Scientific publications of the Saarland University
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Prediction of lesion-based response to PRRT using baseline somatostatin receptor PET
Full text linkAim: The heterogeneous expression of somatostatin receptors in
gastroenteropancreatic neuroendocrine tumors (GEP-NET) leads to significant
intra-individual variability in tracer uptake during pre-therapeutic [68Ga]Ga DOTATOC PET/CT for patients receiving peptide receptor radionuclide therapy
(PRRT). This study aims to evaluate the lesion-based relationship between
receptor-mediated tracer uptake and the functional response to PRRT.
Methods: A retrospective analysis was conducted on 32 patients with
metastatic GEP-NET (12 pancreatic and 20 non-pancreatic), all treated with
[
177Lu]Lu-octreotate (4 cycles, with a mean of 7.9 GBq per cycle). [68Ga]Ga DOTATOC PET/CT was performed at baseline and 3 months after the final
PRRT cycle. Tumor uptake was quantified using the standardized uptake value
(SUV). For each patient, 2 to 3 well-delineated tumor lesions were selected as
target lesions. SUVmax, SUVmean (automated segmentation with a 50% SUVmax
threshold), and corresponding tumor-to-liver ratios (SUVmaxT/L and SUVmeanT/L)
were calculated. Functional tumor response was assessed based on the relative
change in metabolic tumor volume (%ΔTVPET). The correlation between baseline
SUV parameters and lesion-based functional response was analyzed using
Spearman’s rank correlation.
Results: A total of 71 lesions were included in the analysis. The mean baseline
SUVmax and SUVmean were 28.1 ± 15.9 and 13.6 ± 5.1, respectively. Three months
after PRRT completion, the mean %ΔTVPET was 39.6 ± 52.1%. Baseline SUVmax and
SUVmean demonstrated a poor correlation with lesion-based response (p = 0.706
and p = 0.071, respectively). In contrast, SUVmaxT/L and SUVmeanT/L were significantly
correlated with lesion-based response (SUVmeanT/L: p = 0.011, r = 0.412; SUVmaxT/L:
p = 0.004, r = 0.434). Among patient characteristics—including primary tumor
origin, baseline tumor volume, and metastatic sites—only pancreatic origin
was significantly associated with functional tumor volume reduction (ΔTVPET%:
56.8 ± 39.8 in pancreatic vs. 28.4 ± 50.1 in non-pancreatic NET; p = 0.020).
Conclusion: The lesion-based molecular response to PRRT correlates with
pretreatment somatostatin receptor PET uptake, particularly when expressed as
tumor-to-liver SUV ratios (SUVmaxT/L and SUVmeanT/L)
Repeatability of biometric measures from the LenStar LS900 in a cataractous population
Full text linkPurpose
To investigate the repeatability of biometric measures and assess interactions between
their uncertainties for use in an error propagation model, using patient data.
Methods
Cross-sectional non-randomised study evaluating a dataset containing 969 LenStar 900
biometric measurements taken before cataract surgery. Only complete scans with at least
3 successful measurements for each eye performed on the same day were considered.
For each sequence, the aggregated mean (AMEAN) and population standard deviations
(ASD) were derived. The within-subject standard deviation Sw was extracted for: corneal
thickness, CCT, anterior chamber depth ACD, lens thickness LT, axial length AL, corneal
diameter WTW, and the keratometric power vector components equivalent power KEQ, and
the projections of corneal astigmatism KC0 and KC45. Correlations between the uncertain ties were assessed using Spearman rank correlations.
Results
For the 266 eyes matching the inclusion criteria, Sw was 3.6/ 24.7/35.5/ 17.7/ 107.5 µm for
CCT/ ACD/ LT/ AL WTW and 0.18/ 0.12/ 0.10 dioptres for KEQ/ KC0/ KC45. The kerato metric axis ASD is inversely proportional to the keratometric astigmatism AMEAN. LT
and ACD uncertainties are strongly negatively correlated, with KEQ and KC0 uncertainties
moderately correlated.
