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Advancing miRNA Research: Computational Approaches for Single-Cell and Tissue-Resolved Analyses
No full textSince their discovery in 1993, microRNAs have been an active topic in molecular biology, a breakthrough that was honored with the 2024 Nobel Prize, reflecting their profound impact on the field. Despite the many years of research focused on microRNAs across species, their precise functional roles are still not fully understood. In particular, the dynamics behind timing and location of microRNA-mediated target repression or activation are yet to be discovered for most tissue and cell contexts. Moreover, these localized microRNA expression profiles are known to change throughout the lifespan of organisms. Recently, single-cell RNA sequencing has revealed age-modulated expression patterns such as waves of activation with exceptional detail by capturing cellular heterogeneity. Yet, the currently limited scalability and high costs involved with single-cell high-throughput microRNA protocols prevent large-scale, cell type-resolved application studies. As an alternative, fine-grained study designs which consider multiple tissues investigate microRNA expression heterogeneity with established bulk-sequencing protocols. Eventually, either approach results in large, multi-faceted datasets where computational methods are necessary to select promising microRNAs or identify behavior-driving sample properties, such as sex or age. To this end, this thesis presents a flexible computational framework for the downstream analysis of such complex microRNA datasets.
Three publications investigating individual application scenarios of microRNA functionality emphasize the customizability of the developed framework. In the first, which explored small non-coding RNAs in two mouse plasma fractions, nonnegative matrix factorization of the expression profiles was used to cluster samples based on their age. Second, in a case-control study investigating the effects of non-thermal plasma treatment, differential expression analysis revealed a set of microRNAs previously implicated in wound healing and tissue regeneration. Third, a clustering of time-series data in stem cell differentiation identified increasing expression trajectories for genes related to cell-type differentiation. The adaptability of the computational framework was demonstrated by providing normalized count tables alongside detailed quality control metrics to optimize library preparation protocols for single-cell microRNA sequencing. Building upon this, the accessibility aspect of the framework was addressed with the development of a web-based platform to enable scientists world-wide to process and evaluate their sequencing runs, facilitating the rapid prototyping of single-cell microRNA preparation protocols.
Applying the computational framework to large-scale, multi-faceted datasets resulting from fine-grained bulk studies highlighted its scalability. Investigating an organ-resolved expression dataset (771 samples from 16 organs across ten time points) revealed both organ-specific and global microRNA profiles. Examining these recurrent expression patterns at multiple time points across the mouse lifespan uncovered dynamic expression patterns influenced by aging. A subsequent study focussed on the mouse brain (844 samples from 15 brain regions across seven time points), which is characterized by its substantial structural and functional heterogeneity. By leveraging all aspects of the developed computational framework, including embedding, differential expression analysis, and clustering of time-series data, the study identified brain region-specific and global aging signatures within a sex-specific dataset. Further, in a unique case-control study which involved accommodating mice at the International Space Station for 40 days, a profiling of single-cell messenger-RNA expression levels revealed the down-regulation of ribosomal protein genes. Both, the analysis of the single-cell RNA and the associated bulk microRNA dataset showed effects of spaceflight on the extracellular matrix and the immune system.
