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Quantifying fat zonation in liver lobules: an integrated multiscale in silico model combining disturbed microperfusion and fat metabolism via a continuum biomechanical bi-scale, tri-phasic approach
No full textMetabolic zonation refers to the spatial separation of metabolic functions along the sinusoidal axes of the liver. This phenomenon forms the foundation for adjusting hepatic metabolism to physiological requirements in health and disease (e.g., metabolic dysfunction-associated steatotic liver disease/MASLD). Zonated metabolic functions are influenced by zonal morphological abnormalities in the liver, such as periportal fibrosis and pericentral steatosis. We aim to analyze the interplay between microperfusion, oxygen gradient, fat metabolism and resulting zonated fat accumulation in a liver lobule. Therefore we developed a continuum biomechanical, tri-phasic, bi-scale, and multicomponent in silico model, which allows to numerically simulate coupled perfusion-function-growth interactions two-dimensionally in liver lobules. The developed homogenized model has the following specifications: (i) thermodynamically consistent, (ii) tri-phase model (tissue, fat, blood), (iii) penta-substances (glycogen, glucose, lactate, FFA, and oxygen), and (iv) bi-scale approach (lobule, cell). Our presented in silico model accounts for the mutual coupling between spatial and time-dependent liver perfusion, metabolic pathways and fat accumulation. The model thus allows the prediction of fat development in the liver lobule, depending on perfusion, oxygen and plasma concentration of free fatty acids (FFA), oxidative processes, the synthesis and the secretion of triglycerides (TGs). The use of a bi-scale approach allows in addition to focus on scale bridging processes. Thus, we will investigate how changes at the cellular scale affect perfusion at the lobular scale and vice versa. This allows to predict the zonation of fat distribution (periportal or pericentral) depending on initial conditions, as well as external and internal boundary value conditions.Peer Reviewe
The inhibitory action of the chaperone BRICHOS against the α-Synuclein secondary nucleation pathway
No full textThe complex kinetics of disease-related amyloid aggregation of proteins such as α-Synuclein (α-Syn) in Parkinson’s disease and Aβ42 in Alzheimer’s disease include primary nucleation, amyloid fibril elongation and secondary nucleation. The latter can be a key accelerator of the aggregation process. It has been demonstrated that the chaperone domain BRICHOS can interfere with the secondary nucleation process of Aβ42. Here, we explore the mechanism of secondary nucleation inhibition of the BRICHOS domain of the lung surfactant protein (proSP-C) against α-Syn aggregation and amyloid formation. We determine the 3D NMR structure of an inactive trimer of proSP-C BRICHOS and its active monomer using a designed mutant. Furthermore, the interaction between the proSP-C BRICHOS chaperone and a substrate peptide has been studied. NMR-based interaction studies of proSP-C BRICHOS with α-Syn fibrils show that proSP-C BRICHOS binds to the C-terminal flexible fuzzy coat of the fibrils, which is the secondary nucleation site on the fibrils. Super-resolution fluorescence microscopy demonstrates that proSP-C BRICHOS runs along the fibrillar axis diffusion-dependently sweeping off monomeric α-Syn from the fibrils. The observed mechanism explains how a weakly binding chaperone can inhibit the α-Syn secondary nucleation pathway via avidity where a single proSP-C BRICHOS molecule is sufficient against up to ~7-40 α-Syn molecules embedded within the fibrils.Peer Reviewe
In utero exposure to violence and child health in Iraq
No full textThis paper examines the impact of exposure to violence during pregnancy on anthropometric and cognitive outcomes of children in the medium run. I combine detailed household-level data on more than 36,000 children with geo-coded information on civilian casualties in the aftermath of the US invasion of Iraq between 2003 and 2009 and exploit within-mother differences in prenatal exposure to violence. I find that one violent incident during pregnancy decreases height- and weight-for-age z-scores by 0.13 standard deviations and lowers cognitive and behavioral skills of children. Leveraging information on the severity, type and perpetrator of violence, I isolate the effect of stress from access to prenatal care. The analysis reveals that stressful events, particularly those involving direct threats to personal safety (violence directed at the civilian population and involving execution and torture), exert an even larger negative impact on child health than those incidents that disrupt health infrastructure and access to prenatal care.Peer Reviewe
The HZB F2X‐Facility—An Efficient Crystallographic Fragment Screening Platform
No full textCrystallographic fragment screening (CFS) has recently matured into an important method for the early stages of drug discovery projects. It is based on high‐throughput structure determination and thus requires a high degree of automation as well as specialized workflows and robust analysis tools. Consequently, large‐scale research facilities such as synchrotrons have embraced the method, and developed platforms to perform CFS campaigns with the help of crystallography experts and specific tools. The BESSY II synchrotron, operated by the Helmholtz–Zentrum Berlin (HZB), is one of these synchrotron facilities that offer a CFS platform, named the F2X‐facility. Here, the specialized F2X workflow is described along with the relevant differences to other existing CFS platforms, and the ongoing developments aimed at supporting users of the facility. The different stages of a CFS campaign including requirements, beamline capabilities, and the software environment are detailed and explained. A unique F2X‐GO kit is featured, which allows users the possibility of performing all sample preparation in their home laboratories. Furthermore, at the HZB a computational workflow has been built to support users beyond the hit identification stage. The advantages of the F2X‐facility at HZB are described and references are provided to successfully conduct CFS.These developments were supported by the German Ministry of Science and Education (BMBF) via the projects Frag2Xtal (No. 05K13RM1) and Frag4Lead (No. 05K16RM1), as well as by iNEXT‐Discovery, project No. 871037, funded by the Horizon 2020 program of the European Commission, the German Research Foundation (DFG) via the project NECESSITY (FE2166/1‐1) and the German Academic Exchange Service (DAAD) via the project CFS‐Pipeline (57654470).Peer Reviewe
