilen eine Fettgewebs-spezifische Matrixzusammensetzung auf, die eine ausgeprägte Ähnlichkeit zu der des nativen Fettgewebes zeigt. Darüber hinaus konnte eine verbesserte Differenzierungsfähigkeit der ASC-Sphäroide nach einem kurzen induktiven Stimulus gegenüber der 2D kultivierten Zellen gezeigt werden. Dies wurde sowohl hinsichtlich des Triglyceridgehalts, sowie der Expression adipogener Markergene nachgewiesen. Diese verbesserte Differenzierbarkeit und die Möglichkeit mit den Sphäroiden fettgewebeähnliche Mikrogewebe herzustellen, machen diese Zellaggregate zu vielversprechenden Bausteinen für Ansätze im Fettgewebe-Engineering. 
Inzwischen ist bekannt, dass die Extrazellulärmatrix nicht nur als inertes, unterstützendes Gerüst wirkt, sondern auch zelluläre Prozesse, einschließlich der Differenzierung, durch die Interaktion mit zellulären Rezeptoren beeinflusst. Laminin als wichtige ECM Komponente der Basalmembran reifer Adipozyten konnte in der ECM der adipogen differenzierenden Sphäroide im Gegensatz zu 2D Kulturen zu einem sehr frühen Zeitpunkt der Adipogenese nachgewiesen werden. Um einen positiven Einfluss des Laminins auf den Prozess der adipogenen Differenzierung weitergehend zu untersuchen, wurde ein shRNA-vermittelter Knockdown eines spezifischen Laminin-Gens, welches für die Lamininkette α4 des adipospezifischen Laminin-8 Heterotrimers kodiert, durchgeführt. Obwohl ein stabiler Knockdown des LAMA4 Gens in den ASCs erreicht wurde, so konnte dennoch keine direkte Korrelation zur adipogenen Differenzierungsfähigkeit der Zellen festgestellt werden, da die reduzierte Expression dieses einzelnen Laminin-Gens sich nicht konsequent in der Expression des Gesamtlaminins auf Proteinebene durchsetzte. 
Das verbesserte therapeutische Potenzial mesenchymaler Stammzellen in einer dreidimensionalen Umgebung beschränkt sich nicht nur auf ihre verbesserte Differenzierungsfähigkeit, sondern umfasst auch die parakrine Sekretion der Zellen, die angiogene, anti-apoptotische, entzündungshemmende und immunmodulatorische Eigenschaften vermittelt. Um dies auch für ASCs zu bestätigen, wurden im letzten Teil dieser Arbeit die Genexpression von ASC-basierten Sphäroiden im Vergleich zu 2D kultivierten Zellen untersucht. Durch mRNA Genexpressionsanalysen konnte für ausgewählte entzündungshemmende, anti-apoptotische und anti-tumor wirksame Zytokine eine signifikant höhere Expression in den Sphäroiden gegenüber der 2D Kultur gezeigt werden. Für einen der wichtigsten entzündungshemmenden Faktoren, Prostaglandin E2, konnte eine erhöhte Sekretion von ASCs, kultiviert als 3D Sphäroide, auch auf Sekretionsebene bestätigt werden.
Die Identifizierung intrinsischer Faktoren, welche zu dem verbesserten therapeutischen Potenzial der Zellen in einer dreidimensionalen Umgebung beitragen, ist noch ausstehend. Zur Untersuchung des Einflusses von Zell-Zellkontakten diente ein PCR-Array zum Screening hierfür relevanter Gene. Durch den Vergleich der beiden Kulturbedingungen, 2D Monolayer und 3D Sphäroide, sollten mögliche Unterschiede in den ASCs festgestellt werden können, welche eventuell für das verbesserte therapeutische Potenzial der Sphäroide mitunter verantwortlich sind. Dabei konnten eindeutige Unterschiede zwischen ASCs aus der 3D bzw. 2D-Kultur festgestellt werden. Diese Ergebnisse bilden die Grundlage für weitere Untersuchungen auf diesem Gebiet, um einem umfassenden Verständnis der Rolle von Zell-Zell- und Zell-ECM-Interaktionen in einem 3D-Sphäroid-Kultursystem näherzukommen.
Zusammengefasst tragen die Ergebnisse dieser Arbeit zu einer umfangreichen Charakterisierung der ASC Sphäroide hinsichtlich struktureller Merkmale, Differenzierungsfähigkeit und sekretorischer Eigenschaften bei. Es wurde gezeigt, dass ASCs der 3D Sphäroide nicht nur eine verbesserte Differenzierungsfähigkeit, sowie eine erhöhte Expression von Genen aufweisen, welche für verschiedene Zytokine codieren, sondern ebenso in der Lage sind Fettgewebs-ähnliche Mikrogewebe zu bilden. Diese Erkenntnisse tragen dadurch insgesamt zur Förderung der ASC Sphäroide in ihrer effektiven Anwendung in der regenerativen Medizin und im Bereich des Fettgewebe-Engineerings bei.
KW  - adipose
KW  - Extracellular Matrix
KW  - adipose-derived
KW  - mesenchymal stem cells
KW  - 3D spheroid culture
KW  - adipogenic differentiation
KW  - secretory properties
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204249
N1  - Journal of Tissue Engineering Part A
ER  - 
TY  - THES
A1  - Herz, Michaela
T1  - Genome wide expression profiling of Echinococcus multilocularis
T1  - Genomweite Expressionsanalysen von Echinococcus multilocularis
N2  - Alveolar echinococcosis, which is caused by the metacestode stage of the small fox tapeworm Echinococcus multilocularis, is a severe zoonotic disease with limited treatment options. For a better understanding of cestode biology the genome of E. multilocularis, together with other cestode genomes, was sequenced previously. While a few studies were undertaken to explore the E. multilocularis transcriptome, a comprehensive exploration of global transcription profiles throughout life cycle stages is lacking. This work represents the so far most comprehensive analysis of the E. multilocularis transcriptome. Using RNA-Seq information from different life cycle stages and experimental conditions in three biological replicates, transcriptional differences were qualitatively and quantitatively explored. The analyzed datasets are based on samples of metacestodes cultivated under aerobic and anaerobic conditions as well as metacestodes obtained directly from infected jirds. Other samples are stem cell cultures at three different time points of development as well as non-activated and activated protoscoleces, the larval stage that can develop into adult worms. In addition, two datasets of metacestodes under experimental conditions suitable for the detection of genes that are expressed in stem cells, the so-called germinative cells, and one dataset from a siRNA experiment were analyzed. Analysis of these datasets led to expression profiles for all annotated genes, including genes that are expressed in the tegument of metacestodes and play a role in host-parasite interactions and modulation of the host's immune response. Gene expression profiles provide also further information about genes that might be responsible for the infiltrative growth of the parasite in the liver.