Conclusions
The uncertainty and correlation data presented here could be used to define a
Monte-Carlo based error propagation model mapping the biometric measures and uncer tainties to variations in predicted refraction after cataract surgery. We recommend using
power vector components for error propagation models since the large decay over kerato metric astigmatism makes keratometric axis uncertainty unreliable
Relationship Between Prostaglandin and Interleukin Concentrations in Seminal Fluid and Their Influence on the Rate of Fertilization in Men Undergoing ICSI
Full text linkSperm count, motility, and morphology are semen parameters that directly affect male
fertility. The presence of cytokines in seminal plasma negatively or positively influences
these parameters. Interleukins and prostaglandins are proinflammatory cytokines present
in human seminal plasma and play crucial roles in fertilization, in general and after
intracytoplasmic sperm injection (ICSI) procedures. This study aimed to investigate the
possible influence of interleukins IL-17 and IL-18, and prostaglandins PGE2 and PGF2α
on male infertility. Semen samples were collected from 58 males who underwent the ICSI
procedure. An enzyme-linked immunosorbent assay (ELISA) was used to determine the
levels of IL-17, IL-18, PGE2, and PGF2α, and these concentrations were then correlated
with semen parameters and the rate of fertilization. Furthermore, the chromatin integrity
of the sperm was evaluated with an Acridine Orange (AO) assay. The results showed an
inversely proportional relationship between the AO binding intensity and fertilization
rate (r = −0.394; p ≤ 0.002). Furthermore, a negative correlation was observed between
the IL-18 concentration and positive AO (p ≤ 0.021). Moreover, the IL-18 concentration
was positively correlated with the fertilization rate (p ≤ 0.05). In contrast, IL-17 did not
significantly correlate with any semen parameters or with the fertilization rate. Seminal
PGE2 levels were significantly correlated with embryo cleavage at 72 h (p ≤ 0.05). To
conclude, this study revealed that denaturation of sperm nuclear deoxyribonucleic acid
(DNA) contributes to low fertilization rates. In addition, this study proposed a potential
role for IL-18 in fertilization. PGE2 likely influences embryo development, but further
studies are needed to examine the impact of seminal PGE2 on the oocyte to fully elucidate
its contribution to this complex biological process
Bidirektionale Kommunikation von Eukaryoten und Prokaryoten über extrazelluläre Vesikel
No full textExtrazelluläre Vesikel sind kleine Lipid-Membranpartikel, die von Pro- und Eukaryoten in den extrazellulären Raum sezerniert werden und eine Reihe von verschiedenen Molekülen wie Proteine, Lipide aber auch Nukleinsäuren wie etwa RNA transportieren können (Yáñez-Mó et al., 2015). In den vergangenen Jahren konnte gezeigt werden, dass extrazelluläre Vesikel eine wichtige Funktion bei der Cross-Kingdom Kommunikation zwischen Bakterien und humanen Zellen ausüben. Insbesondere hat dabei die Rolle der mit den extrazellulären Vesikeln assoziierten RNAs sowie der Zusammenhang mit der Entstehung und Progression von verschiedenen Erkrankungen immer weiter an Interesse gewonnen (Amatya et al., 2021; Iyaswamy et al., 2023; Munhoz da Rocha et al., 2020; Q. Shen et al., 2022).
Morbus Parkinson ist eine der häufigsten neurodegenerative Erkrankung der Welt (Poewe et al., 2017). Zahlreiche Studien haben gezeigt, dass bei Parkinson-Patienten Veränderungen in der Zusammensetzung des Darmmikrobioms auftreten (Hill-Burns et al., 2017; Hopfner et al., 2017; A. Lin et al., 2018). Kürzlich konnte zudem nachgewiesen werden, dass diese Veränderungen im Zusammenhang mit bei Parkinson-Patienten häufig auftretenden Obstipationen stehen (Fu et al., 2022), welche zum Teil Jahre vor der Diagnose der Erkrankung in Erscheinung treten können (Adams-Carr et al., 2016; Noyce et al., 2012; Svensson et al., 2016). In den vergangenen Jahren wurde daher vermehrt der Gastrointestinaltrakt als Ursprung von M. Parkinson diskutiert (Breen et al., 2019; Houser & Tansey, 2017; Lionnet et al., 2018). Voraussetzung für den Einfluss des Darmmikrobioms auf die Pathogenese von Morbus Parkinson ist jedoch eine wechselseitige Kommunikation den Bakterien auf der einen und den Darmepithelzellen auf der anderen Seite.
