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Medieval texts reveal the normalised presence of Saami peoples in medieval Fennoscandia, suggesting close interactions involving trade, relationships, rituals, and magic. Despite growing recognition of these relations, the Saami remain overlooked in general studies of the Middle Ages, often relegated to symbolic roles or footnotes. As a result, Saami characters are typically depicted as the exotic Other within Norse society, often being stripped of agency and humanity in historical narratives. To counter these biases and distorted narratives, an essential step is analysing exclusionary structures in medieval literature and critically reviewing existing research on Saami representation. This process challenges dehumanising portrayals and confronts present-day stereotypes. The present study aims to ‘re-humanize’ (as Paulette F. C. Steeves puts it) the medieval Saami past by using decolonising frameworks and perspectives offered by the so-called ‘Indigenous turn’ of medieval studies, bridging medieval studies and Indigenous studies within a Norse context.
During infections, innate immune cells are crucial for initiating a pro-inflammatory immune response and clearing the invading pathogen. Delay in pathogen clearance or initiation of an immune response due to impaired functionality of immune cells can result in devastating consequences. The cellular compartment of the innate immune system comprises an array of specialized cell types: Macrophages are tissue-resident professional phagocytes that clear cellular debris, pathogens, and foreign objects. Dendritic cells (DCs) are immune sentinels specialized in antigen uptake and subsequent T cell priming. They are primary sources of cytokines in response to infection. Neutrophils are efficient effector cells that respond rapidly to infection and clear bacteria by different mechanisms. If effector mechanisms of these cells are affected by either bacterial or other factors, infections might not be resolved and can spread throughout the host. Cobalt-chromium-molybdenum biomaterial is widely used in arthroplasty. Implant-derived wear particles and ions lead to macrophage-driven adverse local tissue reactions: Such reactions have been linked to an increased risk of periprosthetic joint infection after revision arthroplasty. While metal-induced cytotoxicity is well characterized in human macrophages, direct effects on their functionality remain elusive. In Paper I, we show that local peri-implant tissue is exposed to Co and Cr in situ. Influx of macrophages is also evident. Exposure of isolated human monocytes/macrophages to Cr3+ in vitro had only minor effects. However, exposure of monocytes/macrophages to pathologic concentrations of Co2+ significantly impaired both phenotype and functionality. High concentrations of Co2+ induced loss of surface markers, including CD14 and CD16. Both Co2+ and Cr3+ impaired macrophage responses to Staphylococcus aureus infection. Co2+ -exposed macrophages, in particular, showed decreased phagocytic activity. These findings demonstrate the immunosuppressive effects of locally elevated metal ions on the innate immune response. Streptococcus pyogenes (group A streptococcus, GAS) causes a variety of diseases ranging from mild to severe necrotizing soft tissue infections (NSTIs). In the host environment hypervirulent GAS variants carrying mutations within the genes encoding for control of virulence (Cov)R/S two component system are enriched. This adaptation is associated with loss of SpeB secretion. In Paper II, we show that in vitro infections with hyper-virulent GAS variants harboring dysfunctional CovR/S suppress secretion of IL-8 and IL-18 by human monocytic cells. This phenotype was mediated by a caspase-8 dependent mechanism. Knockout of streptococcal SLO in a GAS strain carrying functional CovR/S even increased secretion of IL1β and IL-18 by moDCs. Of 67 fully sequenced GAS NSTI isolates, 28 contained covS or covR mutations that rendered the TCS dysfunctional. However, no differences in systemic IL-8 and IL-18 were detected in these patients. GAS isolates recovered from patients often display a mixed phenotype, consisting of SpeB positive (SpeB+ ) and SpeB negative (SpeB- ) clones. Irreversible loss of SpeB expression is often caused by loss of function mutations in regulatory components (CovR/S, RopB). Loss of SpeB is often associated with hyper-virulence. In Paper III, we show that the host environment induces transiently abrogated secretion of SpeB by GAS. Tissue inflammation, neutrophil influx, and degranulation correlated with increased frequencies of SpeB- GAS clones. Isolates recovered from tissue expressed but did not secrete SpeB, which was reversible. Neutrophilderived ROS were identified as the main factor responsible for abrogated SpeB secretion. Hyper-virulent SpeB- clones also exhibit better survival within and induce excessive degranulation of neutrophils.
Materials and Methods:
Literature search was conducted using electronic MEDLINE/ Cochrane databases, relevant references, citations and hand search was conducted. Academic Colleges were contacted to identify relevant studies and full texts. Inclusion Criteria were Randomized clinical trials, human cohort and case series reporting increasing vertical dimension and restoring worn dentition in adults suffering from tooth wear using fixed, minimal invasive and adhesive techniques.
The search period spanned from 2000 up to January 2023. Of the 550 articles identified, 111 went throw full text screening for eligibility and 12 studies were included in our study.
Failure, follow-up period for all the studies were assessed. Attrition , Bruxism, increase of vertical dimension rates and mean time of failure were calculated using random effect models.
Results:
Tooth wear was reported equally in anterior and posterior region, and restorations were done in direct and indirect manners, mostly with pre-evaluation of the needed increase of vertical dimension. The mean of increased vertical dimension was 2.3 mm. The mean observation time of the restorations was 41.3 months with a minimum observation period of 12 months and a maximum of 84 months. Failure rate of all the included studies was 9.9% (95% CI: 91.00 % to 95.80%) high heterogeneity was detected in Failure rate with I2 of (93.85). Time to fail was calculated to be 37.5 months for 2458 cases (95% CI:32.32 to 91.13%). A fixed effect model was performed to calculate the event of increasing vertical dimension , the event rate was 81.72% (95% CI: 0.00 to 88.10%).
