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Role of GDF15 in active lifestyle induced metabolic adaptations and acute exercise response in mice
(2019)
Physical activity is an important contributor to muscle adaptation and metabolic health. Growth differentiation factor 15 (GDF15) is established as cellular and nutritional stress-induced cytokine but its physiological role in response to active lifestyle or acute exercise is unknown. Here, we investigated the metabolic phenotype and circulating GDF15 levels in lean and obese male C57BI/6J mice with long-term voluntary wheel running (VWR) intervention. Additionally, treadmill running capacity and exercise-induced muscle gene expression was examined in GDF15-ablated mice. Active lifestyle mimic via VWR improved treadmill running performance and, in obese mice, also metabolic phenotype. The post-exercise induction of skeletal muscle transcriptional stress markers was reduced by VWR. Skeletal muscle GDF15 gene expression was very low and only transiently increased post-exercise in sedentary but not in active mice. Plasma GDF15 levels were only marginally affected by chronic or acute exercise. In obese mice, VWR reduced GDF15 gene expression in different tissues but did not reverse elevated plasma GDF15. Genetic ablation of GDF15 had no effect on exercise performance but augmented the post exercise expression of transcriptional exercise stress markers (Atf3, Atf6, and Xbp1s) in skeletal muscle. We conclude that skeletal muscle does not contribute to circulating GDF15 in mice, but muscle GDF15 might play a protective role in the exercise stress response.
Interfacial properties of morpholine-2,5-dione-based oligodepsipeptides and multiblock copolymers
(2019)
Oligodepsipeptides (ODPs) with alternating amide and ester bonds prepared by ring-opening polymerization of morpholine-2,5-dione derivatives are promising matrices for drug delivery systems and building blocks for multifunctional biomaterials. Here, we elucidate the behavior of three telechelic ODPs and one multiblock copolymer containing ODP blocks at the air-water interface. Surprisingly, whereas the oligomers and multiblock copolymers crystallize in bulk, no crystallization is observed at the air-water interface. Furthermore, polarization modulation infrared reflection absorption spectroscopy is used to elucidate hydrogen bonding and secondary structures in ODP monolayers. The results will direct the development of the next ODP-based biomaterial generation with tailored properties for highly sophisticated applications.
A common feature in Answer Set Programming is the use of a second negation, stronger than default negation and sometimes called explicit, strong or classical negation. This explicit negation is normally used in front of atoms, rather than allowing its use as a regular operator. In this paper we consider the arbitrary combination of explicit negation with nested expressions, as those defined by Lifschitz, Tang and Turner. We extend the concept of reduct for this new syntax and then prove that it can be captured by an extension of Equilibrium Logic with this second negation. We study some properties of this variant and compare to the already known combination of Equilibrium Logic with Nelson's strong negation.
Temperature-memory technology was utilized to generate flat substrates with a programmable stiffness pattern from cross-linked poly(ethylene-co-vinyl acetate) substrates with cylindrical microstructures. Programmed substrates were obtained by vertical compression at temperatures in the range from 60 to 100 degrees C and subsequent cooling, whereby a flat substrate was achieved by compression at 72 degrees C, as documented by scanning electron microscopy and atomic force microscopy (AFM). AFM nanoindentation experiments revealed that all programmed substrates exhibited the targeted stiffness pattern. The presented technology for generating polymeric substrates with programmable stiffness pattern should be attractive for applications such as touchpads. optical storage, or cell instructive substrates.
