The life span development of decision making

Die vorliegende Dissertation setzt sich mit der Lebensspannenentwicklung von Entscheidungsverhalten auseinander. Sie beschäftigt sich insbesondere damit, wie sich das Zusammenspiel von Umwelt und Kognition auf Entscheidungen auswirkt, wenn Personen älter werden. Dabei liegt ein Schwerpunkt auf der Lebensspannenentwicklung der Bereitschaft Risiken einzugehen (drei Manuskripte) und ein weiterer darauf, zu untersuchen, wie sich steigende kognitive Anforderungen beim Treffen von Entscheidungen auf Altersunterschiede der Entscheidungsqualität auswirken (ein Manuskript). Im ersten Manuskript, „Stability and change in risk-taking propensity across the adult lifespan“ wird anhand eines repräsentativen Längsschnittdatensatzes untersucht, wie sich die Bereitschaft Risiken einzugehen in Abhängigkeit des Lebensbereiches und über die Lebensspanne verändert. Die Resultate zeigen, dass die Risikobereitschaft Charakteristika ähnlich zu denen eines Persönlichkeitsmerkmals aufweist: Am unteren und oberen Ende der Lebensspanne ist die individuelle Stabilität über die Zeit hinweg im Vergleich zum mittleren Alter am geringsten. Die Risikobereitschaft nimmt im Mittel jedoch ab und diese Abnahme ist nicht in jedem Lebensbereich gleich. Die individuelle Veränderung der Risikobereitschaft über die Zeit steht mit individuellen Veränderungen anderer Persönlichkeitsmerkmale wie Extraversion und Offenheit für Erfahrungen in Zusammenhang. Das zweite Manuskript „Age differences in risk-taking propensity are related to perceptions of risk and reward but not perceived control“ untersucht mögliche psychologische Mechanismen hinter der alters- und bereichsspezifischen Veränderung der Risikobereitschaft. Anhand eines weiteren repräsentativen Datensatzes wird analysiert, in wie weit altersbedingte Veränderungen in der Wahrnehmung von Risiko, Nutzen, und Kontrolle in verschiedenen Lebensbereichen eine Rolle spielen. Die Resultate zeigen, dass eine veränderte Wahrnehmung von Kosten und Nutzen die Veränderungen erklären können, nicht jedoch eine veränderte Kontrollwahrnehmung. Das dritte Manuskript „Propensity for risk taking across the life span and around the globe“ untersucht, ob die generelle mittlere Abnahme der Risikobereitschaft für Menschen auf der ganzen Welt gültig ist. Die Annahme ist, dass Merkmale wie Armut, Mordrate, und Einkommensungleichheit Einfluss auf die individuelle Risikobereitschaft nehmen, weil Menschen, in Ländern in denen Ressourcen knapp sind, stärker miteinander konkurrieren müssen als Menschen in Ländern, in denen dies nicht der Fall ist. Die Ergebnisse zeigen einen deutlichen Zusammenhang zwischen der Situation in einem Land und der Abnahme der Risikoneigung über die Lebensspanne. Das vierte Manuskript „How cognitive aging affects decision making under increased memory demands“ untersucht, wie sich steigende kognitive Anforderungen beim Treffen von Entscheidungen auf Altersunterschiede in der Entscheidungsqualität und die Strategieselektion auswirken. Gedächtnisfähigkeiten unterliegen einer stetigen Veränderung über die Lebensspanne und insbesondere ältere Personen zeigen Defizite in der Erinnerungsleistung. Die Ergebnisse zeigen, dass mit zunehmenden Gedächtnisanforderungen, Altersunterschiede in der Entscheidungsqualität größer werden. Individuelle Gedächtnisfähigkeiten mediierten diesen Zusammenhang. Die Ergebnisse sind zudem dadurch zu erklären, dass ältere Erwachsene im Vergleich zu jüngeren Erwachsenen in geringerem Maße zu kompensatorischen Entscheidungsstrategien wählen. Insgesamt unterstreichen die Ergebnisse dieser Dissertation, dass für die Untersuchung von Phänomenen menschlicher Entwicklung das Zusammenspiel von Mensch und Umwelt berücksichtigt werden muss. Diese Dissertation zeigt, dass Veränderungen dieser Phänomene, wie zum Beispiel menschliches Entscheidungsverhalten, oft eine Anpassungsleistungen des Menschen an unterschiedliche Lebensbereiche, kulturelle Umwelten, oder an eine sich verändernde kognitive Leistungsfähigkeit sind. Abstract Individuals of all ages are often confronted with situations varying in their complexity and situational characteristics. Normal aging is associated with changes in cognitive capacities such as learning and memory but also notable alterations in physical fitness, health, and the social environment. These changes most likely affect not only the necessary cognitive tools but also the perception of gains and losses in relation to available resources and personal goals when making decisions. This dissertation shows that age differences in decision making cannot be understood without considering the fit between the individual resources and the characteristics of the choice environment. It comprises three papers studying the effect of aging on the propensity to take risks as well as one paper on inference decisions in choice ecologies that differ in memory demand. The first paper investigates longitudinal changes in risk-taking propensity across the life span. It shows that the propensity to take risks varies as a function of age and domain. Interestingly, different conceptions of change suggest that risk-taking propensity has trait-like properties similar to those found in major personality traits such as the Big Five. The second paper studies the psychological mechanisms of age- and domain-differences in risk-taking propensity. It finds that individual differences in the perceptions of costs and benefits, but not control beliefs, account for the prominent age-related but domain-variant change in risk-taking propensity. The third paper presents a cross-cultural investigation of life span changes in risk-taking propensity. It suggests that age-related changes in risk taking are associated with local characteristics: Countries in which hardship (i.e., homicide rate, gross domestic product, income/gender inequality) is largest show least changes in risk-taking propensity over the life span. Finally, the fourth paper summarizes empirical studies on the effects of memory demand on age differences in inference decisions. It displays that individual memory ability is crucial for the maintenance of adequate decision outcomes in choice environments that pose high demands on memory. Overall, these findings emphasize that in order to predict life span changes in decision making, one needs to take the interaction between the individual and the environment into account. Developmental phenomena such as changes in decision making can be understood as individual efforts to adapt one’s performance to both internal and external changes such as in the environment surrounding them or their own motivations and cognitive capacity

