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The prevalence of diseases associated with misfolded proteins increases with age. When cellular defense mechanisms become limited, misfolded proteins form aggregates and may also develop more stable cross-β structures ultimately forming amyloid aggregates. Amyloid aggregates are associated with neurodegenerative diseases such as Alzheimer’s disease and Huntington’s disease. The formation of amyloid deposits, their toxicity and cellular defense mechanisms have been intensively studied. However, surprisingly little is known about the effects of protein aggregates on cellular signal transduction. It is also not understood whether the presence of aggregation-prone, but still soluble proteins affect signal transduction.
In this study, the still soluble aggregation-prone HttExon1Q74 and its amyloid aggregates were used to analyze the effect of amyloid aggregates on internalization and receptor activation of G protein-coupled receptors (GPCRs), the largest protein family of mammalian cell surface receptors involved in signal transduction. The aggregated HttExon1Q74, but not its soluble form, could inhibit ligand-induced clathrin-mediated endocytosis (CME) of various GPCRs. Most likely this inhibitory effect is based on a terminal sequestration of the HSC70 chaperone to the aggregates which is necessary for CME. Using the vasopressinV1a receptor (V1aR) and the corticotropin-releasing factor receptor 1 (CRF1R) as a model, it could be shown that the presence of HttExon1Q74 aggregates and the inhibition of ligand-induced CME leads to an accumulation of desensitized receptors at the plasma membrane. In turn, this disrupts Gq-mediated Ca2+ signaling and Gs-mediated cAMP signaling of the V1aR and the CRF1R respectively. In contrast to HttExon1Q74 amyloid aggregates, soluble HttExon1Q74 as well as amorphous aggregates did not inhibit GPCR internalization and signaling demonstrating that cellular signal transduction mechanisms are specifically impaired in response to the formation of amyloid aggregates.
In addition, preliminary experiments could show that HttExon1Q74 aggregates provoke an increase in membrane expression of a protein from a structurally and functionally unrelated membrane protein family, namely the serotonin transporter SERT. As SERT is the main pharmacological target to treat depression this could shed light on this commonly occurring comorbidity in neurodegenerative diseases, in particular in early disease states.
Adaptive Force (AF) reflects the capability of the neuromuscular system to adapt adequately to external forces with the intention of maintaining a position or motion. One specific approach to assessing AF is to measure force and limb position during a pneumatically applied increasing external force. Through this method, the highest (AFmax), the maximal isometric (AFisomax) and the maximal eccentric Adaptive Force (AFeccmax) can be determined. The main question of the study was whether the AFisomax is a specific and independent parameter of muscle function compared to other maximal forces. In 13 healthy subjects (9 male and 4 female), the maximal voluntary isometric contraction (pre- and post-MVIC), the three AF parameters and the MVIC with a prior concentric contraction (MVICpri-con) of the elbow extensors were measured 4 times on two days. Arithmetic mean (M) and maximal (Max) torques of all force types were analyzed. Regarding the reliability of the AF parameters between days, the mean changes were 0.31–1.98 Nm (0.61%–5.47%, p = 0.175–0.552), the standard errors of measurements (SEM) were 1.29–5.68 Nm (2.53%–15.70%) and the ICCs(3,1) = 0.896–0.996. M and Max of AFisomax, AFmax and pre-MVIC correlated highly (r = 0.85–0.98). The M and Max of AFisomax were significantly lower (6.12–14.93 Nm; p ≤ 0.001–0.009) and more variable between trials (coefficient of variation (CVs) ≥ 21.95%) compared to those of pre-MVIC and AFmax (CVs ≤ 5.4%). The results suggest the novel measuring procedure is suitable to reliably quantify the AF, whereby the presented measurement errors should be taken into consideration. The AFisomax seems to reflect its own strength capacity and should be detected separately. It is suggested its normalization to the MVIC or AFmax could serve as an indicator of a neuromuscular function.