In the future, as more single-cell protocols become accessible and sequencing costs further decrease, fine-grained microRNA studies will be even more relevant. The computational framework presented in this dissertation provides a foundation for their analysis by offering customizable, adaptable, and scalable evaluation methods. Ultimately, these developments support the translation of findings to clinical applications, facilitate the development of intricate analysis methods, and therefore advance microRNA research.Seit ihrer Entdeckung im Jahr 1993 sind microRNAs ein zentrales Thema der
Molekularbiologie. Ihre Bedeutung für das Fachgebiet wurde mit der Verleihung
des Nobelpreises für Medizin im Jahr 2024 gewürdigt. Trotz jahrelanger Forschung
an microRNAs sind ihre genauen und umfassenden Funktionen jedoch
noch nicht vollständig verstanden. Insbesondere die Dynamik der zeitlichen
und räumlichen Regulation durch microRNAs ist in den meisten Gewebe- und
Zellkontexten unklar. Bekannt ist hingegen, dass sich diese lokalisierten Expressionsprofile
im Laufe des Lebens eines Organismus verändern. Kürzlich hat die
RNA-Sequenzierung einzelner Zellen altersbedingte Expressionsmuster, zum
Beispiel Aktivierungswellen, mit außergewöhnlicher zellulärer Auflösung sichtbar
gemacht. Derzeit verhindern jedoch die begrenzte Skalierbarkeit und die
hohen Kosten solcher experimenteller Protokolle für microRNAs deren breiten
Einsatz in Anwendungsstudien. Alternativ dazu ermöglichen Studiendesigns, die
aus mehreren Einzelgeweben bestehen, die Untersuchung der Heterogenität der
microRNA-Expression mittels etablierter Bulk-Sequenzierungstechniken. Beide
Ansätze führen zu großen und vielfältigen Datensätzen, die computergestützte
Methoden erfordern, um vielversprechende microRNA-Kandidaten auszuwählen
oder regulatorisch relevante Merkmale wie Geschlecht oder Alter zu identifizieren.
In dieser Dissertation wird ein computergestütztes Framework zur Analyse
solcher komplexer microRNA-Datensätze vorgestellt.
Zunächst wird die Flexibilität des entwickelten Frameworks in drei Publikationen
zu spezifischen Anwendungsfällen von microRNA-beeinflusster Funktionen
demonstriert. In der ersten Studie wurden nichtkodierende RNAs in
zwei Mausplasmen untersucht, wobei eine nichtnegative Matrixfaktorisierung
der Expressionsprofile zur altersbasierten Clusterbildung der Proben verwendet
wurde. In einer zweiten Fall-Kontroll-Studie, in der die Auswirkungen einer
nicht-thermischen Plasmabehandlung betrachtet wurden, konnten durch differentielle Expressionsanalysen microRNAs identifiziert werden, die bereits mit
Wundheilung und Geweberegeneration in Verbindung gebracht wurden. Eine
Clusteranalyse von Zeitreihendaten zur Stammzelldifferenzierung in der dritten
Studie ergab ansteigende Expressionsmuster von Genen, die an der Zelltypdifferenzierung
beteiligt sind. Die Anpassungsfähigkeit des Frameworks wurde
anhand eines Einzelzell-microRNA-Datensatzes demonstriert für den eine normalisierte
Expressionstabelle und detaillierte Metriken zur Qualitätskontrolle erstellt
wurden. Darauf aufbauend wurde die Zugänglichkeit des Systems durch die
Entwicklung einer webbasierten Plattform verbessert, die es Forschern weltweit
ermöglicht, ihre Sequenzierungsdaten zu analysieren und damit die schnelle
Prototypisierung von Einzelzellprotokollen für microRNAs unterstützt. Die weitere
Anwendung des Frameworks auf große und komplexe Bulk-Datensätze,
die aus mehreren Geweben bestehen, unterstreicht seine Skalierbarkeit. Die Untersuchung
eines hochaufgelösten Expressionsdatensatzes (771 Proben aus 16
Organen über zehn Zeitpunkte) zeigte sowohl organspezifische als auch globale
microRNA-Profile. Durch die Analyse von wiederkehrender Expressionsmuster
über mehrere Zeitpunkte konnten dynamische, altersabhängige Expressionsmuster
nachgewiesen werden. Eine Folgestudie mit Fokus auf das Mausgehirn (844
Proben aus 15 Hirnregionen zu sieben Zeitpunkten) wurde durchgeführt, da
dieses Organ eine erhebliche strukturelle und funktionelle Heterogenität aufweist.
Unter Verwendung aller Aspekte des entwickelten Frameworks, einschließlich
Einbettungsmethoden, differentieller Expressionsanalyse und Clusteranalyse von
Zeitreihendaten, wurden in einer geschlechtsspezifischen Untersuchung des
Datensatzes sowohl regionsspezifische als auch globale Alterungssignaturen identifiziert.