Das Ziel der vorliegenden Arbeit bestand somit darin die Kommunikation von Bakterien, bei denen eine Verbindung zu Morbus Parkinson besteht, und humanen intestinalen Epithelzellen über extrazelluläre Vesikel zu untersuchen. Zu diesem Zweck wurde zunächst die Zusammensetzung des Darmmikrobioms von Parkinson-Patienten im Vergleich zu gesunden Kontrollprobanden untersucht, um Bakterienfamilien und -spezies mit veränderter Häufigkeit zu identifizieren. Im Folgenden wurden die Bakterien Lacticaseibacillus casei, Enterococcus faecalis und Proteus mirabilis exemplarisch ausgewählt und deren extrazelluläre Vesikel näher charakterisiert. Dabei zeigte sich, dass alle untersuchten Bakterien in unterschiedlichem Maße extrazelluläre Vesikel sezernieren und diese sowohl zeit- als auch konzentrationsabhängig von humanen Darmepithelzellen aufgenommen werden, wobei die extrazellulären Vesikel von Enterococcus faecalis und Proteus mirabilis deutlich schneller internalisiert wurden als die von Lacticaseibacillus casei. Darüber hinaus wurde gezeigt, dass alle bakteriellen extrazellulären Vesikel unterschiedliche RNA-Fragmente transportieren, wobei der größte Anteil kleine RNAs mit einer Länge unter 200 Nukleotiden waren. Die Analyse des Transkriptoms der Darmepithelzellen zeigte, dass sowohl die bakteriellen extrazellulären Vesikel als auch die damit assoziierte RNA selbst zu spezifischen Veränderungen in der Genexpression unter anderem von Zytokinen und Chemokinen führen kann. Zusätzlich konnte gezeigt werden, dass die durch die extrazellulären Vesikel von Proteus mirabilis hervorgerufenen Effekte nicht alleine durch die in den extrazellulären Vesikeln enthaltenen Lipopolysaccharide erklärt werden konnten.
Um die Kommunikation der humanen Zellen mit Bakterien näher analysieren zu können, wurden die bereits untersuchten Bakterienspezies mit extrazellulären Vesikeln, welche von Darmepithelzellen sezerniert wurden, inkubiert. Dabei zeigte sich, dass vor allem Enterococcus faecalis dazu in der Lage war, eukaryotische extrazelluläre Vesikel zu internalisieren, wodurch das Wachstum der Bakterien beeinflusst werden konnte. Mit Hilfe einer smallRNA-Sequenzierung konnten anschließend microRNAs, unter anderem die miR 192-5p, identifiziert werden, die in extrazellulären Vesikel von Darmepithelzellen sezerniert wurden. Weitere Analysen haben gezeigt, dass Proteus mirabilis im Gegensatz zu den anderen beiden Bakterien dazu in der Lage war, die humane miR-192-5p zu internalisieren. Durch die Verpackung der miRNA in artifizielle Liposomen konnte die Aufnahme in Lacticaseibacillus casei und Enterococcus faecalis jedoch deutlich gesteigert werden.
