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Finding the needle in the haystack : archival research in European political science
No full textThis short article offers a practical introduction to archival research for political scientists working on European politics. Archival documents are increasingly recognized as a relevant data source for process tracing analyses in small-N or mixed methods studies. Previously classified archival documents are exceptionally trustworthy due to their original confidentiality. Their rich and detailed content facilitates the understanding of causal mechanisms. Still, the hurdles for working with archival sources are high for political scientists. Lack of experience, no special training in handling historic documents, and a shortage of textbooks meeting their demands are a few of the problems political scientists planning archival research face. In the article, I highlight the opportunities of archival research and demonstrate how challenges can be overcome. I emphasize that the archival field trip should only be planned once researchers have gained substantive context knowledge. In their preparation, researchers should use all the resources archives offer and develop measurable expectations from theories.publishe
Characterization of novel compounds discovered in neurodegeneration models
No full textThe prevalence of neurodegenerative diseases is increasing and treatments so far are limited to alleviating symptoms. This creates a severe socioeconomic burden and a need for a better understanding of disease initiation and progression, which could lead to the development of curative or disease-modifying treatments. In vitro neurodegeneration models can offer the opportunity to study disease mechanisms and pharmacological intervention.
When working with in vitro models that employ tool compounds to elicit pathological phenotypes, there is always the danger of confusing an experimentally generated artefact for a real effect. Glutathione and its precursors are reportedly capable of protecting neurons from MG-132-induced proteasome inhibition. However, since MG-132 is a peptide-aldehyde known to form hemithioacetals with free thiols, manuscript 1 aimed to determine whether this protection resulted from the thiols’ antioxidative properties (physiological effect) or a chemical inactivation of the inhibitor (artefact). The chemical reaction of MG-132 with glutathione, cysteine and N-acetyl-cysteine was confirmed to occur at very high thiol concentrations. It was irreversible in the case of cysteine, which led to a significant prevention of proteasome inhibition in a cell-free setup. However, transcriptome analysis showed a persistent proteasome inhibition unaffected by thiol co-incubation, which proves that a chemical inactivation does not occur within cells, probably because the necessary thiol concentrations cannot be reached even after supplementation. Instead, downstream damage pathways were attenuated by the thiols’ protective antioxidative properties. Taken together, these results confirm the physiological relevance of thiol-mediated protection of neurons from proteotoxic stress. On a more general level, caution should be exercised when co- or pre-incubating any kind of pharmacological modulator containing an aldehyde moiety with high concentrations of cysteine to prevent artefact generation.
Iron chelation by deferiprone is currently being explored as a disease-modifying treatment for Parkinson’s disease. Since clinical trials yielded mixed results, the second manuscript of this thesis aimed to generate improved iron chelators based on deferiprone. As low blood-brain-barrier passage was hypothesized to be responsible for the variable effect of deferiprone in clinical trials, structural elements allowing transport to the brain via the neutral amino acid transporter LAT1 were introduced to the iron chelator. Five candidate molecules were synthesized and screened, revealing SK4 as the most promising iron chelator. Selective iron chelation within the physiological pH range and its uptake by LAT1 were confirmed. Cell death and neurite loss induced by parkinsonian neurotoxicants in LUHMES neurons could be prevented by 10-20 μM of the new iron chelator.
Microbial metabolites and their delivery to the brain via the gut-brain-axis are hypothesized to contribute to the increasing prevalence of Parkinson’s disease. The third manuscript of this thesis follows up on the previous discovery of an unidentified metabolite of Streptomyces venezuelae, which caused specific dopaminergic neurodegeneration in Caenorhabditis elegans, and aimed to identify and characterize said metabolite. A screening of sequentially purified bacterial extracts on LUHMES neurons revealed aerugine and aeruginol as active cytotoxic compounds. The further characterization of re-synthesized aerugine (C10H11NO2S; 2-[4-(hydroxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]phenol) revealed its striking cell-type specificity in vitro and in vivo. Half maximal dopaminergic neurotoxicity was triggered by 3-4 μM in vitro, other neurons were less sensitive (10-20 μM) and common human cell lines were unaffected at concentrations of up to 100 μM. In transgenic Caenorhabditis elegans, dopaminergic neurons were also degenerated specifically without compromising general nematode viability or the morphology of γ-aminobutyric acid-neurons. This further led to a functional toxicity as observed by a reduced basal slowing response. Mechanistically, aerugine-induced cell death was shown to be highly dependent on iron and prevented by distinct antioxidants or a caspase inhibitor.
