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Prospektive Kohortenstudie zur Prädiktion des Effektes der medikamentösen Therapie am multizellulären Sphäroidmodell bei Patientinnen mit primärem Ovarialkarzinom
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„Music For Men“? Die diskursive Geschlechterordnung in Musikzeitschriften des Indie-Rock im beginnenden 21. Jahrhundert
Get PDFGenetic fate specification of inhibitory neurons
Get PDFUnderstanding how an enormous diversity of neuronal cell types is generated has been a major objective of neurobiology. This task is particularly challenging in the case of inhibitory neurons because they migrate long distances during development. It is believed that a combi-nation of intrinsic factors and external signals influence progenitor cells to differentiate into distinct types of inhibitory cells, such as interneurons or long-range projection neurons.
To tackle this issue, one approach involves examining the clonal relationships between inhibitory cell types in the brain. In this thesis, I established a single-cell RNA sequencing compatible, lineage-tracing method, TrackerSeq, that enables both the identity of a neuron and its developmental history to be retrieved simultaneously to analyze developmental relationships of inhibitory cell types in the mouse brain. TrackerSeq achieves this by tagging progenitors with inheritable DNA barcodes followed by transcriptome sequencing at a later time point to ana-lyze developmental relationships of inhibitory cell types in the mouse brain. Using TrackerSeq, I found different inhibitory cell types occupying different regions in the brain shared inherited the same lineage barcodes, suggesting that mitotic progenitors can give rise to different cell types.
Subsequently, I explored whether specific transcription factors expressed in inhibitory neurons, such as Meis2 and Lhx6, play a crucial role in determining the fate of inhibitory cell types. Single-cell sequencing compatible perturbation methods, like tCROP-seq, have emerged as an effective way to interrogate the impact of these factors on the outcome of neuronal fates. In a typical tCROP-seq protocol, sgRNAs are delivered to cycling progenitors via in utero electropo-ration to introduce fameshift mutations in genes of interest, followed by sequencing of neurons at a later timepoint.
By analyzing the tCROP-seq data obtained from perturbing Meis2, I observed that interneu-ron genes were upregulated in projection neuron cell types, leading to an increased proportion of interneurons. Interestingly, perturbing Lhx6 had the opposite effect. These findings suggest that when Meis2 is perturbed, progenitor cells originally destined to become projection neurons may instead differentiate into interneurons. To confirm this possibility, I employed TrackerSeq barcodes to tag non-perturbed and Meis2-perturbed cells. The analysis revealed that Meis2-perturbed mitotic cells shared more clones with interneurons than projection neurons, providing further evidence that Meis2 perturbation promotes the preferential differentiation of progenitor cells into interneurons.
My findings reveal that specification of inhibitory subtypes already takes place at the pro-genitor stage and require the expression of select transcription factors. Gaining a better under-standing of how genetic programs such as lineage and transcription factor expression influence subtype specification can improve our modeling of neurodevelopmental disorders
Chrono-Nutrition - the impact of regularity, time-of-day and frequency of energy and energy from macronutrient consumption on body mass index in children
Get PDFEvidenzbasierte Behandlungspfade für die Notfallbildgebung beim älteren Patienten nach Sturz aus niedriger Fallhöhe
Get PDFDer niederenergetische Sturz des älteren Menschen mit Verletzungsfolgen ist ein häufiges und sowohl für den Patienten als auch das Gesundheitssystem relevantes Ereignis. Die vorliegenden Daten deuten darauf hin, dass die derzeit praktizierten klinischen Entscheidungs- und Diagnostikpfade beim älteren Sturzpatienten eine gesonderte und differenzierte Betrachtung erfordern. Notfall- und akutmedizinische Prozesse und Standards während der Behandlung dieser vulnerablen Patientengruppe sind, v.a. in der Notaufnahme, anzupassen, um Ressourcen gezielt einzusetzen bzw. zu schonen, die Patientensicherheit und -zufriedenheit zu erhöhen, und möglicherweise deren Prognose zu verbessern und Kosten zu senken.Low energy falls in older adults resulting in injuries are a frequent event that is relevant for both the patient and the healthcare systems. The presented data indicate that the currently practised clinical decision-making and diagnostic pathways for elderly fall patients require separate and more differentiated considerations. Emergency and acute medical processes and standards during the treatment of this vulnerable patient group must be adapted, especially in the emergency departments, in particular to utilise or conserve resources in a targeted manner, increase patient safety and satisfaction, and possibly improve their prognosis and reduce costs
Anwendung und Optimierung eingeschränkter Hamiltonians
Get PDFQuantum Computing Hardware ist noch immer begrenzt in der Anzahl der Qubits, deren Kohärenzeigenschaften und deren Konnektivität auf den Quantenprozessoren. Um daher bereits frühzeitig einen möglichen praktischen Quantenvorteil zum klassischen Computing zu erzielen, gilt es deshalb, sowohl relevante Anwendungsfälle mit großem Potenzial, als auch entsprechend umsetzbare Algorithmen für die aktuell verfügbare Noisy Intermediate-Scale Quantum (NISQ) Computer zu identifizieren. Viele relevante Problemstellungen der Industrie und Wissenschaft lassen sich auf Optimierungs- und Suchprobleme abbilden. Die Komplexität aus Anwendersicht ist die Transformation der Probleme in entsprechende Repräsentationen und Algorithmen für sowohl gatterbasierte als auch annealingbasierte Quantum Computing Hardware. Während Gatter-Architekturen das Problem in Form eines Quantenschaltkreis als Eingabe bekommen, werden zur Problembeschreibung für Quantum Annealing Hardware Ising-Hamiltonians oder Quadratic Unconstrained Binary Optimization (QUBO) Probleme verwendet. Viele Realwelt-Anwendungsfälle enthalten zudem Nebenbedingungen, die bei der Lösung berücksichtigt werden müssen. In Bezug auf die Ising-Hamiltonians werden diese Bedingungen in Penalty-Terme kodiert und mit Penalty-Parametern gewichtet, die bei einer Verletzung die entsprechende Lösung als invalide kennzeichnen. Diese Eigenheit beschreibt dann sogenannte eingeschränkte Ising-Hamiltonians.