Darüber hinaus wurde in einer einzigartigen Fall-Kontroll-Studie an
Mäusen, die für 40 Tage an Bord der Internationalen Raumstation untergebracht
wurden, mittels einer Einzelzell-mRNA-Expressionsanalyse eine Herunterregulierung
ribosomaler Proteingene nachgewiesen. Zusammen mit der begleitenden
Bulk-Analyse von microRNAs zeigte sie Effekte des Weltraumfluges auf die
extrazelluläre Matrix und das Immunsystem.
Mit der zunehmender Verfügbarkeit von Einzelzellprotokollen und sinkenden
Sequenzierungskosten werden detaillierte microRNA-Studien in Zukunft an
7
Relevanz gewinnen. Das in dieser Dissertation vorgestellte computergestützte
Framework bietet eine Grundlage für deren Analyse, indem es anpassbare, flexible
und skalierbare Analysemethoden bereitstellt. Diese Entwicklungen unterstützen
letztlich den Transfer von Forschungsergebnissen in die klinische Anwendung,
ermöglichen die Entwicklung neuartiger Analysemethoden und tragen somit zur
Forschung auf dem Gebiet der microRNAs bei
Scholarly Publishing in Transition : Open Access, Peer Review, Quality, Research Evaluation, Standards
Get PDFAcademic visibility and recognition have become more crucial than ever for career advancement and funding opportunities. But how can researchers publish successfully, responsibly, and strategically in the digital age?
Ulrich Herb-sociologist, information scientist, publishing consultant, open science expert, and long-time lecturer-takes you on a vivid journey through the world of scholarly publishing and research evaluation. Since 2001, he has advised researchers, academics, and institutions. His extensive experience from countless workshops and consulting projects, paired with a keen eye for trends and pitfalls, makes his insights especially valuable.
In this practical guide, he explores current publishing models, explains how peer review, open science, impact metrics, and Creative Commons work, warns about predatory publishing, and offers concrete tips on how to maximize the visibility of your research output.
Packed with case studies, methodological recommendations, digital tools, and a critical perspective on reform movements in academia, this book is an essential companion for anyone looking to shape their academic career with confidence and insight.
Whether you're just starting out or already an experienced researcher-benefit from Ulrich Herb's expertise, hands-on knowledge, and clear-eyed view of the opportunities and challenges of scholarly publishing in the 21st century.
Dr. Ulrich Herb is a sociologist and information scientist specializing in scholarly communication and Open Access. He works as an independent consultant, advising researchers, academic institutions, and policy makers on strategies for Open Science and scientific publishing. Herb has conducted in-depth analyses of major initiatives such as Plan S and has contributed expert reports on various multinational scholarly projects. Widely acknowledged as an authority in the field, he combines practical experience with academic research to advance open and transparent scholarly communication. Dr. Herb is committed to promoting Open Access and Open Science at both national and international levels, regularly leading workshops, publishing critical articles, and supporting infrastructure development for the academic community
Untersuchungen zum Einfluss der Intensität eines Ausdauertrainings auf die Entwicklung der körperlichen Leistungsfähigkeit und ausgewählte Gesundheitsindikatoren
Get PDFEinleitung:
Die kardiozirkulatorische Fitness (KZF) ist ein wichtiger Prädiktor für die körperliche Gesundheit
und kann durch Ausdauertraining effektiv gesteigert werden. Der Einfluss der Intensität in
der Dosis-Wirkungs-Beziehung des Ausdauertrainings ist jedoch noch unzureichend untersucht.
Vor diesem Hintergrund war das Ziel dieser Arbeit, den Einfluss verschiedener Ausdauertrainingsintensitäten
bei gleicher Gesamttrainingsbelastung auf ergometrische Deskriptoren
für die körperliche Leistungsfähigkeit und prognostische Faktoren für kardiovaskuläre Erkrankungen
zu untersuchen.
