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Social Interactions in Daily Life: Personality Processes in Contexts
Full text linkPeople spend much of their day interacting with other people, and such social interactions are pivotal for health and well-being. While previous research thoroughly elaborated on stable interindividual differences in social relationships, such as associations between personality and the composition of people’s social networks, much less research has focused on the processes governing daily social interactions and interindividual differences therein. In this dissertation, three empirical studies, involving more than 1,000 adults from a broad age range and diverse backgrounds, examined the interplay between personality, daily social interactions, as well as micro-, meso-, and macro-context factors. The dissertation extends previous research in two ways: First, various methodological approaches to measuring daily social interactions and social traits are compared and their unique strengths and weaknesses are elaborated. Second, context effects on daily social interactions are empirically demonstrated on various timescales and analysis levels (i.e., micro, meso, and macro). Following the general introduction, the three studies are presented in five chapters:
In Chapter 2, three different methods for the assessment of social interactions in daily life are compared: day reconstruction, experience sampling, and mobile sensing. Measurements of face-to-face interactions showed substantial agreement and agreement between measurements of smartphone-mediated interactions was high. Yet, none of the methods comprehensively measured social interactions, that is, many social interactions were captured by only one of the methods, and qualitative aspects of social interactions remained difficult to capture with smartphone sensors.
Chapter 3 focuses on a comparison of social traits related to dynamic social processes in daily life. The chapter describes the development of a brief self-report questionnaire of social dynamics, the Social Dynamics Scale, and examines its predictive validity regarding changes in social contact across time and different social relationships. The results showed considerable overlap between social traits. Additionally, the new scale measured individual differences in social dynamics reliably, validly, and with predictive value for changes in daily contact. Still, next to the assessment of social traits, the measurement of processes at a higher time resolution is needed for understanding processes governing social interactions as they occur in daily life.
Chapter 4 examines the temporal dynamics of momentary social desires and social interactions within and across days, accounting for social traits as well as contributions of the micro-context, i.e., situational affordances. The affiliation motive predicted momentary social desires but no changes in future social interactions, except when social interactions were
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assessed with mobile sensing. Situational affordances, such as the valence and voluntariness of social interactions, predicted social desires and future contact.
Chapter 5 explores how aspects of the meso-context, that is, the number of relationships people maintain and the density of people’s living arrangements, contribute to social interactions in daily life. While transitions from solitude to social interactions were faster for people living in densely populated households, contrary to expectations, they were slower for people living in dwellings with more homes. Additionally, people living in densely populated households transitioned slower from social interactions to solitude. Current social desires predicted subsequent social interactions within days, but not across days—independent of individuals’ social network size or social density.
Chapter 6 examines changes in social contact, life satisfaction, and depressivity/anxiety during a time that was characterized by the macro-context of the COVID-19 pandemic and associated pervasive social contact restrictions. The affiliation motive, need to be alone, and social anxiety moderated the resumption of personal contact under loosened restrictions, as well as associated changes in life satisfaction and depressivity/anxiety.
Overall, the chapters demonstrate how innovative multi-method intensive longitudinal studies can provide unprecedented opportunities for researchers to study social behaviors in the contexts they are embedded in. The results call for a greater integration of specific context factors in theories on the dynamic regulation of social interaction in daily life and for a continued development of measurement and analysis methods
Free-Form Flows: Generative Models for Scientific Applications
Full text linkThis thesis explores advanced generative modeling techniques with a focus on scientific applications. It addresses two main areas: free-form flows and machine learning applications in particle physics.
Free-form flows are a novel family of generative models that combine the benefits of normalizing flows—exact maximum likelihood training and fast generation—with unrestricted neural network architectures. This approach overcomes the limitations of traditional normalizing flows, allowing for more flexible and domain-specific models.
The thesis also presents a collection of machine learning applications in particle physics, leveraging models with rich representational spaces. These techniques aim to accelerate the processing of vast data streams from the Large Hadron Collider, potentially uncovering new physics beyond the Standard Model.