Furthermore, germinative cell-specific genes were identified. Germinative cells are the only proliferating cells in E. multilocularis and therefore of utmost importance for the development and growth of the parasite. Using a combination of germinative cell depletion and enrichment methods, genes with specific expression in germinative cells were identified. As expected, many of these genes are involved in translation, cell cycle regulation or DNA replication and repair. Also identified were transcription factors, many of which are involved in cell fate commitment. As an example, the gene encoding the telomerase reverse transcriptase (TERT) was studied further. Expression of E. multilocularis tert in germinative cells was confirmed experimentally. Cell culture experiments indicate that TERT is required for proliferation and development of the parasite, which makes TERT a potentially interesting drug target for chemotherapy of alveolar echinococcosis.

Germinative cell specific genes in E. multilocularis also include genes of densoviral origin. More than 20 individual densovirus loci with information for non-structural and structural densovirus proteins were identified in the E. multilocularis genome. Densoviral elements were also detected in many other cestode genomes. Genomic integration of these elements suggests that densovirus-based vectors might be suitable tools for genetic manipulation of tapeworms. Interestingly, only three of more than 20 densovirus loci in the E. multilocularis genome are expressed. Since the canonical piRNA pathway is lacking in cestodes, this raises the question about potential silencing mechanisms. Exploration of RNA-Seq information indicated natural antisense transcripts as a potential gene regulation mechanism in E. multilocularis. Preliminary experiments further suggest DNA-methylation, which was previously shown to occur in platyhelminthes, as an interesting avenue to explore in future.

The transcriptome datasets also contain information about genes that are expressed in differentiated cells, for example the serotonin transporter gene that is expressed in nerve cells. Cell culture experiments indicate that serotonin and serotonin transport play an important role in E. multilocularis proliferation, development and survival.

Overall, this work provides a comprehensive transcription data atlas throughout the E. multilocularis life cycle. Identification of germinative cell-specific genes and genes important for host-parasite interactions will greatly facilitate future research. A global overview of gene expression profiles will also aide in the detection of suitable drug targets and the development of new chemotherapeutics against alveolar echinococcosis.
N2  - Alveoläre Echinokokkose wird durch das Metazestodenstadium des kleinen Fuchsbandwurms Echinococcus multilocularis verursacht und medizinisch als eine schwere Zoonose mit begrenzten Behandlungsmöglichkeiten betrachtet. Um ein besseres Verständnis für die Biologie der Zestoden zu erlangen, wurde das Genom von E. multilocularis, zusammen mit denen anderer Zestoden, bereits sequenziert. Bisher wurden nur wenige Studien zum Transkriptom von E. multilocularis durchgeführt und eine umfassende Analyse der Transkriptionsprofile über verschiedene Stadien des Lebenszyklus hinweg fehlt bislang. Diese Arbeit stellt die bisher umfassendste Untersuchung des Transkriptoms von E. multilocularis dar. Unterschiede in der Genexpression in verschiedenen Stadien des Lebenszyklus und unter experimentellen Bedingungen wurden qualitativ und quantitativ untersucht. Dazu wurden Daten aus RNA-Sequenzierungen in drei biologischen Replikaten verwendet. Die untersuchten Datensätze beruhen auf Proben von Metazestoden, die unter aeroben und anaeroben Bedingungen kultiviert, sowie von Metazestoden, die direkt aus Gerbilen isoliert wurden. Weitere Proben umfassen Stammzellkulturen zu drei verschiedenen Entwicklungszeitpunkten sowie nicht-aktivierte und aktivierte Protoskolizes, das Larvenstadium das sich zu Adulten entwickeln kann. Zusätzlich wurden zwei Datensätze von Metazestoden unter experimentellen Bedingungen, die zur Identifizierung stammzellspezifischer (keimzellspezifischer) Gene geeignet sind, sowie ein Datensatz von einem siRNA-Experiment untersucht. Die Analyse dieser Datensätze führte zu Genexpressionsprofilen für alle annotierten Gene, unter anderem für Gene, die im Tegument des Metazestoden exprimiert werden und eine Rolle spielen bei Wirt-Parasit-Interaktionen und der Modulierung der Immunantwort des Wirts. Genexpressionsprofile liefern zudem Informationen über Gene, die für das infiltrative Wachstum des Parasiten in der Leber verantwortlich sein könnten.

Des Weiteren wurden keimzellspezifische Gene identifiziert. Keimzellen sind die einzigen proliferierenden Zellen in E. multilocularis und daher von essentieller Bedeutung für die Entwicklung und das Wachstum des Parasiten. Durch eine Kombination von Keimzelldepletierungs- und Keimzellanreicherungsverfahren wurden Gene mit keimzellspezifischer Expression identifiziert. Wie erwartet, sind viele dieser Gene in der Translation, der Zellzyklusregulation oder DNA-Replikation und –Reparatur involviert. Darüber hinaus wurden keimzellspezifisch exprimierte Transkriptionsfaktoren detektiert, von denen viele in der Festlegung des Zellschicksals eine Rolle spielen. Als Beispiel eines keimzellspezifischen Genes wurde das Gen, das für die reverse Transkriptase (TERT) kodiert, genauer untersucht. Die Expression von E. multilocularis tert in Keimzellen wurde experimentell bestätigt. Zellkulturexperimente weisen darauf hin, dass TERT für die Proliferation und die Entwicklung essentiell ist. TERT ist daher ein potentiell interessantes Wirkstofftarget für die chemotherapeutische Behandlung der alveolären Echinokokkose.

Zu den keimzellspezifischen Genen in E. multilocularis gehören auch Gene densoviralen Ursprungs. Es wurden mehr als 20 Densovirusloci mit Informationen für nicht-strukturelle und strukturelle Densovirusproteine im E. multilocularis-Genom identifiziert. Densovirale Elemente wurden auch in vielen anderen Zestodengenomen detektiert. Die genomische Integration dieser Elemente deutet darauf hin, dass densovirus-basierte Vektoren zur genetischen Manipulation von Zestoden geeignet sein könnten. Interessanterweise sind nur drei von mehr als 20 Densovirusloci im E. multilocularis-Genom exprimiert. Da es in Zestoden keinen kanonischen piRNA-Signalweg gibt, stellt sich die Frage nach möglichen Genabschaltungsmechanismen. Die Analyse der RNA-Sequenzierdaten ergab Hinweise auf natürliche Antisense-Transkripte als einen möglichen Genregulationsmechanismus in E. multilocularis. Vorläufige Experimente und bisherige Studien deuten weiterhin darauf hin, dass DNA-Methylierung ein Mechanismus der Genregulation und -abschaltung in Zestoden sein könnte.

Die Transkriptionsdaten enthalten auch Informationen zu Genen, die in differenzierten Zellen exprimiert werden, wie zum Beispiel das Serotonintransportergen, das in Nervenzellen exprimiert wird. Zellkulturversuche weisen darauf hin, dass Serotonin und Serotonintransport eine wichtige Rolle bei der Proliferation, der Entwicklung und dem überleben von E. multilocularis spielen.