Cold-regulated (COR) 15A is an intrinsically disordered protein (IDP) from Arabidopsis thaliana important for freezing tolerance. During freezing-induced cellular dehydration, COR15A transitions from a disordered to mostly alpha-helical structure. We tested whether mutations that increase the helicity of COR15A also increase its protective function. Conserved glycine residues were identified and mutated to alanine. Nuclear magnetic resonance (NMR) spectroscopy was used to identify residue-specific changes in helicity for wildtype (WT) COR15A and the mutants. Circular dichroism (CD) spectroscopy was used to monitor the coil-helix transition in response to increasing concentrations of trifluoroethanol (TFE) and ethylene glycol. The impact of the COR15A mutants on the stability of model membranes during a freeze-thaw cycle was investigated by fluorescence spectroscopy. The results of these experiments showed the mutants had a higher content of alpha-helical structure and the increased alpha-helicity improved membrane stabilization during freezing. Comparison of the TFE- and ethylene glycol-induced coil-helix transitions support our conclusion that increasing the transient helicity of COR15A in aqueous solution increases its ability to stabilize membranes during freezing. Altogether, our results suggest the conserved glycine residues are important for maintaining the disordered structure of COR15A but are also compatible with the formation of alpha-helical structure during freezing induced dehydration.
Farber disease is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments for Farber disease are clinically available, and affected patients have a severely shortened lifespan. We have recently reported a novel acid ceramidase deficiency model that mirrors the human disease closely. Acid sphingomyelinase is the enzyme that generates ceramide upstream of acid ceramidase in the lysosomes. Using our acid ceramidase deficiency model, we tested if acid sphingomyelinase could be a potential novel therapeutic target for the treatment of Farber disease. A number of functional acid sphingomyelinase inhibitors are clinically available and have been used for decades to treat major depression. Using these as a therapeutic for Farber disease, thus, has the potential to improve central nervous symptoms of the disease as well, something all other treatment options for Farber disease can’t achieve so far. As a proof-of-concept study, we first cross-bred acid ceramidase deficient mice with acid sphingomyelinase deficient mice in order to prevent ceramide accumulation. Double-deficient mice had reduced ceramide accumulation, fewer disease manifestations, and prolonged survival. We next targeted acid sphingomyelinase pharmacologically, to test if these findings would translate to a setting with clinical applicability. Surprisingly, the treatment of acid ceramidase deficient mice with the acid sphingomyelinase inhibitor amitriptyline was toxic to acid ceramidase deficient mice and killed them within a few days of treatment. In conclusion, our study provides the first proof-of-concept that acid sphingomyelinase could be a potential new therapeutic target for Farber disease to reduce disease manifestations and prolong survival. However, we also identified previously unknown toxicity of the functional acid sphingomyelinase inhibitor amitriptyline in the context of Farber disease, strongly cautioning against the use of this substance class for Farber disease patients
Zinc is an essential trace element, making it crucial to have a reliable biomarker for evaluating an individual’s zinc status. The total serum zinc concentration, which is presently the most commonly used biomarker, is not ideal for this purpose, but a superior alternative is still missing. The free zinc concentration, which describes the fraction of zinc that is only loosely bound and easily exchangeable, has been proposed for this purpose, as it reflects the highly bioavailable part of serum zinc. This report presents a fluorescence-based method for determining the free zinc concentration in human serum samples, using the fluorescent probe Zinpyr-1. The assay has been applied on 154 commercially obtained human serum samples. Measured free zinc concentrations ranged from 0.09 to 0.42 nM with a mean of 0.22 ± 0.05 nM. It did not correlate with age or the total serum concentrations of zinc, manganese, iron or selenium. A negative correlation between the concentration of free zinc and total copper has been seen for sera from females. In addition, the free zinc concentration in sera from females (0.21 ± 0.05 nM) was significantly lower than in males (0.23 ± 0.06 nM). The assay uses a sample volume of less than 10 µL, is rapid and cost-effective and allows us to address questions regarding factors influencing the free serum zinc concentration, its connection with the body’s zinc status, and its suitability as a future biomarker for an individual’s zinc status.