Conclusion:
The performance of direct and indirect restorations is satisfactory, and the failure rate is low, which leads us to conclude that these non-invasive restorations are a reliable and cost-effective middle-term treatment method to restore vertical dimension in moderate to severe worn dentition.
Conflict of interest: None
In their idealized forms, enzymes can facilitate complex reactions with extreme specificity and selectivity. Additionally, in this imaginative form, they only require mild reaction conditions, resulting in low energy consumption, and they are biodegradable, efficient, reusable, and sustainable. Unfortunately, this idealized form often deviates significantly from reality, where enzymes are more likely to be associated with marginal stability and low reaction rates, leaving them less than desirable for many industrial applications. As such, if we could master the process of engineering the configuration of a protein towards a given task, the implications could be staggering.
This thesis aims to contribute to the process of protein engineering, mainly how computational tools can be used to make the protein engineering process more efficient and accessible.
Article I explores the current state of the art in machine learning-guided directed evolution and serves as a foundation for Article II, which is a concrete application of these techniques to an engineering campaign. Despite successfully improving overall activity and selectivity, we also observe limitations and constraints within the methodology. Article III then delves into these drawbacks and attempts to lay the foundation for a more generalizable and, more importantly, efficient engineering workflow, balancing the strengths and weaknesses of computational techniques with advances in gene synthesis. We then validated this novel pipeline in Article IV, where we show the potential of this methodology. Article V describes a more standard protein engineering campaign on squalene-hopene cyclases for potentially interesting products in the flavor and fragrance industry. Lastly, Article VI outlines a PyMol plugin for molecular docking.
In Zeiten von youtube und tiktok sind Musikvideos immer noch beliebte populäre Texte, die es gilt lesen zu können. Die Analyse von Musikvideos ist eine gute Übung in Visual Literacy, knüpft sie doch an die Lebenswelten junger Menschen an und durchdringt aufgrund der intertextuellen Zusammenhänge von Text, Musik, Bild und Celebrity Culture viele Bereiche des (pop-)kulturell geprägten sozialen Zusammenlebens.
Mit diesem Arbeitsblatt lässt sich die visuelle Ebene des Musikvideos, deren Komposition, Bedeutung und Interpretation in einfachen Schritten erarbeiten. Das Arbeitsblatt ist in englischer Sprache konzipiert und fördert so auch die Ausdrucksfähigkeit in derselben.
The combination of the Layer-by-Layer (LbL) method, a nano-material such as carbon nanotubes (CNTs), and charged polyelectrolytes (PEs) is a reliable approach to produce highly functionalized surface coatings. These coatings are stable, controllable, ultra-thin, and most importantly, biocompatible. The ability to tune their properties by varying the preparation conditions and the terminating layer opens up a wide range of applications in the fields of biology and medicine. Here, the goal was to create electrically conductive coatings on which cells grow and proliferate. To achieve this goal, a coating with a stable conductive film structure, a suitable film surface topography, and suitable surface potential (and 𝜁-potential) must be prepared.
At the beginning of this thesis, the focus was on the fabrication of electrically conductive multilayer films, whose electrical properties should be stable and adjustable in a controlled manner (Article 1). The combination of chemically modified CNTs as polyanions, a strong linear polycation like poly(diallyldimethylammonium chloride) (PDADMA), and the LbL-method allowed us to prepare such films. Their characterization was carried out in air at ambient conditions. Since PDADMA is non-conductive, the charge transfer within the film and thus the electrical conductivity itself depends mainly on the CNTs and their arrangement. It was found that four CNT/PDADMA bilayers (BL) were always necessary to create a lateral network structure with multiple CNT crossing points to enable and support electron transport within the film. Moreover, additional CNT/PDADMA BL resulted in decreasing sheet resistance, while the conductivity remained constant at ≈ 4 kS/m regardless of the number of bilayers. Increasing the PDADMA molecular weight (Mw) from 44.4 kDa to 322 kDa did not affect film properties such as thickness or electrical conductivity.
However, increasing the CNT concentration from 0.15 mg/ml to 0.25 mg/ml in the deposition suspension resulted in thicker and less conductive films. This is attributed to a faster adsorption process of the CNTs leading to more adsorption sites for the polycation. We found an increased PDADMA monomer/CNT ratio compared to films prepared with the lower CNT concentration in the deposition suspension. The electrical conductivity decreased by a factor of four down to 1.1 kS/m, which can be attributed to fewer contact points between the CNTs. Overall, we were able to prepare stable and electrically conductive multilayer films. Additionally, by varying the preparation conditions tuning of the electrical conductivity is possible.
To fulfill requirements regarding i.e., medical implants, film properties not only have to be stable and controllable in a dry state (described in Article 1) but also in a biological aqueous environment. Therefore, in Article 2 we immersed our coated samples in three different solutions usually employed in biological research and compared their properties with their dry state, respectively. Also, hydration/swelling effects that normally occur for polyelectrolyte multilayer films (PEMs) in solutions were investigated.
For the film preparation, PDADMA (Mw = 322 kDa) and a deposition suspension of modified CNTs with two different concentrations (0.15 mg/ml and 0.25 mg/ml), which aged for two years, were used. Independent of the CNT suspension concentration, it turned out that the film thickness of the samples, prepared from the aged suspension, decreased significantly compared to the film thickness previously measured in Article 1. As a cross-check a new and fresh CNT suspension was made, which allowed us to reproduce the film thickness described in Article 1.