Zusammenfassend konnten die Ergebnisse dieser Arbeit die individuellen Auswirkungen der verschiedenen bakteriellen extrazellulären Vesikel sowie der damit assoziierten RNA bei der Kommunikation mit humanen Darmepithelzellen zeigen. Darüber hinaus liefern die Untersuchungen Einblicke in die Fähigkeit von eukaryotischen Zellen mit Bakterien über humane microRNAs zu kommunizieren. Die gewonnenen Erkenntnisse sollen somit dazu beitragen die bidirektionale Kommunikation zwischen Pro- und Eukaryoten im Rahmen von verschiedenen Erkrankungen besser zu verstehen.Extracellular vesicles are small membrane particles that can be secreted by prokaryotes and eukaryotes into the extracellular space. Their cargo can include a variety of different molecules such as proteins, lipids, and nucleic acids like RNA (Yáñez-Mó et al., 2015). Recently, it has been demonstrated that extracellular vesicles play a critical role in cross-kingdom communication between bacteria and human cells. In this context, the role of EV-associated RNAs and their connection to the development and progression of various diseases have gained increasing interest (Amatya et al., 2021; Iyaswamy et al., 2023; Munhoz da Rocha et al., 2020; Q. Shen et al., 2022).
Parkinson's disease is one of the most common neurodegenerative diseases in the world (Poewe et al., 2017). Numerous studies have demonstrated changes in the composition of the gut microbiome in Parkinson's patients (Hill-Burns et al., 2017; Hopfner et al., 2017; A. Lin et al., 2018). Recent findings suggest that these alterations are associated with constipation, a common symptom in Parkinson’s patients (Fu et al., 2022), which can manifest years for the diagnosis of the disease (Adams-Carr et al., 2016; Noyce et al., 2012; Svensson et al., 2016). In the past years, the gastrointestinal tract has therefore increasingly been discussed as a potential origin of Parkinson’s disease (Breen et al., 2019; Houser & Tansey, 2017; Lionnet et al., 2018). However, a prerequisite for the influence of the gut microbiome on the pathogenesis of Parkinson's disease is the bidirectional communication between bacteria on one side and intestinal epithelial cells on the other.
Hence, the aim of this thesis was to investigate the communication between bacteria associated with Parkinson's disease and human intestinal epithelial cells via extracellular vesicles. At first, the composition of the gut microbiome in Parkinson’s patients was compared to that of healthy controls to identify bacterial families and species with altered abundances. Subsequently, the bacteria Lacticaseibacillus casei, Enterococcus faecalis, and Proteus mirabilis were selected for further characterization of their extracellular vesicles. It was found that all examined bacteria secrete extracellular vesicles to varying degrees, which were taken up by human intestinal epithelial cells in a time- and concentration-dependent manner. Notably, extracellular vesicles from Enterococcus faecalis and Proteus mirabilis were internalized significantly faster than those from Lacticaseibacillus casei. Furthermore, it was shown that all bacterial extracellular vesicles transport various RNA fragments, with a majority of these RNAs being smallRNAs with a length under 200 nucleotides. Transcriptome analysis of intestinal epithelial cells revealed that both bacterial extracellular vesicles and associated RNA itself can lead to specific changes in the expression of genes, including those encoding for cytokines and chemokines. Moreover, it was shown that the effects caused by extracellular vesicles from Proteus mirabilis were not exclusively caused by lipopolysaccharides contained in these vesicles.
To further analyze the communication between human cells and bacteria, the previously studied bacterial species were incubated with extracellular vesicles secreted from intestinal epithelial cells. It has been observed that especially Enterococcus faecalis could internalize eukaryotic extracellular vesicles, which subsequently influenced the bacterial growth. Using smallRNA sequencing, microRNAs including miR-192-5p have been identified, which were secreted in extracellular vesicles from intestinal epithelial cells. Further analyses demonstrated that, unlike the other two bacteria, Proteus mirabilis was able to internalize human miR-192-5p. However, packaging of the microRNA into artificial liposomes significantly increased the uptake in Lacticaseibacillus casei and Enterococcus faecalis.
