Entwicklung von monoklonalen Antikörpern, spezifisch für krankheitsrelevante Lamine als neues Werkzeug zum Studium von Laminopathien

Diese Arbeit befaßt sich mit möglichen Wegen zur Generierung monoklonaler Antikörper, deren Erkennungssequenz sich in einer Aminosäure unterscheiden soll. So könnten eine punktmutierte und eine Wildtyp-Form eines Proteins einfacher zu untersuchen sein (auch in einer betroffenen Zelle). Diese Studie wurde anhand von Laminen (LaminA und Lap2alpha), deren Punktmutationen zu Laminopathien führen können, durchgeführt. Mittels unterschiedlicher Immunisierungsansätze konnten, neben einem für humanes Lap2alpha spezifischen Antikörper, bestehende Hinweise verstärkt werden, dass dies grundsätzlich möglich ist.This diploma thesis is about ways to generate monclonal antibodies, which differ in their recognitionsite in one single amino acid. With this tools a mutated form and the wild type form of a protein could be distinguished in an affected cell. This study was done based on lamins (laminA and lap2alpha), which pointmutations can cause laminopathies. With different immuniationapproaches I was able to isolate an antibody specific for human lap2alpha and furthermore I could strength the existing evidences that it is possible to generate this desired antibodies

Will the world run out of land? A Kaya-type decomposition to study past trends of cropland expansion

Globally, the further expansion of cropland is limited by the availability of adequate land and by the necessity to spare land for nature conservation and carbon sequestration. Analyzing the causes of past land-use changes can help to better understand the potential drivers of land scarcities of the future. Using the FAOSTAT database, we quantify the contribution of four major factors, namely human population growth, rising per-capita caloric consumption (including food intake and household waste), processing losses (including conversion of vegetal into animal products and non-food use of crops), and yield gains, to cropland expansion rates of the past (1961–2007). We employ a Kaya-type decomposition method that we have adapted to be applicable to drivers of cropland expansion at global and national level. Our results indicate that, all else equal, without the yield gains observed globally since 1961, additional land of the size of Australia would have been put under the plough by 2007. Under this scenario the planetary boundary on global cropland use would have already been transgressed today. By contrast, without rising per-capita caloric consumption and population growth since 1961, an area as large as nearly half and all of Australia could have been spared, respectively. Yield gains, with strongest contributions from maize, wheat and rice, have approximately offset the increasing demand of a growing world population. Analyses at the national scale reveal different modes of land-use transitions dependent on development stage, dietary standards, and international trade intensity of the countries. Despite some well-acknowledged caveats regarding the non-independence of decomposition factors, these results contribute to the empirical ranking of different drivers needed to set research priorities and prepare well-informed projections of land-use change until 2050 and beyond

Will the world run out of land?

Globally, the further expansion of cropland is limited by the availability of adequate land and by the necessity to spare land for nature conservation and carbon sequestration. Analyzing the causes of past landuse changes can help to better understand the potential drivers of land scarcities of the future. Using the FAOSTAT database, we quantify the contribution of four major factors, namely human population growth, rising percapita caloric consumption (including food intake and household waste), processing losses (including conversion of vegetal into animal products and nonfood use of crops), and yield gains, to cropland expansion rates of the past (1961–2007). We employ a Kayatype decomposition method that we have adapted to be applicable to drivers of cropland expansion at global and national level. Our results indicate that, all else equal, without the yield gains observed globally since 1961, additional land of the size of Australia would have been put under the plough by 2007. Under this scenario the planetary boundary on global cropland use would have already been transgressed today. By contrast, without rising percapita caloric consumption and population growth since 1961, an area as large as nearly half and all of Australia could have been spared, respectively. Yield gains, with strongest contributions from maize, wheat and rice, have approximately offset the increasing demand of a growing world population. Analyses at the national scale reveal different modes of landuse transitions dependent on development stage, dietary standards, and international trade intensity of the countries. Despite some wellacknowledged caveats regarding the nonindependence of decomposition factors, these results contribute to the empirical ranking of different drivers needed to set research priorities and prepare wellinformed projections of landuse change until 2050 and beyond.Peer Reviewe