These results indicated that something happened with the CNT suspension over a two-year period. An analysis via X-ray photoelectron spectroscopy (XPS) showed a decrease in the percentage of functional groups in the CNTs from the aged suspension. The loss of functional groups resulted in less negatively charged CNTs and thus in fewer adsorption sites for the polycation PDADMA. Consequently, the PDADMA monomer/CNT ratio decreased, which lowered the thickness per bilayer by a factor of three, compared to films prepared with a freshly prepared CNT suspension. The lower linear charge density of the aged CNTs also enhanced their hydrophobicity, which is, in combination with the electrostatic forces, another important factor for multilayer cohesion. In contrast to PEMs made from polycations and polyanions, no swelling of the films occurred when immersed in solutions. This can be attributed to the fact that the increased hydrophobicity of the CNTs and the hydrophobic nature of the PDADMA backbone prevent the incorporation of water into the multilayer film. In solution, the films slightly shrink (by ≈ 2 nm), which makes them even more compact. Yet they remain stable. The result is an increased electrical conductivity from 9.6 kS/m, in the dry state, up to 15.3 kS/m immersed in solutions. To summarize, we showed that by tuning the interpolyelectrolyte forces the swelling and the ensuing decrease of the electrical conductivity of the films can be prevented.
Regarding the application in biology and medicine, we must consider that long-term exposure of cells to nano-materials like CNTs could lead to damage and inflammation of adjacent tissue. Therefore, it is necessary to prevent direct contact between the electrically conductive multilayer, i.e., CNT/PDADMA film, and the cells. The solution to this problem is a biocompatible top film that covers the CNT/PDADMA multilayer completely and still provides a lateral surface structure that supports cell adhesion and proliferation. Additional layers consisting solely of PEs could provide such a top film.
In Article 3 we investigated the self-patterning of PEM films as function of deposition steps. After preparation in water, the films were dried, characterized in air, and in vacuum. The films were built with high and low molecular weight PEs. PDADMA was used as polycation and poly(styrene sulfonate) sodium salt (PSS) as polyanion. The observation via Atomic Force Microscopy (AFM) showed that films prepared with high molecular weight PEs are laterally homogeneous and form no patterns, due to the chain immobility. The flat surfaces are ineligible as a substrate for cell adhesion.
In contrast, films built with a short PSS, especially at Mw, PSS = 10.7 kDa, began to self-pattern after seven deposited PDADMA/PSS bilayers. With each additionally deposited bilayer, the surface got more and more structured, from grooves over stripes to circular domains. Increasing film thickness led to an increased lateral mean distance between the surface structures. Scanning Electron Microscopy (SEM) images showed that exposure to a vacuum resulted in a decrease in the film thickness attributed to water removal, while the mean distance between the domains increased. Thus, by using this self-pattering process we are able to prepare PEMs with a highly structured surface. By adding PDADMA/PSS bilayers, not only the CNT/PDADMA film can be covered completely, but also a suitable surface morphology for cells can be created. Controlling the number of deposited bilayers allows the preparation of suitable coatings for cells.
To further improve the interaction of the cell and coated substrate not only the lateral structure but also the interacting electrostatic forces between cells and substrate are important for the nature of cell adhesion, function, and proliferation. In Article 4 we investigated PEMs, consisting of strong PEs with a low (PDADMA) and high (PSS) linear charge density. We performed asymmetric force measurements with the help of the colloidal probe technique (CP). Here, the forces between a PEM-covered surface and a colloidal probe (silica sphere) glued to a cantilever were investigated. The colloidal probe was either bare or covered with polycation poly(ethylenimine) (PEI). The surfaces were immersed in NaCl solutions with different ionic strengths (INaCl), starting with deionized water, then enriched up to 1 mol/L NaCl. The interaction force between a CP and the surface was measured. Thus, insight into the surface potential/charge was obtained.
During film preparation, two growth regimes (parabolic and linear) exist. These regimes and the terminating layer determine the surface force of the PEM. PEMs with a terminating PSS layer are predominantly flat and negatively charged when the ion concentration is low and the film is in the parabolic growth regime (between 1 and ≈ 15 BL). This indicates charge reversal on PSS adsorption. At the transition point between the parabolic and linear growth regimes, the ratio between polyanion and polycation monomers starts to switch and some cationic monomers are neutralized not by anionic monomers but by monovalent ions. Therefore, the surface charge density in diluted NaCl solutions changed from slightly positive near the transition to positive in the linear growth regime. At the lowest ionic strengths (INaCL) the range of the surface potential goes from – 40.5 mV (9 BL, parabolic) up to + 50 mV (19 BL, linear).
In contrast, polycation (PDADMA) terminated films are overall positive in diluted NaCl solutions. At the beginning of the parabolic growth regime, the layers are more compact and flat. However, with each additional layer deposited, the film becomes less compact and the chains begin to loosen. The now more loosely bound chains start to protrude into the solution and form pseudo-brushes. This could already be observed for 10.5 BL.
It intensifies in the linear growth regime (begin at ≈ 15 BL) and results in steric surface forces. Changing the surrounding INaCl affects this behavior and the pseudo-brushes scale as polyelectrolyte brushes.