FMNL formins boost lamellipodial force generation

Migration frequently involves Rac-mediated protrusion of lamellipodia, formed by Arp2/3 complex-dependent branching thought to be crucial for force generation and stability of these networks. The formins FMNL2 and FMNL3 are Cdc42 effectors targeting to the lamellipodium tip and shown here to nucleate and elongate actin filaments with complementary activities in vitro. In migrating B16-F1 melanoma cells, both formins contribute to the velocity of lamellipodium protrusion. Loss of FMNL2/3 function in melanoma cells and fibroblasts reduces lamellipodial width, actin filament density and -bundling, without changing patterns of Arp2/3 complex incorporation. Strikingly, in melanoma cells, FMNL2/3 gene inactivation almost completely abolishes protrusion forces exerted by lamellipodia and modifies their ultrastructural organization. Consistently, CRISPR/Cas-mediated depletion of FMNL2/3 in fibroblasts reduces both migration and capability of cells to move against viscous media. Together, we conclude that force generation in lamellipodia strongly depends on FMNL formin activity, operating in addition to Arp2/3 complex-dependent filament branching

The Bacillus subtilis Minimal Genome Compendium

To better understand cellular life, it is essential to decipher the contribution of individual components and their interactions. Minimal genomes are an important tool to investigate these interactions. Here, we provide a database of 105 fully annotated genomes of a series of strains with sequential deletion steps of the industrially relevant model bacterium Bacillus subtilis starting with the laboratory wild type strain B. subtilis 168 and ending with B. subtilis PG38, which lacks approximately 40% of the original genome. The annotation is supported by sequencing of key intermediate strains as well as integration of literature knowledge for the annotation of the deletion scars and their potential effects. The strain compendium presented here represents a comprehensive genome library of the entire MiniBacillus project. This resource will facilitate the more effective application of the different strains in basic science as well as in biotechnology

Patient-specific image-based bone marrow dosimetry in Lu-177-[DOTA(0),Tyr(3)]-Octreotate and Lu-177-DKFZ-PSMA-617 therapy: investigation of a new hybrid image approach