(Micro)saccade-related potentials during face recognition: A study combining EEG, eye-tracking, and deconvolution modeling
No full textUnder natural viewing conditions, complex stimuli such as human faces are typically looked at several times in succession, implying that their recognition may unfold across multiple eye fixations. Although electrophysiological (EEG) experiments on face recognition typically prohibit eye movements, participants still execute frequent (micro)saccades on the face, each of which generates its own visuocortical response. This finding raises the question of whether the fixation-related potentials (FRPs) evoked by these tiny gaze shifts also contain psychologically valuable information about face processing. Here, we investigated this question by corecording EEG and eye movements in an experiment with emotional faces (happy, angry, neutral). Deconvolution modeling was used to separate the stimulus ERPs to face onset from the FRPs generated by subsequent microsaccades-induced refixations on the face. As expected, stimulus ERPs exhibited typical emotion effects, with a larger early posterior negativity (EPN) for happy/angry compared with neutral faces. Eye tracking confirmed that participants made small saccades in 98% of the trials, which were often aimed at the left eye of the stimulus face. However, while each saccade produced a strong response over visual areas, this response was unaffected by the face’s emotional expression, both for the first and for subsequent (micro)saccades. This finding suggests that the face’s affective content is rapidly evaluated after stimulus onset, leading to only a short-lived sensory enhancement by arousing stimuli that does not repeat itself during immediate refixations. Methodologically, our work demonstrates how eye tracking and deconvolution modeling can be used to extract several brain responses from each EEG trial, providing insights into neural processing at different latencies after stimulus onset.Peer Reviewe
Identifying clusters of precipitation for the Brazilian Legal Amazon based on magnitude of trends and its correlation with sea surface temperature
No full textPrioritizing watershed management interventions relies on delineating homogeneous precipitation regions. In this study, we identify these regions in the Brazilian Legal Amazon based on the magnitude of Sen’s Slope trends using annual precipitation data from September to August, employing the Google Earth Engine platform. Utilizing the silhouette method, we determine four distinct clusters representing zones of homogeneous precipitation patterns. Cluster 0 exhibits a significant median increase in precipitation of 3.20 mm year −1 over the period from 1981 to 2020. Cluster 1 shows a notable increase of 8.13 mm year −1 , while Clusters 2 and 3 demonstrate reductions in precipitation of − 1.61 mm year −1 and − 3.87 mm year −1 , respectively, all statistically significant. Notably, the region known as the arc of deforestation falls within Cluster 2, indicating a concerning trend of reduced precipitation. Additionally, our analysis reveals significant correlations between Sea Surface Temperature (SST) in various oceanic regions and precipitation patterns over the Brazilian Legal Amazon. Particularly noteworthy is the strong positive correlation with SST in the South Atlantic, while negative correlations are observed with SST in the South Pacific and North Atlantic. These findings provide valuable insights for enhancing climate adaptation strategies in the Brazilian Legal Amazon region.Peer Reviewe
Same, but different: similar states of forest structure in temperate mountain regions of Europe despite different social-ecological forest disturbance regimes
No full textContext: Ecosystem services provided by mountain forests are critically linked to forest structure. Social-ecological disturbance regimes (i.e., the rate, frequency, and patch size distribution of disturbances driven by interacting natural and anthropogenic processes) and land use affect forest structure, but their specific impacts are not fully understood. Objectives: We examine how differences in disturbance regimes affect patterns of forest structure across three European mountain ranges with similar vegetation types but different land-use histories: the European Alps, the Carpathians, and the Caucasus. Methods: We related data on horizontal and vertical forest structure, measured by spaceborne lidar (GEDI), with Landsat-derived information on forest disturbances (1986–2020) and topographic, climatic, and anthropogenic predictors. Results: We found similar social-ecological disturbance regimes in the Alps and Carpathians (average annual disturbance rates of 0.34% and 0.39%, respectively, and median patch size < 0.5 ha), yet much lower disturbance rates and patch sizes in the Caucasus (0.08% yr −1 and < 0.2 ha). Despite different disturbance regimes, we found similar patterns of forest structure. Two alternative states emerged consistently across all mountain ranges: a tall and closed-canopy state in 74–80% of forests and a low and open-canopy state (< 50% canopy cover) in the rest. While forest structure responded consistently to abiotic drivers such