In conclusion, this thesis presents several new, neurologically relevant compounds and provides their basic characterization utilizing multiple neurodegeneration models. Aldehyde-thiol reaction products are possible sources for artefacts in in vitro models. SK4 is a novel iron-chelator combining iron selectivity with blood-brain-barrier passage via LAT1. Aerugine is a potential new tool compound for Parkinson’s disease models and could have implications in human pathology.publishe
Advancing next-generation brain organoid platforms for investigating traumatic brain injury from repeated blast exposures
No full textService members and law enforcement personnel are frequently exposed to blast overpressure during training and combat due to the use of heavy weaponry such as large-caliber rifles, explosives, and ordnance. The cumulative effects of these repeated low-level (<4 psi) blast exposures can lead to physical and cognitive deficits that are poorly understood. Brain organoids—human stem cell-derived three-dimensional in vitro culture systems that self-organize to recapitulate the in vivo environment of the human brain—are a promising alternative biological model to traditional cellular cultures and animal models, offering a unique opportunity for studying the mechanisms of mild blast-induced traumatic brain injury (mbTBI) resulting from repeated exposure. In this article, we review the current state of brain organoid models and discuss future directions for advancing their physiological relevance for studying mbTBI. These will be presented within a framework for developing next-generation platforms that integrate relevant loading devices, as well as non-invasive technologies for assessing the brain organoid’s response while increasing throughput. These next-generation platforms aim to accelerate the development of new interventions for mbTBI.publishe
Energy offset between femtosecond and thermal electrons in nanometer field-emitter tips
No full textWe investigate the ultrafast photoelectric effect at sharp tungsten needles and find a considerable energy offset between thermally emitted and photoemitted electrons. Neither changes in temperature nor tuning the work function by the Schottky effect strongly affect the free-space energy of the photoelectrons. We explain these discoveries by a direct optical excitation within the band structure of tungsten, followed by scatter-free transport to the surface and emission into free space. Experiments at different photon energies support that the material and not the photon energy determines the primary properties of the electron beam.publishe
The WWP1–JARID1B axis sustains acute myeloid leukemia chemoresistance
No full textTo uncover substrates mediating the oncogenic activity of WWP1 in acute myeloid leukemia (AML), we performed a proteomic analysis that identified the histone demethylase KDM5B /JARID1B as a candidate target. Of note, JARID1B is indispensable for efficient recruitment of several DNA damage repair factors and for damage resolution, thus negatively influencing the sensitivity of cancer cells to chemo- and radiation therapies. Validation of JARID1B as a substrate of WWP1 revealed a positive regulation of JARID1B half-life by WWP1 through the establishment of K63-linked polyubiquitin chains. As a result, downregulation of JARID1B rising from WWP1 inactivation was associated with higher H3K4me3 enrichment at JARID1B target genes in WWP1-depleted relatively to control AML cells. Integration of RNA-seq and H3K4me3 ChIP-seq data uncovered a highly significant overlap between upregulated gene expression and enriched H3K4me3 peaks after shWWP1 inactivation. We confirmed transcriptional activation of JARID1B targets in WWP1-depleted cells, supporting a role for WWP1 in regulating JARID1B activity. Coherently, upon WWP1 inactivation, we observed a defective recruitment of repair proteins after DNA damage, with subsequent reduced DNA damage repair efficiency and enhanced sensitization of AML cells to the cytotoxic activity of chemotherapeutic drugs. All together, these data identify JARID1B as a bona fide target of WWP1 and imply that WWP1-mediated regulation of JARID1B impacts its ability to modify chromatin and to recruit DNA damage repair factors, thus ultimately affecting chemosensitivity of AML cells.publishe
Visual pigment chromophore usage in Nicaraguan Midas cichlids : phenotypic plasticity and genetic assimilation of cyp27c1 expression
No full textThe wide-ranging photic conditions found across aquatic habitats may act as selective pressures that potentially drive the rapid evolution and diversity of the visual system in teleost fish. Teleost fish fine-tune their visual sensitivities by regulating the two components of visual pigments, the opsin protein and the chromophore. Compared with opsin protein variation, chromophore usage across photic habitats has received little attention. The Nicaraguan Midas cichlid species complex, Amphilophus cf citrinellus [Günther 1864], has independently colonized seven isolated crater lakes with different photic conditions, resulting in several recent adaptive radiations. Here, we investigate variation in cyp27c1, the main enzyme modulating chromophore exchange. We measured cyp27c1 expression in photic environments in the wild, its genetic component in laboratory-reared fish, and its response to different light conditions during development. We found that photic environments significantly predict variation in cyp27c1 expression in wild populations and that this variation seems to be genetically assimilated in two populations. Furthermore, light-induced cyp27c1 expression exhibited genotype-by-environment interactions in our manipulative experiments. Overall, within-lake variation in cyp27c1 expression was higher and inversely related to variation in opsin gene expression along the photic gradient, emphasizing the key role of cyp27c1 in the visual ecology of cichlid fish.publishe
