Mechanotransduction via yes-associated protein (YAP) is a central mechanism for decision-making in mouse embryonic stem cells (mESCs). Nuclear localization of YAP is tightly connected to pluripotency ...and increases the cell division rate (CDR). How the geometry of the extracellular environment influences mechanotransduction, thereby YAP localization, and decision-making of single isolated mESCs is largely unknown. To investigate this relation, we produced well-defined 2D and 2.5D microenvironments and monitored CDR and subcellular YAP localization in single mESCs hence excluding cell-cell interactions. By systematically varying size and shape of the 2D and 2.5D substrates we observed that the geometry of the growth environment affects the CDR. Whereas CDR increases with increasing adhesive area in 2D, CDR is highest in small 2.5D micro-wells. Here, mESCs attach to all four walls and exhibit a cross-shaped cell and nuclear morphology. This observation indicates that changes in cell shape are linked to a high CDR. Inhibition of actomyosin activity abrogate these effects. Correspondingly, nuclear YAP localization decreases in inhibitor treated cells, suggesting a relation between cell shape, intracellular forces, and cell division rate. The simplicity of our system guarantees high standardization and reproducibility for monitoring stem cell reactions and allows addressing a variety of fundamental biological questions on a single cell level.
Street dust is a major source of pollution and exposure of residents of West Africa to toxic chemicals. There is however, limited knowledge about the chemical composition and sources of street dust ...in urban areas of sub-Saharan Africa. The total carbon (TC), nitrogen (TN), sulfur (TS) and the stable carbon isotope ratios (δ13C) contents of street dust sampled from 25 sites distributed across Kumasi (a metropolis in Ghana with a population of ca. 2 million) were determined. In addition, black carbon (BC) and their subunits (soot and char) in these samples were also determined. The concentrations of TC, TN and TS in the dusts were 5–71 mg g−1, 0.3–4.3 mg g−1 and 0.2–1.4 mg g−1, respectively. The concentrations of TC, TN and TS were higher than at the background site of the metropolis by a factor of 5.1 (range: 1.7–12), 3.9 (1.1–13) and 2.8 (0.7–5), respectively. The BC, char and soot concentrations in these samples averaged 1.6 mg g−1 (0.13–4.4), 1.2 mg g−1 (0.08–3.7) and 0.36 mg g−1 (0.05–1.5), respectively. The concentrations of BC, char and soot in the street dust were higher than in the background location by factors of 5 (range: 0.8–13), 6 (0.7–17) and 3 (0.5–12), respectively. The TC, TN, TS, BC, soot and char concentrations were positively correlated with each other and with polycyclic aromatic compounds (PAHs, oxygenated PAHs and azaarenes from a previous study), indicating their common origin and fate. The δ13C values ranged from −27 to −24 ‰, with more polluted sites being more depleted in 13C. Based on the chemical composition of the street dusts, the 25 sites could be clustered into four groups by hierarchical cluster analysis which reflect areas of varying anthropogenic influence and, accordingly, exposure to hazardous chemicals.
Display omitted
•C, N, S, black carbon, soot, char and δ13C are determined in street dust of a major city.•The concentrations of the above species are strongly positively correlated with each other.•Auto repair shops, major roads & markets are more contaminated than residential areas.•The δ13C is more depleted in street dusts with higher concentrations of other species.•C, N, S, black carbon and PAC concentrations are strongly positively correlated.