Es wurden drei übergeordnete Forschungsfragen analysiert:
i) Führt eine Steigerung der Trainingsintensität eines Ausdauertrainings bei energieäquivalentem
Trainingsreiz zu einer höheren KZF (Veröffentlichung 1)?
ii) Führt eine Steigerung der Trainingsintensität eines Ausdauertrainings bei energieäquivalentem
Trainingsreiz zu einer Steigerung der Rate der Responder (Veröffentlichung
2)?
iii) Beeinflusst die Steigerung der Trainingsintensität eines Ausdauertrainings ausgewählte
Marker des Tryptophan-Metabolismus (Veröffentlichung 3)?
Methodik:
Die Daten zur Beantwortung der Forschungsfragen stammen aus einer zweiarmigen randomisierten
Trainingsinterventionsstudie (TRAIN-Studie). Insgesamt wurden 48 gesunde, untrainierte
Männer und Frauen im Alter zwischen 30 und 60 Jahren ohne ausgeprägte Risikofaktoren
in die Studie eingeschlossen. Die Trainingseinheiten erfolgten dreimal wöchentlich über
einen Zeitraum von 26 Wochen. Zunächst trainierten alle Studienteilnehmer 10 Trainingswochen
mit moderater Intensität (55% der Herzfrequenzreserve [HRR]). Anschließend erfolgte
die Aufteilung in zwei Studienarme mittels stratifizierter Randomisierung anhand der Kriterien
Alter, Geschlecht, VO2max, ΔVO2max und Response nach 10 Wochen Training (ja/nein). Die
Studienteilnehmer des ersten Studienarms (CON) setzten das Training weitere 16 Wochen
fort, wobei die Belastung und der Energieverbrauch konstant blieben. Die Studienteilnehmer
des zweiten Studienarms (INC) trainierten über 8 Wochen mit einer gesteigerten Intensität
(70% HRR). Anschließend führten sie weitere 8 Wochen lang ein hochintensives Intervalltraining
(HIIT, 95% der maximalen Herzfrequenz [HRmax]) nach dem „4x4-Protokoll“ durch. Der
durchschnittliche Energieverbrauch betrug 401±105 kcal pro Trainingseinheit und wurde innerhalb
der Studienteilnehmer während der gesamten Studie konstant gehalten. Hierzu wurden
der Sauerstoffverbrauch bei individuellen Trainingsherzfrequenzen analysiert und die
Trainingszeiten entsprechend angepasst.
Ergebnisse:
i) In der ersten Veröffentlichung wurden die Anpassungseffekte an die Trainingsintervention
auf Gruppenebene untersucht. Die Parameter für die maximale Leistungsfähigkeit zeigten eine
Überlegenheit von INC im Vergleich zu CON. INC steigerte die maximale Sauerstoffaufnahme
(VO2max) und die maximale Laufgeschwindigkeit (Vmax) stärker als CON (3,4±2,7 vs.
0,4±2,9 mL•kg-1•min-1; p = ,020 bzw. 1,7±0,7 vs. 1,0±0,5 km•h-1; p < ,001). Die Parameter
der submaximalen Leistungsfähigkeit, wie die Laufökonomie und die Herzfrequenz-Leistungskurve,
zeigten in beiden Gruppen Trainingsanpassungen, jedoch keine signifikanten Unterschiede
(p ≥ ,05).
ii) Die zweite Veröffentlichung untersuchte auf Individualebene, ob die Rate der Responder
durch INC im Vergleich zu CON erhöht werden kann. Dazu wurde auf Basis der individuellen
Tag-zu-Tag-Schwankung die individuelle Response nach 10, 18 und 26 Wochen Training ermittelt.