Insgesamt bietet diese Arbeit einen umfassenden Transkriptionsdatenatlas über die Stadien des Lebenszyklus von E. multilocularis. Die Identifizierung von keimzellspezifischen Genen und Genen, die für die Interaktion zwischen Wirt und Parasit wichtig sind, wird die zukünftige Forschung erheblich erleichtern. Ein globaler Überblick über die Genexpressionsprofile wird zudem hilfreich sein bei der Entdeckung geeigneter Wirkstofftargets und bei der Entwicklung neuer Chemotherapeutika gegen die alveoläre Echinokokkose.
KW  - Fuchsbandwurm
KW  - Serotonin
KW  - Telomerase
KW  - Stammzelle
KW  - Transkriptomanalyse
KW  - foxtapeworm
KW  - transcriptome data analysis
KW  - germinative cell
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-203802
ER  - 
TY  - JOUR
A1  - Orouji, Elias
A1  - Peitsch, Wiebke K.
A1  - Orouji, Azadeh
A1  - Houben, Roland
A1  - Utikal, Jochen
T1  - Unique role of histone methyltransferase PRDM8 in the tumorigenesis of virus-negative Merkel cell carcinoma
JF  - Cancers
N2  - Merkel cell carcinoma (MCC) is a deadly skin cancer, and about 80% of its cases have been shown to harbor integrated Merkel polyomavirus in the tumor cell genome. Viral oncoproteins expressed in the tumor cells are considered as the oncogenic factors of these virus-positive Merkel cell carcinoma (VP-MCC). In contrast, the molecular pathogenesis of virus-negative MCC (VN-MCC) is less well understood. Using gene expression analysis of MCC cell lines, we found histone methyltransferase PRDM8 to be elevated in VN-MCC. This finding was confirmed by immunohistochemical analysis of MCC tumors, revealing that increased PRDM8 expression in VN-MCC is also associated with increased H3K9 methylation. CRISPR-mediated silencing of PRDM8 in MCC cells further supported the histone methylating role of this protein in VN-MCC. We also identified miR-20a-5p as a negative regulator of PRDM8. Taken together, our findings provide insights into the role of PRDM8 as a histone methyltransferase in VN-MCC tumorigenesis.
KW  - histone
KW  - histone methyltransferase PRDM8
KW  - chromatin regulator
KW  - EGR1
KW  - miRNA
KW  - MCV-negative
KW  - Merkel cell carcinoma
KW  - MCPyV
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-203815
SN  - 2072-6694
VL  - 12
IS  - 4
ER  - 
TY  - THES
A1  - Liess [née Eller], Anna Katharina Luise
T1  - Understanding the regulation of the ubiquitin-conjugating enzyme UBE2S
T1  - Die Regulation des Ubiquitin-konjugierenden Enzyms UBE2S
N2  - The ubiquitination of proteins serves as molecular signal to control an enormous number of physiological processes and its dysregulation is connected to human diseases like cancer. The versatility of this signal stems from the diverse ways by which ubiquitin can be attached to its targets. Thus, specificity and tight regulation of the ubiquitination are pivotal requirements of ubiquitin signaling. Ubiquitin-conjugating enzymes (E2s) act at the heart of the ubiquitination cascade, transferring ubiquitin from a ubiquitin-activating enzyme (E1) to a ubiquitin ligase (E3) or substrate. When cooperating with a RING-type E3, ubiquitin-conjugating enzymes can determine linkage specificity in ubiquitin chain formation. Our understanding of the regulation of E2 activities is still limited at a structural level. 
The work described here identifies two regulation mechanisms in UBE2S, a cognate E2 of the human RING-type E3 anaphase-promoting complex/cyclosome (APC/C). UBE2S elongates ubiquitin chains on APC/C substrates in a Lys11 linkage-specific manner, thereby targeting these substrates for degradation and driving mitotic progression. In addition, UBE2S was found to have a role in DNA repair by enhancing non-homologous end-joining (NHEJ) and causing transcriptional arrest at DNA damage sites in homologous recombination (HR). Furthermore, UBE2S overexpression is a characteristic feature of many cancer types and is connected to poor prognosis and diminished response to therapy.
The first regulatory mechanism uncovered in this thesis involves the intramolecular auto-ubiquitination of a particular lysine residue (Lys+5) close to the active site cysteine, presumably through conformational flexibility of the active site region. The Lys+5-linked ubiquitin molecule adopts a donor-like, ‘closed’ orientation towards UBE2S, thereby conferring auto-inhibition. Notably, Lys+5 is a major physiological ubiquitination site in ~25% of the human E2 enzymes, thus providing regulatory opportunities beyond UBE2S. Besides the active, monomeric state and the auto-inhibited state caused by auto-ubiquitination, I discovered that UBE2S can adopt a dimeric state. The latter also provides an auto-inhibited state, in which ubiquitin transfer is blocked via the obstruction of donor binding. UBE2S dimerization is promoted by its unique C-terminal extension, suppresses auto-ubiquitination and thereby the proteasomal degradation of UBE2S. 

Taken together, the data provided in this thesis illustrate the intricate ways by which UBE2S activity is fine-tuned and the notion that structurally diverse mechanisms have evolved to restrict the first step in the catalytic cycle of E2 enzymes.
N2  - Die Ubiquitinierung von Proteinen fungiert als molekulares Signal zur Kontrolle einer Vielzahl physiologischer Prozesse, wobei eine gestörte Regulation der Ubiquitinierung eng mit zahlreichen Erkrankungen, wie beispielsweise Krebs, verbunden ist. Aufgrund der verschiedenen Verknüpfungsmöglichkeiten von Ubiquitin, die das zelluläre Schicksal des Zielproteins bestimmen, sind Spezifität und stringente Regulation unabkömmliche Voraussetzungen im Ubiquitinierungsprozess.
Ubiquitin-konjugierende Enzyme (E2s) fungieren in der Mitte der Ubiquitinierungskaskade. Sie übernehmen ein Ubiquitinmolekül vom Ubiquitin-aktivierenden Enzym (E1) und übertragen es auf eine Ubiquitin-Ligase (E3) oder direkt auf das Zielprotein. Arbeiten Ubiquitin-konjugierende Enzyme mit E3s des RING-Typus zusammen, so bestimmen E2s die Art der Verknüpfung. Die Regulation der Aktivität Ubiquitin-konjugierender Enzyme auf struktureller Ebene ist jedoch bisher nur bedingt verstanden. 
Die hier dargelegte Arbeit umfasst die Identifizierung zweier Regulationsmechanismen des Ubiquitin-konjugierenden Enzyms UBE2S. UBE2S arbeitet mit einem humanen E3 des RING-Typus‚ dem ‚Anaphase Promoting Complex/Cyclosome‘ (APC/C) zusammen und bildet Lys11-spezifische Ubiquitinketten auf Substraten des APC/Cs. Hierdurch werden die Substrate für den Abbau durch das Proteasom markiert, was das Fortschreiten der Mitose bedingt. Zusätzlich wird UBE2S eine Rolle in der DNS-Reparatur zugeschrieben. Hierbei verstärkt UBE2S die nicht-homologe Rekombination (NHEJ) und verhindert außerdem die Transkription an DNS-Bruchstellen, die durch Homologe Rekombination (HR) repariert werden. Die Überexpression von UBE2S ist ein Charakteristikum verschiedenster Krebsarten, vermindert den Erfolg herkömmlicher Krebstherapien, und führt somit zu schlechten Prognosen für betroffenen Patienten. 

