A layer of laminins, assembled on a thin sheet of collagen type IV (Col-IV) forms the backbone of the basal lamina, which controls biological processes such as embryogenesis, tissue homeostasis, and development. Here, the dynamic functions of laminin-111 (Lam-111) in ultrathin films at the air–water interface are investigated. It is shown that the 2D confinement induces polymerization and that expansion via adlayer formation occurs only with extended growth time. The highly robust self-assembly enables the functionalization of surfaces with cross-linked 2D Lam-111 networks of defined thickness using little more than a beaker. The 2D laminin material also displays two dynamic functions required for the maintenance of tissues – the capability for self-renewal and self-healing. By assembling Lam-111 2D networks at the surface of Col-IV sheets, freestanding bilayers closely mimicking the basal lamina can be produced in vitro. There is a marked difference in miPSC spreading and adhesion force between Lam-111 sheets assembled in the presence or absence of Col-IV. These fundamental studies highlight the importance of dynamic functions, encoded into the molecular structure of the building blocks, for the assembly, maintenance, and functioning of the complex material systems found in natural tissues and can provide cues for the molecular design of resilient technical systems.
View lessOne of the most natural connections between quantum and classical machine learning has been established in the context of kernel methods. Kernel methods rely on kernels, which are inner products of feature vectors living in large feature spaces. Quantum kernels are typically evaluated by explicitly constructing quantum feature states and then taking their inner product, here called embedding quantum kernels. Since classical kernels are usually evaluated without using the feature vectors explicitly, we wonder how expressive embedding quantum kernels are. In this work, we raise the fundamental question: can all quantum kernels be expressed as the inner product of quantum feature states? Our first result is positive: Invoking computational universality, we find that for any kernel function there always exists a corresponding quantum feature map and an embedding quantum kernel. The more operational reading of the question is concerned with efficient constructions, however. In a second part, we formalize the question of universality of efficient embedding quantum kernels. For shift-invariant kernels, we use the technique of random Fourier features to show that they are universal within the broad class of all kernels which allow a variant of efficient Fourier sampling. We then extend this result to a new class of so-called composition kernels, which we show also contains projected quantum kernels introduced in recent works. After proving the universality of embedding quantum kernels for both shift-invariant and composition kernels, we identify the directions towards new, more exotic, and unexplored quantum kernel families, for which it still remains open whether they correspond to efficient embedding quantum kernels.
View lessCompartmentalization by membranes is a common feature of eukaryotic cells and serves to spatiotemporally confine biochemical reactions to control physiology. Membrane‐bound organelles such as the endoplasmic reticulum (ER), the Golgi complex, endosomes and lysosomes, and the plasma membrane, continuously exchange material via vesicular carriers. In addition to vesicular trafficking entailing budding, fission, and fusion processes, organelles can form membrane contact sites (MCSs) that enable the nonvesicular exchange of lipids, ions, and metabolites, or the secretion of neurotransmitters via subsequent membrane fusion. Recent data suggest that biomolecule and information transfer via vesicular carriers and via MCSs share common organizational principles and are often mediated by proteins with intrinsically disordered regions (IDRs). Intrinsically disordered proteins (IDPs) can assemble via low‐affinity, multivalent interactions to facilitate membrane tethering, deformation, fission, or fusion. Here, we review our current understanding of how IDPs drive the formation of multivalent protein assemblies and protein condensates to orchestrate vesicular and nonvesicular transport with a special focus on presynaptic neurotransmission. We further discuss how dysfunction of IDPs causes disease and outline perspectives for future research.