Adaptive Force (AF) reflects the capability of the neuromuscular system to adapt adequately to external forces with the intention of maintaining a position or motion. One specific approach to assessing AF is to measure force and limb position during a pneumatically applied increasing external force. Through this method, the highest (AFmax), the maximal isometric (AFisomax) and the maximal eccentric Adaptive Force (AFeccmax) can be determined. The main question of the study was whether the AFisomax is a specific and independent parameter of muscle function compared to other maximal forces. In 13 healthy subjects (9 male and 4 female), the maximal voluntary isometric contraction (pre- and post-MVIC), the three AF parameters and the MVIC with a prior concentric contraction (MVICpri-con) of the elbow extensors were measured 4 times on two days. Arithmetic mean (M) and maximal (Max) torques of all force types were analyzed. Regarding the reliability of the AF parameters between days, the mean changes were 0.31–1.98 Nm (0.61%–5.47%, p = 0.175–0.552), the standard errors of measurements (SEM) were 1.29–5.68 Nm (2.53%–15.70%) and the ICCs(3,1) = 0.896–0.996. M and Max of AFisomax, AFmax and pre-MVIC correlated highly (r = 0.85–0.98). The M and Max of AFisomax were significantly lower (6.12–14.93 Nm; p ≤ 0.001–0.009) and more variable between trials (coefficient of variation (CVs) ≥ 21.95%) compared to those of pre-MVIC and AFmax (CVs ≤ 5.4%). The results suggest the novel measuring procedure is suitable to reliably quantify the AF, whereby the presented measurement errors should be taken into consideration. The AFisomax seems to reflect its own strength capacity and should be detected separately. It is suggested its normalization to the MVIC or AFmax could serve as an indicator of a neuromuscular function.
One third of the world's population lives in areas where earthquakes causing at least slight damage are frequently expected. Thus, the development and testing of global seismicity models is essential to improving seismic hazard estimates and earthquake-preparedness protocols for effective disaster-risk mitigation. Currently, the availability and quality of geodetic data along plate-boundary regions provides the opportunity to construct global models of plate motion and strain rate, which can be translated into global maps of forecasted seismicity. Moreover, the broad coverage of existing earthquake catalogs facilitates in present-day the calibration and testing of global seismicity models. As a result, modern global seismicity models can integrate two independent factors necessary for physics-based, long-term earthquake forecasting, namely interseismic crustal strain accumulation and sudden lithospheric stress release.
In this dissertation, I present the construction of and testing results for two global ensemble seismicity models, aimed at providing mean rates of shallow (0-70 km) earthquake activity for seismic hazard assessment. These models depend on the Subduction Megathrust Earthquake Rate Forecast (SMERF2), a stationary seismicity approach for subduction zones, based on the conservation of moment principle and the use of regional "geodesy-to-seismicity" parameters, such as corner magnitudes, seismogenic thicknesses and subduction dip angles. Specifically, this interface-earthquake model combines geodetic strain rates with instrumentally-recorded seismicity to compute long-term rates of seismic and geodetic moment. Based on this, I derive analytical solutions for seismic coupling and earthquake activity, which provide this earthquake model with the initial abilities to properly forecast interface seismicity. Then, I integrate SMERF2 interface-seismicity estimates with earthquake computations in non-subduction zones provided by the Seismic Hazard Inferred From Tectonics based on the second iteration of the Global Strain Rate Map seismicity approach to construct the global Tectonic Earthquake Activity Model (TEAM). Thus, TEAM is designed to reduce number, and potentially spatial, earthquake inconsistencies of its predecessor tectonic earthquake model during the 2015-2017 period. Also, I combine this new geodetic-based earthquake approach with a global smoothed-seismicity model to create the World Hybrid Earthquake Estimates based on Likelihood scores (WHEEL) model. This updated hybrid model serves as an alternative earthquake-rate approach to the Global Earthquake Activity Rate model for forecasting long-term rates of shallow seismicity everywhere on Earth.