Matching participants (as suggested by Hope, 2015) may be one promising option for research on a potential bilingual advantage in executive functions (EF). In this study we first compared performances in three EF-tasks of a naturally heterogeneous sample of monolingual (n = 69, age = 9.0 y) and multilingual children (n = 57, age = 9.3 y). Secondly, we meticulously matched participants pairwise to obtain two highly homogeneous groups to rerun our analysis and investigate a potential bilingual advantage. The initally disadvantaged multilinguals (regarding socioeconomic status and German lexicon size) performed worse in updating and response inhibition, but similarly in interference inhibition. This indicates that superior EF compensate for the detrimental effects of the background variables. After matching children pairwise on age, gender, intelligence, socioeconomic status and German lexicon size, performances became similar except for interference inhibition. Here, an advantage for multilinguals in the form of globally reduced reaction times emerged, indicating a bilingual executive processing advantage.
Trace elements, like Cu, Zn, Fe, or Se, are important for the proper functioning of antioxidant enzymes. However, in excessive amounts, they can also act as pro-oxidants. Accordingly, trace elements influence redox-modulated signaling pathways, such as the Nrf2 pathway. Vice versa, Nrf2 target genes belong to the group of transport and metal binding proteins. In order to investigate whether Nrf2 directly regulates the systemic trace element status, we used mice to study the effect of a constitutive, whole-body Nrf2 knockout on the systemic status of Cu, Zn, Fe, and Se. As the loss of selenoproteins under Se-deprived conditions has been described to further enhance Nrf2 activity, we additionally analyzed the combination of Nrf2 knockout with feeding diets that provide either suboptimal, adequate, or supplemented amounts of Se. Experiments revealed that the Nrf2 knockout partially affected the trace element concentrations of Cu, Zn, Fe, or Se in the intestine, liver, and/or plasma. However, aside from Fe, the other three trace elements were only marginally modulated in an Nrf2-dependent manner. Selenium deficiency mainly resulted in increased plasma Zn levels. One putative mediator could be the metal regulatory transcription factor 1, which was up-regulated with an increasing Se supply and downregulated in Se-supplemented Nrf2 knockout mice.
Using two crystals for spontaneous parametric down-conversion in a parallel setup, we observe two-photon interference with high visibility. The high visibility is consistent with complementarity and the absence of which-path information. The observations are explained as the effects of entanglement or equivalently in terms of interfering probability amplitudes and also by the calculation of a second-order field correlation function in the Heisenberg picture. The latter approach brings out explicitly the role of the vacuum fields in the down-conversion at the crystals and in the photon coincidence counting. For comparison, we show that the Hong–Ou–Mandel dip can be explained by the same approach in which the role of the vacuum signal and idler fields, as opposed to entanglement involving vacuum states, is emphasized. We discuss the fundamental limitations of a theory in which these vacuum fields are treated as classical, stochastic fields.
Peroxisome biogenesis disorders (PBDs) are nontreatable hereditary diseases with a broad range of severity. Approximately 65% of patients are affected by mutations in the peroxins Pex1 and Pex6. The proteins form the heteromeric Pex1/Pex6 complex, which is important for protein import into peroxisomes. To date, no structural data are available for this AAA+ ATPase complex. However, a wealth of information can be transferred from low-resolution structures of the yeast scPex1/scPex6 complex and homologous, well-characterized AAA+ ATPases. We review the abundant records of missense mutations described in PBD patients with the aim to classify and rationalize them by mapping them onto a homology model of the human Pex1/Pex6 complex. Several mutations concern functionally conserved residues that are implied in ATP hydrolysis and substrate processing. Contrary to fold destabilizing mutations, patients suffering from function-impairing mutations may not benefit from stabilizing agents, which have been reported as potential therapeutics for PBD patients.