By controlling the number of bilayers (thus the growth regime), the surrounding ionic strength, and the conformation of PEs at the PEM surface, it is possible to prepare a suitable range of surface properties i.e., for cell adhesion and proliferation. To prove that these multilayers can provide a suitable surface and have a positive effect on cell behavior, we coated in Article 5 titanium-covered samples with PEMs. Investigated was the cell interaction with the surface at different zeta(ζ) - potentials, a parameter for dynamic surface potential. Here the cell activity is measured by the mobilization of calcium (Ca2+) within the cell as a function of the ζ - potential of the substrate and the externally applied electrical potential. The cell activity indicates if the ζ - potential, provided by the sample surface, is suitable or not for the cells. The favorable interaction with the substrate is also reflected in the cell morphology and proliferation. The results showed that highly negative ζ - potentials between - 90 and - 3 mV led to a decreasing/reduced Ca2+ mobilization which correlates with reduced cell activity. Nearly neutral to moderate positive surfaces (ζ - potential + 1 to + 10 mV) i.e., PSS-terminated PEMs are able to promote cell adhesion and growth as demonstrated by an increased Ca2+ mobilization. The access to the intracellular Ca2+ stores, provided by the external stimulus, is now more effective and suggests a higher cell activity. Increasing the ζ - potentials up to ≈ + 50 mV (highly positive), i.e., PDADMA - terminated PEMs with pseudo-brushes, resulted in restricted cell viability and impaired Ca2+ mobilization, which led to a disturbed cell morphology and proliferation. In conclusion, only surfaces, terminated with i.e., PEI, with moderate positive charges (ζ - potential + 1 to + 10 mV) are able to improve the Ca2+ mobilization and thus the cell activity and proliferation. PEMs with a PSS termination provide negative 𝜁−potentials, onto which cells adhere, and proliferate. Therefore, they are a good alternative for surface functionalization for implant surfaces. In summary, the objective set at the beginning of the thesis is addressed within articles written as part of this thesis. It is possible to fabricate PEMs with modified CNTs to produce coatings that are electrically conductive with tunable sheet resistance, whether dry in air or immersed in an aqueous solution (Articles 1 and 2). Also, for pure PEMs, it is shown that with the right molecular weight of PEs and a certain number of bilayers, a suitable surface structure for cell adhesion can be produced (Article 3). Additional surface properties such as a suitable surface charge density can be provided by PEMs which can improve the cell activity as monitored with Ca2+ mobilization (Articles 4 and 5). The next step is to combine the knowledge gained from Articles 1 – 5 and link it to the application of external electrical fields to cells.
Physics-regularized Machine Learning To Approximate 3D Ideal-MHD Equilibria At Wendelstein 7-X
(2024)
The magnetohydrodynamic (MHD) equilibrium model is one of the fundamental building blocks in the description of a magnetically confined plasma. The computational cost of constructing solutions to the 3D ideal-MHD equilibrium problem is one of the limiting factors in stellarator research and design; in particular, it limits the extent to which we can perform sample-intensive applications, applications which require many samples to be evaluated to yield meaningful results. Sample-intensive applications in stellarator research and design include, for example, equilibrium reconstruction, stellarator optimization, and flight simulators. In this thesis, we investigate how faithfully artificial neural networks (NNs) can quickly approximate ideal-MHD equilibria in stellarator geometries, starting with Wendelstein 7-X (W7-X), the world’s most advanced stellarator. In particular, we investigate (see section 1.7):
RQI: to what extent can NN models approximate the MHD equilibrium solution for different W7-X configurations and plasma profiles? What
is the speed-accuracy trade-off offered by NN models?
RQII: to what degree the NN model faithfully reproduces equilibrium quantities of interest (e. g., MHD stability)? To what extent can NN models meet the requirements of downstream applications (e. g., Bayesian
inference, stellarator optimization) in terms of equilibrium quantities
accuracy?
RQIII: whether we can exploit the implicit representation of a MHD equilibrium, i. e., the equilibrium solution should satisfy the ideal-MHD force
balance equation, to improve the NN approximation’s accuracy;
RQIV: the reconstruction of the full posterior istribution of plasma parameters and equilibrium quantities with self-consistent MHD equilibria; moreover, how does the adoption of MHD equilibria approximated by NN models affect the inferred plasma parameters?
A deep NN model is developed to learn the ideal-MHD solution operator in W7-X operational subspace, yielding 3D equilibria up to six orders of magnitude faster than currently available MHD equilibrium codes. Physics domain knowledge is embeded into the NN model: equilibrium solution symmetries are satisfied by construction, and the MHD force balance regularizes the NN model to satisfy the ideal-MHD equations. The model accurately predicts the equilibrium solution and it faithfully reproduces global equilibrium quantities and proxy functions used in stellarator optimization. Finally, the developed fast NN equilibrium model has been applied in downstream applications to obtain W7-X configurations with improved fast-particle confinement and to infer plasma parameters with self-consistent MHD equilibria at W7-X.
The maintenance of protein homeostasis in muscle by degradation systems, e.g. the autophagy lysosomal pathway (ALP) and the ubiquitin-proteasome system (UPS), is of great importance. It prevents the accumulation of nonfunctioning and not properly folded proteins, which can lead to protein aggregate myopathies (PAMs) and several other protein storage diseases. Degradation by the UPS depends on the transfer of ubiquitin to a target protein. This happens in a cascade of E1-E2-E3 proteins. This process is also involved in protein location and regulation of protein activity. E3 ligases are often tissue specific. Muscle RING-finger proteins (MuRFs) are a family of really interesting new gene (RING)-Finger E3 ubiquitin ligases, that are almost exclusively expressed in the striated muscle. They play a role in muscle wasting, but are also important for the maintenance of the structure of striated muscle. MuRF proteins are also involved in the regulation of the striated muscle energy metabolism. Previous work has demonstrated that MuRF1/MuRF3 DKO mice show a protein surplus myopathy characterized by an accumulation of myosin heavy chain proteins in striated muscles and a reduction in function of both heart and skeletal muscle. The aim of this study was to test the hypothesis that the myopathic phenotype of MuRF1/MuRF3 DKO mice is mediated by a disturbed energy homeostasis in the heart and skeletal muscle, with focus on mitochondrial function. Because sex-specific differences have not been investigated in these mice so far, a further aim was to investigate any differences between male and female mice.
