223 research outputs found
Evidence from a German Pension Reform
To counteract the financial pressure emerging in aging societies, statutory
payâasâyouâgo pension schemes are undergoing fundamental reforms in many
Western countries. Starting with cohort 1937, Germany introduced permanent
pension deductions for early retirement. This paper examines the evolution of
the profitability of pension contributions against the background of this
reform for cohorts 1935â1945. I measure the profitability with the internal
rate of return (IRR) and use high quality administrative data. For men the IRR
declines from 2.4% to 1.2% and for women from 5.2% to 3.7%. The results
suggest that the deductions introduced by the reform only cause some part of
this trend. The majority of the trend, about 75%â80%, is caused by increased
pension contributions
Perturbation Analysis of Colorectal Cancer Cell Plasticity and Therapy Resistance at Single Cell Resolution
Das normale Kolonepithel weist eine strenge Zellhierarchie auf, die aus bekannten Zelltypen besteht. Bei Darmkrebs (CRC) ist die Struktur weniger konserviert und nicht gut verstanden. Krebsauslösende Mutationen können die PrÀvalenz von Zelltypen verÀndern, und Zellen können sich auch dedifferenzieren, um einer gezielten Krebstherapie zu entgehen.
Mein Ziel ist es, die Existenz heterogener Zelltypen in Organoiden zu bestĂ€tigen und Signalnetzwerke in CRC zu untersuchen, indem ich mit pharmakologischen Eingriffen spezifische Signalwege inhibiere, die Zellhierarchien im normalen Darm kontrollieren. Strategisch ausgewĂ€hlte Medikamente wurden eingesetzt, um Knotenpunkte in verschiedenen Signalwegen zu hemmen, die fĂŒr das Fortschreiten von Darmkrebs relevant sind. Ich untersuchte, ob die Inhibition von Signalwegen die Zusammensetzung der Zelltypen und den Differenzierungszustand verĂ€ndert oder welche Kombinationen von Inhibitoren PlastizitĂ€t oder Apoptose auslösen könnten.
Von Patienten stammende Organoide mit verschiedenen onkogenen Treibermutationen wurden kultiviert und 48 Stunden lang mit einer Reihe von Inhibitoren und Inhibitorkombinationen behandelt. Diese Organoide wurden hauptsÀchlich auf zwei Ebenen untersucht: durch scRNA seq zur Ermittlung ihres Transkriptoms und durch CyTOF, das die ProteinhÀufigkeit pro Zelle misst, um die AktivitÀt von Signaltransduktionskaskaden zu beurteilen. Beide Methoden wurden eingesetzt, um die HeterogenitÀt des CRC zu quantifizieren.
Ich konnte feststellen, dass sich Organoide mit denselben Treibermutationen Ă€hnlicher verhalten und dass die molekularen Grundlagen der verschiedenen Linien Unterschiede im Therapieerfolg bedingen. Heterogene Transkriptome und Proteinexpression wurden durch einen Differenzierungsgradienten beeinflusst und konnten durch die Zugabe von Inhibitoren verĂ€ndert werden. Die MAPK-AktivitĂ€t folgt diesem Differenzierungsgradienten und eine MAPK-Inhibition verringerte die ZellheterogenitĂ€t und fĂŒhrte zu PlastizitĂ€t. DarĂŒber hinaus stellte ich fest, dass ein Teil der Zellen in Apoptose geht und die verbleibenden Zellen einen nicht-proliferativen Stammzellzustand annehmen, der es den Zellen ermöglicht, sich nach Aussetzung der Behandlung zu erholen.
Es wurden in silico und in vitro Analysen durchgefĂŒhrt, um neuartige Inhibitorkombinationen zur Maximierung der Apoptose in CRC-Organoiden zu finden, um die Entstehung therapieresistenter Subpopulationen weiter zu reduzieren. Wirksame Behandlungskombinationen bleiben jedoch zelllinienabhĂ€ngig.