Der erste hier beschriebene Regulationsmechanismus beinhaltet die intramolekulare Ubiquitinierung eines Lysins (Lys+5) nahe des katalytischen Cysteins, mutmaßlich durch strukturelle Flexibilität der Region des aktiven Zentrums. Das Lys+5-verknüpfte Ubiquitin nimmt eine Donorubiquitin-ähnliche Position auf UBE2S ein, wodurch UBE2S gehemmt wird. Da ein Lysin an der Position +5 in ~25% der humanen E2-Enzyme vorhanden und eine physiologische Ubiquitinierungsstelle ist, birgt dieser Mechanismus Regulationsmöglichkeiten über UBE2S hinaus. Zusätzlich zum aktiven monomeren Zustand und dem durch Autoubiquitinierung ausgelösten inhibierten Zustand, kann UBE2S auch als Dimer vorliegen. In diesem Zustand ist es ebenfalls inaktiv, da die Donorubiquitin-Bindestelle auf UBE2S durch ein zweites Molekül des E2s blockiert wird. Begünstigt wird die Dimerisierung durch die C-terminale Verlängerung von UBE2S und verhindert so deren Autoubiquitinierung, und folglich den proteasomalen Abbau von UBE2S. Es handelt sich hierbei somit um einen zweiten Regulationsmechanismus von UBE2S.
Zusammenfassend veranschaulichen die in dieser Arbeit dargelegten Daten die komplexen Möglichkeiten, durch die die Aktivität von UBE2S reguliert werden kann, sowie die Erkenntnis, dass strukturell unterschiedliche Mechanismen existieren, um den ersten Schritt der von Ubiquitin-konjugierenden Enzymen katalysierten Reaktion zu hemmen.
KW  - E2
KW  - Regulation
KW  - Ubiquitin
KW  - Mechanismus
KW  - UBE2S
KW  - structural mechanism
KW  - Ubiquitin-conjugating enzyme
KW  - regulation
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204190
ER  - 
TY  - JOUR
A1  - Beer, Katharina
A1  - Schenk, Mariela
A1  - Helfrich-Förster, Charlotte
A1  - Holzschuh, Andrea
T1  - The circadian clock uses different environmental time cues to synchronize emergence and locomotion of the solitary bee Osmia bicornis
JF  - Scientific Reports
N2  - Life on earth adapted to the daily reoccurring changes in environment by evolving an endogenous circadian clock. Although the circadian clock has a crucial impact on survival and behavior of solitary bees, many aspects of solitary bee clock mechanisms remain unknown. Our study is the first to show that the circadian clock governs emergence in Osmia bicornis, a bee species which overwinters as adult inside its cocoon. Therefore, its eclosion from the pupal case is separated by an interjacent diapause from its emergence in spring. We show that this bee species synchronizes its emergence to the morning. The daily rhythms of emergence are triggered by temperature cycles but not by light cycles. In contrast to this, the bee’s daily rhythms in locomotion are synchronized by light cycles. Thus, we show that the circadian clock of O. bicornis is set by either temperature or light, depending on what activity is timed. Light is a valuable cue for setting the circadian clock when bees have left the nest. However, for pre-emerged bees, temperature is the most important cue, which may represent an evolutionary adaptation of the circadian system to the cavity-nesting life style of O. bicornis.
KW  - Behavioural ecology
KW  - Evolutionary developmental biology
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202721
VL  - 9
ER  - 
TY  - JOUR
A1  - Maierhofer, Anna
A1  - Flunkert, Julia
A1  - Oshima, Junko
A1  - Martin, George M.
A1  - Poot, Martin
A1  - Nanda, Indrajit
A1  - Dittrich, Marcus
A1  - Müller, Tobias
A1  - Haaf, Thomas
T1  - Epigenetic signatures of Werner syndrome occur early in life and are distinct from normal epigenetic aging processes
JF  - Aging Cell
N2  - Werner Syndrome (WS) is an adult‐onset segmental progeroid syndrome. Bisulfite pyrosequencing of repetitive DNA families revealed comparable blood DNA methylation levels between classical (18 WRN‐mutant) or atypical WS (3 LMNA‐mutant and 3 POLD1‐mutant) patients and age‐ and sex‐matched controls. WS was not associated with either age‐related accelerated global losses of ALU, LINE1, and α‐satellite DNA methylations or gains of rDNA methylation. Single CpG methylation was analyzed with Infinium MethylationEPIC arrays. In a correspondence analysis, atypical WS samples clustered together with the controls and were clearly separated from classical WS, consistent with distinct epigenetic pathologies. In classical WS, we identified 659 differentially methylated regions (DMRs) comprising 3,656 CpG sites and 613 RefSeq genes. The top DMR was located in the HOXA4 promoter. Additional DMR genes included LMNA, POLD1, and 132 genes which have been reported to be differentially expressed in WRN‐mutant/depleted cells. DMRs were enriched in genes with molecular functions linked to transcription factor activity and sequence‐specific DNA binding to promoters transcribed by RNA polymerase II. We propose that transcriptional misregulation of downstream genes by the absence of WRN protein contributes to the variable premature aging phenotypes of WS. There were no CpG sites showing significant differences in DNA methylation changes with age between WS patients and controls. Genes with both WS‐ and age‐related methylation changes exhibited a constant offset of methylation between WRN‐mutant patients and controls across the entire analyzed age range. WS‐specific epigenetic signatures occur early in life and do not simply reflect an acceleration of normal epigenetic aging processes.
KW  - (classical and atypical) Werner syndrome
KW  - bisulfite pyrosequencing
KW  - methylation array
KW  - premature aging
KW  - segmental progeria
KW  - transcription deficiency
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202733
VL  - 18
ER  - 
TY  - THES
A1  - Schilling, Klaus Jussi
T1  - Liquid chromatographic analysis of weakly- and non-chromophore compounds focusing on Charged Aerosol Detection
T1  - Flüssigchromatographische Analyse von schwach- und nicht-chromophoren Substanzen mit Schwerpunkt auf Charged Aerosol Detektion
N2  - Liquid chromatography has become the gold standard for modern quality control and purity analytics since its establishment in the 1930s. However, some analytical questions remain very challenging even today. Several molecules and impurities do not possess a suitable chromophore for the application of UV detection or cannot be retained well on regular RP columns. Possible solutions are found in derivatization procedures, but they are time consuming and can be prone to errors. In order to detect non chromophore molecules underivatized, the concept of aerosol based universal detection was established with the introduction of the evaporative light scattering detector (ELSD) in the 1970s and the charged aerosol detector (CAD) followed in 2002. These two challenging fields – polar and non chromophore molecules – are tackled in this thesis.
An overview of applications of the CAD in the literature and a comparison to its aerosol based competitors and MS is presented, emphasizing on its high sensitivity and robustness. Parameters and techniques to overcome the drawbacks of CAD, such as the use of gradient compensation or adjusted evaporation temperatures are discussed. A consideration of aspects and drawbacks of data transformation such as the integrated power function value (PFV) in the GMP environment is performed.
A method for the fatty acid analysis in polysorbate 80 that was developed on HPLC CAD was transferred to UHPLC CAD. Time and eluent savings of over 75% and 40%, respectively, as well as ways to determine the optimal CAD parameters resulted from this investigation. The evaporation temperature was determined as the most crucial setting, which has to be adjusted with care. Optimal signal to noise ratios are found at a compromise between maintaining analyte signal and reducing background noise. The incorporation of semi volatile short chain fatty acids enabled the observation of differences based on volatility of the analyte. E.g. for semi volatiles, an improved linearity by means of adjusting the PFV is achieved at values below 1.0 instead of at elevated PFVs.
Using sugars and sugar related antibiotics, a proof-of-concept was given that artificial neural networks can describe correlations between the structure and physicochemical properties of molecules and their response in CAD. Quantitative structure property relationships obtained by design of experiment approaches were able to predict the response of unseen substances and yielded insights on the response generation of the detector, which heavily relies on the formed surface area of the dried particle. Further work can substantiate upon these findings, eventually building a library of diverse eluent compositions, analytes and settings.
In order to cope with a chromatographically challenging substances, the application of ion pairing reversed phase chromatography coupled to low wavelength UV detection has been shown as a possible approach for the amino acid L asparagine. A method capable of compendial purity analysis in one single HPLC approach, thus making the utilization of the semi quantitative TLC-ninhydrin analysis obsolete, resulted from this. One cyclic dipeptide impurity (diketoasparagine) that was formerly not assessed, could be identified in several batches and added to the monograph of the Ph.Eur.
Studying ibandronate sodium with CAD and ELSD, it was found that randomly occurring spike peaks represent a major flaw of the ELSD when high sample load is present. The research with this non chromophore bisphosphonate drug furthermore shed light on possible drawbacks of mixed mode chromatography methods and ways to overcome these issues. Due to strong adsorption of the analyte onto the column, over ten injections of the highly concentrated test solution were found to be necessary to ensure reproducible peak areas. Preconditioning steps should thus be evaluated for mixed mode approaches during method development and validation.
Last, using a ternary mixed mode stationary phase coupled to CAD, a method for the impurity profiling of pamidronate disodium, also applicable to the assessment of phosphate and phosphite in four other bisphosphonate drugs, has been developed. This represents a major advantage over the Ph.Eur. impurity profiling of pamidronate, which requires two different methods, one of which is only a semi quantitative TLC approach.