Background: The bone marrow (BM) is a main organ at risk in Lu-177-PSMA-617 therapy of prostate cancer and Lu-177-Octreotate therapy of neuroendocrine tumours. BM dosimetry is challenging and time-consuming, as different sequential quantitative measurements must be combined. The BM absorbed dose from the remainder of the body (ROB) can be determined from sequential whole-body planar (WB-P) imaging, while quantitative Lu-177-SPECT allows for more robust tumour and organ absorbed doses. The aim was to investigate a time-efficient and patient-friendly hybrid protocol (HP) for the ROB absorbed dose to the BM. It combines three abdominal quantitative SPECT (QSPECT) scans with a single WB-P acquisition and was compared with a reference protocol (RP) using sequential WB-P in combination with sequential QSPECT images. We investigated five patients receiving 7. 4 GBq Lu-177-Octreotate and five patients treated with 3.7 GBq Lu-177-PSMA-617. Each patient had WB-P and abdominal SPECT acquisitions 24 (+ CT), 48, and 72 h post-injection. Blood samples were drawn 30 min, 80 min, 24 h, 48 h, and 72 h post-injection. BM absorbed doses from the ROB were estimated from sequential WB-P images (RP), via a mono-exponential fit and mass-scaled organ-level S values. For the HP, a mono-exponential fit on the QSPECT data was scaled with the activity of one WB-P image acquired either 24, 48, or 72 h post-injection (HP24, HP48, HP72). Total BM absorbed doses were determined as a sum of ROB, blood, major organ, and tumour contributions. Results: Compared with the RP and for Lu-177-Octreotate therapy, median differences of the total BM absorbed doses were 13% (9-17%), 8% (4-15%), and 1% (0-5%) for the HP24, HP48, and HP72, respectively. For Lu-177-PSMA-617 therapy, total BM absorbed doses deviated 10% (2-20%), 3% (0-6%), and 2% (0-6%). Conclusion: For both Lu-177-Octreotate and Lu-177-PSMA-617 therapy, BM dosimetry via sequential QSPECT imaging and a single WB-P acquisition is feasible, if this WB-P image is acquired at a late time point (48 or 72 h post-injection). The reliability of the HP can be well accepted considering the uncertainties of quantitative Lu-177 imaging and BM dosimetry using standardised organ-level S values

The coding and non-coding transcriptional landscape of subependymal giant cell astrocytomas

Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited neurocutaneous disorder caused by inactivating mutations in TSC1 or TSC2, key regulators of the mechanistic target of rapamycin complex 1 (mTORC1) pathway. In the CNS, TSC is characterized by cortical tubers, subependymal nodules and subependymal giant cell astrocytomas (SEGAs). SEGAs may lead to impaired circulation of CSF resulting in hydrocephalus and raised intracranial pressure in patients with TSC. Currently, surgical resection and mTORC1 inhibitors are the recommended treatment options for patients with SEGA. In the present study, high-throughput RNA-sequencing (SEGAs n = 19, periventricular control n = 8) was used in combination with computational approaches to unravel the complexity of SEGA development. We identified 9400 mRNAs and 94 microRNAs differentially expressed in SEGAs compared to control tissue. The SEGA transcriptome profile was enriched for the mitogen-activated protein kinase (MAPK) pathway, a major regulator of cell proliferation and survival. Analysis at the protein level confirmed that extracellular signal-regulated kinase (ERK) is activated in SEGAs. Subsequently, the inhibition of ERK independently of mTORC1 blockade decreased efficiently the proliferation of primary patient-derived SEGA cultures. Furthermore, we found that LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 were overexpressed at both gene and protein levels in SEGA compared to control tissue. Taken together LAMTOR1-5 can form a complex, known as the 'Ragulator' complex, which is known to activate both mTORC1 and MAPK/ERK pathways. Overall, this study shows that the MAPK/ERK pathway could be used as a target for treatment independent of, or in combination with mTORC1 inhibitors for TSC patients. Moreover, our study provides initial evidence of a possible link between the constitutive activated mTORC1 pathway and a secondary driver pathway of tumour growth

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Risk-taking propensity across the life span and around the globe

Past empirical work suggests that aging is associated with decreases in risk taking. But are such effects universal? Life-history theory suggests that the link between age and risk taking is a function of specific reproductive strategies that can be more or less risky depending on the ecology. We assessed variation in the age-risk curve using World Values Survey data from 77 countries (N = 147,118). The results suggest that propensity for risk taking tends to decline across the life span in the vast majority of countries. In addition, there is systematic variation among countries: Countries in which hardship (e.g., high infant mortality) is higher are characterized by higher levels of risk taking and flatter age-risk curves. These findings suggest that hardship may function as a cue to guide life-history strategies. Age-risk relations thus cannot be understood without reference to the demands and affordances of the environment