To test these hypotheses, we measured the weight of the heart and the hindlimb muscles tibialis anterior and soleus to detect a possible hypertrophy in the DKO mice. Hematoxylin and eosin staining of histological cross sections of the tibialis anterior were performed to investigate protein accumulations. Muscle function was quantitated via grip strength and specific force measurements. Possible changes in protein amounts were detected via mass spectrometry analyses and western blot analyses. Changes in gene expression were investigated by qRT-PCR. Coimmunoprecipitation was used to determine direct interactions between proteins. Protein stability and ubiquitination were investigated by cycloheximide (CHX) and ubiquitination assays, respectively.
DKO mice showed an increase in heart and skeletal muscle weights. Grip strength assays revealed limb weakness of DKO mice. H&E staining of histological cross sections of the tibialis anterior muscle (TA) showed protein aggregates within myofibers. Mass spectrometry analyses of proteins isolated from TA and heart muscle revealed an increase of muscle stress markers and structural proteins in DKO mice, while proteins involved in the energy metabolism were reduced. Especially interesting here were the proteins of the mitochondrial electron transport chain (ETC), which play a major role in the energy production of the mitochondria by catalyzing the phosphorylation of ADP to ATP, the universal energy carrier in all living organisms. These changes were more pronounced in TA compared to heart. Western blot and qRT-PCR results of ETC subunits supported our proteome data. They also revealed a sex-specific difference, in which the reduction ETC subunits was more pronounced in females than males. In female
TA NDUFB8, SDHB, UQCRC2, MTCO1 and ATP5 were significantly reduced compared to controls, while only UQCRC2 and ATP5 were decreased in male TA compared to controls. A significant reduction in gene expression of Ndufb8, Sdhb, Mtco1 and Atp5 was detected in TA of female mice compared to controls, while only Ndufb8, Sdhb and Atp5 were decreased in male TA compared to controls. We observed the same pattern in Heart of male (protein: NDUFB8; mRNA: Mtco1) and female (protein: UQCRC2, MTCO1, ATP5; mRNA: Sdhb, Mtco1) DKO mice compared to their controls. The reduction in ETC subunits was paralleled by a reduction in complex I and complex III activity in the TA of DKO mice, but not in heart. However, this was only significant in the TA of female but not male mice. Mechanistical analyses using coimmunoprecipitation, cycloheximide chase and ubiquitination assays showed that MuRF1 physically interacted with the transcriptional repressor histone deacetylase 5 (HDAC5), mediated its ubiquitination as well as its UPS-dependent degradation. The absence of MuRF1 and MuRF3 in DKO mice let to an increase in the amounts of HDAC5 in TA. Because HDAC5 binds to PGC-1α, the master regulator of mitochondrial biogenesis (encoded by Ppargc1a), we investigated its gene expression in DKO muscle and found it to be reduced.
These data connect MuRF1 and MuRF3 directly to the striated muscle energy metabolism, by regulating mitochondrial function. The results provide insights into the development of PAMs and possibly other protein storage diseases, where a decrease of mitochondrial function has already been described.
Changes in the microcirculation of the skin are a frequently observed accompanying phenomenon of many diseases, far beyond the spectrum of dermatological diseases. Not all of these changes are pathological, many are transient and have no serious consequences. This is true for many inflammatory diseases such as psoriasis vulgaris or atopic eczema.
However, there are also diseases in which functionally and morphologically recognizable microangiopathies lead to severe disease consequences. One of the most important diseases in this context is systemic sclerosis, an autoimmune systemic disease with multiple organ manifestations. Investigations of the cutaneous microcirculation are of great importance for the initial diagnosis as well as for prognosis and assessment of disease progression.
In peripheral hemodynamic disorders such as peripheral arterial disease (PAD) and chronic venous insufficiency (CVI), understanding microcirculatory disturbances also plays an important role in therapy and in monitoring the success of therapeutic interventions.
Pregnancy involves adaptations of the cellular composition in utero to establish a functioning fetal-maternal interface. Different subsets of leukocytes populate the endometrium and contribute to tolerance of the fetal allograft while protecting it from potentially threatening infections or rejection. ¬¬Innate lymphoid cells are recently discovered immune cells that, besides the gut, lung and skin, possess immunoregulatory functions in the female reproductive tract, especially during gestation. Although present at the fetal-maternal interface, the dynamics of ILC migration during pregnancy remains poorly investigated. The involvement of homing receptors in ILC migration to the uterus was the main subject of the present work.
First, the expression of homing receptors on ILCs from miscellaneous organs was assessed across the course of murine pregnancy in vivo by means of flow cytometry. Then, their migratory capacity towards pregnancy-relevant chemokines was investigated in vitro. The impact of pregnancy related hormones on the migration and homing of ILCs was then analysed in vitro via migration assays.
The results confirm altered proportions of ILCs in utero and the altered expression of homing receptors in ILCs in pregnancy. Different murine lymphoid organs showed augmented expression of chemokine receptors and decreased levels of homing integrin α4β7 in the first trimester, suggesting enhanced migration patterns of ILCs during early pregnancy. Subsequently, migration assays were used to demonstrate the role of different chemokine ligands in enhancing ILC migration.
Eventually, the alterations in homing receptor expression were correlated with female pregnancy hormones. Progesterone treatment caused similar effects on homing receptor expression in ILCs as observed during early gestation. These results represent the first study evaluating the effect of sex steroid hormones on ILC chemokine receptor distribution.
