Co2 emission reduction in Germany - from a public perspective

Following the Paris Agreement, Germany set targets and interim goals in its Climate Action Plan to become climate neutral by 2045, but the implementation needs to catch up. This thesis analyzes CO2 reduction measures that Germany takes in the public sector by examining the study 'Climate Protection Potentials in Municipalities' and comparing it with the other levels of science, private cooperations, start-ups, and NGOs. Based on a grounded theory approach and interviews, a comparative analysis of the examination reveals that systemic change is required. One important recommendation is that new laws and regulations are needed to achieve climate neutralit

Essays on Time Preferences and Expectations in Dynamic Decision Making

The three chapters of this dissertation provide new insights in modeling and estimating dynamic discrete choice models. Building on previous identification results, several new strategies are presented to estimate important aspects of dynamic decision processes. A focus lies on hyperbolic discounting and biased expectations, two elements that the vast majority of the literature on female labor supply ignores. Furthermore, the empirical analyses demonstrate that the proposed models describe behavior better than the models dominantly used in the literature. Estimations show that these elements have an economic meaning, as they increase the costs of child-related career breaks. The first chapter provides new exclusion restrictions for identifying the exponential discount factor in dynamic discrete choice models. It demonstrates how exogenous changes in restriction probabilities can be used to recover time preferences from choice data. The second chapter further extends this strategy and analytically shows the identification of hyperbolic discounting parameters within a three-period model of dynamic discrete choice. Furthermore, the chapter discusses how the identification carries over to models with more than three periods. Focusing on women's child-related career breaks, a dynamic discrete choice model of female labor supply, human capital accumulation and labor market frictions is developed. Data from the German Socio-Economic Panel is used to estimate the model, finding a present-bias of 0.77 that significantly deviates from an exponential discounting model. Interestingly, the yearly discount factor for two subsequent future periods is close to values usually assumed for exponential discounters in the literature, with a value of 0.92. This result implies that women do not tend to be myopic per se since even utilities 20 years away receive an overall weight of 0.14 in the lifetime utility. Instead, it is that instantaneous utility is valued much more than any future utility, thus providing evidence that women postpone their re-entry into the labor market, by overvaluing current leisure over future career advancements. The third chapter concentrates on another crucial aspect of dynamic choice, expectations about future states of the world. It represents one of the first analyses in the literature on female labor supply that deviates from the rational expectations hypothesis. This hypothesis assumes that individuals, on average, correctly predict future events. After presenting some suggestive evidence that economic agents systematically mispredict their future employment opportunities, I develop a structural life-cycle model of labor supply, human capital accumulation, and labor market frictions. Nesting the rational expectations framework, the model allows job offer expectations to deviate from their real probability. In this chapter, I develop an identification strategy to recover expectations within the model that allows estimating the key parameters from observed labor supply choices. Estimations provide evidence that mothers strongly overestimate their chances on the labor market since they expect the half-yearly job arrival rate to be 66% higher than the actual rate. The structural framework allows for quantifying the costs stemming from these biased beliefs. The results are striking. Overestimating future employment opportunities prolongs career breaks on average between five and eight months, depending on the length of employment protection. In total, the bias causes a reduction of lifetime earnings from employment, as measured at the first birth of a child, between 12% and 18%. Various benefits and the earnings of a potential husband mitigate some of these losses, causing consumption losses to only range from 3.1 % to 4.1 %

Role of ATP-sensitive potassium channels on hypoxic pulmonary vasoconstriction in endotoxemia