In summary, the findings of this thesis highlight the individual effects of bacterial extracellular vesicles and their associated RNAs in communication with human intestinal epithelial cells. Furthermore, the results provide insights into the ability of eukaryotic cells to communicate with bacteria via human microRNAs. These findings aim to enhance the understanding of bidirectional communication between prokaryotes and eukaryotes in the context of various diseases
Entwicklung von Pflege-Wohngemeinschaften für Menschen mit Demenz und deren Perspektiven im Hinblick auf den demographischen Wandel
Full text linkMitte der 1990er Jahre wurde die erste Pflege-Wohngemeinschaft für Menschen mit Demenz (MmD) in Berlin gegründet. Seither sind in Deutschland zahlreiche Pflege-Wohngemeinschaften entstanden, im vierstelligen Bereich, etwa zwischen 3.500 und 4.000, selbst ohne spezielle Ausrichtung. Diese Entwicklung wurde insbesondere durch das Pflege-Neuausrichtungsgesetz (PNG) im Jahr 2012 maßgeblich beschleunigt. Aufgrund des demographischen Wandels, mit der Verrentung der geburtenstarken Jahrgänge und der gleichzeitig ansteigenden pflegebedürftigen Gesellschaft ist die Sicherstellung der Gesundheitsversorgung als eine große gesellschaftliche Herausforderung der nächsten Jahre zu sehen. Gleichsam verändern sich Familienstrukturen, so dass die häusliche Pflege durch An- und Zugehörige nicht mehr als fester Bestandteil der Betreuungs- und Sorgearbeit angenommen werden kann. Das Konzept der Pflege-Wohngemeinschaften scheint zusätzlich stimmig zu sein mit den Vorstellungen von Pflege und Wohnen im Alter der neuen alternden Generation, da Individualität, Autonomie und Selbstbestimmung im Vordergrund stehen.Abstract
The first residential care community for people with dementia was founded in Berlin in the mid-1990s. Since then, numerous residential care communities have been established in Germany, even without a special focus, in the four-digit range between 3,500 and 4,000. In particular, this development was significantly accelerated by the Care Reorganisation Act (PNG) in 2012. Due to demographic change, with the retirement of the baby boomers and the simultaneous rise in the number of people requiring care, securing healthcare provision must be seen as a major social challenge in the coming years. At the same time, family structures are changing, so that home care by relatives can no longer be accepted as an integral part of caring work. The concept of residential care communities also appears to be consistent with the ideas of care and living in old age of the new ageing generation, as individuality, autonomy and self-determination are at the forefront.
Research question
This dissertation examines the current development of residential care communities for people with dementia and their perspective in the context of demographic change. However, it is only partially possible to fully answer the underlying question. The lack of transparency regarding the number and specific orientation of residential care communities makes it difficult to clearly identify trends at state and national level.
Methodological approach
An extensive literature review was conducted on the topic, the results of which are analysed in detail.
Results and findings
Due to considerable differences in the distribution of small-scale residential care arrangements at a national level and the lack of valid data, it is currently not possible to make concrete statements about current developments or the future prospects of outpatient residential communities. The identification of dementia residential communities in particular poses a major challenge, as people with dementia can also live in residential care communities, although these do not have to be explicitly designated as dementia residential communities. In addition, the availability of coordination and advice centres for shared care homes is not guaranteed in every federal state, which makes start-up projects more difficult and underlines the above-mentioned lack of transparency. Within the analysis, this results in four recommendations for action relating to security of supply, planning security, sustainability, and counselling structures. If the recommendations for action are observed and taken into account, a structured supply and demand management system can be derived that strengthens a further branch of care that will certainly be needed in the future alongside the established structures of outpatient and inpatient long-term care
Pex30-dependent membrane contact sites maintain ER lipid homeostasis
Full text linkIn eukaryotic cells, communication between organelles and the coordination of their activities depend on membrane contact
sites (MCS). How MCS are regulated under the dynamic cellular environment remains poorly understood. Here, we investigate
how Pex30, a membrane protein localized to the endoplasmic reticulum (ER), regulates multiple MCS in budding yeast. We
show that Pex30 is critical for the integrity of ER MCS with peroxisomes and vacuoles. This requires the dysferlin (DysF)
domain on the Pex30 cytosolic tail. This domain binds to phosphatidic acid (PA) both in vitro and in silico, and it is important for
normal PA metabolism in vivo. The DysF domain is evolutionarily conserved and may play a general role in PA homeostasis
across eukaryotes. We further show that the ER–vacuole MCS requires a Pex30 C-terminal domain of unknown function and
that its activity is controlled by phosphorylation in response to metabolic cues. These findings provide new insights into the
dynamic nature of MCS and their coordination with cellular metabolism
Weighted Composition Operators on Hilbert Function Spaces on the Ball
Full text linkA weighted composition operator on a reproducing kernel
Hilbert space is given by a composition, followed by a multiplication.