Taken together, our results indicate the involvement of pregnancy-relevant chemokines, including CCL4, CCL20 and CCL28, in the recruitment of ILCs to the uterus during pregnancy. The data highlight an endocrinological-immune crosstalk in the regulation of ILC homing to the female reproductive tract. Gestation alters chemokine receptor expression in order to regulate the access of immune cell subsets to the fetal-maternal interface. An adequate regulation is highly needed, as a lack or abundance of different subgroups could result in pregnancy complications, including fetal loss, pre-eclampsia or pre-term birth. Thus, the role of ILC chemotaxis to the pregnant uterus and its regulation are of interest in the understanding, prevention and treatment of the clinically relevant obstetric diseases.
Numerous insertions of mitochondrial DNA in the genome of the northern mole vole, Ellobius talpinus
(2024)
Background
Ellobius talpinus is a subterranean rodent representing an attractive model in population ecology studies due to its highly special lifestyle and sociality. In such studies, mitochondrial DNA (mtDNA) is widely used. However, if nuclear copies of mtDNA, aka NUMTs, are present, they may co-amplify with the target mtDNA fragment, generating misleading results. The aim of this study was to determine whether NUMTs are present in E. talpinus.
Methods and results
PCR amplification of the putative mtDNA CytB-D-loop fragment using ‘universal’ primers from 56 E. talpinus samples produced multiple double peaks in 90% of the sequencing chromatograms. To reveal NUMTs, molecular cloning and sequencing of PCR products of three specimens was conducted, followed by phylogenetic analysis. The pseudogene nature of three out of the seven detected haplotypes was confirmed by their basal positions in relation to other Ellobius haplotypes in the phylogenetic tree. Additionally, ‘haplotype B’ was basal in relation to other E. talpinus haplotypes and found present in very distant sampling sites. BLASTN search revealed 195 NUMTs in the E. talpinus nuclear genome, including fragments of all four PCR amplified pseudogenes. Although the majority of the NUMTs studied were short, the entire mtDNA had copies in the nuclear genome. The most numerous NUMTs were found for rrnL, COXI, and D-loop.
Conclusions
Numerous NUMTs are present in E. talpinus and can be difficult to discriminate against mtDNA sequences. Thus, in future population or phylogenetic studies in E. talpinus, the possibility of cryptic NUMTs amplification should always be taken into account.
Semiosis is the process in which a sign unfolds its effect—the meaning that humans ‘suddenly’ see in acts, objects or facts. The semiotic tenet is applied to the event and the question of why we narrate it. The graphics are dedicated to the author’s contribution: ‘The event and its consequences: a semiotic analysis.’
Our study examined whether potentially critical indications from depression questionnaires, interviews, and single items on suicidal ideation among partici-pants in a large prospective population-based study are related to short-term sui-cides within one year. For this purpose, we studied the association between (a) the severity of depressive symptoms according to the M-CIDI and the PHQ-9, BDI-II, and CID-S depression screening and (b) elevated scores on single sui-cidal ideation items and mortality according to claims databases.
In the baseline cohort, the frequency of depressive symptoms measured by CID-S was 12.90% (SHIP-START-0). The frequency for “Moderate” to “Severe de-pression” measured by the PHQ-9 (≥ 10 points) and BDI-II (≥ 20 points) ques-tionnaires ranged from 5.40% (SHIP-LEGENDE) to 8.80% (SHIP-TREND Morbid-ity follow-up). The 1-month prevalence of unipolar depression, measured by the M-CIDI in SHIP LEGENDE, was 2.31%.
Between 5.90% (SHIP-TREND Morbidity follow-up) and 6.60% (SHIP-LEGENDE) of respondents showed a certain degree of suicidal ideation in the two weeks preceding the assessment, according to BDI-II and PHQ-9.
Our results show the high frequency of depressive symptoms in the study region, with women being affected more frequently than men, especially in the higher categories. Furthermore, women were more frequently affected by suicidal idea-tion, although this difference was not evident in the highest categories.
There was one potential suicide in the year after a SHIP examination.
From our results, we cannot conclude that severe self-reported symptoms from depression questionnaires should be reported back to participants of an obser-vational population-based study to prevent suicide deaths within one year.
In course of the recent results from Wendelstein 7-X, stellarators are on the brink for assessing their maturity as a fusion reactor. To this end, stellarator specific transport regimes need detailed exploration both with appropriate systematic experimental investigations and models. A way to enhance the efficiency of this process is seen in an systematic evaluation of existing experimental data. We propose appropriate tools developed in information theory for examining large datasets. Information entropy calculations, that have proven to assist the systematic assessment of datasets in many other scientific fields, are used for novelty detection.
Potentially, as a first use-case of this holistic process, this thesis attempts to link and to develop approaches to examine the stellarator specific core-electron-root-confinement (CERC) regime. The specific interest for CERC emerges from the behavior of the radial electric field. While ion-root conditions exhibit negative radial electric fields, CERC’s positive field in the very core of fusion grade plasmas adds an outward thermodynamic force to high-Z impurities and could add to potential actuators to control impurity influx as to be examined for full-metal wall operation in large stellarators. Recently, this feature received revived intent for reactor scale stellarators.
Also, in this work, parameter regions close to the transition from ion-root to CERC are
examined. At lower rotational transform (a characteristic feature of the magnetic field confining fusion grade plasmas), transitions were detected when the plasma current evolved. As in smaller stellarators, it is concluded that low-order rationals and magnetic islands are related to the transitions. This is widely supported by extensive MHD simulations which finally provide indications for the role of zonal flow oscillations. As one of the outcomes, gyrokinetic instabilities are seen interacting for the first time with the neoclassical mechanisms in experiments.
In order to cope with the vast number of highly sampled spatio-temporal plasma data, new
techniques for novelty detection are required. Fundamental prerequisites for the detailed
physics investigations were the feasibility study of entropy-based data analysis techniques, and their adaptation to detect previously unrevealed transition mechanisms. These tools were applied to multivariate bulk plasma emissivity data, which allowed the exploration of large parameter spaces and provided insights in the spatio-temporal dynamics of CERC transitions.