View lessOne of the most challenging endeavors for students is choosing a career path that best fits their interests, wills and skills, and setting their professional goals accordingly. Such decisions are often made from within the culture of academia, in which mentors and peers are mainly familiar with the academic job market and lack the knowledge necessary to consult about other types of careers. We aimed to address this gap for ecology and related fields by creating an engaging and effective tool to help students and professionals to familiarize themselves with the diversity of potential career paths available to ecologists. The tool is an applied card game – the Ecologist's Career Compass – which is provided here freely. The game is played as a trump card game and includes 33 cards, each representing a combination of one of four job-market sectors and one of nine types of positions. Each card indicates the level of seven skill categories required to likely be hired and succeed in the focal position at the focal sector, as well as more specific examples for typical jobs in the focal combination. The information in the game largely relies on input from a global survey we conducted among 315 ecologists from 35 countries. While the challenges faced by early-career ecologists in developing their professional path are substantial and diverse, this game can assist in gaining a broad comparative overview of the whole ecology job market and the skills required to likely excel in different paths. We hope this applied game will act as a conversation starter about the diversity of aspirations and opportunities in ecology classrooms and labs.
View lessThe structure-based design of antigens holds promise for developing vaccines with higher efficacy and improved safety profiles. We postulate that abrogation of host receptor interaction bears potential for the improvement of vaccines by preventing antigen-induced modification of receptor function as well as the displacement or masking of the immunogen. Antigen modifications may yet destroy epitopes crucial for antibody neutralization. Here, we present a methodology that integrates deep mutational scans to identify and score SARS-CoV-2 receptor binding domain variants that maintain immunogenicity, but lack interaction with the widely expressed host receptor. Single point mutations were scored in silico, validated in vitro, and applied in vivo. Our top-scoring variant receptor binding domain-G502E prevented spike-induced cell-to-cell fusion, receptor internalization, and improved neutralizing antibody responses by 3.3-fold in rabbit immunizations. We name our strategy BIBAX for body-inert, B-cell-activating vaccines, which in the future may be applied beyond SARS-CoV-2 for the improvement of vaccines by design.
View lessAmines are a very important class of compounds and the selective synthesis of differently substituted primary, secondary and tertiary alkyl amines is challenging. Here we present the synthesis of primary, secondary, and tertiary alkyl amines from ammonia and alcohols, aldehydes, ketones and hydrogen by combining borrowing hydrogen or hydrogen autotransfer and reductive amination with hydrogen. The key is a nanostructured, bimetallic Co/Sc catalyst able to mediate both reactions or concepts efficiently. We observe a broad product scope, a very good functional group tolerance, upscaling is easily accomplished and our catalyst is reusable.
View lessUsing unnatural amino acid mutagenesis, we made a mutant of CaMKII that forms a covalent linkage to Calmodulin upon illumination by UV light. Like wild-type CaMKII, the L308BzF mutant stoichiometrically binds to Calmodulin, in a calcium-dependent manner. Using this construct, we demonstrate that Calmodulin binding to CaMKII, even under these stochiometric conditions, does not perturb the CaMKII oligomeric state. Furthermore, we were able to achieve activation of CaMKII L308BzF by UV-induced binding of Calmodulin, which, once established, is further insensitive to calcium depletion. In addition to the canonical auto-inhibitory role of the regulatory segment, inter-subunit crosslinking in the absence of CaM indicates that kinase domains and regulatory segments are substantially mobile in basal conditions. Characterization of CaMKIIL308BzF in vitro, and its expression in mammalian cells, suggests it could be a promising candidate for control of CaMKII activity in mammalian cells with light.
View lessWe predict a novel metallic state of matter that emerges in a Weyl-semimetal superstructure with spatially varying Weyl-node positions. In the new state, the Weyl nodes are stretched into extended, anisotropic Fermi surfaces, which can be understood as being built from Fermi arclike states. This “Fermi-arc metal” exhibits the chiral anomaly of the parental Weyl semimetal. However, unlike in the parental Weyl semimetal, in the Fermi-arc metal the “ultraquantum state,” in which the anomalous chiral Landau level is the only state at the Fermi energy, is already reached for a finite energy window at zero magnetic field. The dominance of the ultraquantum state implies a universal low-field ballistic magnetoconductance and the absence of quantum oscillations, making the Fermi surface “invisible” to de Haas–van Alphen and Shubnikov–de Haas effects, although it signifies its presence in other response properties.