Die vorliegende Arbeit beschäftigt sich mit der Anwendung und Optimierung eingeschränkter Ising-Hamiltonians.
Zu Beginn werden hybride Algorithmen, die unter anderem auf einem eingeschränkten Ising-Hamiltonian basieren, für die Domäne der Spieltheorie vorgestellt. Die Ansätze werden sowohl auf gatter- als auch annealingbasierter Hardware evaluiert und ihre Anwendbarkeit bestimmt. Anschließend wird eine adaptierte Kreuzentropie-Methode, zur Optimierung der Penalty-Parameter eingeschränkter Ising-Hamiltonians verschiedener akademischer kombinatorischer und graphbasierter Optimierungsprobleme, präsentiert. Die Evaluation der Hamiltonians mit den optimierten Penalty-Parametern zeigt eine signifikant gesteigerte Lösungsqualität, die mit einer größeren minimalen Spektrallücke in dem jeweiligen Eigenspektrum korreliert. Schließlich werden Methoden des maschinellen Lernens eingesetzt, um allgemeine Muster und Richtlinien zur Wahl der Penalty-Parameter für ausgewählte eingeschränkte Ising-Hamiltonians zu identifizieren und zu lernen.
Zusammenfassend hebt diese Arbeit die Bedeutung der Optimierung eingeschränkter Ising-Hamiltonians hervor.Quantum computing hardware is still limited in the number of qubits, their coherence properties and their connectivity on quantum processors. Therefore, in order to achieve a possible practical quantum advantage over classical computing at an early stage, it is necessary to identify both relevant use cases with great potential and correspondingly implementable algorithms for currently available Noisy Intermediate-Scale Quantum (NISQ) computers. Many relevant problems from industry and science can be understood as optimization and search problems. The complexity from the user's perspective is the transformation of the problems into appropriate representations and algorithms for both gate-based and annealing-based quantum computing hardware. While quantum gate architectures receive the problem in the form of a quantum circuit as input, Ising-Hamiltonians or Quadratic Unconstrained Binary Optimization (QUBO) problems are used to describe the problem for quantum annealing hardware. Some real-world use cases also contain constraints that must be considered in the solution. With respect to Ising-Hamiltonians, these constraints are encoded in penalty-terms and weighted by penalty-parameters which, when violated, mark the corresponding solution as invalid. This characteristic then describes so-called constrained Ising-Hamiltonians.
The present work deals with the application and optimization of constrained Ising-Hamiltonians.
At the beginning, hybrid algorithms based on a constrained Ising-Hamiltonian are presented for the domain of game theory. The approaches are evaluated on both gate- and annealing-based quantum hardware and their applicability is determined. Subsequently an adapted cross-entropy method, for optimizing the penalty-parameters of constrained Ising-Hamiltonians of various academic combinatorial and graph-based optimization problems is presented. The evaluation of the Hamiltonians with the optimized penalty-parameters shows a significantly increased solution quality, which correlates with a larger minimum spectral gap in the respective eigenspectrum. Finally, machine learning methods are used to identify and learn general patterns and guidelines for choosing penalty-parameters for selected constrained Ising-Hamiltonians.
In summary, this work highlights the importance of optimizing constrained Ising-Hamiltonians
Multimorbidity and mortality: evidence from epidemiological tudies in older adults
Get PDFThe coexistence of several chronic diseases is very common in older adults, making it crucial to understand multimorbidity (MM) patterns and associated mortality. We aimed to determine the prevalence of MM and common chronic disease combinations, as well as their impact on mortality in men and women aged 65 years and older using the population-based KORA-Age study, based in South of Germany. The chronic disease status of the participants was determined in 2008/9, and mortality status was followed up until 2016. MM was defined as having at least two chronic diseases. We used Cox proportional hazard models to calculate the hazard ratios (HRs) and the 95% confidence intervals (CIs) for associations between MM and all-cause mortality. During the study period 495 men (24.6%) and 368 women (17.4%) died. Although the MM prevalence was almost the same in men (57.7%) and women (60.0%), the overall effect of MM on mortality was higher in men (HR: 1.81, 95% CI: 1.47–2.24) than in women (HR: 1.28, 95% CI: 1.01–1.64; p-value for interaction <0.001). The type of disease included in the MM patterns had a significant impact on mortality risk. For example, when both heart disease and diabetes were included in the combinations of two and three diseases, the mortality risk was highest. The risk of premature death does not only depend on the number of diseases but also on the specific disease combinations. In this study, life expectancy depended strongly on a few diseases, such as diabetes, hypertension, and heart disease