Durch die getrennte Analyse des Zelldifferenzierungszustands und des Zellsignalisierungszustands habe ich dazu beigetragen zu verstehen, wie Tumorzellen einer gezielten Therapie durch nicht-genetische Resistenzmechanismen entgehen können. Die MAPK-Inhibition zur Verringerung der ZellheterogenitÀt in Kombination mit anderen Inhibitoren könnte in Zukunft zur Optimierung des Therapieerfolgs eingesetzt werden.Normal colon epithelium has a strict cell hierarchy consisting of well-known cell types. In colorectal cancer (CRC) the structure is less conserved and poorly understood. Cancer driver mutations may modulate the prevalence of cell types, and cells may also dedifferentiate to overcome targeted cancer therapy.
My aim is to confirm the existence of heterogeneous cell types in organoids and investigate signaling networks in CRC by targeting specific signaling pathways with pharmacological intervention, which control cell hierarchies in the normal intestine. Strategically selected drugs were used to inhibit nodes in different signaling pathways relevant to the progression of CRC. I explored whether signaling inhibition changes cell type composition and differentiation state, or which inhibitor combinations might induce plasticity or apoptosis.
Patient-derived organoids with different oncogenic diver mutations were cultured and treated with a panel of inhibitors and inhibitor combinations for 48 hours. These organoids were mainly examined on two levels: by scRNA seq to assess their transcriptome and by CyTOF, which measures protein abundance to assess the activity of pathways. Both methods were used to quantify CRC heterogeneity.
I was able to see that organoids with the same driver mutations behave more similarly and that the molecular underpinnings of the different lines drive differences in therapy response. Heterogeneous transcriptomes and protein expression were affected by a differentiation gradient and could be altered by inhibitor addition. MAPK activity was graded along this differentiation gradient, and MAPK inhibition reduced cell heterogeneity and induced plasticity. Additionally, I found that a fraction of cells undergo apoptosis, and the remaining cells adopt a non-proliferative stem cell state, which allows cells to recover after suspension of treatment. \textit{In silico} and \textit{in vitro} analyses were performed to find novel inhibitor combinations to maximize apoptosis in CRC organoids to further reduce the emergence of therapy-resistant subpopulations. However, effective treatment combinations remain cell-line dependent.
By separately analyzing cell differentiation state and cell signaling state I contributed to our understanding of how tumor cells can evade targeted therapy by non-genetic resistance mechanisms. Using MAPK inhibition to reduce cell heterogeneity in combination with other inhibitors may be used in the future to optimize therapy success
Lifetime Earnings Inequality in Germany
This paper documents the magnitude, pattern, and evolution of lifetime earnings inequality in Germany. Based on a large sample of earning biographies from social security records, we show that the intra-generational distribution of lifetime earnings of male workers has a Gini coefficient around .2 for cohorts born in the late 1930s and early 1940s; this amounts to about 2/3 of the value of the Gini coefficient of annual earnings. Within cohorts, mobility in the distribution of yearly earnings is substantial at the beginning of the lifecycle, decreases after-wards and virtually vanishes after age forty. Earnings data for thirty-one cohorts reveals striking evidence of a secular rise of intra-generational inequality in lifetime earnings: West-German men born in the early 1960s are likely to experience about 80 % more lifetime inequality than their fathers. In contrast, both short-term and long-term intra-generational mobility have been rather stable. Longer unemployment spells of workers at the bottom of the distribution of younger cohorts contribute to explain 30 to 40 % of the overall increase in life-time earnings inequality.Lifetime Earnings, Earnings Distribution, Inequality, Mobility, Germany
Lifetime Earnings Inequality in Germany
This paper documents the magnitude, pattern, and evolution of lifetime earnings inequality in Germany. Based on a large sample of earning biographies from social security records, we show that the intra-generational distribution of lifetime earnings of male workers has a Gini coefficient around .2 for cohorts born in the late 1930s and early 1940s; this amounts to about 2/3 of the value of the Gini coefficient of annual earnings. Within cohorts, mobility in the distribution of yearly earnings is substantial at the beginning of the lifecycle, decreases afterwards and virtually vanishes after age forty. Earnings data for thirty-one cohorts reveals striking evidence of a secular rise of intra-generational inequality in lifetime earnings: West-German men born in the early 1960s are likely to experience about 80 % more lifetime inequality than their fathers. In contrast, both short-term and long-term intra-generational mobility have been rather stable. Longer unemployment spells of workers at the bottom of the distribution of younger cohorts contribute to explain 30 to 40 % of the overall increase in lifetime earnings inequality.lifetime earnings, earnings distribution, inequality, mobility, Germany