By advancing both the theoretical foundations and practical implementations of generative models, this work contributes to their increased adoption and impact across diverse scientific disciplines. Applications range from chemistry to particle physics, demonstrating the broad potential of these methods in modeling complex data distributions
From data need to data use: Exploring the potential of data use for equitable policymaking in long-term care for persons with dementia in the German state of Baden-Wuerttemberg
Full text linkAccording to SGB XI § 69, long-term care in Germany should be organised according to need. A particular challenge here is the increasing need for long-term care, especially due to age-related illnesses such as dementia. For those affected, this is associated with in-creasing restrictions on activities of daily living and usually leads to a need for care. Dementia is one of the most common diagnoses requiring nursing care. In Baden-Wuerttemberg, the aim is to meet these challenges with data-based care planning that is orientated towards regional care needs in accordance with the “Gesundheitsleitbild”. Particularly over the last two decades, administrative data from health and long-term care insurers throughout Germany has been increasingly made available and their potential for use in regionalised analyses, especially for medical care, have been developed. The growing number of data sources and indicators present local decision-makers with the challenge of selecting relevant indicators for policymaking. However, studies also show that data availability alone is not enough for policymaking to be data-based. And even if reports are available, there is little knowledge about how decision-makers use and read these quantitative data reports, a common format in which data is provided.
This dissertation explores the potential of data-based policymaking in Baden-Wuerttem-berg using the example of needs-based long-term care for people with dementia. To this end, it was investigated (1) which data decision-makers consider relevant for regional policymaking in this area, (2) which data is available, in particular for assessing the need for care and its adequacy on a small-area level, and (3) how this data is used in the format of a report by individual decision-makers. Indicators on the absolute and relative fre-quency of dementia and comorbidities, on care utilisation, and on existing care services were identified as relevant indicators from the perspective of decision-makers in an online survey. The estimation of regional care needs on the basis of secondary data revealed differences between the administrative districts, both in absolute terms and relative to the size of the population. It was found that access to long-term homecare is fundamentally orientated towards need factors such as comorbidity and age. In addition, access to care was to a lesser extent also linked to factors such as sex, nationality and the density of outpatient care services. It could not be clearly determined whether there also is a relation between access to care and the social status of the place of residence of persons with dementia. A quantitative data report on care needs and services as part of a hypothetical decision scenario was generally read in full, but less attention was paid to the methods section. When prioritising the different care settings in the hypothetical allocation of financial resources, other sources of knowledge and personal aspects played a role along-side the information from the report. Also, an attempt was made to adopt different perspectives when making the decision. Overall, it was found that for data-based regional care planning the necessary information on the care needs of people with dementia and whether this care is equitable is available, however with significant data gaps. Available data on the care situation of people with dementia is used in regional settings, but it is unclear to what extent this goes beyond pilot projects. Finally, there are indications that information on data quality plays a subordinate role for (future) decision-makers
Spectroscopy on trapped highly charged ions with soft X-ray synchrotron and FEL radiation
Full text linkSpectroscopic investigation of highly charged ions (HCI) in the X-ray regime enables precise benchmarking of theoretical calculations including effects of bound-state quantum electrodynamics and nuclear origin.
It further aids in extracting properties and dynamics of hot astrophysical plasmas by means of plasma modeling.
In the framework of this cumulative thesis, an electron beam ion trap has been combined with bright X-ray light sources, such as synchrotrons and X-ray free-electron lasers (XFEL) to investigate HCIs with X-rays of various properties.\\
In particular, high-precision transition energy measurements of astrophysically relevant diagnostic lines of light lithium-like elements and neon-like iron have been performed with ppm precision, made possible by resolving a key issue in monochromator-based X-ray absorption spectroscopy. These improved transition energy measurements not only allow to test theoretical predictions but also nail down the doppler velocity of astrophysical plasma to few km/s.
Furthermore, two techniques for assessing transition oscillator strengths have been developed. A novel synchrotron-based approach using the Hanle effect in the soft X-ray regime for measuring femto- to picosecond lifetimes of allowed transitions in helium-like nitrogen is demonstrated. Second, a pioneering lifetime measurement of femtosecond transitions of helium-like neon and fluorine using an all-X-ray pump-probe technique at an XFEL is presented. Finally, an investigation of well-controlled multi-photon ionization in neon-like krypton producing charge-states well beyond the single-photon ionization limit is presented, which served as a basis for the lifetime measurement
Barrieren der Inanspruchnahme von Unterstützungs- und Entlastungsleistungen für pflegende Angehörige und das Potenzial digitaler Technologien
Full text linkPflegende Angehörige (PA) übernehmen den überwiegenden Anteil der häuslichen Pflegearbeit. Dabei kann es sich neben der praktischen Pflege auch um organisatorische oder bürokratische Aufgaben handeln. Während die Pflege einer nahestehenden Person mit positiven Aspekte einhergehen kann, wie beispielsweise ein persönliches Kompetenzerleben sowie die Möglichkeit weiterhin Zeit mit der pflegebedürftigen Person (PB) verbringen zu können, werden von PA auch Belastungen beschrieben. Diese können physischer (z.B. muskuloskelettale Beschwerden) und psychischer (z.B. Ängste, depressive Symptomatik) sowie finanzieller und organisatorischer Form vorliegen. Dem Belastungserleben kann durch Ressourcen der PA entgegengewirkt werden. Dazu zählen neben der Erwerbstätigkeit auch der Erhalt sozialer Kontakte sowie eine regelmäßige Auszeit von der Pflege.