Global seismicity models provide scientific hypotheses about when and where earthquakes may occur, and how big they might be. Nonetheless, the veracity of these hypotheses can only be either confirmed or rejected after prospective forecast evaluation. Therefore, I finally test the consistency and relative performance of these global seismicity models with independent observations recorded during the 2014-2019 pseudo-prospective evaluation period. As a result, hybrid earthquake models based on both geodesy and seismicity are the most informative seismicity models during the testing time frame, as they obtain higher information scores than their constituent model components. These results support the combination of interseismic strain measurements with earthquake-catalog data for improved seismicity modeling. However, further prospective evaluations are required to more accurately describe the capacities of these global ensemble seismicity models to forecast longer-term earthquake activity.
The particle noch (‘still’) can have an additive reading similar to auch (‘also’). We argue that both particles indicate that a previously partially answered QUD is re-opened to add a further answer. The particles differ in that the QUD, in the case of auch, can be re-opened with respect to the same topic situation, whereas noch indicates that the QUD is re-opened with respect to a new topic situation. This account predicts a difference in the accommodation behavior of the two particles. We present an experiment whose results are in line with this prediction.
The particle noch (‘still’) can have an additive reading similar to auch (‘also’). We argue that both particles indicate that a previously partially answered QUD is re-opened to add a further answer. The particles differ in that the QUD, in the case of auch, can be re-opened with respect to the same topic situation, whereas noch indicates that the QUD is re-opened with respect to a new topic situation. This account predicts a difference in the accommodation behavior of the two particles. We present an experiment whose results are in line with this prediction.
Portal Wissen = Change
(2021)
Change makes everything different. Let’s be honest: Just about everything is constantly in transformation. Even huge massifs that seem like eternity turned to stone will eventually dissolve into dust. So is change itself the only constant? The Greek philosopher Heraclitus certainly thought so. He said, “The only thing that is constant is change.”
Change is frightening. A change that we cannot explain throws us into turmoil – like a magic trick we cannot decipher. Viruses that mutate, ecosystems that collapse, stars that perish – they all seem to threaten the fragile balance that makes our existence possible. Humanity is late in recognizing that we ourselves are all too often the impetus for dangerous transformations.
Change gives hope. People have always been fascinated by change and felt compelled to explore its origin and essence. Quite successfully. We understand many things much better than generations before. But well enough? Not at all. Alexander von Humboldt said, “Every law of nature that reveals itself to the observer suggests a higher, as yet unrecognized one.” There is still much to be done.
The current issue of Portal Wissen is all about change. We spoke to an astrophysicist who has found her happiness in researching the formation and change of stars. We also look at different aspects of the very earthly climate change and its consequences: A geoscientist explains how global warming affects the stability of mountain ranges.
A legal expert makes clear that the call for a right to climate protection has gone largely unheard until now. How human land use affects biodiversity is being investigated by young researchers of the “Bio- Move” research training group, who have provided us with insights into their work on brown hares, water fleas, and mallard ducks. Other researchers focus on change in the contexts of humans. A group of nutrition scientists at the German Institute of Human Nutrition (DIfE) and sports scientists at the University of Potsdam are investigating the factors that cause our bodies to change as we age – and why some people lose muscles more quickly than others.
Despite all these changes, we do not lose sight of the diversity of research at the University of Potsdam. A visit to the laboratory of the project “OptiZeD” gives us an idea of the possibilities offered by optical sensors for the personalized medicine of tomorrow, while an educational researcher explains why cultural diversity is an asset beneficial to our education. In addition, a cultural scientist reports on the fascination of comics. They are all part of the hopeful change that science is initiating and accomplishing! Enjoy the read!
The mitochondrial chaperone complex HSP60/HSP10 facilitates mitochondrial protein homeostasis by folding more than 300 mitochondrial matrix proteins. It has been shown previously that HSP60 is downregulated in brains of type 2 diabetic (T2D) mice and patients,
causing mitochondrial dysfunction and insulin resistance. As HSP60 is also decreased in peripheral tissues in T2D animals, this thesis investigated the effect of overall reduced HSP60 in the development of obesity and associated co-morbidities.