View lessComplex non-linear systems biology models comprise relevant knowledge on processes of pharmacological interest. They are, however, too complex to be used in inferential settings, for example, to allow for the estimation of patient-specific parameters for individual dose optimisation. Thus, there is a need for simple models with interpretable components to infer the drug effect in a clinical setting. In particular, it is essential to accurately quantify and simulate the interindividual variability in the drug response in order to account for covariates like body weight, age and genetic disposition. To this end, non-linear model order reduction and simplification methods can be used if they maintain model interpretability during reduction and consider an entire population rather than just a single reference individual. We present a sample-based approach for robust model order reduction and propose two improvements for efficiency. In particular, we introduce a new sampling method to generate the virtual population based on transformed latin hypercube sampling. Thereby, the sample is stratified in the relevant parameter-space directions, which are identified using empirical observability Gramians. We illustrate our approach in application to a blood coagulation pathway model, where we reduce the complexity from a 62-dimensional highly non-linear to a six-dimensional and a nine-dimensional system of ordinary differential equations for two scenarios, respectively.
View lessThe topological classification of gapped band structures depends on the particular definition of topological equivalence. For translation-invariant systems, stable equivalence is defined by a lack of restrictions on the numbers of occupied and unoccupied bands, while imposing restrictions on one or both leads to “fragile” and “delicate” topology, respectively. In this article, we describe a homotopic classification of band structures—which captures the topology beyond the stable equivalence—in the presence of additional lattice symmetries. As examples, we present complete homotopic classifications for spinless band structures with twofold rotation, fourfold rotation and fourfold dihedral symmetries, both in presence and absence of time-reversal symmetry. Whereas the rules of delicate and fragile topology do not admit a bulk-boundary correspondence, we identify a version of stable topology, which restricts the representations of bands, but not their numbers, which does allow for anomalous states at symmetry-preserving boundaries, which are associated with nontrivial bulk topology.
View lessThe phase before an extreme weather event is crucial for the actual reaction to the impacts of such an event. In this phase, professionals in the field of civil protection and emergency management anticipate the intensity and impact of the event and use these expectations for action. We argue that anticipation is—beyond others—shaped by the organizations’ shared narratives of past crisis that resulted from extreme weather events. The findings focus on the frame of ‘blame’ in the narration and are based on two fields of study, road maintenance services and forest fire control. Qualitative group discussions and semistructured interviews show two very different views on blame depending on the organization: human factors and fate. This contrast can be traced back to the character of the weather events itself, but also with the self-image of the organization and perceived external expectations. Depending on the narrative plot and threshold of the event, narratives can affect and alter practices of anticipation through narrations of renewal. Findings contribute to the understanding of organizational sensemaking through narratives of blame and consequences.
View lessUterine rupture during a trial of labor after caesarean delivery (CD) is a serious complication for mother and fetus. The lack of knowledge on histological features and molecular pathways of uterine wound healing has hindered research in this area from evolving over time. We analysed collagen content and turnover in uterine scars on a histological, molecular and ultrastructural level. Therefore, tissue samples from the lower uterine segment were obtained during CD from 16 pregnant women with at least one previous CD, from 16 pregnant women without previous CD, and from 16 non-pregnant premenopausal women after hysterectomy for a benign disease. Histomorphometrical collagen quantification showed, that the collagen content of the scar area in uterine wall specimens after previous CD was significantly higher than in the unscarred myometrium of the same women and the control groups. Quantitative real-time PCR of uterine scar tissue from FFPE samples delineated by laser microdissection yielded a significantly higher COL3A1 expression and a significantly lower COL1A2/COL3A1 ratio in scarred uteri than in samples from unscarred uteri. Histological collagen content and the expression of COL1A2 and COL3A1 were positively correlated, while COL1A2/COL3A1 ratio was negatively correlated with the histological collagen content. Transmission electron microscopy revealed a destroyed myometrial ultrastructure in uterine scars with increased collagen density. We conclude that the high collagen content in uterine scars results from an ongoing overexpression of collagen I and III. This is a proof of concept to enable further analyses of specific factors that mediate uterine wound healing.