Nach 18 Wochen konnte in beiden Gruppen keine Steigerung der Responder-Rate
beobachtet werden (p = 0,189). Die Ergebnisse zeigten jedoch eine Überlegenheit der hochintensiven
Trainingsintensitäten. Nach 26 Wochen stieg die Responder-Rate in INC signifikant
an (p = 0,031), während sie in CON sogar leicht abnahm (p = 0,754, Interaktionseffekt
p = 0,012) und betrug 87% für INC und 37% für CON.
iii) Die dritte Veröffentlichung untersuchte auf Gruppenebene, ob die Steigerungen der Trainingsintensität
in INC im Vergleich zu CON ausgewählte Interleukine sowie Marker des
Kynureninpfads (KP) beeinflussen. Hierfür wurde erstmals in einer Trainingsstudie der Metabolit
3-Hydroxianthranilsäure (3-HAA) analysiert. Die Ergebnisse zeigten keine signifikanten
Interaktionseffekte sowie Zeiteffekte der (anti-)inflammatorischen Marker IL-6 und IL-10. Nach
26 Wochen Ausdauertraining stieg der 3-HAA – Spiegel in beiden Gruppen, unabhängig von
der Trainingsintensität, signifikant an (INC: 134%, p < ,001; CON: 85%; p < ,001).
Diskussion und Schlussfolgerung:
Diese zweiarmige randomisierte Trainingsstudie untersuchte den Einfluss steigender Ausdauertrainingsintensitäten
bei gleicher Gesamttrainingsbelastung bei gesunden, untrainierten Erwachsenen.
Alle drei Veröffentlichungen zeigen, dass sowohl Ausdauertraining mit moderater
als auch schrittweise ansteigender Trainingsintensität bei konstantem Energieverbrauch günstig
auf die Gesundheit wirkende Effekte erzielt. Submaximale Leistungsparameter passen sich
unabhängig von der Trainingsintensität an ein langfristiges Ausdauertraining an. Maximale
Leistungsparameter werden hingegen durch ein Ausdauertraining im hochintensiven Bereich
positiv beeinflusst. Darüber hinaus zeigen Marker des Tryptophan-Metabolismus positive Effekte
durch Ausdauertraining. Hervorzuheben ist der Metabolit 3-HAA, der erstmals in einer
Trainingsstudie quantifiziert wurde und eine geringe Sensitivität gegenüber der Trainingsintensität
zeigt.
Die Ergebnisse zeigen außerdem, dass eine Intensitätssteigerung von 55 auf 70% HRR nach
mehrwöchigem Ausdauertraining nicht ausreicht, um bei konstantem Energieverbrauch zusätzliche
Effekte zu erzielen. In diesem Zusammenhang hat sich HIIT als die wirksamste Trainingsmethode
erwiesen. HIIT reduzierte zudem die individuellen Schwankungen der Anpassungseffekte
und führte zu einer höheren Responder-Rate. Somit profitieren mehr Personen
von einem Ausdauertraining mit hochintensiver Intensität als mit moderater Intensität.
Man kann insgesamt festhalten, dass HIIT ein breiteres Spektrum und ein größeres Ausmaß
an Anpassungseffekten hervorruft. Darüber hinaus ist HIIT zeitökonomisch und weist eine
Compliance auf, die sich nicht relevant von der moderater Trainingseinheiten unterscheidet.
Aus diesem Grund ist der Einsatz hochintensiver Trainingsmethoden im Rahmen eines präventiv
orientierten Ausdauertrainings für gesunde Erwachsene zu empfehlen, um Trainingseffekte
zu optimieren und Stagnationen in der Leistungsentwicklung zu vermeiden.Introduction:
Cardiocirculatory fitness (KZF) is an important predictor of physical health and can be effectively
improved by endurance training. However, the influence of intensity on the dose-response
relationship of endurance training is poorly understood. The aim of this study was to
investigate the effects of increased endurance training intensities, with equivalent energy expenditure,
on performance parameters and prognostic factors for cardiovascular disease.
The study addressed three overarching questions:
i) Does an increase in exercise intensity yield improvements in KZF in endurance
training with constant energy expenditure (publication 1)?
ii) Does an in increase in exercise intensity yield higher proportions of responders in
endurance training with constant energy expenditure (publication 2)?
iii) Does an increase exercise in intensity affect specific marker of the tryptophan metabolism
in endurance training with constant energy expenditure (publication 3)?