Background: ATP-regulated potassium channels (KATP) regulate pulmonary vascular tone and are involved in hypoxic pulmonary vasoconstriction (HPV). In patients with inflammation like sepsis or ARDS, HPV is impaired, resulting in a ventilation-perfusion mismatch and hypoxia. Since increase of vascular KATP channel Kir6.1 has been reported in animal models of endotoxemia, we studied the expression and physiological effects of Kir6.1 in murine endotoxemic lungs. We hypothesized that inhibition of overexpressed Kir6.1 increases HPV in endotoxemia. Methods: Mice (C57BL/6; n = 55) with (n = 27) and without (n = 28) endotoxemia (35 mg/kg LPS i.p. for 18 h) were analyzed for Kir6.1 gene as well as protein expression and HPV was examined in isolated perfused mouse lungs with and without selective inhibition of Kir6.1 with PNU-37883A. Pulmonary artery pressure (PAP) and pressure-flow curves during normoxic (FiO2 0.21) and hypoxic (FiO2 0.01) ventilation were obtained. HPV was quantified as the increase in perfusion pressure in response to hypoxic ventilation in mmHg of baseline perfusion pressure (ΔPAP) in the presence and absence of PNU-37883A. Results: Endotoxemia increases pulmonary Kir6.1 gene (+ 2.8 ± 0.3-fold) and protein expression (+ 2.1 ± 0.3-fold). Hypoxia increases HPV in lungs of control animals, while endotoxemia decreases HPV (∆PAP control: 9.2 ± 0.9 mmHg vs. LPS: 3.0 ± 0.7 mmHg, p < 0.05, means ± SEM). Inhibition of Kir6.1 with 1 μM PNU-37883A increases HPV in endotoxemia, while not increasing HPV in controls (∆PAP PNU control: 9.3 ± 0.7 mmHg vs. PNU LPS: 8.3 ± 0.9 mmHg, p < 0.05, means ± SEM). Conclusion: Endotoxemia increases pulmonary Kir6.1 gene and protein expression. Inhibition of Kir6.1 augments HPV in murine endotoxemic lungs

The Lymnaea Cardioexcitatory Peptide (LyCEP) Receptor: A G-Protein–Coupled Receptor for a Novel Member of the RFamide Neuropeptide Family

A novel G-protein–coupled receptor (GRL106) resembling neuropeptide Y and tachykinin receptors was cloned from the molluscLymnaea stagnalis. Application of a peptide extract from the Lymnaea brain to Xenopus oocytes expressing GRL106 activated a calcium-dependent chloride channel. Using this response as a bioassay, we purified the ligand for GRL106,Lymnaea cardioexcitatory peptide (LyCEP), an RFamide-type decapeptide (TPHWRPQGRF-NH2) displaying significant similarity to the Achatina cardioexcitatory peptide (ACEP-1) as well as to the recently identified family of mammalian prolactin-releasing peptides. In the Lymnaeabrain, the cells that produce egg-laying hormone are the predominant site of GRL106 gene expression and appear to be innervated by LyCEP-containing fibers. Indeed, LyCEP application transiently hyperpolarizes isolated egg-laying hormone cells. In theLymnaea pericardium, LyCEP-containing fibers end blindly at the pericardial lumen, and the heart is stimulated by LyCEPin vitro. These data confirm that LyCEP is an RFamide ligand for GRL10

Plasma-binding globulins and acute stress response

Within studies of acute stress physiology an increase in glucocorticoid secretion is thought to be the primary mediator of tissue response to stress. Corticosteroid-binding globulin may regulate tissue availability of steroids, but has not been considered a dynamic component of the acute stress response. Here, we examined CBG level over the common 60-minute time frame in an acute capture and handling protocol to investigate whether CBG capacity is dynamic or static over short stressors. Using a comparative approach, we measured CBG response to capture and handling stress in nine species of birds, representing five orders and nine families. CBG capacity significantly declined within 30-60 minutes of capture in five of the nine species examined. This decline may serve to significantly increase the level of corticosterone reaching tissues during acute stress. © Georg Thieme Verlag KG Stuttgart

Plasma-binding globulins and acute stress response

Within studies of acute stress physiology an increase in glucocorticoid secretion is thought to be the primary mediator of tissue response to stress. Corticosteroid-binding globulin may regulate tissue availability of steroids, but has not been considered a dynamic component of the acute stress response. Here, we examined CBG level over the common 60-minute time frame in an acute capture and handling protocol to investigate whether CBG capacity is dynamic or static over short stressors. Using a comparative approach, we measured CBG response to capture and handling stress in nine species of birds, representing five orders and nine families. CBG capacity significantly declined within 30-60 minutes of capture in five of the nine species examined. This decline may serve to significantly increase the level of corticosterone reaching tissues during acute stress. © Georg Thieme Verlag KG Stuttgart

Safety and efficacy of ruxolitinib in an open-label, multicenter, single-arm phase 3b expanded-access study in patients with myelofibrosis: A snapshot of 1144 patients in the JUMP trial

