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- N-2030-2015 (1)
- N-3741-2015 (1)
Computer simulations of mathematical models open up the possibility of assessing hypotheses generated by experiments on pathogen immune evasion in human whole-blood infection assays. We apply an interdisciplinary systems biology approach in which virtual infection models implemented for the dissection of specific immune mechanisms are combined with experimental studies to validate or falsify the respective hypotheses. Focusing on the assessment of mechanisms that enable pathogens to evade the immune response in the early time course of a whole-blood infection, the least-square error (LSE) as a measure for the quantitative agreement between the theoretical and experimental kinetics is combined with the Akaike information criterion (AIC) as a measure for the model quality depending on its complexity. In particular, we compare mathematical models with three different types of pathogen immune evasion as well as all their combinations: (i) spontaneous immune evasion, (ii) evasion mediated by immune cells, and (iii) pre-existence of an immune-evasive pathogen subpopulation. For example, by testing theoretical predictions in subsequent imaging experiments, we demonstrate that the simple hypothesis of having a subpopulation of pre-existing immune-evasive pathogens can be ruled out. Furthermore, in this study we extend our previous whole-blood infection assays for the two fungal pathogens Candida albicans and C. glabrata by the bacterial pathogen Staphylococcus aureus and calibrated the model predictions to the time-resolved experimental data for each pathogen. Our quantitative assessment generally reveals that models with a lower number of parameters are not only scored with better AIC values, but also exhibit lower values for the LSE. Furthermore, we describe in detail model-specific and pathogen-specific patterns in the kinetics of cell populations that may be measured in future experiments to distinguish and pinpoint the underlying immune mechanisms.
Ex vivo immune profiling in patient blood enables quantification of innate immune effector functions
(2021)
The assessment of a patient’s immune function is critical in many clinical situations. In complex clinical immune dysfunction like sepsis, which results from a loss of immune homeostasis due to microbial infection, a plethora of pro- and anti-inflammatory stimuli may occur consecutively or simultaneously. Thus, any immunomodulatory therapy would require in-depth knowledge of an individual patient’s immune status at a given time. Whereas lab-based immune profiling often relies solely on quantification of cell numbers, we used an ex vivo whole-blood infection model in combination with biomathematical modeling to quantify functional parameters of innate immune cells in blood from patients undergoing cardiac surgery. These patients experience a well-characterized inflammatory insult, which results in mitigation of the pathogen-specific response patterns towards Staphylococcus aureus and Candida albicans that are characteristic of healthy people and our patients at baseline. This not only interferes with the elimination of these pathogens from blood, but also selectively augments the escape of C. albicans from phagocytosis. In summary, our model could serve as a valuable functional immune assay for recording and evaluating innate responses to infection.
Plants, as sessile organisms, gained the ability to sense and respond to biotic and abiotic stressors to survive severe changes in their environments. The change in our climate comes with extreme dry periods but also episodes of flooding. The latter stress condition causes anaerobiosis-triggered cytosolic acidosis and impairs plant function. The molecular mechanism that enables plant cells to sense acidity and convey this signal via membrane depolarization was previously unknown. Here, we show that acidosis-induced anion efflux from Arabidopsis (Arabidopsis thaliana) roots is dependent on the S-type anion channel AtSLAH3. Heterologous expression of SLAH3 in Xenopus oocytes revealed that the anion channel is directly activated by a small, physiological drop in cytosolic pH. Acidosis-triggered activation of SLAH3 is mediated by protonation of histidine 330 and 454. Super-resolution microscopy analysis showed that the increase in cellular proton concentration switches SLAH3 from an electrically silent channel dimer into its active monomeric form. Our results show that, upon acidification, protons directly switch SLAH3 to its open configuration, bypassing kinase-dependent activation. Moreover, under flooding conditions, the stress response of Arabidopsis wild-type (WT) plants was significantly higher compared to SLAH3 loss-of-function mutants. Our genetic evidence of SLAH3 pH sensor function may guide the development of crop varieties with improved stress tolerance.
Electron–phonon scatterings in solid-state systems are pivotal processes in determining many key physical quantities such as charge carrier mobilities and thermal conductivities. Here, we report direct probing of phonon mode specific electron–phonon scatterings in layered semiconducting transition metal dichalcogenides WSe2, MoSe2, WS2, and MoS2 through inelastic electron tunneling spectroscopy measurements, quantum transport simulations, and density functional calculation. We experimentally and theoretically characterize momentum-conserving single- and two-phonon electron–phonon scatterings involving up to as many as eight individual phonon modes in mono- and bilayer films, among which transverse, longitudinal acoustic and optical, and flexural optical phonons play significant roles in quantum charge flows. Moreover, the layer-number sensitive higher-order inelastic electron–phonon scatterings, which are confirmed to be generic in all four semiconducting layers, can be attributed to differing electronic structures, symmetry, and quantum interference effects during the scattering processes in the ultrathin semiconducting films.
Gate-tuned anomalous Hall effect driven by Rashba splitting in intermixed LaAlO3/GdTiO3/SrTiO3
(2021)
The Anomalous Hall Effect (AHE) is an important quantity in determining the properties and understanding the behaviour of the two-dimensional electron system forming at the interface of SrTiO3-based oxide heterostructures. The occurrence of AHE is often interpreted as a signature of ferromagnetism, but it is becoming more and more clear that also paramagnets may contribute to AHE. We studied the influence of magnetic ions by measuring intermixed LaAlO3/GdTiO3/SrTiO3 at temperatures below 10 K. We find that, as function of gate voltage, the system undergoes a Lifshitz transition while at the same time an onset of AHE is observed. However, we do not observe clear signs of ferromagnetism. We argue the AHE to be due to the change in Rashba spin-orbit coupling at the Lifshitz transition and conclude that also paramagnetic moments which are easily polarizable at low temperatures and high magnetic fields lead to the presence of AHE, which needs to be taken into account when extracting carrier densities and mobilities.