To this end, both female and male C57Bl/6N control (i.e. without further alterations in their genome, Ctrl) and heterozygous whole-body Hsp60 knock-out (Hsp60+/-) mice, which exhibit a 50 % reduction of HSP60 in all tissues, were fed a normal chow diet (NCD) or a highfat diet (HFD, 60 % calories from fat) for 16 weeks and were subjected to extensive metabolic phenotyping including indirect calorimetry, NMR spectroscopy, insulin, glucose and pyruvate tolerance tests, vena cava insulin injections, as well as histological and molecular analysis.
Interestingly, NCD feeding did not result in any striking phenotype, only a mild increase in energy expenditure in Hsp60+/- mice. Exposing mice to a HFD however revealed an increased body weight due to higher muscle mass in female Hsp60+/- mice, with a simultaneous decrease in energy expenditure. Additionally, these mice displayed decreased fasting glycemia. Opposingly, male Hsp60+/- compared to control mice showed lower body weight gain due to decreased fat mass and an increased energy expenditure, strikingly independent of lean mass. Further, only male Hsp60+/- mice display improved HOMA-IR and Matsuda
insulin sensitivity indices.
Despite the opposite phenotype in regards to body weight development, Hsp60+/- mice of both sexes show a significantly higher cell number, as well as a reduction in adipocyte size in the subcutaneous and gonadal white adipose tissue (sc/gWAT). Curiously, this adipocyte hyperplasia – usually associated with positive aspects of WAT function – is disconnected from metabolic improvements, as the gWAT of male Hsp60+/- mice shows mitochondrial dysfunction, oxidative stress, and insulin resistance. Transcriptomic analysis of gWAT shows an up
regulation of genes involved in macroautophagy. Confirmatory, expression of microtubuleassociated protein 1A/1B light chain 3B (LC3), as a protein marker of autophagy, and direct measurement of lysosomal activity is increased in the gWAT of male Hsp60+/- mice.
In summary, this thesis revealed a novel gene-nutrient interaction. The reduction of the crucial chaperone HSP60 did not have large effects in mice fed a NCD, but impacted metabolism during DIO in a sex-specific manner, where, despite opposing body weight and
body composition phenotypes, both female and male Hsp60+/- mice show signs of protection from high fat diet-induced systemic insulin resistance.
Learning to read in German
(2021)
In the present dissertation, the development of eye movement behavior and the perceptual span of German beginning readers was investigated in Grades 1 to 3 (Study 1) and longitudinally within a one-year time interval (Study 2), as well as in relation to intrinsic and extrinsic reading motivation (Study 3). The presented results are intended to fill the gap of only sparse information on young readers’ eye movements and completely missing information on German young readers’ perceptual span and its development. On the other hand, reading motivation data have been scrutinized with respect to reciprocal effects on reading comprehension but not with respect to more immediate, basic cognitive processing (e.g., word decoding) that is indicated by different eye movement measures. Based on a longitudinal study design, children in Grades 1–3 participated in a moving window reading experiment with eye movement recordings in two successive years. All children were participants of a larger longitudinal study on intrapersonal developmental risk factors in childhood and adolescence (PIER study). Motivation data and other psychometric reading data were collected during individual inquiries and tests at school. Data analyses were realized in three separate studies that focused on different but related aspects of reading and perceptual span development. Study 1 presents the first cross-sectional report on the perceptual span of beginning German readers. The focus was on reading rate changes in Grades 1 to 3 and on the issue of the onset of the perceptual span development and its dependence on basic foveal reading processes. Study 2 presents a successor of Study 1 providing first longitudinal data of the perceptual span in elementary school children. It also includes information on the stability of observed and predicted reading rates and perceptual span sizes and introduces a new measure of the perceptual span based on nonlinear mixed-effects models. Another issue addressed in this study is the longitudinal between-group comparison of slower and faster readers which refers to the detection of developmental patterns. Study 3 includes longitudinal reading motivation data and investigates the relation between different eye movement measures including perceptual span and intrinsic as well as extrinsic reading motivation. In Study 1, a decelerated increase in reading rate was observed between Grades 1 to 3. Grade effects were also reported for saccade length, refixation probability, and different fixation duration measures. With higher grade, mean saccade length increased, whereas refixation probability, first-fixation duration, gaze duration, and total reading time decreased. Perceptual span