Methods:
The data were obtained TRAIN-study, which is a two-arm randomised training intervention
trial. A total of 48 healthy, untrained men and women aged 30 to 60 years, free of risk factors,
were included in the study. Participants trained three times per week for 26 weeks. Initially, all
participants completed 10 weeks of moderate-intensity training (55% heart rate reserve
[HRR]). Subsequently, the participants were randomly assigned to one of the two groups by
stratified randomisation. Factors for balancing were age, sex, baseline VO2max, ΔVO2max and
response at week 10 (yes/no). The participants in the control group (CON) continued for a
further 16 weeks at a moderate intensity (55% HRR) and constant energy expenditure. The
incremental group (INC) trained at an increased intensity (70% HRR) for 8 weeks, followed by
8 weeks of high-intensity interval training (HIIT) at 95% of maximal heart rate (HRmax) following
the "4x4 protocol". The average energy expenditure was 401 ± 105 kcal per session and was
maintained throughout the study by adjusting training duration in INC based on individual heart
rates and oxygen consumption.
Results:
i) The initial publication examined the effects of the training intervention at group-level. The
parameters for maximal performance indicated a superior performance of INC in comparison
to CON. INC shows greater increases in maximal oxygen uptake (VO2max) and maximal running
speed (Vmax) compared to the CON (3,4±2,7 vs. 0,4±2,9 mL•kg-1•min-1; p = ,020 bzw.
1,7±0,7 vs. 1,0±0,5 km•h-1; p < ,001). The parameters of submaximal performance, such as running economy and heart rate performance curve, showed training adaptations in both
groups, but not significant differences (p ≥ ,05).
ii) The second publication analysed whether the proportion of responders could be increased
by INC versus CON. For this purpose, the individual response after 10, 18 and 26 weeks of
training were determined, based on the individual day-to-day variation. After 18 weeks, no
increase in the responder rate was observed in either group (interaction effect: p = ,189). However,
the results show a superiority of the high-intensity training intensities. After 26 weeks, the
responder rate increased significantly in INC (p = ,031), but decreased slightly in CON
(p = ,754, interaction effect p = ,012), reaching 87% in INC and 37% in CON.
iii) The third publication investigated whether the increase in training intensity in INC compared
to CON affects interleukins and selected markers of the kynurenine pathway (KP) at the group
level. For this purpose, the metabolite 3-hydroxyanthranilic acid (3-HAA) was analysed for the
first time in a training study. There were no changes in IL-6 and IL-10 in either group. After 26
weeks of endurance training, 3-HAA levels increased significantly in both groups, unaffected
by training intensity (INC: 134%, p < ,001; CON: 85%, p < ,001).
Discussion and conclusion:
This two-arm randomised trial investigated the influence of increased endurance training intensities
with a constant energy expenditure in healthy, untrained adults. All publications show
that endurance training at moderate and gradually increasing training intensities with a constant
energy expenditure has health-promoting effects. Submaximal performance parameters
adapt to long-term endurance training unaffected by training intensity. However, maximal performance
parameters are positively influenced by high-intensity endurance training. In addition,
markers of tryptophan metabolism show positive effects of endurance training. In particular,
the metabolite 3-HAA, which was quantified for the first time in a training study, showed
a low sensitivity to training intensity.
Moreover, the findings suggest that an increase in intensity from 55 to 70% HRR is insufficient
to elicit additional effects with constant energy expenditure following a period of moderate
training. In this context, HIIT has proven to be the most efficacious training method. HIIT diminished
the interindividual variability in the adaptation effects and resulted in a higher responder
rate. These findings suggest that a greater proportion of individuals benefit from endurance
training at a high intensity than at a moderate intensity.