In this manner, this research highlights the feasibility of information flow measure analysis in fusion studies. Applications of different entropy-based complexity measures are explored and this work sheds light on the capabilities, added value and limitations of these techniques. This investigation presents the integration of information flow measures to gain deeper understanding of plasma transport phenomena, by providing an approach to fast systematic data mining suited for real-time analysis. This work paves the way for further development and implementation of information-theoretic methods for plasma data analysis.
In summary, this research highlights the gained insight on CERC transitions, while showcasing the feasibility, added values and limitations of information flow measure analysis for fusion studies, to induce theory based analysis revealing new insights in fundamental, stellarator-specific transport mechanisms.
Clear cell renal cell carcinoma is the most frequent malignant kidney tumor in adults. It is often associated with biallelic VHL mutations. We characterized our cell lines according to their HIF expression pattern. Cell lines RCC4, UOK-220 and CaKi-2 were assigned to subtype H1H2, cell lines 786-O and A-498 were assigned to subtype H2 and cell lines CaKi-1 and Rc-124 were assigned to subtype VHLwt.
Previous work of our group had shown, that p53 can be activated in ccRCC following irradiation but is not able to induce apoptosis. An important link to p53 activity with strong antiapoptotic qualities is the NFB pathway, which can be activated e. g. by irradiation.
We irradiated the three subtypes previously established as well as two control cell lines, SAOS-2 (p53 negative cell line) and HEK 293 (contains functioning p53) with 2 Gy and 10 Gy and analyzed several proteins of the pathway by using western blots. Several target genes with antiapoptotic qualities were analyzed by using rt-PCR.
We found, that out of the cell lines analyzed, both control cell lines (SAOS-2, HEK 293) showed the strongest response (activation of the NFB pathway) following irradiation. Among the three ccRCC subtypes the VHLwt cell lines showed the strongest response. H2 cell lines showed almost no response at all.
A connection between the missing ability of p53 to induce apoptosis and an induction of transcription factors by the NFB pathway could not be determined. We also could not determine biological differences between the subtypes.
We analyzed, whether any NFB proteins were present in the nucleus following irradiation and found, that only p50 homodimers were present in the nucleus. This might point towards p50 homodimers, which have been described to have different characteristics than heterodimers. More research is needed to analyze this important finding.
With high prevalence and mortality, myocardial infarction constitutes a social and economic burden in Germany and worldwide. Current guidelines for MI treatment require prompt reperfusion to salvage heart tissue and minimize short- and long-term complications. However, there are currently no treatments available to attenuate reperfusion injury. Ischemic as well as pharmacological post-conditioning have been identified as important clinical strategies to improve outcome. Membrane stabilizers, like Poloxamer 188 (P188), have been shown to improve myocardial ischemia reperfusion (IR) injury and mitochondrial function but have not yet been proven to directly offer mitochondrial protection. Mitochondrial function is crucial for cardiomyocyte function, and mitochondrial dysfunction plays an important role in myocardial injury.
In this study, hearts from 79 Sprague Dawley rats were isolated and perfused ex-vivo with oxygenated Krebs Buffer for 20 min before 30 min of no-flow ischemia. Hearts were reperfused for 10 min with Krebs buffer or 1 mM P188. Cardiac mitochondria were isolated with 1 mM P188 vs 1 mM polyethylene glycol (PEG) vs vehicle by differential centrifugation. Mitochondrial function was assessed as adenosine triphosphate (ATP) synthesis, oxygen consumption and calcium retention for complex I and II substrates of the respiratory chain.
An improvement of myocardial function with 10 min P188 post-conditioning could not be shown. Direct mitochondrial protection of P188 or PEG could not be observed in this model either. Further research is needed to ascertain whether P188 has a direct protective effect on mitochondria and, if so, on what pathways of IR injury it acts.
Global change is one of the major challenges our society faces in recent times and is becoming increasingly noticeable in all aspects of our lives. In the last ten years, reports about droughts in Europe increased, contrary to expected natural climate variations and are attributed as indicators of climate change. Droughts resulted in a severe decrease in water levels of lakes, rivers and reservoirs, posing socio-economic and environmental challenges. Climate scenarios by the Intergovernmental Panel on Climate Change (IPCC) project increasing temperatures, more frequent, longer and/or more intense heat waves and warm spells, and an increase in aridity with short-term droughts in the upcoming decades for Western and Central Europe. Some areas – such as Northeast Germany – are already affected by negative water balances and the lowering of lake and groundwater levels. Additionally to possible challenges in water availability, excess nutrients and heavy metals from industrial emissions, agricultural fertilisers and land use changes lead to declining water quality. In the past century, extensive eutrophication and environmental pollution have become major water quality issues in many freshwater bodies.
Nonetheless, water and its availability in a sufficient quantity and quality are prerequisites for life and must be prioritised in future development. The European Union aims for a good status in all surface and groundwater bodies by 2027 regarding their ecological, chemical and quantitative status. However, a profound understanding of eutrophication, pollution sources, and water bodies' reference conditions – referring to pre-anthropogenic conditions – should be available for each system to apply integrated restoration strategies. Moreover, an in-depth understanding of long-term climate variability and its dynamics is indispensable to approach these climate change challenges and reliably predict water availability.