JUMP is a phase 3b expanded-access trial for patients without access to ruxolitinib outside of a clinical study; it is the largest clinical trial to date in patients with myelofibrosis who have been treated with ruxolitinib. Here, we present safety and efficacy findings from an analysis of 1144 patients with intermediate- or high-risk myelofibrosis, as well as a separate analysis of 163 patients with intermediate-1-risk myelofibrosis – a population of patients not included in the phase 3 COMFORT studies. Consistent with ruxolitinib’s mechanism of action, the most common hematologic adverse events were anemia and thrombocytopenia, but these led to treatment discontinuation in only a few cases. The most common non-hematologic adverse events were primarily grade 1/2 and included diarrhea, pyrexia, fatigue, and asthenia. The rates of infections were low and primarily grade 1/2, and no new or unexpected infections were observed. The majority of patients achieved a ≥50% reduction from baseline in palpable spleen length. Improvements in symptoms were rapid, with approximately half of all patients experiencing clinically significant improvements, as assessed by various quality-of-life questionnaires. The safety and efficacy profile in intermediate-1-risk patients was consistent with that in the overall JUMP population and with that previously reported in intermediate-2- and high-risk patients. Overall, ruxolitinib provided clinically meaningful reductions in spleen length and symptoms in patients with myelofibrosis, including those with intermediate-1-risk disease, with a safety and efficacy profile consistent with that observed in the phase 3 COMFORT studies. This trial was registered as NCT01493414 at ClinicalTrials.gov

Therapeutic targeting of the PLK1-PRC1-axis triggers cell death in genomically silent childhood cancer.

Chromosomal instability (CIN) is a hallmark of cancer1. Yet, many childhood cancers, such as Ewing sarcoma (EwS), feature remarkably 'silent' genomes with minimal CIN2. Here, we show in the EwS model how uncoupling of mitosis and cytokinesis via targeting protein regulator of cytokinesis 1 (PRC1) or its activating polo-like kinase 1 (PLK1) can be employed to induce fatal genomic instability and tumor regression. We find that the EwS-specific oncogenic transcription factor EWSR1-FLI1 hijacks PRC1, which physiologically safeguards controlled cell division, through binding to a proximal enhancer-like GGAA-microsatellite, thereby promoting tumor growth and poor clinical outcome. Via integration of transcriptome-profiling and functional in vitro and in vivo experiments including CRISPR-mediated enhancer editing, we discover that high PRC1 expression creates a therapeutic vulnerability toward PLK1 inhibition that can repress even chemo-resistant EwS cells by triggering mitotic catastrophe.Collectively, our results exemplify how aberrant PRC1 activation by a dominant oncogene can confer malignancy but provide opportunities for targeted therapy, and identify PRC1 expression as an important determinant to predict the efficacy of PLK1 inhibitors being used in clinical trials.This work was mainly supported by a grant from the German Cancer Aid (DKH-70114111). In addition, the laboratory of T.G.P.G. was supported by the LMU Munich’s Institutional Strategy LMUexcellent within the framework of the German Excellence Initiative, the ‘Mehr LEBEN für krebskranke Kinder—Bettina-Bräu-Stiftung’, the Matthias-Lackas Foundation, the Dr. Leopold and Carmen Ellinger Foundation, the Boehringer-Ingelheim Foundation, the Wilhelm Sander-Foundation (2016.167.1), the Barbara and Hubertus Trettner Foundation, the Dr. Rolf M. Schwiete Foundation, the Friedrich-Baur Foundation, the German Cancer Aid (DKH-70112257 and DKH-111886), the Gert und Susanna Mayer Foundation, the Barbara und Wilfried Mohr Foundation, the SMARCB1 association, and the Deutsche Forschungsgemeinschaft (DFG-391665916). J.L. was supported by a scholarship of the Chinese Scholarship Council (CSC), and a grant of the German Cancer Aid (DKH-70114111). M.D. was by a scholarship of the ‘Deutsche Stiftung für junge Erwachsene mit Krebs‘, J.M. by a scholarship of the Kind-Philipp-Foundation, and C.M.F., M.K. and T.L.B.H. by scholarships from the German Cancer Aid. The laboratory of J.A. was supported by grants from the Instituto de Salud Carlos III (PI16CIII/00026; DTS18CIII/00005), Asociación Pablo Ugarte, ASION, Fundación Sonrisa de Alex, Asociación Todos somos Iván y Asociación Candela Riera. Freely available clipart used for design of parts of figures was kindly provided by Servier Medical Art (https://smart.servier.com/).S