During the last few decades, the rapid separation of the Small Aral Sea from the isolated basin has changed its hydrological and ecological conditions tremendously. In the present study, we developed and validated the hybrid model for the Syr Darya River basin based on a combination of state-of-the-art hydrological and machine learning models. Climate change impact on freshwater inflow into the Small Aral Sea for the projection period 2007–2099 has been quantified based on the developed hybrid model and bias corrected and downscaled meteorological projections simulated by four General Circulation Models (GCM) for each of three Representative Concentration Pathway scenarios (RCP). The developed hybrid model reliably simulates freshwater inflow for the historical period with a Nash–Sutcliffe efficiency of 0.72 and a Kling–Gupta efficiency of 0.77. Results of the climate change impact assessment showed that the freshwater inflow projections produced by different GCMs are misleading by providing contradictory results for the projection period. However, we identified that the relative runoff changes are expected to be more pronounced in the case of more aggressive RCP scenarios. The simulated projections of freshwater inflow provide a basis for further assessment of climate change impacts on hydrological and ecological conditions of the Small Aral Sea in the 21st Century.
The aim of this study is to monitor short-term seasonal development of young Olympic weightlifters’ anthropometry, body composition, physical fitness, and sport-specific performance. Fifteen male weightlifters aged 13.2 ± 1.3 years participated in this study. Tests for the assessment of anthropometry (e.g., body-height, body-mass), body-composition (e.g., lean-body-mass, relative fat-mass), muscle strength (grip-strength), jump performance (drop-jump (DJ) height, countermovement-jump (CMJ) height, DJ contact time, DJ reactive-strength-index (RSI)), dynamic balance (Y-balance-test), and sport-specific performance (i.e., snatch and clean-and-jerk) were conducted at different time-points (i.e., T1 (baseline), T2 (9 weeks), T3 (20 weeks)). Strength tests (i.e., grip strength, clean-and-jerk and snatch) and training volume were normalized to body mass. Results showed small-to-large increases in body-height, body-mass, lean-body-mass, and lower-limbs lean-mass from T1-to-T2 and T2-to-T3 (∆0.7–6.7%; 0.1 ≤ d ≤ 1.2). For fat-mass, a significant small-sized decrease was found from T1-to-T2 (∆13.1%; d = 0.4) and a significant increase from T2-to-T3 (∆9.1%; d = 0.3). A significant main effect of time was observed for DJ contact time (d = 1.3) with a trend toward a significant decrease from T1-to-T2 (∆–15.3%; d = 0.66; p = 0.06). For RSI, significant small increases from T1-to-T2 (∆9.9%, d = 0.5) were noted. Additionally, a significant main effect of time was found for snatch (d = 2.7) and clean-and-jerk (d = 3.1) with significant small-to-moderate increases for both tests from T1-to-T2 and T2-to-T3 (∆4.6–11.3%, d = 0.33 to 0.64). The other tests did not change significantly over time (0.1 ≤ d ≤ 0.8). Results showed significantly higher training volume for sport-specific training during the second period compared with the first period (d = 2.2). Five months of Olympic weightlifting contributed to significant changes in anthropometry, body-composition, and sport-specific performance. However, hardly any significant gains were observed for measures of physical fitness. Coaches are advised to design training programs that target a variety of fitness components to lay an appropriate foundation for later performance as an elite athlete.
Many human infants grow up learning more than one language simultaneously but only recently has research started to study early language acquisition in this population more systematically. The paper gives an overview on findings on early language acquisition in bilingual infants during the first two years of life and compares these findings to current knowledge on early language acquisition in monolingual infants. Given the state of the research, the overview focuses on research on phonological and early lexical development in the first two years of life. We will show that the developmental trajectory of early language acquisition in these areas is very similar in mono- and bilingual infants suggesting that these early steps into language are guided by mechanisms that are rather robust against the differences in the conditions of language exposure that mono- and bilingual infants typically experience.