View lessBackground Higher social support protects people from developing mental disorders. Limited evidence is available on the mechanism through which social support plays this protective role.
Objective To investigate the stress-buffering process of social support on depressive symptoms using a novel longitudinal dynamic symptom network approach.
Methods A total of 4242 adult participants who completed the first two waves (from May to October 2020) of the International Covid Mental Health Survey were included in the study. Cross-lagged panel network modelling was used to estimate a longitudinal network of self-reported social support, loneliness and depressive symptoms. Standardised regression coefficients from regularised cross-lagged regressions were estimated as edge weights of the network.
Findings The results support a unidirectional protective effect of social support on key depressive symptoms, partly mediated through loneliness: A higher number of close confidants and accessible practical help was associated with decreased anhedonia (weight=−0.033) and negative self-appraisal symptoms (weight=−0.038). Support from others was also negatively associated with loneliness, which in turn associated with decreased depressed mood (weight=0.086) and negative self-appraisal (weight=0.077). We identified a greater number of direct relationships from social support to depressive symptoms among men compared with women. Also, the edge weights from social support to depression were generally stronger in the men’s network.
Conclusions Reductions in negative self-appraisal might function as a bridge between social support and other depressive symptoms, and, thus, it may have amplified the protective effect of social support. Men appear to benefit more from social support than women.
Clinical implications Building community-based support networks to deliver practical support, and loneliness reduction components are critical for depression prevention interventions after stressful experiences.
View lessObjective Dietary sodium intake represents a risk factor for cardiovascular disease and mortality. The study sought to analyse the sodium content of effervescent dietary supplements and drugs in Germany and the USA.
Design Comparative cross-sectional study.
Setting and methods The sodium content of 39 dietary supplement effervescent tablets available in Germany was measured in May and June 2022 using optical emission spectrometry with inductively coupled argon plasma. The sodium content of 33 common pharmacy-only effervescent tablets (over-the-counter (OTC) drugs) in Germany was obtained from the summary of product characteristics. We compared the sodium content of the measured German dietary supplement effervescent tablets to that of 51 dietary supplement effervescent tablets available in the USA (data: National Institutes of Health’s Dietary Supplement Label Database).
Results The measured sodium content in the German dietary supplements was 283.9±122.6 mg sodium/tablet, equivalent to 14±6% of the maximum recommended daily sodium intake (MRDSI). Vitamin products had the highest (378.3±112.8 mg, 19±6% of MRDSI), and calcium products had the lowest mean sodium content (170.4±113.2 mg, 9±6% of MRDSI). Vitamin products contained significantly more sodium than magnesium (378.3 mg vs 232.7 mg; p=0.004), calcium (378.3 mg vs 170.4 mg; p=0.006) and mineral products (378.3 mg vs 191.6 mg; p=0.048). The sodium content measured in products available in Germany was higher when compared with the declared sodium content on the label of the products sold in the USA (283.9 mg vs 190.0 mg; p<0.001). The median summary of product characteristics-declared sodium content of a single dose of the German OTC drugs was 157.0 mg (IQR: 98.9–417.3 mg); pain/common cold drugs contained the most sodium (median: 452.1 mg; IQR: 351.3–474.0 mg).
Conclusion Effervescent tablets of nutritional supplements and OTC drugs contain high amounts of sodium, which often is not disclosed.
View lessThe effect of spin fluctuations on the α (bcc)-γ (fcc)-δ (bcc) structural phase transitions in iron is investigated with a tight-binding (TB) model. The orthogonal d-valent TB model is combined with thermodynamic integration, spin-space averaging, and Hamiltonian Monte Carlo to compute the temperature-dependent free-energy difference between bcc and fcc iron. We demonstrate that the TB model captures experimentally observed phonon spectra of bcc iron at elevated temperatures. Our calculations show that spin fluctuations are crucial for both the α−γ and γ−δ phase transitions but they enter through different mechanisms. Spin fluctuations impact the α−γ phase transition mainly via the magnetic/electronic free-energy difference between bcc and fcc iron. The γ−δ phase transition, in contrast, is influenced by spin fluctuations only indirectly via the spin-lattice coupling. Combining the two mechanisms, we obtain both the α−γ and γ−δ phase transitions with our TB model. The calculated transition temperatures are in very good agreement with experimental values.