N2  - Flüssigchromatographische Untersuchungen sind seit deren Einführung in den 1930er Jahren zum Goldstandard für die moderne Qualitätskontrolle und Reinheitsanalytik geworden. Allerdings sind auch noch heutzutage einige Fragestellungen sehr herausfordernd. Viele Moleküle und Verunreinigungen besitzen keinen geeigneten Chromophor, das die Anwendung klassischer UV Detektion ermöglicht, oder erfahren auf gewöhnlichen Umkehrphasen keine ausreichende Retention. Lösungsansätze in Form von Derivatisierungsverfahren sind zeitaufwändig und fehleranfällig. Um underivatisierte Moleküle ohne geeignetes Chromophor zu analysieren, wurde das Prinzip der auf Aerosolen basierenden universellen Detektion mit dem „Evaporative Light Scattering Detector (ELSD)“ in den 1970er Jahren entwickelt und 2002 folgte der „Charged Aerosol Detector (CAD)“. Diese zwei Felder - polare und nicht chromophore Analyte - werden in der vorliegenden Dissertation bearbeitet.
Eine Literaturübersicht und  analyse von Applikationen des CAD, sowie ein Vergleich zu seinen auf Aerosoltechnik basierenden Konkurrenten und der Massenspektroskopie wird dargestellt; besonders die hohe Sensitivität und Robustheit werden ersichtlich. Geräteeinstellungen und Techniken, mit denen sich Nachteile des CAD ausgleichen lassen, werden erläutert und diskutiert. Hierbei werden beispielsweise die Gradientenkompensation oder die Veränderung der Verdampfungstemperatur diskutiert. Ein Überblick über Möglichkeiten und Nachteile der Datentransformation des CAD Signals mittels des eingebauten „Power Function Values (PFV)“ im GMP Umfeld wird gegeben.
Ein Methodentransfer der Analytik von Fettsäuren in Polysorbat 80 von HPLC CAD zu UHPLC CAD wurde durchgeführt. Chemikalien  und Zeitersparnisse jenseits von 40 bzw. 75%, sowie Herangehensweisen für die Optimierung der CAD Einstellungen resultierten hieraus. Die Verdampfungstemperatur ist der wichtigste Parameter des Detektors und sollte stets feinjustiert werden. Die höchste Sensitivität findet sich für einen Kompromiss aus verringertem Rauschen und auch erhaltenem Analytsignal. Durch die Analyse von semi flüchtigen Fettsäuren konnten Unterschiede, die auf der Flüchtigkeit von Substanzen basieren, erarbeitet werden. Für semi flüchtige Stoffe ist die Linearisierung mittels PFV bespielsweise bei Werten unter 1.0 erfolgreich, wohingegen für nicht flüchtige Analyte Werte jenseits von 1.0 optimal sind.
Für Zucker und zuckerverwandte Antibiotika konnte ein konzeptioneller Beweis erbracht werden, dass künstliche neuronale Netzwerke Korrelationen zwischen den physikochemischen Eigenschaften der Moleküle und deren Signal im CAD herstellen können. Ein solches Netzwerk wurde mittels Methoden des experimentellen Designs erstellt. Die CAD Detektorantwort, die stark von der Oberfläche der Partikel abhängt, konnte auf diese Weise für Substanzen innerhalb des Experimentalraumes vorhergesagt werden. Hierauf aufbauend kann eine Bibliothek aus Analyten, Fließmitteln und Detektorparametern erarbeitet werden, um weiteres Detailwissen über den CAD zu erhalten.
Die Aminosäure L Asparagin stellt eine chromatographische Herausforderung dar. Es wurde eine Ionenpaar Umkehrphasen Methode mit UV Detektion bei 210 nm als erfolgreicher Ansatz gezeigt. Die arzneibuchkonforme Bestimmung des Verunreinigungsprofils ist mit dieser Methode in einem Lauf möglich, wodurch die Nutzung der halbquantitativen Dünnschichtchromatographie obsolet wird. Weiterhin konnte ein cyclisches Dipeptid (Diketoasparagin), welches zuvor nicht im Verunreinigungsprofil gelistet war, in einigen Batches gefunden und so der Monographie des Ph.Eur. hinzugefügt werden.
Bei der Untersuchung von Natrium-Ibandronat mit dem CAD und dem ELSD konnte gezeigt werden, dass zufällig auftretende „spike peaks“ bei hohen Probenkonzentrationen ein enormes analytisches Problem des ELSD darstellen. Weiterhin wurde mit der Analyse der nicht chromophoren Bisphosphonaten ein Problem von „mixed mode“ Chromatographie aufgedeckt. Durch die starke Adsorption des Analyten auf der Säule waren über zehn Injektionen der konzentrierten Testlösung notwendig, um reproduzierbare Peakflächen zu erhalten. Derartige Sättigungs- und Vorkonditionierungsprozesse sollten für „mixed mode“ Chromatographie während der Entwicklung und Validierung untersucht werden.
Zuletzt wurde eine ternäre „mixed mode“ stationäre Phase gekoppelt mit CAD verwendet, um das Verunreinigungsprofil von Pamidronat Dinatrium zu analysieren. Diese entwickelte Methode konnte auch für die Bestimmung von Phosphat und Phosphit in vier anderen Bisphosphonaten genutzt werden. Erneut ergibt sich ein Vorteil gegenüber der Arzneibuchmethode für Pamidronat, welche zwei verschiedene Methoden - eine davon nur eine halbquantitative Dünnschichtchromatographie - nutzt.
KW  - HPLC
KW  - Flüssigkeitschromatographie
KW  - Instrumentelle Analytik
KW  - Chemische Reinheit
KW  - Charged Aerosol Detection
KW  - mixed-mode chromatography
KW  - ion-pair chromatography
KW  - non-chromophore analytes
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202114
ER  - 
TY  - JOUR
A1  - Fayez, Shaimaa
A1  - Feineis, Doris
A1  - Aké Assi, Laurent
A1  - Seo, Ean-Jeong
A1  - Efferth, Thomas
A1  - Bringmann, Gerhard
T1  - Ancistrobreveines A–D and related dehydrogenated naphthylisoquinoline alkaloids with antiproliferative activities against leukemia cells, from the West African liana Ancistrocladus abbreviatus
JF  - RSC Advances
N2  - A unique series of six biaryl natural products displaying four different coupling types (5,10 , 7,10 , 7,80 , and 5,80) were isolated from the roots of the West African liana Ancistrocladus abbreviatus (Ancistrocladaceae). Although at first sight structurally diverse, these secondary metabolites all have in common that they belong to the rare group of naphthylisoquinoline alkaloids with a fully dehydrogenated isoquinoline portion. Among the African Ancistrocladus species, A. abbreviatus is so far only the second one that was found to produce compounds with such a molecular entity. Here, we report on four new representatives, named ancistrobreveines A–D (12–14, and 6). They were identified along with the two known alkaloids 6-O-methylhamateine (4) and entdioncophylleine A (10). The two latter naphthylisoquinolines had so far only been detected in Ancistrocladus species from Southeast Asia. All of these fully dehydrogenated alkaloids have in common being optically active despite the absence of stereogenic centers, due to the presence of the rotationally hindered biaryl axis as the only element of chirality. Except for ent-dioncophylleine A (10), which lacks an oxygen function at C-6, the ancistrobreveines A–D (12–14, and 6) and 6-O-methylhamateine (4) are 6-oxygenated alkaloids, and are, thus, typical ‘Ancistrocladaceae-type’ compounds. Ancistrobreveine C (14), is the first – and so far only – example of a 7,80-linked fully dehydrogenated naphthylisoquinoline discovered in nature that is configurationally stable at the biaryl axis. The stereostructures of the new alkaloids were established by spectroscopic (in particular HRESIMS, 1D and 2D NMR) and chiroptical (electronic circular dichroism) methods. Ancistrobreveine C (14) and 6-O-methylhamateine (4) exhibited strong antiproliferative activities against drug-sensitive acute lymphoblastic CCRF-CEM leukemia cells and their multidrugresistant subline, CEM/ADR5000.
KW  - chemistry
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201686
VL  - 9
IS  - 28
ER  - 
TY  - JOUR
A1  - Trappe, Julian
A1  - Kneisel, Christof
T1  - Geophysical and sedimentological investigations of Peatlands for the assessment of lithology and subsurface water pathways
JF  - Geosciences
N2  - Peatlands located on slopes (herein called slope bogs) are typical landscape units in the Hunsrueck, a low mountain range in Southwestern Germany. The pathways of the water feeding the slope bogs have not yet been documented and analyzed. The identification of the different mechanisms allowing these peatlands to originate and survive requires a better understanding of the subsurface lithology and hydrogeology. Hence, we applied a multi-method approach to two case study sites in order to characterize the subsurface lithology and to image the variable spatio-temporal hydrological conditions. The combination of Electrical Resistivity Tomography (ERT) and an ERT-Monitoring and Ground Penetrating Radar (GPR), in conjunction with direct methods and data (borehole drilling and meteorological data), allowed us to gain deeper insights into the subsurface characteristics and dynamics of the peatlands and their catchment area. The precipitation influences the hydrology of the peatlands as well as the interflow in the subsurface. Especially, the geoelectrical monitoring data, in combination with the precipitation and temperature data, indicate that there are several forces driving the hydrology and hydrogeology of the peatlands. While the water content of the uppermost layers changes with the weather conditions, the bottom layer seems to be more stable and changes to a lesser extent. At the selected case study sites, small differences in subsurface properties can have a huge impact on the subsurface hydrogeology and the water paths. Based on the collected data, conceptual models have been deduced for the two case study sites.
KW  - peatland
KW  - slope bogs
KW  - geomorphology
KW  - subsurface hydrology
KW  - electrical resistivity tomography
KW  - ground penetrating radar
KW  - boreholes
KW  - Hunsrueck
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201699
VL  - 9
IS  - 3
ER  - 
TY  - JOUR
A1  - Schuler, Michael
A1  - Murauer, Kathrin
A1  - Stangl, Stephanie
A1  - Grau, Anna
A1  - Gabriel, Katharina
A1  - Podger, Lauren
A1  - Heuschmann, Peter U.
A1  - Faller, Hermann
T1  - Pre-post changes in main outcomes of medical rehabilitation in Germany: protocol of a systematic review and meta-analysis of individual participant and aggregated data
JF  - BMJ Open
N2  - Introduction 
Multidisciplinary, complex rehabilitation interventions are an important part of the treatment of chronic diseases. However, little is known about the effectiveness of routine rehabilitation interventions within the German healthcare system. Due to the nature of the social insurance system in Germany, randomised controlled trials examining the effects of rehabilitation interventions are challenging to implement and scarcely accessible. Consequently, alternative pre-post designs can be employed to assess pre-post effects of medical rehabilitation programmes. We present a protocol of systematic review and meta-analysis methods to assess the pre-post effects of rehabilitation interventions in Germany.