We study unitary and co-isometric weighted composition operators on
unitarily invariant spaces on the Euclidean unit ball Bd. We establish a
dichotomy between the spaces Hγ with reproducing kernel (1 − z, w )
−γ
for γ > 0, and all other spaces. Whereas the former admit many unitary
weighted composition operators, the latter only admit trivial ones. This
extends results of Mart´ın, Mas and Vukoti´c from the disc to the ball.
Some of our results continue to hold when d = ∞
Synthesis and reactivity of the smallest diboraheterocycles and diboratabutadienes
No full textThe unique properties of boron compounds make them extremely valuable and versatile in chemical reactions and applications. While various acyclic and cyclic organoboron compounds have been extensively studied, the smallest neutral and charged diboron-containing heterocycles remain underexplored, likely due to their limited accessibility. To facilitate investigations on B2C-heterocycles, this thesis deals with the straightforward access to non-classical diboriranes and diboriranides through functionalization of simple diboranes(4). While the obtained diboriranides act as sigma-donating ligands towards different metals, non-classical diboriranes give rise to transition metal pi-complexes. Furthermore, the obtained complexes derived from non-classical diboriranes were shown to incorporate carbon monoxide in ring expansion reactions in side-on or end-on fashion depending on the nature of the bridging moiety BRB. As for the smallest B-B containing heterocycles, small charged acyclic diboron compounds have received little attention compared to the rapidly growing field of neutral diborane applications. Although the structural motif of a 2,3-diboratabutadiene has been known for decades, the choice of unsuitable substituents presumably precluded the formation of butadiene metal complexes with internal B-B bond. In this thesis a novel tetraarylated 2,3-diboratabutadiene was shown to be a suitable ligand for Group 4 metallocenes.Die einzigartigen Eigenschaften von Borverbindungen machen sie für chemische Reaktionen und Anwendungen äußerst wertvoll und vielseitig. Während verschiedene zyklische und azyklische Organoborverbindungen ausgiebig untersucht wurden, sind die kleinsten neutralen oder geladenen diborhaltigen Heterozyklen noch nicht ausreichend erforscht, was wahrscheinlich auf ihre begrenzte Zugänglichkeit zurückzuführen ist. Um Untersuchungen an B2C-Heterozyklen zu erleichtern, befasst sich die vorliegende Arbeit mit einem geradlinigen Zugang zu nicht-klassischen Diboriranen und Diboriraniden durch Funktionalisierung einfacher Diborane(4). Während die erhaltenen Diboriranide als -donierende Liganden gegenüber verschiedenen Metallen fungieren, führen nicht-klassische Diborirane zu Übergangsmetall -Komplexen. Darüber hinaus wurde gezeigt, dass die erhaltenen Komplexe, die von nicht-klassischen Diboriranen abgeleitet sind, CO in Ringerweiterungsreaktionen in Abhängigkeit von der Art der verbrückenden Einheit BRB side-on oder end-on einbauen können. Wie schon bei den kleinsten B-B-haltigen Heterozyklen haben kleine geladene azyklische Diborverbindungen im Vergleich zum schnell wachsenden Bereich der neutralen Diboran-Anwendungen wenig Aufmerksamkeit erhalten. Obwohl das Motiv eines 2,3-Diboratabutadiens seit Jahrzehnten bekannt ist, hat die Wahl ungeeigneter Substituenten vermutlich die Bildung von Butadien Metallkomplexen mit interner B-B-Bindung verhindert. In dieser Arbeit wurde gezeigt, dass ein neuartiges tetraaryliertes 2,3-Diboratabutadien ein geeigneter Ligand für Metallocene der Gruppe 4 ist
Water-Induced Transparency Loss in Styrene Butadiene Block Copolymers: Mechanism, Morphology, and Predictive Modeling
Full text linkWater-induced transparency loss in styrene−butadiene block copolymers (SBCs) has been investigated under a
variety of conditions. Consistent with earlier work on homopolymers, the opacity after prolonged water exposure is expected to be