How Migration Shapes Integration : Early Patterns of Migration and Sociocultural Integration of New Immigrants in Germany
No full textMigration research observes increasingly complex migration patterns: migrants follow various migration motives and have different migration experiences. Their individual characteristics, intentions to stay, and migration behavior are very heterogeneous. These complex migration patterns challenge the understanding of integration as an inevitable successive process, which is prevailing in migration research and mainly based on the assumption of ‘coming to stay’. Against this backdrop, this cumulative doctoral dissertation encompasses three research articles on the influence of migration on the early sociocultural integration trajectories of newly arrived immigrants in Germany. In each of these articles German language acquisition, contact to Germans as well as identification with Germany are studied as dimensions of sociocultural integration. The data used in these research articles come from two different surveys among newly arrived immigrants: the „Project on Sociocultural Integration Processes among New Immigrants in Europe (SCIP)“ and the project „Recent Immigration Processes and Early Integration Trajectories in Germany (ENTRA)“. Data for SCIP were collected in two waves between 2010 and 2013. ENTRA contains data from three surveys conducted between 2019 and 2021.
The first research article uses Latent Class Analysis to test the empirical prevalence of two migrant types that feature prominently in the literature – settlers and target-earners – among newly arrived Poles and Turks in Germany. Thereby, an additional type called young learner/professional is identified. The early integration trajectories of these three types mostly reflect differences in their intentions to stay, individual resources and opportunities to integrate. Belonging to a particular migrant type per se, and thus having a particular combination of characteristics, is not superior to the individual variables used to identify each type in explaining differences in the sociocultural integration of newly arrived immigrants.
The second research article describes two theoretical perspectives on migrants’ integration – integration ‘over time’ and integration as a result of migrants’ individual motivation and corresponding investments. By analyzing mini-panel data from newly arrived Italians, Poles, Syrians, and Turks in Germany, this article shows that migrants who intend to stay in Germany permanently have higher levels of integration shortly after arrival but do not integrate faster than other migrants. Moreover, migrants’ duration of stay is important for the acquisition of German language skills. Yet, for the identification with Germany migrants’ intention to stay in terms of motivation is especially relevant.
The third research article compares two cohorts of newly arrived Turks which came to Germany at different points in time. This article is based on the assumption, that changes in cohort composition can explain differences in the integration between both cohorts. In a first step, descriptive results show that migrants belonging to the recent cohort are higher educated, hold more political migration motives, and are less religious than migrants from the earlier cohort. These differences in cohort composition can explain differences in contact to Germans, other immigrants and other Turks as well as in the identification with Germany and Turkey. There is no correlation between differences in German language skills and identification with Europe and differences in the educational level, migration motives, or religiosity of both groups.
Overall, this dissertation highlights that migration is a highly complex phenomenon that (in its multifaceted nature) has an impact on the sociocultural integration of migrants. It shows that migrant types are a suited tool to illustrate complex migration patterns. However, they do not contribute significantly to the explanation of early integration trajectories. Further, this dissertation reveals that successful host country integration requires more than just time spent in this country and that the integration of certain migrant groups changes with their composition – thus, for example, ‘the’ Turks in Germany do not exist.publishe
Cooperative and selective redox doping switches single-molecule magnetism
No full textThe controlled manipulation of electronic and magnetic states in single-molecule magnets (SMMs) is crucial for their implementation in molecular electronics, spintronics, and quantum computation. In typical SMMs, key properties like magnetic anisotropy and slow magnetic relaxation are imposed by complex ligand shells, whose bulky and three-dimensional structures hamper efficient manipulation of the molecular magnetism by chemical methods. This work demonstrates highly selective redox doping of an Fe4 nanomagnet on a Pb(111) surface using lithium atoms. Scanning tunneling microscopy, x-ray absorption spectroscopy, and ab initio calculations reveal the cooperative incorporation of three Li atoms per Fe4 molecule, resulting in a selective, threefold reduction of its iron-based magnetic core. The doping modifies the intramolecular exchange interaction, turning from antiferromagnetic to ferromagnetic, and changes the molecular magnetic anisotropy from easy-axis to easy-plane. This study demonstrates successful chemical redox doping of individual polynuclear molecular magnets, exploits a rare showcase of cooperative binding, and highlights a route for tuning magnetic properties of complex SMMs.publishe