Die Förderung dieser Ressourcen kann durch die Nutzung vorhandener Unterstützungs- und Entlastungsleistungen erfolgen. Während Beratungsangebote unterstützende und entlastend
Unveiling the Complexity of Colorectal Cancer Heterogeneity. From Clonal Evolution to Cancer Stem Cells
Full text linkColorectal cancer (CRC) is one of the main contributors to cancer-related fatality.
Patient survival highly depends on tumour stage at diagnosis, as the 5-year overall survival
rate drops drastically from ~64% for patients diagnosed in stage I–II to 12% for patients
diagnosed in stage IV. Thus, ~90% of CRC related deaths are associated with metastatic
disease that does not respond to currently available systemic treatments. Emerging evidence
suggests that inter- and intra-tumour heterogeneity significantly contributes to cancer
progression and therapy-resistance. In this PhD thesis, I focus on two main sources of intra-tumour heterogeneity: clonal dynamics and stem cell hierarchy.
During CRC progression, the tumour ecosystem is subjected to continuous evolution.
However, the patterns of clonal dynamics and their dependence on the surrounding
environment are not yet well understood. To investigate this, I used an optical barcoding
system (LeGO) in mouse tumour-derived organoids to longitudinally track individual clones in
different environments. My findings revealed a key bottleneck both in vitro and in vivo,
suggesting that clonal selection plays a major role during CRC progression. Moreover, my
results indicate that clonal selection is highly influenced by the tumour microenvironment,
which critically contributes to tumour heterogeneity and has implications for therapeutic
intervention.
Furthermore, CRC cells are hierarchically organized with cancer stem cells (CSCs) at
the apex, initiating and fuelling tumour growth. LGR5 has been suggested as the marker for
CSCs in CRC. However, a significant number of CRCs present none of few LGR5+ cells.
LGR5+ CSCs become absent during metastasis initiation and therapy response. Instead, a
foetal intestinal stem cell program is reactivated. In this thesis, I propose TROP2 as a marker
for these foetal-like CSCs in CRC and functionally characterized them. My findings suggest a
mutually exclusive distribution of LGR5+ and TROP2+ CSC populations in both, mouse and
human CRC, implying that they represent distinct CSC populations. I demonstrated that while
LGR5 marks CSCs in Apcmut CRCs, TROP2 marks CSCs in Apcwt
(WNT-low, serrated) CRCs.
Furthermore, TROP2 expression is associated with advanced tumour stages and poor
prognosis. Here, I showed that, in CRC, TROP2 marks the cells located at the tumour invasive
front as well as the metastasis-initiating cell. Additionally, TROP2 gain-of-function and loss-of-function experiments revealed its direct, but yet unknown, role in CRC progression. Finally,
TROP2 represents a promising therapeutic target in CRC due to the potent therapeutic activity
of the TROP2 antibody-drug conjugated, Sacituzumab Govitecan (SG). Thus, we have
launched a multicentre randomized investigator-initiated trial (phase II/III; NCT06243393) to
test SG as a 3rd line treatment versus standard-of-care in metastatic CRC patients
38°C: Fever, Thermometry, and the Coming into Being of a Global Norm, ca. 1868–1890
Full text linkThis article traces the global biography of the idea that, if the thermometer read 38°C, ‘one need not be afraid’ to speak of a fever, as one early advocate of thermometry put it in 1873. The article revisits how the idea of fever as quantifiable temperature and the related numerical standards first came into being in mid-nineteenth century Leipzig and Berlin. Subsequently, it traces these numerical thresholds’ dissemination across the globe over the 1870s and 1880s and endeavors to explain their ready acceptance, in places as diverse as Japan or Mexico. It argues that thermometry, though initially quite controversial, could become unquestioned within decades not so much on account of its medical utility but a range of other reasons: its suitability for standardization, association with technological modernity, the period’s gendered epistemic order and the very fact of its being a number – the period’s broader penchant for quantifying objectification
Molecular Nano-Architecture of Synaptic Vesicle Clusters in Mammalian Synapses
Full text linkChemical synapses are essential for neuronal processing of information. Synaptic plasticity, the ability to alter the strength of a synapse, is the basis for learning and higher cognitive functions. The properties of synaptic transmission are strongly affected by the organisation of synaptic vesicles (SV) into SV pools. The majority of SV pool concepts agrees on the following three main classes: the readily releasable pool (RRP), which is capable of immediately responding to an AP event, 2) the recycling pool which consists of SVs that are actively participating in the SV cycle but are not release-competent yet, and 3) the reserve pool which is comprised of SVs that are immobile or irresponsive under physiological conditions; the latter also being referred to as “mature” SVs. This maturation process is tightly linked to the age of a given SV and therefore must include a molecular or spatial marker of sort. A handful of candidate proteins has been investigated in vitro but convincing evidence in vivo is lacki
Dissection of heterogeneous hematopoietic stem cell biology in the homeostatic and disease-associated states
Full text linkThe hematopoietic stem cell (HSC) compartment is considered heterogeneous at both functional and molecular levels in its ability to continuously generate all mature blood cells throughout life. With age, clonal hematopoiesis can develop, where an HSC clone disproportionally contributes to the blood cell lineages. This phenomenon has been associated with an increased risk of various diseases.