The core diagram of a double Lie algebroid consists of the core of the double Lie algebroid, together with the two core-anchor maps to the sides of the double Lie algebroid. If these two core-anchors are surjective, then the double Lie algebroid and its core diagram are called transitive. This paper establishes an equivalence between transitive double Lie algebroids, and transitive core diagrams over a fixed base manifold. In other words, it proves that a transitive double Lie algebroid is completely determined by its core diagram.
The comma double Lie algebroid associated to a morphism of Lie algebroids is defined. If the latter morphism is one of the core-anchors of a transitive core diagram, then the comma double algebroid can be quotiented out by the second core-anchor, yielding a transitive double Lie algebroid, which is the one that is equivalent to the transitive core diagram.
Brown's and Mackenzie's equivalence of transitive core diagrams (of Lie groupoids) with transitive double Lie groupoids is then used in order to show that a transitive double Lie algebroid with integrable sides and core is automatically integrable to a transitive double Lie groupoid.
Land-use intensification is a major driver of biodiversity loss. However, understanding how different components of land use drive biodiversity loss requires the investigation of multiple trophic levels across spatial scales. Using data from 150 agricultural grasslands in central Europe, we assess the influence of multiple components of local- and landscape-level land use on more than 4,000 above- and belowground taxa, spanning 20 trophic groups. Plot-level land-use intensity is strongly and negatively associated with aboveground trophic groups, but positively or not associated with belowground trophic groups. Meanwhile, both above- and belowground trophic groups respond to landscape-level land use, but to different drivers: aboveground diversity of grasslands is promoted by diverse surrounding land-cover, while belowground diversity is positively related to a high permanent forest cover in the surrounding landscape. These results highlight a role of landscape-level land use in shaping belowground communities, and suggest that revised agroecosystem management strategies are needed to conserve whole-ecosystem biodiversity.
We compared the feasibility of 4 cytomegalovirus (CMV)- and Aspergillus-reactive T-cell immunoassay protocols in allogenic stem cell transplant recipients. While enzyme-linked immunospot performed best overall, logistically advantageous whole blood–based assays performed comparably in patients with less severe lymphocytopenia. CMV-induced interferon-gamma responses correlated strongly across all protocols and showed high concordance with serology.
Co-occurrence patterns of tree-related microhabitats: A method to simplify routine monitoring
(2021)
A Tree-related Microhabitat (TreM) is a distinct, well-delineated morphological singularity occurring on living or standing dead trees, which constitutes a crucial substrate or life site for various species. TreMs are widely recognized as key features for biodiversity. Current TreM typology identifies 47 TreM types according to their morphology and their associated taxa. In order to provide a range of resolutions and make the typology more user-friendly, these 47 TreM types have been pooled into 15 groups and seven forms. Depending on the accuracy required and the time available, a user can now choose to describe TreMs at resolution levels corresponding to type, group or form. Another way to more easily record TreMs during routine management work would be to use co-occurrence patterns to reduce the number of observed TreMs required. Based on a large international TreM database (2052 plots; 70,958 individual trees; 78 tree species), we evaluated both the significance and the magnitude of TreM co-occurrence on living trees for 11 TreM groups. We highlighted 33 significant co-occurrences for broadleaves and nine for conifers. Bark loss, rot hole, crack and polypore had the highest number of positive co-occurrences (N = 8) with other TreMs on broadleaves; bark loss (N = 4) had the highest number for conifers. We found mutually exclusive occurrences only for conifers: Exposed Heartwood excluded both dendrotelm and sap run. Among the four variables we tested for their positive contribution to significant co-occurrences, tree diameter at breast height was the most consistent. Based on our results and practical considerations, we selected three TreM groups for broadleaves, and nine for conifers, and formed useful short lists to reduce the number of TreM groups to assess during routine forest management work in the field. In addition, detecting potential similarities or associations between TreMs has potential theoretical value, e.g. it may help researchers identify common factors favouring TreM formation or help managers select trees with multiple TreMs as candidates for retention.
The Cambrian is anomalous among geological systems as many reports divide it into three divisions of indeterminate rank. This use of “lower”, “middle”, and “upper” has been a convenient way to subdivide the Cambrian despite agreement it consists of four global series. Traditional divisions of the system into regional series (Lower, Middle, Upper) reflected local biotic developments not interprovincially correlatable with any precision. However, use of “lower”, “middle”, and “upper” is unsatisfactory. These adjectives lack standard definition, evoke the regional series, and are misused. Notably, there is an almost 50 year use of three Cambrian subsystems and a 1997 proposal to divide the Avalonian and global Cambrian into four series and three subsystems. The global series allow proposal of three formal subsystems: a ca. 32.6 Ma Lower Cambrian Subsystem (Terreneuvian and Series 2/proposed Lenaldanian Series), a ca. 9.8 Ma Middle, and a ca. 10 Ma Upper Cambrian Subsystem (=Furongian Series). Designations as “Lower Cambrian Subsystem” or “global Lower Cambrian” distinguish the new units from such earlier units as “Lower Cambrian Series” and substitute for the de facto subsystem terms “lower”, “middle”, and “upper”. Cambrian subsystems are comparable to the Carboniferous’ Lower (Mississippian) and Upper (Pennsylvanian) Subsystems.