Methods and analysis 
The respective study will be conducted within the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. A systematic literature review will be conducted to identify studies reporting the pre-post effects (start of intervention vs end of intervention or later) in German healthcare. Studies investigating the following disease groups will be included: orthopaedics, rheumatology, oncology, pulmonology, cardiology, endocrinology, gastroenterology and psychosomatics. The primary outcomes of interest are physical/mental quality of life, physical functioning and social participation for all disease groups as well as pain (orthopaedic and rheumatologic patients only), blood pressure (cardiac patients only), asthma control (patients with asthma only), dyspnoea (patients with chronic obstructive pulmonary disease only) and depression/anxiety (psychosomatic patients only). We will invite the principal investigators of the identified studies to provide additional individual patient data. We aim to perform the meta-analyses using individual patient data as well as aggregate data. We will examine the effects of both study-level and patient-level moderators by using a meta-regression method.

Ethics and dissemination 
Only studies that have received institutional approval from an ethics committee and present anonymised individual patient data will be included in the meta-analysis. The results will be presented in a peer-reviewed publication and at research conferences. A declaration of no objection by the ethics committee of the University of Würzburg is available (number 20180411 01).
KW  - medical rehabilitation
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201929
VL  - 9
IS  - 5
ER  - 
TY  - THES
A1  - Hu, Zhongyang
T1  - Earth Observation for the Assessment of Long-Term Snow Dynamics in European Mountains - Analysing 35-Year Snowline Dynamics in Europe Based on High Resolution Earth Observation Data between 1984 and 2018
T1  - Erdbeobachtung für die Beurteilung von Langzeit Schneedynamiken in Europäischen Gebirgen - Die Analyse von Scheegrenzendynamiken über 35 Jahre in Europa basierend auf hochauflösenden Erdbeobachtungsdaten zwischen 1984 und 2018
N2  - Worldwide, cold regions are undergoing significant alterations due to climate change. Snow, the most widely distributed cold region component, is highly sensitive to climate change. At the same time, snow itself profoundly impacts the Earth’s energy budget, biodiversity, and natural hazards, as well as hydropower management, freshwater management, and winter tourism/sports. Large parts of the cold regions in Europe are mountain areas, which are densely populated because of the various ecosystem services and socioeconomic well-being in mountains. At present, severe consequences caused by climate change have been observed in European mountains and their surrounding areas. Yet, large knowledge gaps hinder the development of effective regional and local adaptation strategies. Long-term and evidence-based regional studies are urgently needed to enhance the comprehension of regional responses to climate change.