In a recent line of research, two familiar concepts from logic programming semantics (unfounded sets and splitting) were extrapolated to the case of epistemic logic programs. The property of epistemic splitting provides a natural and modular way to understand programs without epistemic cycles but, surprisingly, was only fulfilled by Gelfond's original semantics (G91), among the many proposals in the literature. On the other hand, G91 may suffer from a kind of self-supported, unfounded derivations when epistemic cycles come into play. Recently, the absence of these derivations was also formalised as a property of epistemic semantics called foundedness. Moreover, a first semantics proved to satisfy foundedness was also proposed, the so-called Founded Autoepistemic Equilibrium Logic (FAEEL). In this paper, we prove that FAEEL also satisfies the epistemic splitting property something that, together with foundedness, was not fulfilled by any other approach up to date. To prove this result, we provide an alternative characterisation of FAEEL as a combination of G91 with a simpler logic we called Founded Epistemic Equilibrium Logic (FEEL), which is somehow an extrapolation of the stable model semantics to the modal logic S5.
The current study investigates how bilingual children encode and produce morphologically complex words. We employed a silent-production-plus-delayed-vocalization paradigm in which event-related brain potentials (ERPs) were recorded during silent encoding of inflected words which were subsequently cued to be overtly produced. The bilingual children's spoken responses and their ERPs were compared to previous datasets from monolingual children on the same task. We found an enhanced negativity for regular relative to irregular forms during silent production in both bilingual children's languages, replicating the ERP effect previously obtained from monolingual children. Nevertheless, the bilingual children produced more morphological errors (viz. over-regularizations) than monolingual children. We conclude that mechanisms of morphological encoding (as measured by ERPs) are parallel for bilingual and monolingual children, and that the increased over-regularization rates are due to their reduced exposure to each of the two languages (relative to monolingual children).
The development of new and better optimization and approximation methods for Job Shop Scheduling Problems (JSP) uses simulations to compare their performance. The test data required for this has an uncertain influence on the simulation results, because the feasable search space can be changed drastically by small variations of the initial problem model. Methods could benefit from this to varying degrees. This speaks in favor of defining standardized and reusable test data for JSP problem classes, which in turn requires a systematic describability of the test data in order to be able to compile problem adequate data sets. This article looks at the test data used for comparing methods by literature review. It also shows how and why the differences in test data have to be taken into account. From this, corresponding challenges are derived which the management of test data must face in the context of JSP research.
Keywords
The innovative dual-purpose chicken approach aims at contributing to the transition towards sustainable poultry production by avoiding the culling of male chickens. To successfully integrate sustainability aspects into innovation, goal congruency among actors and clearly communicating the added value within the actor network and to consumers is needed. The challenge of identifying common sustainability goals calls for decision support tools. The objectives of our research were to investigate whether the tool could assist in improving communication and marketing with respect to sustainability and optimizing the value chain organization. Three actor groups participated in the tool application, in which quantitative and qualitative data were collected. The results showed that there were manifold sustainability goals within the innovation network, but only some goals overlapped, and the perception of their implementation also diverged. While easily marketable goals such as ‘animal welfare’ were perceived as being largely implemented, economic goals were prioritized less often, and the implementation was perceived as being rather low. By visualizing congruencies and differences in the goals, the tool helped identify fields of action, such as improved information flows and prompted thinking processes. We conclude that the tool is useful for managing complex decision processes with several actors involved.
Children's online use of word order and morphosyntactic markers in Tagalog thematic role assignment
(2019)
We investigated whether Tagalog-speaking children incrementally interpret the first noun as the agent, even if verbal and nominal markers for assigning thematic roles are given early in Tagalog sentences. We asked five- and seven-year-old children and adult controls to select which of two pictures of reversible actions matched the sentence they heard, while their looks to the pictures were tracked. Accuracy and eye-tracking data showed that agent-initial sentences were easier to comprehend than patient-initial sentences, but the effect of word order was modulated by voice. Moreover, our eye-tracking data provided evidence that, by the first noun phrase, seven-year-old children looked more to the target in the agent-initial compared to the patient-initial conditions, but this word order advantage was no longer observed by the second noun phrase. The findings support language processing and acquisition models which emphasize the role of frequency in developing heuristic strategies (e.g., Chang, Dell, & Bock, 2006).