During the past decades, numerous paleoenvironmental studies have been carried out on Northern German sediment archives, using mainly lacustrine sediments to reconstruct hydroclimatic variability, often inferring lake-level variations as key indicators. However, most studies were carried out in areas affected by more maritime or continental climate. Studies from the transition zone are rare. Only few existing studies offer high-resolution records and/or robust chronologies, which limits the understanding of past environmental changes significantly. Besides, the Northern German lowlands have been anthropogenically affected since at least the Neolithic (~5.6 ka cal BP) and, in particular, forest composition and density have recently been shown to have at least partially an impact on lake-level variations. However, a reliable distinction between climatic impacts and anthropogenic interferences is widely missing, which is a problem because many studies were conducted on rather small lacustrine systems in which expected anthropogenic signals are higher, and single events may overprint the climatic signals. These biases lead to an incoherent picture of the past hydroclimatic variability in Northern Germany during the Holocene. To overcome this situation, it is inevitable to identify a suitable sedimentary archive from the transition zone – preferably a large lacustrine system in which natural (supra-)regional paleoenvironmental signals are expected to be not overprinted by single events. Moreover, it is necessary to establish robust chronologies and apply high-resolution methods to infer past environmental changes in a high temporal resolution. Taken together, this could contribute to an enhanced understanding of past environmental and climatic changes in Northern Germany.
This thesis consolidates the evidence for Schweriner See to act as a suitable sedimentary archive in Northern Germany for (supra-)regional climate reconstructions. Schweriner See is a large lowland lake in Northern Germany located within the transition zone from maritime to continental climate. In the first step, (paleo)lacustrine landforms, i.e. beach ridges, subaerial nearshore bar, and a silting-up sequence, are investigated along the north-eastern shoreline using a combined approach of sedimentology (e.g. grain size variations) and the relatively novel method of luminescence profiling offering relative age determinations to understand depositional processes and their chronological framework. Absolute age information is mainly inferred by OSL dating. Secondly, an important prerequisite to interpreting information obtained from lacustrine sediment archives is a thorough understanding of processes controlling sedimentation. Schweriner See is characterized by a complex morphometry, which influences in-lake processes, i.e. i) in-lake productivity, ii) carbonate precipitation and iii) wind- and wave-induced processes, resulting in a distinct spatial heterogeneity. This thesis shows that it is crucial first to understand sedimentary depositional processes and controlling mechanisms to i) select suitable coring location(s) and ii) reconstruct paleoenvironmental and hydroclimatic variations reliably.
Based on bathymetric considerations and inferred in-lake processes, two main coring locations were identified to infer i) the anthropogenic impacts and ii) hydroclimatic variations. Short sediment records from the shallow water areas (< 15 m water depth) cover the most recent environmental history of Schweriner See. A well-dated sedimentary record (210Pb/137Cs and 14C dating) links distinct sedimentary and geochemical changes with historical events. Schweriner See was extensively affected by lake-wide eutrophication and contamination, closely related to sewage and population dynamics within the catchment. The water quality only improved after the German Reunification in 1990 CE when sewage was precluded from Schweriner See. Contamination trends at Schweriner See showed similar trends to different archives along the southern Baltic Sea, implying a common regional driving mechanism, e.g. environmental legalisation.
A well-dated sediment record from the profundal zone (52 m water depth) allowed the reconstruction of large-scale atmospheric conditions during the past 3 ka cal BP by inferring winter temperature variability, the moisture source region and/or evaporative lake water enrichment, which resemble variations in the North Atlantic Oscillation (NAO). The NAO greatly influences the Central European climate, affecting, for example, surface air temperature, precipitation or storm tracks. During 3-2.8 ka and 2.1-0.8 ka cal BP, predominantly positive NAO conditions are reconstructed, which are characterized by warmer winter temperatures, moisture conditions bringing isotopically enriched precipitation from the southern/central North Atlantic to Northern Central Europe and/or warmer temperatures that may result in a higher evaporative isotopic lake water enrichment as a result of northwards displaced westerlies. Conversely, during 2.8-2.1 ka and 0.8-0.1 ka cal BP, results correspond to predominantly negative NAO phases influenced by southwards displaced westerlies. Frequent atmospheric blocking allows for the intrusion of northerly or easterly winds, resulting in colder winter temperatures, isotopically depleted precipitation from the Northern Atlantic and Arctic region and/or a lower evaporative lake water enrichment. In addition to these long-term changes in atmospheric conditions, short-term hydroclimatic variations have been reconstructed, mainly reflecting lake-level variations in conjunction with precipitation variability, with the proxy signal being additionally amplified by wind speed and wave motion. Comparisons with other archives support these results.
So far, the paleoenvironmental reconstruction is limited to the Late Holocene, but initial dating results imply possible interferences until the Late Pleistocene. Therefore, future studies should focus on extending the profundal record from Schweriner See further back in time, providing a high-resolution record covering both the Holocene and possibly the Late Pleistocene.
This anthology is about the representations and uses of medieval saints, heroes, and heroic events as elements of popular, local, and national culture during the 19th and 20th centuries in the Baltic Sea region: Scandinavia, Finland, Baltic countries, Northern Germany and North-Western Russia. Authors examine the processes of how medieval saints and heroes have been remembered, commemorated, interpreted, used, and reflected during modernity, and by whom. The focus of the anthology is on "doing" memory as a practice that commemorated the past and shaped spaces and identities in the present. It approaches the memory of saints and heroes, for example, Swedish Saints Birgitta and Eric, Danish Saint Knud, Kyivan Princess Olga, Swedish military leader in Finland Tyrgils Knutsson, Liv/Latvian warrior Imanta and Holsatian count Gerhard III as a shared heritage and as part of national, local and popular culture. The anthology contributes to the understanding of the Baltic Sea region through the study of saints, cults and heroic representations in the longue durée between the Middle Ages and modernity. It also adds nuance to the use of popular concepts of memory studies, particularly an update of Pierre Nora’s lieux de mémoire.