In conclusion, HIIT without increased energy expenditure produces a broader and more pronounced
spectrum of adaptions. Furthermore, HIIT is a time-efficient training method with comparable
compliance rates to moderate-intensity training. For this reason, HIIT is recommended
a spart of preventive endurance training for healthy adults to optimise training effects and avoid
stagnation in performance
A finite‐dimensional counterexample for Arveson's hyperrigidity conjecture
Get PDFWe construct an operator system generated by four operators that is not hyperrigid, although all restrictions of irreducible representations have the unique extension property
Intra-adaptational changes in online adaptive radiotherapy: from the ideal to the real dose
Get PDFBackground and purpose
Online adaptive radiotherapy has demonstrated dosimetric benefits by accounting for interfractional organ variations. However, this study investigates the dosimetric impact of intra-adaptational anatomical changes that take place during the adaptation process.
Methods
Our retrospective analysis was conducted on 155 fractions from 8 prostate cancer patients treated with adaptive radiotherapy using the Varian Ethos system (Varian, Palo Alto, California, USA). Various dose–volume metrics for the targets and organs at risk were assessed for (1) the non-adapted (an original plan on a pretreatment cone-beam CT [CBCT], acquired at the beginning of a treatment session), (2) the adapted (an adapted plan on a pretreatment CBCT), and (3) the delivered dose distributions (an adapted plan on a pre-irradiation CBCT acquired for patient position verification with recontoured organs).
Results
For the target metrics, we quantitatively proved that the delivered dose distribution was still beneficial in comparison to the non-adapted one, despite the anatomical changes during the adaptation process. The bladder dose–volume metrics strongly depended on the bladder volume variations across the planning CT and both CBCTs, frequently showing improvement during the adaptation process as the bladder continued to fill. In contrast, no clear trend was observed for the rectum or posterior rectum wall metrics. In only a small fraction of sessions (up to 5% for most metrics) were the metric objectives not achieved with the delivered dose while they were achieved with the adapted one. Physiological reasons for these occurrences stemmed from meteorism occurring between pretreatment and pre-irradiation CBCTs.
Conclusion
This study confirms that the dosimetric advantages of online adaptive radiotherapy persist in clinical practice, despite anatomical changes due to the time delay needed for the adaptation process
Parameter estimation for cellular automata
Get PDFSelf-organizing complex systems can be modeled using cellular automaton models. However, the parametrization of these models is crucial and significantly determines the resulting structural pattern. In this research, we introduce and successfully apply a sound statistical method to estimate these parameters. The decisive difference to earlier applications of such approaches is that, in our case, both the CA rules and the resulting patterns are discrete. The method is based on constructing Gaussian likelihoods using characteristics of the structures, such as the mean particle size. We show that our approach is robust for the method parameters, domain size of patterns, or CA iterations
Modelling the electrodeposition of nickel on polyurethane foam
Get PDFThe electrodeposition method is among the various methods to produce metal foams by coating
open-cell polymeric foams with a metallic layer. This process is governed by strong mechanical and electrical
interactions which arise due to different factors such as presence of ions in the electrolyte, applied external
current, charged solid surface and ionic concentration gradient. Hence, the related physical effects result in
a nonlinear coupled process at the macroscale, which introduces a complex challenge for modelling and
computational treatment. This work proposes a model to describe the electrocoating of polyurethane foams
with nickel ions at macroscale, in an isothermal process and under the simplifying assumptions such as
rigidity of the foam and incompressibility of the electrolyte. To do so, the multi-phase flow through the porous
medium has to be modelled on a macroscopic scale. The governing equations describing the coating process
are developed from the fundamental balance equations of mixture theory. By reasonable physical assumptions,
different processes contributing to ionic transport, i.e. diffusion, convection and migration, are considered, and
finally, the influence of different parameters in each transport mechanism is investigated. First 1D simulations
show that the presented model is able to describe the experimentally observed effects, at least in a qualitative
way