Temperature-related excess mortality in German cities at 2 °C and higher degrees of global warming

Background: Investigating future changes in temperature-related mortality as a function of global mean temperature (GMT) rise allows for the evaluation of policy-relevant climate change targets. So far, only few studies have taken this approach, and, in particular, no such assessments exist for Germany, the most populated country of Europe. Methods: We assess temperature-related mortality in 12 major German cities based on daily time-series of all-cause mortality and daily mean temperatures in the period 1993–2015, using distributed-lag non-linear models in a two-stage design. Resulting risk functions are applied to estimate excess mortality in terms of GMT rise relative to pre-industrial levels, assuming no change in demographics or population vulnerability. Results: In the observational period, cold contributes stronger to temperature-related mortality than heat, with overall attributable fractions of 5.49% (95%CI: 3.82–7.19) and 0.81% (95%CI: 0.72–0.89), respectively. Future projections indicate that this pattern could be reversed under progressing global warming, with heat-related mortality starting to exceed cold-related mortality at 3 °C or higher GMT rise. Across cities, projected net increases in total temperature-related mortality were 0.45% (95%CI: −0.02–1.06) at 3 °C, 1.53% (95%CI: 0.96–2.06) at 4 °C, and 2.88% (95%CI: 1.60–4.10) at 5 °C, compared to today's warming level of 1 °C. By contrast, no significant difference was found between projected total temperature-related mortality at 2 °C versus 1 °C of GMT rise. Conclusions: Our results can inform current adaptation policies aimed at buffering the health risks from increased heat exposure under climate change. They also allow for the evaluation of global mitigation efforts in terms of local health benefits in some of Germany's most populated cities. © 2020 The Author

Precursors for cytochrome P450 profiling breath tests from an in silico screening approach

The family of cytochrome P450 enzymes (CYPs) is a major player in the metabolism of drugs and xenobiotics. Genetic polymorphisms and transcriptional regulation give a complex patient-individual CYP activity profile for each human being. Therefore, personalized medicine demands easy and non-invasive measurement of the CYP phenotype. Breath tests detect volatile organic compounds (VOCs) in the patients’ exhaled air after administration of a precursor molecule. CYP breath tests established for individual CYP isoforms are based on the detection of 13CO2 or 14CO2 originating from CYP-catalyzed oxidative degradation reactions of isotopically labeled precursors. We present an in silico work-flow aiming at the identification of novel precursor molecules, likely to result in VOCs other than CO2 upon oxidative degradation as we aim at label-free precursor molecules. The ligand-based work-flow comprises five parts: (1) CYP profiling was encoded as a decision tree based on 2D molecular descriptors derived from established models in the literature and validated against publicly available data extracted from the DrugBank. (2) Likely sites of metabolism were identified by reactivity and accessibility estimation for abstractable hydrogen radical. (3) Oxidative degradation reactions (O- and N-dealkylations) were found to be most promising in the release of VOCs. Thus, the CYP-catalyzed oxidative degradation reaction was encoded as SMIRKS (a programming language style to implement reactions based on the SMARTS description) to enumerate possible reaction products. (4) A quantitative structure property relation (QSPR) model aiming to predict the Henry constant H was derived from data for 488 organic compounds and identifies potentially VOCs amongst CYP reaction products. (5) A blacklist of naturally occurring breath components was implemented to identify marker molecules allowing straightforward detection within the exhaled air.peer-reviewe

Evidence of rapid adaptation integrated into projections of temperature-related excess mortality