Earth Observation (EO) provides long-term consistent records of the Earth’s surface. It is a great alternative and/or supplement to conventional in-situ measurements which are usually time-consuming, cost-intensive and logistically demanding, particularly for the poor accessibility of cold regions. With the assistance of EO, land surface dynamics in cold regions can be observed in an objective, repeated, synoptic and consistent way. Thanks to free and open data policies, long-term archives such as Landsat Archive and Sentinel Archive can be accessed free-of-charge. The high- to medium-resolution remote sensing imagery from these freely accessible archives gives EO-based time series datasets the capability to depict snow dynamics in European mountains from the 1980s to the present. In order to compile such a dataset, it is necessary to investigate the spatiotemporal availability of EO data, and develop a spatiotemporally transferable framework from which one can investigate snow dynamics.

Among the available EO image archives, the Landsat Archive has the longest uninterrupted records of the Earth’s land surface. Furthermore, its 30 m spatial resolution fulfils the requirements for snow monitoring in complex terrains. Landsat data can yield a time series of snow dynamics in mountainous areas from 1984 to the present. However, severe Landsat data gaps have occurred across certain regions of Europe. Moreover, the Landsat Level 1 Precision and Terrain (L1TP) data is scarcer (up to 50% less) in high-latitude mountainous areas than in low-latitude mountainous areas. Given the abovementioned facts, the Regional Snowline Elevation (RSE) is selected to characterize the snow dynamics in mountainous areas, as it can handle cloud obstructions in the optical images. In this thesis, I present a five-step framework to derive and densify RSE time series in European mountains, i.e. (1) pre-processing, (2) snow detection, (3) RSE retrieval, (4) time series densification, and (5) Regional Snowline Retreat Curve (RSRC) production.

The results of the intra-annual RSE variations show a uniquely high variation in the beginning of the ablation seasons in the Alpine catchment Tagliamento, mainly toward higher elevation. As for inter-annual variations of RSE, median RSE increases in all selected catchments, with an average speed of around 4.66 m ∙ a−1 (median) and 5.87 m ∙ a−1 (at the beginning of the ablation season). The fastest significant retreat is observed in the catchment Drac (10.66 m ∙ a−1, at the beginning of the ablation season), and the slowest significant retreat is observed in the catchment Uzh (1.74 m ∙ a−1, at the beginning of the ablation season). The increase of RSEs at the beginning of the ablation season is faster than the median RSEs, whose average difference is nearly 1.21 m ∙ a−1, particularly in the catchment Drac (3.72 m ∙ a−1). The results of the RSRCs show a significant rise in RSEs at the beginning of the ablation season, except for the Alpine catchment Alpenrhein and Var, and the Pyrenean catchment Ariege. It indicates that 11.8 and 3.97 degrees Celsius less per year are needed for the regional snowlines to reach the middle point of the RSRC in the Tagliamento and Tysa, respectively. The variation of air temperature is regarded as an example of a potential climate driver in this thesis. The retrieved monthly mean RSEs are highly correlated (mean correlation coefficient "R"  ̅ = 0.7) with the monthly temperature anomalies, which are more significant in months with extremely low/high temperature. Another case study that investigates the correlation between river discharges and RSEs is carried out to demonstrate the potential consequences of the derived snowline dynamics. The correlation analysis shows a good correlation between river discharges and RSEs (correlation coefficient, R=0.52).