caused by water clustering, which results from stronger water−water than water−polymer interactions. The water clusters distort the
surrounding polymer matrix, causing local changes in the refractive index. It was found that the hard phase has only a minor
contribution to the transparency loss, while the rubbery phase appears to be the major contributor. However, the loss of
transparency was found not to be directly proportional to the volume of the soft phase, and a significant effect of the block
copolymer morphology was observed, which was confirmed by a series of transmission electron microscopy and SAXS
measurements. This effect is particularly evident in the transition from a continuous hard phase through a co-continuous
morphology to a continuous soft phase. The acquired insights were subsequently used to predict long-term optical performance in
SBCs to provide a tool in product development. Loss of transparency predictions was proven to be adequate through a classical
regression-extrapolation approach using a limited data set, accurately simulating performance beyond 2600 h exposure time using
only 600 h of measurement time. Additionally, it was shown that artificial neural networks could provide a solid tool in predicting
performance even prior to synthesis, granted that the selection of descriptors is complete and the appropriate amount of data is
supplied with a proper spread over the descriptor space
Explaining goal conflicts in oversubscription planning
Full text linkMany real-world planning scenarios are characterized by oversubscription problems such as logistics with limited vehicle capacity and fuel restrictions, rover mission planning with time and energy constraints, but also your weekly activity and housework plans with insufficient free time. As a result, not all goals within the given task can be satisfied. Conventional approaches assume global optimization objectives, but it is often difficult to identify such objectives, and they are frequently in conflict with one another. An iterative planning approach is more suitable, wherein users consider sample plans and refine their preferences based on these plans. In such a setting, it is crucial to provide not only the plans themselves, but also explanations elucidating the conflicts between goals, preferences and objectives. This facilitates the user's understanding and enable them to identify satisfactory trade-offs. To this end, we introduce a form of contrastive explanation. We support user questions of the form ``Why is Q not achieved by the plan?'', by providing explanations through goals A that conflict with Q, i.e. ``To satisfy Q you have to forgo A''. We develop a set of algorithms that enable this form of explanation by computing the minimal unsolvable goal subsets based on goal space search and state space search. The evaluation of these algorithms shows that the required analysis in terms of scalability is comparable to that of oversubscription planning. Additionally, we conducted a large user study with crowdworkers (N=100 in each of 3 domains) to evaluate our framework. We compared users with and without access to explanations and found that the explanations enabled users to better identify trade-offs, indicating a better understanding of the planning task. Conflicts often arise due to resource or time constraints. We address the follow-up question "Why is A in conflict with Q?" by providing explanations based on the minimum relaxations of constraints under which the conflict resolves. We investigate two approaches to computing such explanations: specialized algorithms and compilation. A basic algorithm involves simply looping over all relaxations and computing the conflicts for each relaxation separately. We improve over this with two algorithms that exploit information such as reachable goal subsets and states across relaxations. Alternatively, we explore a compilation using specialized soft goals that identify each relaxation. In order to provide valuable explanations, it is essential that explanations cover aspects of the plans in which the user is