Triangular Screw Placement to Treat Dysmorphic Sacral Fragility Fractures in Osteoporotic Bone Results in an Equivalent Stability to Cement-Augmented Sacroiliac Screws—A Biomechanical Cadaver Study
Get PDFBackground: Sacroiliac screw fixation in elderly patients with pelvic fractures
remains a challenging procedure for stabilization due to impaired bone quality. To improve
it, we investigated the biomechanical properties of combined oblique sacroiliac and transiliosacral screw stabilization versus the additional cement augmentation of this construct
in a cadaver model of osteoporotic bone, specifically with respect to the maximal force
stability and fracture-site motion in the displacement and rotation of fragments. Methods:
Standardized complete sacral fractures with intact posterior ligaments were created in
osteoporotic cadaver pelvises and stabilized with a triangle of two oblique sacroiliac screws
from each side with an additional transiliosacral screw in S1 (n = 5) and using the same
pelvises with additional cement augmentation (n = 5). A short cyclic loading protocol was
applied, increasing the axial force up to 125 N. Sacral fracture-site motion in displacement
and rotation of the fragments was measured by optical motion tracking. Results: A maximum force of 65N +/− 12.2 N was achieved using the triangular screw stabilization of
the sacrum. Cement augmentation did not provide any significant gain in maximum force
(70 N +/− 29.2 N). Only low fragment displacement was observed (2.6 +/− 1.5 mm) and
fragment rotation (1.3 +/− 1.2◦
) without increased stability (3.0 +/− 1.5 mm; p = 0.799;
1.7 +/− 0.4◦
; p = 0.919) following the cement augmentation. Conclusions: Triangular
stabilization using two obliques and an additional transiliosacral screw provides sufficient
primary stability of the sacrum. Still, the stability achieved seems very low, considering the
forces acting in this area. However, additional cement augmentation did not increase the
stability of the sacrum. Given its lack of beneficial abilities, it should be used carefully, due
to related complications such as cement leakage or nerve irritation. Improving the surgical
methods used to stabilize the posterior pelvic ring will be a topic for future research
Distributive properties of division points and discriminants of Drinfeld modules
Get PDFWe present a new notion of distribution and derived distribution of rank r ∈ N for a global function field K with a
distinguished place ∞. It allows to describe the relations between division points, isogenies, and discriminants both for a
fixed Drinfeld module of rank r for the above data, or for the
corresponding modular forms.
We introduce and study three basic distributions with values
in Q, in the group μ(K) of roots of unity in the algebraic
closure K of K, and in the group U(1)(C∞) of 1-units of the
completed algebraic closure C∞ of K∞, respectively.
There result product formulas for division points and discriminants that encompass known results (e.g. analogues of
Wallis’ formula for (2πı)2 in the rank-1 case, of Jacobi’s formula Δ = (2πı)12q
(1−qn)24 in the rank-2 case, and similar
boundary expansions for r > 2) and several new ones: the definition of a canonical discriminant for the most general case of
Drinfeld modules and the description of the sizes of division
and discriminant forms.
In the now classical case where (K, ∞)=(Fq(T),∞) and
r = 1, 2 or 3, we give explicit values for the logarithms of
such forms
Evaluation of Frequency Effects on Fatigue Life at High Test Frequencies for SAE 1045 Steel Based on Thermography and Electrical Resistance Measurements
Get PDFThis research provides a method for a reliable fatigue life estimation at high testing
frequencies. The investigations are based on the lifetime prediction method StressLifeHCF
considering test frequencies of 80 and 260 Hz for normalized SAE 1045 (C45E, 1.1191) steel.
Therefore, load increase tests and constant amplitude tests were carried out using a resonant
testing rig. To ensure a mechanism-oriented lifetime prediction, the material response to
dynamic loading is monitored via temperature and electrical resistance measurements.
Due to the higher energy input per time unit, when the test frequency is increased, the heat
dissipation also increases. For this reason, a precise differentiation between frequency- and
temperature-related effects for adequate fatigue assessment is challenging. To evaluate
the temperature’s influence on electrical resistance, an electrical resistance-temperature
hysteresis is measured, and the frequency influence is analyzed by considering cyclic
deformation curves. In addition to an extension of the fatigue life due to an increased test
frequency, the lifetime prediction method was validated for high frequencies. The generated
S-N curves show a reliable agreement with the data points from conventional constant
amplitude tests. In this context, the temperature correction of the electrical resistance
proved to be an important input variable for a reliable lifetime prediction