View lessIntroduction The emergence of new SARS-CoV-2 variants, capable of escaping the humoral immunity acquired by the available vaccines, together with waning immunity and vaccine hesitancy, challenges the efficacy of the vaccination strategy in fighting COVID-19. Improved therapeutic strategies are urgently needed to better intervene particularly in severe cases of the disease. They should aim at controlling the hyperinflammatory state generated on infection, reducing lung tissue pathology and inhibiting viral replication. Previous research has pointed to a possible role for the chaperone HSP90 in SARS-CoV-2 replication and COVID-19 pathogenesis. Pharmacological intervention through HSP90 inhibitors was shown to be beneficial in the treatment of inflammatory diseases, infections and reducing replication of diverse viruses.
Methods In this study, we investigated the effects of the potent HSP90 inhibitor Ganetespib (STA-9090) in vitro on alveolar epithelial cells and alveolar macrophages to characterise its effects on cell activation and viral replication. Additionally, the Syrian hamster animal model was used to evaluate its efficacy in controlling systemic inflammation and viral burden after infection.
Results In vitro, STA-9090 reduced viral replication on alveolar epithelial cells in a dose-dependent manner and lowered significantly the expression of proinflammatory genes, in both alveolar epithelial cells and alveolar macrophages. In vivo, although no reduction in viral load was observed, administration of STA-9090 led to an overall improvement of the clinical condition of infected animals, with reduced oedema formation and lung tissue pathology.
Conclusion Altogether, we show that HSP90 inhibition could serve as a potential treatment option for moderate and severe cases of COVID-19.
View lessFoxp3+ regulatory T (Treg) cells of thymic (tTreg) and peripheral (pTreg) developmental origin are thought to synergistically act to ensure immune homeostasis, with self-reactive tTreg cells primarily constraining autoimmune responses. Here we exploited a Foxp3-dependent reporter with thymus-specific GFP/Cre activity to selectively ablate either tTreg (ΔtTreg) or pTreg (ΔpTreg) cell development, while sparing the respective sister populations. We found that, in contrast to the tTreg cell behavior in ΔpTreg mice, pTreg cells acquired a highly activated suppressor phenotype and replenished the Treg cell pool of ΔtTreg mice on a non-autoimmune C57BL/6 background. Despite the absence of tTreg cells, pTreg cells prevented early mortality and fatal autoimmunity commonly observed in Foxp3-deficient models of complete Treg cell deficiency, and largely maintained immune tolerance even as the ΔtTreg mice aged. However, only two generations of backcrossing to the autoimmune-prone non-obese diabetic (NOD) background were sufficient to cause severe disease lethality associated with different, partially overlapping patterns of organ-specific autoimmunity. This included a particularly severe form of autoimmune diabetes characterized by an early onset and abrogation of the sex bias usually observed in the NOD mouse model of human type 1 diabetes. Genetic association studies further allowed us to define a small set of autoimmune risk loci sufficient to promote β cell autoimmunity, including genes known to impinge on Treg cell biology. Overall, these studies show an unexpectedly high functional adaptability of pTreg cells, emphasizing their important role as mediators of bystander effects to ensure self-tolerance.
View lessBackground: Preclinical animal studies and clinical studies indicate that both maternal as well as paternal genetic alterations/gene defects might affect the phenotype of the next-generation without transmissions of the affected gene. Currently, the question of whether the same genetic defect present in the mother or father leads to a similar phenotype in the offspring remains insufficiently elucidated.
Methods: In this head-to-head study, we crossbred female and male mice with heterozygous endothelial eNOS knockout (eNOS+/−) with male and female wild-type (wt) mice, respectively. Subsequently, we compared the phenotype of the resulting wt offspring with that of wt offspring born to parents with no eNOS deficiency.