development was indicated by an increase in window size effects with grade level. Grade level differences with respect to window size effects were stronger between Grades 2 and 3 than between Grades 1 and 2. These results were replicated longitudinally in Study 2. Again, perceptual span size significantly changed between Grades 2 and 3, but not between Grades 1 and 2 or Grades 3 and 4. Observed and predicted reading rates were found to be highly stable after first grade, whereas stability of perceptual span was only moderate for all grade levels. Group differences between slower and faster readers in Year 1 remained observable in Year 2 showing a pattern of stable achievement differences rather than a compensatory pattern. Between Grades 2 and 3, between-group differences in reading rate even increased resulting in a Matthew effect. A similar effect was observed for perceptual span development between Grades 3 and 4. Finally, in Study 3, significant relations between beginning readers’ eye movements and their reading motivation were observed. In both years of measurement, higher intrinsic reading motivation was related to more skilled eye movement patterns as indicated by short fixations, longer saccades, and higher reading rates. In Year 2, intrinsic reading motivation was also significantly and negatively correlated with refixation probability. These correlational patterns were confirmed in cross-sectional linear models controlling for grade level and reading amount and including both reading motivation measures, extrinsic and intrinsic motivation. While there were significant positive relations between intrinsic reading motivation and word decoding as indicated by the above stated eye movement measures, extrinsic reading motivation only predicted variance in eye movements in Year 2 (significant for fixation durations and reading rate), with a consistently opposite pattern of effects as compared to intrinsic reading motivation. Finally, longitudinal effects of Year 1 intrinsic reading motivation on Year 2 word decoding were observed for gaze duration, total reading time, refixation probability, and perceptual span within cross-lagged panel models. These effects were reciprocal because all eye movement measures significantly predicted variance in intrinsic reading motivation. Extrinsic reading motivation in Year 1 did not affect any eye movement measure in Year 2, and vice versa, except for a significant, negative relation with perceptual span. Concluding, the present dissertation demonstrates that largest gains in reading development in terms of eye movement changes are observable between Grades 1 and 2. Together with the observed pattern of stable differences between slower and faster readers and a widening achievement gap between Grades 2 and 3 for reading rate, these results underline the importance of the first year(s) of formal reading instruction. The development of the perceptual span lags behind as it is most apparent between Grades 2 and 3. This suggests that efficient parafoveal processing presupposes a certain degree of foveal reading proficiency (e.g., word decoding). Finally, this dissertation demonstrates that intrinsic reading motivation—but not extrinsic motivation—effectively supports the development of skilled reading.
“Embodied Practices – Looking From Small Places” is an edited transcript of a conversation between theatre and performance scholar Sruti Bala (University of Amsterdam) and sociologist, criminologist and anthropologist Dylan Kerrigan (University of Leicester) that took place as an online event in November 2020. Throughout their talk, Bala and Kerrigan engage with the legacy of Haitian anthropologist Michel-Rolph Trouillot. Specifically, they focus on his approach of looking from small units, such as small villages in Dominica, outwards to larger political structures such as global capitalism, social inequalities and the distribution of power. They also share insights from their own research on embodied practices in the Caribbean, Europe and India and answer questions such as: What can research on and through embodied practices tell us about systems of power and domination that move between the local and the global? How can performance practices which are informed by multiple locations and cultures be read and appreciated adequately? Sharing insights from his research into Guyanese prisons, Kerrigan outlines how he aims to connect everyday experiences and struggles of Caribbean people to trans-historical and transnational processes such as racial capitalism and post/coloniality. Furthermore, he elaborates on how he uses performance practices such as spoken word poetry and data verbalisation to connect with systematically excluded groups. Bala challenges naïve notions about the inherent transformative potential of performance in her research on performance and translation. She points to the way in which performance and its reception is always already inscribed in what she calls global or planetary asymmetries. At the conclusion of this conversation, they broach the question: are small places truly as small as they seem?