as topography and climate, its association with anthropogenic pressures differed between mountain ranges. Stand-replacing disturbances played an important role in the Carpathians, while forest structure in the Caucasus was related to proximity to settlements, reflecting local forest use. Conclusions: Different social-ecological contexts in mountain regions can produce markedly different forest disturbance regimes. Despite these differences, similar states of forest structures emerge, suggesting strong attractors of structure in temperate mountain forests.Open Access funding enabled and organized by Projekt DEAL.Bayerisches Staatsministerium für Ernährung, Landwirtschaft und Forstenhttp://dx.doi.org/10.13039/501100010269Deutsche Forschungsgemeinschafthttp://dx.doi.org/10.13039/501100001659HORIZON EUROPE European Research Councilhttp://dx.doi.org/10.13039/100019180Technische Universität München (1025)Peer Reviewe
Logicality and the picture theory of language
No full textI argue that there is tension in Wittgenstein’s position on trivialities (i.e. tautologies and contradictions) in the Tractatus, as it contains the following claims: (A) sentences are pictures; (B) trivialties are not pictures; (C) trivialities are sentences. A and B follow from the “picture theory” of language which Wittgenstein proposes, while C contradicts it. I discuss a way to resolve this tension in light of Logicality, a hypothesis recently developed in linguistic research. Logicality states that trivialities are excluded by the grammar, and that under the right analysis sentences which look trivial are in fact contingent. The tools necessary to support Logicality, I submit, were not available to Wittgenstein at the time, which explains his commitment to C. I end the paper by commenting on some points of contact between analytic philosophy and the generative enterprise in linguistics which are brought into relief by the discussion.Open Access funding enabled and organized by Projekt DEAL.European Research Councilhttp://dx.doi.org/10.13039/501100000781Leibniz-Zentrum Allgemeine Sprachwissenschaft (ZAS) (4531)Peer Reviewe
Physics-based prediction of moisture-capture properties of hydrogels
No full textMoisture-capturing materials can enable potentially game-changing energy-water technologies such as atmospheric water production, heat storage, and passive cooling. Hydrogel composites recently emerged as outstanding moisture-capturing materials due to their low cost, high affinity for humidity, and design versatility. Despite extensive efforts to experimentally explore the large design space of hydrogels for high-performance moisture capture, there is a critical knowledge gap on our understanding behind the moisture-capture properties of these materials. This missing understanding hinders the fast development of novel hydrogels, material performance enhancements, and device-level optimization. In this work, we combine synthesis and characterization of hydrogel-salt composites to develop and validate a theoretical description that bridges this knowledge gap. Starting from a thermodynamic description of hydrogel-salt composites, we develop models that accurately capture experimentally measured moisture uptakes and sorption enthalpies. We also develop mass transport models that precisely reproduce the dynamic absorption and desorption of moisture into hydrogel-salt composites. Altogether, these results demonstrate the main variables that dominate moisture-capturing properties, showing a negligible role of the polymer in the material performance under all considered cases. Our insights guide the synthesis of next-generation humidity-capturing hydrogels and enable their system-level optimization in ways previously unattainable for critical water-energy applications.Peer Reviewe
A new recumbirostran ‘microsaur’ from the lower Permian Bromacker locality, Thuringia, Germany, and its fossorial adaptations
No full textSeveral recumbirostran ‘microsaurs’ are known from early Permian sites across Germany, including the Tambach Formation in Thuringia, central Germany. The only ‘microsaur’ thus far described from the Tambach Formation was the ostodolepid recumbirostran Tambaroter carrolli . However, there is also the documented presence of an undescribed recumbirostran ‘microsaur’ at the well-known Bromacker locality. The Bromacker locality is highly recognized and best known for its very diverse and extremely well-preserved terrestrial tetrapod assemblage combined with the co-occurrence of an exceptional vertebrate ichnofossil record. Here we describe a second new recumbirostran taxon from the Tambach Formation, which is also the first from the Bromacker locality itself. Phylogenetic analysis indicates that the new taxon, Bromerpeton subcolossus gen. et sp. nov., is a brachystelechid recumbirostran, a group also known elsewhere in Germany. The following features differentiate Bromerpeton from the other members of the clade: the presence of 13 maxillary teeth, narrow postorbitals that do not substantially contribute to the postorbital region of the skull, the frontal does not contribute to the orbital margin, and the presence of five manual digits. This new recumbirostran ‘microsaur’ further adds to the unique ecosystem that is preserved at the Bromacker locality, granting us a better understanding of what was living underfoot the larger more well-known animals at the locality. Likewise, it expands our understanding of the evolution of recumbirostran ‘microsaurs’, especially with regards to digit and limb reduction within the clade.Open Access funding enabled and organized by Projekt DEAL.Bundesministerium für Bildung und Forschunghttp://dx.doi.org/10.13039/501100002347National Geographic SocietyEdward O’Neil Endowment FundM. Graham Netting Research FundDeutsche Forschungsgemeinschafthttp://dx.doi.org/10.13039/501100001659Museum für Naturkunde – Leibniz-Institut für Evolutions- und Biodiversitätsforschung (3498)Peer Reviewe