Evidence from Social Security Records
This paper uncovers ongoing trends in idiosyncratic earnings volatility across
generations by decomposing residual earnings auto-covariances into a permanent
and a transitory component. We employ data on complete earnings life cycles
for prime age men born 1935 through 1974 that covers earnings between 1960 and
2009. Over this period, the German labor market undergoes a heavy
transformation and experiences strong deregulation, deunionization and a shift
in employment from the industrial to the service sector. Our findings of
increases in both components reflect the distinct phases of this
transformation process. In magnitude, the transitory component increases most
strongly in the early 1970s and the 1990s for young workers, whereas the
permanent component displays the strongest increases for older workers in the
early 1980 and the 2000s. Thus, the changes complicate the labor market entry
for young workers while widening wage differences for established workers
The rising longevity gap by lifetime earnings â distributional implications for the pension system
This study uses German social security records to provide novel evidence about
the heterogeneity in life expectancy by lifetime earnings and, additionally,
documents the distributional implications of this earnings-related
heterogeneity. We find a strong association between lifetime earnings and life
expectancy at age 65 and show that the longevity gap is increasing across
cohorts. For West German men born 1926-28, the longevity gap between top and
bottom decile amounts to about 4 years (about 30%). This gap increases to 7
years (almost 50%) for cohorts 1947-49. We extend our analysis to the
household context and show that lifetime earnings are also related to the life
expectancy of the spouse. The heterogeneity in life expectancy has sizable and
relevant distributional consequences for the pension system: when accounting
for heterogeneous life expectancy, we find that the German pension system is
regressive despite a strong contributory link. We show that the internal rate
of return of the pension system increases with lifetime earnings. Finally, we
document an increase of the regressive structure across cohorts, which is
consistent with the increasing longevity gap
individual welfare, distributional and fiscal implications
In aging societies, information on how to reform pension systems is essential
to policy makers. This study scrutinizes effects of early retirement
disincentives on retirement behavior, individual welfare, pensions and public
budget. We employ administrative pension data and a detailed model of the
German tax and social security system to estimate a structural dynamic
retirement model. We find that labor market participation and retirement
behavior in general are strongly influenced by the level of disincentives.
Further, disincentives come at the cost of increasing inequality and
individual welfare losses. Still, net public returns are more than five times
as high as monetarized individual welfare losses. Our estimates also suggest
that similar levels of net public returns achieved by indiscriminating pension
cuts are associated with individual welfare losses that are at least twice as
high
A spectral surrogate model for stochastic simulators computed from trajectory samples
Stochastic simulators are non-deterministic computer models which provide a
different response each time they are run, even when the input parameters are
held at fixed values. They arise when additional sources of uncertainty are
affecting the computer model, which are not explicitly modeled as input
parameters. The uncertainty analysis of stochastic simulators requires their
repeated evaluation for different values of the input variables, as well as for
different realizations of the underlying latent stochasticity. The
computational cost of such analyses can be considerable, which motivates the
construction of surrogate models that can approximate the original model and
its stochastic response, but can be evaluated at much lower cost.
We propose a surrogate model for stochastic simulators based on spectral
expansions. Considering a certain class of stochastic simulators that can be
repeatedly evaluated for the same underlying random event, we view the
simulator as a random field indexed by the input parameter space. For a fixed
realization of the latent stochasticity, the response of the simulator is a
deterministic function, called trajectory. Based on samples from several such
trajectories, we approximate the latter by sparse polynomial chaos expansion
and compute analytically an extended Karhunen-Lo\`eve expansion (KLE) to reduce
its dimensionality. The uncorrelated but dependent random variables of the KLE
are modeled by advanced statistical techniques such as parametric inference,
vine copula modeling, and kernel density estimation. The resulting surrogate
model approximates the marginals and the covariance function, and allows to
obtain new realizations at low computational cost. We observe that in our
numerical examples, the first mode of the KLE is by far the most important, and
investigate this phenomenon and its implications
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