In the first part of this dissertation, I utilized single cell transplantations and mathematical modeling to interrogate the functional potency of individual HSCs and their paired progeny, and assess cell-extrinsic mechanisms modulating the functionality of HSCs. A large-scale comprehensive analysis of single HSC transplants revealed reconstitution kinetics as a novel parameter capable of predicting HSC transplantation outcomes. My data demonstrated a significant correlation between slower reconstitution kinetics and stemness, alongside a “myeloid-biased” behavior. Conversely, fast-reconstituting clones exhibited exhaustion patterns and classical “lymphoid-biased” outputs. Secondary transplantations of single daughter HSCs revealed a profound decline in functional potential compared to their parent HSC. Moreover, daughter HSC clones acquired faster reconstitution kinetics, correlating with loss of sustained myelopoiesis, and overall HSC potency. Mathematical modeling of single cell transplantation outcomes led to the identification of cell-extrinsic feedback mechanisms regulating the activity of individual HSCs. These data highlighted that the functional outcome of a single HSC is, in part, influenced by the activity of the surrounding HSCs, unlike assumptions of intrinsic programs solely governing HSC heterogeneity. This finding was experimentally validated by altering the single cell transplantation scheme, so that the single HSC was surrounded by lymphoid-deficient Rag2-/- cells. Slow and rapid engraftment kinetics could still be detected, indicating that repopulation dynamics are mostly an intrinsic feature of the HSC clone. However, I no longer observed canonical “myeloid-biased” outcomes, denoting that, on the contrary, lineage output of single HSCs is highly dependent on that of neighboring clones.
In the second part of my dissertation, I investigated the role of Tet2 clonal hematopoiesis of indeterminate potential (CHIP) on the evolution of hepatocellular carcinoma (HCC) with a non-alcoholic fatty liver disease (NAFLD) etiology, with the underlying hypothesis that Tet2 CHIP is as a risk factor for this disease. Dietary-induced HCC represents the fastest rising cancer in the western world, predominantly affecting the elderly population. This disease frequently evolves from an advanced stage of NAFLD, which is primarily characterized by chronic liver inflammation driven by infiltrating-hematopoietic cells. In this project, I employed a mouse model of Tet2-driven CHIP, combined with the administration of a high caloric “Western diet”, able to induce liver damage and faithfully recapitulate the sequential evolution of NAFLD and HCC observed in humans. Long-term assessment of disease progression demonstrated a synergistic effect when combining a Western diet and Tet2 CHIP. This was evidenced by increased serum levels of the biomarkers alanine and aspartate aminotransferases (ALT, AST), higher histopathological NAFLD assessment score (NAS), and a higher incidence of transition to HCC from premalignant stages. Molecular characterization of Western diet liver homogenates further confirmed this synergy, revealing higher degree of fibrosis, inflammation and dysregulated metabolism in Tet2 CHIP livers compared to wild type (WT) counterparts. To this end, a substantial part of my thesis focused on elucidating the mechanisms via which Tet2 CHIP contributes to HCC development. A combination of functional and molecular analysis, including scRNA-seq, bulk RNA-seq and metabolomics, have revealed synergistic programs in Tet2 CHIP Western diet mice.