interested. However, users often find it difficult to formalize their preferences. Therefore, we explore the potential of learning preferences from example plans, focusing on a single preference at a time and requesting that the user rates examples as either good or bad. Based on prior work on learning LTLf formulas, we then extract a preference from these examples. We conduct an empirical study of this approach in a classical planning setting, using hidden target formulas to simulate user preferences.Viele reale Planungsszenarien sind durch Überschreibungsprobleme gekennzeichnet, z. B. die Logistik mit begrenzter Fahrzeugkapazität und Treibstoffbeschränkungen, die Planung von Rover-Missionen mit Zeit- und Energiebeschränkungen, aber auch die Planung der wöchentlichen Aktivitäten und Hausarbeiten bei unzureichender Freizeit. Infolgedessen können nicht alle Ziele erfüllt werden. Herkömmliche Ansätze gehen von globalen Optimierungszielen aus, doch ist es oft schwierig, solche Ziele zu identifizieren, und sie stehen häufig in Konflikt zueinander. Besser geeignet ist ein iterativer Planungsansatz, bei dem die Benutzer Musterpläne betrachten und ihre Präferenzen auf der Grundlage dieser Pläne verfeinern. Bei einem solchen Ansatz ist es von entscheidender Bedeutung, nicht nur die Pläne selbst, sondern auch Erklärungen zu den Konflikten zwischen Zielen, Präferenzen bereitzustellen. Dies erleichtert das Verständnis des Nutzers und versetzt ihn in die Lage, zufriedenstellende Kompromisse zu finden. Zu diesem Zweck führen wir eine Form der kontrastiven Erklärung ein. Wir unterstützen Nutzerfragen der Form ``Warum wird Q nicht durch den Plan erreicht''. Wir beantworten diese in Form von Zielen A, die mit Q in Konflikt stehen, d.h.``Um Q zu erfüllen, muss man auf A verzichten''. Wir entwickeln eine Reihe von Algorithmen, die diese Form der Erklärung ermöglichen, indem sie die minimalen unlösbaren Zielteilmengenauf der Grundlage von Zielraumsuche und Zustandsraumsuche berechnen. Die Evaluierung dieser Algorithmen zeigt, dass die erforderliche Analyse in Bezug auf Skalierbarkeit sich ähnlich wie Überschreibungsprobleme verhält. Darüber hinaus führen wir eine große Crowd-Worker-Benutzerstudie durch (N=100 in jeder von 3 Domänen), in der wir unser Framework evaluieren. Im Vergleich zwischen Nutzern mit und ohne Zugang zu den Erklärungen stellen wir fest, dass die Erklärungen es den Nutzern ermöglicht, Kompromisse besser zu erkennen, was auf ein besseres Verständnis der Planungsaufgabe hindeutet. Konflikte entstehen oft aufgrund von Ressourcen- oder Zeitmangel. Wir adressieren die Folgefragen ``Warum ist A im Konflikt mit Q?'' mit Erklärungen, die auf den minimalen Relaxierung der Beschränkungen basieren, unter denen die Konflikte verschwinden. Wir untersuchen zwei Ansätze zur Berechnung solcher Erklärungen: spezialisierte Algorithmen und Kompilierung. Der Basis-Algorithmus besteht darin, über alle Relaxierungen zu iterieren und die Konflikte für jede einzeln zu berechnen. Wir verbessern diesen Ansatz mit zwei Algorithmen, die Informationen wie erreichbare Zielteilmengen und Zustände über die Relaxierungen hinweg nutzen. Alternativ dazu erforschen wir eine Kompilierung unter Verwendung spezialisierter weicher Ziele, die die Relaxierungen identifizieren. Um nützliche Erklärungen geben zu können, ist es wichtig, dass die Erklärungen die Aspekte der Pläne abdecken, an denen der Nutzer interessiert ist.Allerdings fällt es den Nutzern oft schwer, ihre Präferenzen zu formalisieren. Daher untersuchen wir das Potenzial des Lernens von Präferenzen anhand von Beispielplänen. Wir konzentrieren uns jeweils auf eine einzelne Präferenz und fordern den Nutzer auf, Beispiele entweder als gut oder schlecht zu bewerten. Basierend auf früheren Arbeiten zum Lernen von LTLf-Formeln extrahieren wir dann eine Präferenz aus diesen Beispielen. Wir führen eine empirische Studie dieses Ansatzes in einer klassischen Planungsumgebung durch, wobei wir versteckte Zielformeln verwenden, um Benutzerpräferenzen zu simulieren