Results: Wt female offspring of mothers with heterozygous eNOS showed elevated liver fat accumulation, while wt male offspring of fathers with heterozygous eNOS exhibited increased fasting insulin, heightened insulin levels after a glucose load, and elevated liver glycogen content. By quantitative mass-spectrometry it was shown that concentrations of six serum metabolites (lysoPhosphatidylcholine acyl C20:3, phosphatidylcholine diacyl C36:2, phosphatidylcholine diacyl C38:1, phosphatidylcholine acyl-alkyl C34:1, phosphatidylcholine acyl-alkyl C36:3, and phosphatidylcholine acyl-alkyl C42:5 (PC ae C42:5) as well as four liver carbon metabolites (fructose 6-phosphate, fructose 1,6-bisphosphate, glucose 6-phosphate and fumarate) were different between wt offspring with eNOS+/− mothers and wt offspring with eNOS+/− fathers. Importantly, fumarate was inversely correlated with the liver fat accumulation in female offspring with eNOS+/− mothers and increased liver glycogen in offspring of both sexes with eNOS+/− fathers. The qRT-PCR results revealed that the gene expression patterns were different between wt offspring with eNOS+/− mothers and those offspring with eNOS+/− fathers. Different gene expression patterns were correlated with different observed phenotypic changes in male/female offspring born to mothers or fathers with a heterozygous eNOS genotype.
Conclusion: The identical parental genetic alteration (heterozygous eNOS deficiency), without being passed on to the offspring, results in distinct metabolic, liver phenotype, and gene expression pattern variations depending on whether the genetic alteration originated from the father or the mother.
View lessNitrate (NO3-) and potassium (K+) are distributed in plants via short and long-distance transport. These two pathways jointly regulate NO3- and K+ levels in all higher plants. The Arabidopsis thaliana transporter NPF7.3/NRT1.5 is responsible for loading NO3- and K+ from root pericycle cells into the xylem vessels, facilitating the long-distance transport of NO3- and K+ to shoots. In this study, we demonstrate a protein-protein interaction of NPF7.3/NRT1.5 with the proton pump AHA2 in the plasma membrane by split ubiquitin and bimolecular complementation assays, and we show that a conserved glycine residue in a transmembrane domain of NPF7.3/NRT1.5 is crucial for the interaction. We demonstrate that AHA2 together with NRT1.5 affects the K+ level in shoots, modulates the root architecture, and alters extracellular pH and the plasma membrane potential. We hypothesize that NRT1.5 and AHA2 interaction plays a role in maintaining the pH gradient and membrane potential across the root pericycle cell plasma membrane during K+ and/or NO3- transport.
View lessIt has long been debated how humans estimate the numerosity of sets of elements and what role continuous visual properties play in this process. The dot comparison task, in which the more numerous of two dot arrays must be selected, is a dominant method to investigate this phenomenon. It has been shown that the visual properties of the two dot patterns strongly influence the comparison. This influence can be systematically investigated by manipulating visual properties congruently and incongruently with numerosity. However, it remains unclear how learning and prior experience affect the influence of the visual properties. To address this question, we introduced feedback into the classical dot comparison task: during the learning phase, participants in the experimental group received feedback after each trial indicating whether their answer was correct whereas participants in the control group did not. After the learning phase, neither group received feedback. The convex hull of the dot patterns and the average dot diameter were manipulated congruently and incongruently with numerosity. Our results show that feedback had no effect on overall performance. However, when manipulated separately, dot diameter no longer affected performance in the experimental group after the learning phase, but it did in the control group. Moreover, this effect remained visible even when diameter and convex hull were manipulated simultaneously. This pattern of results is consistent with the notion of sensory integration which proposes that weights are assigned to different visual cues and that numerical judgments depend on an additive combination of these weights. We also found a correlation between performance on an arithmetic task and performance on trials in which dot size was manipulated incongruently with numerosity. However, there were no correlations between an inhibition task and performance in the dot comparison task. Taken together, the current results suggest that learning with feedback may affect some visual properties but not others. Future studies should further investigate a wider range of visual properties to examine which of them can be influenced by learning and under what conditions learning occurs.
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