Taken together, this dissertation advances the field of hematology from two angles; homeostatic and disease. It provides a comprehensive understanding on HSC heterogeneity using large-scale and fine experimental approaches and mathematical modeling. Additionally, it identifies Tet2 CHIP as a potential risk factor for diet-induced liver cancer, offering mechanistic insights which could be exploited for therapeutic interventions
Optimization and standardization of computed tomography perfusion and development of low radiation exposure CT perfusion alternative for clinical applications in oncologic imaging
Full text linkThe pancreas located in abdominal cavity of the human body, plays essential role in digestion and blood sugar regulation. Various medical conditions such as pancreatic tumors or cystic lesions can disrupt its normal functioning. CT perfusion is the most commonly used functional imaging technique in diagnosing these tumors. However, its widespread adoption in clinical practice has been limited by several challenges. One significant obstacle is the absence of standardized protocols for image acquisition. Moreover, image noise can negatively impact perfusion measurements, resulting in inaccuracies when quantifying tissue perfusion, thereby compromising it’s clinical effectiveness. Efforts to mitigate image noise and improve image quality are essential to enhance the accuracy of CT perfusion measurements. Another critical limitation of CT perfusion is the associated radiation exposure, which poses risks to patients, particularly in vulnerable populations such as children and pregnant women.
The objective of this thesis was to conduct a comprehensive meta-analysis of CT perfusion within the context of pancreatic research articles. This involves collecting and analyzing a large number of published research articles related to pancreatic CT perfusion, with a focus on including studies that report quantitative perfusion parameters derived from CT perfusion. Furthermore, the aim was to identify acquisition parameters that influence quantitative measurements, facilitating standardization of those parameters. Additionally, noise correction algorithm was developed using digital perfusion phantoms to mitigate the negative impact of image noise on BF perfusion measurements. Further, for reducing radiation exposure and acquisition time of CT perfusion, a novel perfusion technique namely, FPA was implemented. FPA model was validated using the most commonly used CT perfusion model, MSM. In contrast to CT perfusion using multiple volume acquisitions, FPA uses only two volume acquisitions. The timing for these two volume acquisitions was estimated and optimized based on the information about contrast agent injection. The reduction in number of volume acquisitions reduces the radiation dose, hence, overcoming one of the critical limitations of CT perfusion.
The meta-analysis findings indicated an upward trend in number of CT perfusion studies and sample size since 2009. Furthermore, there was an increase in amount of contrast agent and iodine levels used over the years. The tube potential showed a slight decrease, while tube current-time product increased gradually. Anatomical coverage expanded, and slice thickness decreased over time. Most studies reported significant differences in BF and BV between normal pancreatic tissue and pathological conditions. However, the findings for permeability were less consistent, with only about half of the studies showing significant differences. Additionally, most research studies preferred vendor-supplied software for post-processing, and MSM is the most commonly used model to quantify pancreatic perfusion. It has been found that certain CT acquisition parameters had statistically significant effect on quantitative perfusion measurements, particularly when comparing normal versus pathological pancreatic tissue.
The findings from noise correction algorithm demonstrated a significant improvement in the accuracy of BF measurements. Detailed analysis of GTBF, noiseimpacted BF, and corrected BF values across various tissue regions showed the efficacy of noise correction in mitigating the adverse effects of noise on BF perfusion measurements, leading to more precise quantification of tissue perfusion. Moreover, the observed enhancements in CNR and agreement between GTBF and noise-corrected BF measurements further underscored the utility of noise-correction algorithms in refining BF measurements.
The results from FPA technique demonstrated a strong correlation in perfusion measurements when compared to the reference method, MSM. Small COV and box plot analysis revealed reduced BF variation over acquisition time, particularly in parenchyma tissue. Therefore, a high correlation to MSM could be achieved depending upon selection of acquisition time within the optimum time range. Variations across tissue types were statistically significant, emphasizing the discriminative capabilities of FPA. Moreover, FPA exhibited advantages in terms of reduced radiation exposure and acquisition times compared to conventional CT perfusion techniques.
For clinical application of FPA, the process begins with intravenous injection of a nonionic iodinated contrast agent, followed by a bolus of saline solution (NaCl). Specifically for pancreatic imaging, first volume scan is to be acquired after contrast agent bolus reaches a threshold of 120 HU in the abdominal aorta, which can be precisely achieved by bolus tracking. Subsequently, the second volume scan is planned after a delay ranging from 15.5 to 20.0 seconds, based on the findings of current thesis.
In conclusion, this thesis has addressed critical challenges of CT perfusion, emphasizing the need for standardization of protocols, the impact of image noise, and concerns related to radiation exposure. The development and application of the noise correction algorithm and FPA technique represent significant steps toward making CT perfusion scans more clinically acceptable