In this thesis, the developed framework signifies a better understanding of the snow dynamics in mountain areas, as well as their potential triggers and consequences. Nonetheless, an urgent need persists for: (1) validation data to assess long-term snow-related observations based on high-resolution EO data; (2) further studies to reveal interactions between snow and its ambient environment; and (3) regional and local adaptation-strategies coping with climate change. Further studies exploring the above-mentioned research gaps are urgently needed in the future.
N2  - Weltweit erleben kalte Regionen signifikante Veränderungen durch den Klimawandel. In kalten Regionen ist der Schnee die am weitesten verbreitete Komponente, welche sehr sensibel auf Klimaänderungen reagiert. Zugleich beeinflusst der Schnee selbst das Energiebudget der Erde, die Biodiversität, Naturgefahren sowie Wasserenergiegewinnung, Süßwassergewinnung, Wintertourismus und Wintersport. Große Teile der kalten Regionen in Europa sind Gebirgsregionen. Diese sind dicht besiedelt, da Gebirgsregionen verschiedenste Ökosystemservices bereitstellen und sozioökonomisches Wohlbefinden ermöglichen. Heute kann man schwerwiegende Konsequenzen in Europäischen Gebirgen und deren angrenzenden Gebieten wahrnehmen. Dennoch verhindern große Wissenslücken die Entwicklung effektiver und regionaler/lokaler Anpassungsstrategien. Um regionaler Auswirkungen durch den Klimawandel besser verstehen zu können, ist es enorm wichtig Langzeitstudien und beweisorientierte regionale Studien durchzuführen.
Erdbeobachtung (EO) bietet durchgängige Langzeitaufzeichnungen der Erdoberfläche. Dies ist eine großartige Alternative und/oder Ergänzung zu konventionellen in-situ Messungen, welche meist zeitaufwändig, teuer und logistisch herausfordernd sind – vor allem in kalten Regionen, die schwer zugänglich sind. Mit der Hilfe von Erdbeobachtung können Oberflächendynamiken objektiv, wiederholt, synoptisch und kontinuierlich aufgenommen werden. Dank freier und offener Datenpolitik, Langzeitmissionen wie Landsat und Sentinel sind diese Daten inzwischen ohne zusätzliche Kosten zugänglich. Durch die oben genannten Rahmenbedingungen, besteht die Möglichkeit aus hoch bis mittel aufgelöste Satellitenbilder erdbeobachtungsbasierte Zeitreihen zu erstellen, die die Schneedynamiken in Europäischen Gebirgen abbilden. Um dieses Ziel zu erreichen, muss die räumliche und zeitliche Verfügbarkeit von Erdbeobachtungsdaten überprüft werden und ein Rahmenwerk geschaffen werden (übertragbar in Zeit und Raum), um Schneedynamiken aus Erdbeobachtungsdaten großflächig ableiten zu können.
Unter den verfügbaren Erdbeobachtungsarchiven bietet das Landsat Archiv die längsten und kontinuierlichsten Aufzeichnungen der Landoberfläche. Zudem erfüllt die räumliche Auflösung von 30 m die Anforderungen, Schnee in komplexem Terrain zu monitoren. Basierend auf Landsat L1TP Daten (z.B. terrainkorrigiert) ist es möglich, Zeitreihen von Schneedynamiken in Gebirgsregionen zwischen 1984 und 1991/1999 zu erstellen. Des Weiteren ist Landsat L1TP in hohen Breitengraden seltener verfügbar (bis zu 50 % weniger) als in Gebirgsregionen der gemäßigten Breiten. Basierend auf den oben genannten Fakten wurde die Regionale Höhe der Schneefallgrenze (RSE) ausgewählt um Schneedynamiken in Gebirgsregionen zu charakterisieren, da diese Wolken in optischen Szenen bewältigen kann. In dieser Arbeit wurde ein fünf-Stufen Rahmenwerk geschaffen, um RSE-Zeitserien in Europäischen Gebirgen abzuleiten und zu verdichten. Die Prozessierungskette besteht aus (1) Vorprozessierung, (2) Schneedetektion, (3) RSE-Ableitung, (4) Zeitreihenverdichtung und (5) Erstellung einer regionalen Schneegrenzen-Rückgangsfunktion (RSRC).
Die Ergebnisse der intra-annuellen RSE Variationen zeigen eine einzigartige hohe Variation im Beginn der Abschmelzsaison im alpinen Einzugsgebiet Tagliamento, meist in höheren Gebieten. Wie für die inter-annuellen Variationen des RSE, steigt auch der Median des RSE in allen ausgewählten Einzugsgebieten mit einer durchschnittlichen Geschwindigkeit von 4.66 m ∙ a−1 (median) und 5.87 m ∙ a−1 (zum Beginn der Schmelze). Der schnellste signifikante Rückgang kann im Einzugsgebiet Drac (10.66 m ∙ a−1, Beginn der Schmelze) beobachtet werden, der langsamste Rückgang im Einzugsgebiet Uzh (1.74 m ∙ a−1, Beginn der Schmelze). Der Anstieg des RSE zu Beginn der Schmelzsaison ist schneller als der Median des RSE, dessen mittlere Differenz 1.21 m ∙ a−1 beträgt. Insbesondere für das Drac Einzugsgebiet (3.72 m ∙ a−1). Die Ergebnisse des RSRC zeigen signifikante Anstiege des RSE zu Beginn des Schmelzsaison, ausgenommen davon sind die alpinen Einzugsgebiete Alpenrhein und Var und das Einzugsgebiet Ariege in den Pyrenäen. Dies lässt darauf zurückschließen, dass 11.8 °C und 3.97 °C Grad weniger pro Jahr nötig sind für Tagliamento und Tysa, damit die regionalen Schneegrenzen den Mittelpunkt des RSRC erreicht. Zudem wird die Variation der Lufttemperatur als beispielhafter Treiber des Klimas in dieser Thesis gesehen. Die monatlich abgeleiteten mittleren RSE korrelieren stark (mittlerer korrelations Coeffizient R ̅ = 0.7) mit monatlichen Temperaturanomalien. In Monaten mit extrem hohen/tiefen Temperaturen ist die Korrelation am stärksten. Ein anderes Fallbeispiel untersucht die Korrelation zwischen Abfluss in Flüssen und RSE, um die potenziellen Konsequenzen der abgeleiteten Schneefallgrenzendynamiken zu ermitteln. Die Korrelationsanalyse weist eine gute Korrelation auf (R=0.52). 
Das in dieser Arbeit entwickelte Rahmenwerk ist nur ein Beginn, um das Wissen über Schneedynamiken in Gebirgsregionen zu verbessern und potentiell auslösende Faktoren und Konsequenzen zu verstehen. Dennoch wird folgendes dringend benötigt: (1) Validierungsdaten für schneebasierte Langzeitbeobachtungen aus hochaufgelösten Erdbeobachtungsdaten; (2) weitere Studien zu Interaktionen zwischen Schnee und der umgebende Umwelt; und (3) regionale und lokale Anpassungsstrategien, um Auswirkungen des Klimawandels zu meistern. Weitere Studien in den oben genannten Punkten werden in der Zukunft stark frequentiert sein, damit Wissens- und Forschungslücken geschlossen werden können.
KW  - Fernerkundung
KW  - Schnee
KW  - Europa
KW  - Remote Sensing
KW  - Snow
KW  - Europe
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200441
ER  - 
TY  - THES
A1  - Schlereth, Raimund
T1  - New techniques and improvements in the MBE growth of Hg-containing narrow gap semiconductors
T1  - Neue Techniken und Verbesserung des MBE Wachstums Hg-haltiger Halbleiter mit schmaler Bandlücke
N2  - The subject of this thesis is the growth of Hg\(_{1-x}\)Cd\(_2\)Te layers via molecular beam epitaxy (MBE).
This material system gives rise to a number of extraordinary physical phenomena related to its electronic band structure and therefore is of fundamental interest in research.
The main results can be divided into three main areas, the implementation of a temperature measurement system based on band edge thermometry (BET), improvements of CdTe virtual substrate growth and the investigation of Hg\(_{1-x}\)Cd\(_2\)Te for different compositions.
N2  - Gegenstand dieser Arbeit ist das Wachstum von Hg\(_{1-x}\)Cd\(_2\)Te-Schichten mittels Molekularstrahlepitaxie (MBE).
Die elektronische Bandstruktur dieses Materials führt zu einer Reihe außergewöhnlicher physikalischer Phänomene. 
Es ist daher für die Forschung von grundlegendem Interesse.
Die Ergebnisse lassen sich in drei Hauptbereiche unterteilen: die Implementierung eines Temperaturmessgeräts basierend auf dem Prinzip der Bandkantenthermometrie (BET), die Verbesserung des Wachstums von virtuellen CdTe-Substraten und die Untersuchung von Hg\(_{1-x}\)Cd\(_2\)Te-Schichten für verschiedene Materialkonzentrationen.
KW  - Halbleiter
KW  - Band edge thermometry
KW  - Molekularstrahlepitaxie
KW  - Molecular Beam Epitaxy
KW  - Semiconductor
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200790
ER  -