Few studies have used empirical evidence of past adaptation to project temperature-related excess mortality under climate change. Here, we assess adaptation in future projections of temperature-related excess mortality by employing evidence of shifting minimum mortality temperatures (MMTs) concurrent with climate warming of recent decades. The study is based on daily non-external mortality and daily mean temperature time-series from 11 Spanish cities covering four decades (1978–2017). It employs distributed lag non-linear models (DLNMs) to describe temperature-mortality associations, and multivariate mixed-effect meta-regression models to derive city- and subperiod-specific MMTs, and subsequently MMT associations with climatic indicators. We use temperature projections for one low- and one high-emission scenario (ssp126, ssp370) derived from five global climate models. Our results show that MMTs have closely tracked mean summer temperatures (MSTs) over time and space, with meta-regression models suggesting that the MMTs increased by 0.73 °C (95%CI: 0.65, 0.80) per 1 °C rise in MST over time, and by 0.84 °C (95%CI: 0.76, 0.92) per 1 °C rise in MST across cities. Future projections, which include adaptation by shifting MMTs according to observed temporal changes, result in 63.5% (95%CI: 50.0, 81.2) lower heat-related excess mortality, 63.7% (95%CI: 30.2, 166.7) higher cold-related excess mortality, and 11.2% (95%CI: −5.5, 39.5) lower total temperature-related excess mortality in the 2090s for ssp370 compared to estimates that do not account for adaptation. For ssp126, assumptions on adaptation have a comparatively small impact on excess mortality estimates. Elucidating the adaptive capacities of societies can motivate strengthened efforts to implement specific adaptation measures directed at reducing heat stress under climate change

Einführung und Optimierung eines praxisorientierten Problem-based-Learning-Moduls im Life-Science-Bereich

Der vorliegende Beitrag soll zur Diskussion rund um effektive Lehrkonzepte unter Anwendung des Problem-based-Learning-Ansatzes beitragen. Anhand eines konkreten Beispiels aus dem Life-Science-Bereich Tissue Engineering werden zunächst Herausforderungen in der Einführungsphase eines PBL-Moduls beleuchtet. Anschließend werden das aktuelle Konzept des Moduls, die vorgenommenen Maßnahmen zur Optimierung während dessen kontinuierlicher Weiterentwicklung sowie deren Wirksamkeit aus Sicht der Studierenden dargestellt. 13.05.2016 | Christine Leeb, Rita Leitner, Verena Pichler, Carina Huber-Gries, Dominik Rünzler & Veronika Jesenberger (Wien

Projecting Temperature-Attributable Mortality and Hospital Admissions due to Enteric Infections in the Philippines

Background: Enteric infections cause significant deaths, and global projection studies suggest that mortality from enteric infections will increase in the future with warmer climate. However, a major limitation of these projection studies is the use of risk estimates derived from nonmortality data to project excess enteric infection mortality associated with temperature because of the lack of studies that used actual deaths.Objective: We quantified the associations of daily temperature with both mortality and hospital admissions due to enteric infections in the Philippines. These associations were applied to projections under various climate and population change scenarios.Methods: We modeled nonlinear temperature associations of mortality and hospital admissions due to enteric infections in 17 administrative regions of the Philippines using a two-stage time-series approach. First, we quantified nonlinear temperature associations of enteric infections by fitting generalized linear models with distributed lag nonlinear models. Second, we combined regional estimates using a meta-regression model. We projected the excess future enteric infections due to nonoptimal temperatures using regional temperature–enteric infection associations under various combinations of climate change scenarios according to representative concentration pathways (RCPs) and population change scenarios according to shared socioeconomic pathways (SSPs) for 2010–2099.Results: Regional estimates for mortality and hospital admissions were significantly heterogeneous and had varying shapes in association with temperature. Generally, mortality risks were greater in high temperatures, whereas hospital admission risks were greater in low temperatures. Temperature-attributable excess deaths in 2090–2099 were projected to increase over 2010–2019 by as little as 1.3% [95% empirical confidence intervals (eCI): −3.1%, 6.5%] under a low greenhouse gas emission scenario (RCP 2.6) or as much as 25.5% (95% eCI: −3.5%, 48.2%) under a high greenhouse gas emission scenario (RCP 8.5). A moderate increase was projected for temperature-attributable excess hospital admissions, from 0.02% (95% eCI: −2.0%, 1.9%) under RCP 2.6 to 5.2% (95% eCI: −12.7%, 21.8%) under RCP 8.5 in the same period. High temperature-attributable deaths and hospital admissions due to enteric infections may occur under scenarios with high population growth in 2090–2099.Discussion: In the Philippines, futures with hotter temperatures and high population growth may lead to a greater increase in temperature-related excess deaths than hospital admissions due to enteric infections. Our results highlight the need to strengthen existing primary health care interventions for diarrhea and support health adaptation policies to help reduce future enteric infections. https://doi.org/10.1289/EHP932