It is generally accepted that the spatial distribution of neutral genetic diversity within a species’ native range mostly depends on effective population size, demographic history, and geographic ...position. However, it is unclear how genetic diversity at adaptive loci correlates with geographic peripherality or with habitat suitability within the ecological niche. Using exome‐wide genomic data and distribution maps of the Alpine range, we first tested whether geographic peripherality correlates with four measures of population genetic diversity at > 17,000 SNP loci in 24 Alpine populations (480 individuals) of Swiss stone pine (Pinus cembra) from Switzerland. To distinguish between neutral and adaptive SNP sets, we used four approaches (two gene diversity estimates, FST outlier test, and environmental association analysis) that search for signatures of selection. Second, we established ecological niche models for P. cembra in the study range and investigated how habitat suitability correlates with genetic diversity at neutral and adaptive loci. All estimates of neutral genetic diversity decreased with geographic peripherality, but were uncorrelated with habitat suitability. However, heterozygosity (He) at adaptive loci based on Tajima's D declined significantly with increasingly suitable conditions. No other diversity estimates at adaptive loci were correlated with habitat suitability. Our findings suggest that populations at the edge of a species' geographic distribution harbour limited neutral genetic diversity due to demographic properties. Moreover, we argue that populations from suitable habitats went through strong selection processes, are thus well adapted to local conditions, and therefore exhibit reduced genetic diversity at adaptive loci compared to populations at niche margins.
Nonradiative processes limit optoelectronic functionality of nanocrystals and curb their device performance. Nevertheless, the dynamic structural origins of nonradiative relaxations in such materials ...are not understood. Here, femtosecond electron diffraction measurements corroborated by atomistic simulations uncover transient lattice deformations accompanying radiationless electronic processes in colloidal semiconductor nanocrystals. Investigation of the excitation energy dependence in a core/shell system shows that hot carriers created by a photon energy considerably larger than the bandgap induce structural distortions at nanocrystal surfaces on few picosecond timescales associated with the localization of trapped holes. On the other hand, carriers created by a photon energy close to the bandgap of the core in the same system result in transient lattice heating that occurs on a much longer 200 picosecond timescale, dominated by an Auger heating mechanism. Elucidation of the structural deformations associated with the surface trapping of hot holes provides atomic-scale insights into the mechanisms deteriorating optoelectronic performance and a pathway towards minimizing these losses in nanocrystal devices.
Coronavirus disease 2019 (COVID-19) is a mild to moderate respiratory tract infection, however, a subset of patients progress to severe disease and respiratory failure. The mechanism of protective ...immunity in mild forms and the pathogenesis of severe COVID-19 associated with increased neutrophil counts and dysregulated immune responses remain unclear. In a dual-center, two-cohort study, we combined single-cell RNA-sequencing and single-cell proteomics of whole-blood and peripheral-blood mononuclear cells to determine changes in immune cell composition and activation in mild versus severe COVID-19 (242 samples from 109 individuals) over time. HLA-DRhiCD11chi inflammatory monocytes with an interferon-stimulated gene signature were elevated in mild COVID-19. Severe COVID-19 was marked by occurrence of neutrophil precursors, as evidence of emergency myelopoiesis, dysfunctional mature neutrophils, and HLA-DRlo monocytes. Our study provides detailed insights into the systemic immune response to SARS-CoV-2 infection and reveals profound alterations in the myeloid cell compartment associated with severe COVID-19.
Display omitted
•SARS-CoV-2 infection induces profound alterations of the myeloid compartment•Mild COVID-19 is marked by inflammatory HLA-DRhiCD11chi CD14+ monocytes•Dysfunctional HLA-DRloCD163hi and HLA-DRloS100Ahi CD14+ monocytes in severe COVID-19•Emergency myelopoiesis with immature and dysfunctional neutrophils in severe COVID-19
Analysis of patients with mild and severe COVID-19 reveals the presence of dysfunctional neutrophils in the latter that is linked to emergency myelopoiesis.
Due to increasing digitization, the amount of data in the Internet of Things (IoT) is constantly increasing. In order to be able to process queries efficiently, strategies must, therefore, be found ...to reduce the transmitted data as much as possible. SPARQL is particularly well-suited to the IoT environment because it can handle various data structures. Due to the flexibility of data structures, however, more data have to be joined again during processing. Therefore, a good join order is crucial as it significantly impacts the number of intermediate results. However, computing the best linking order is an NP-hard problem because the total number of possible linking orders increases exponentially with the number of inputs to be combined. In addition, there are different definitions of optimal join orders. Machine learning uses stochastic methods to achieve good results even with complex problems quickly. Other DBMSs also consider reducing network traffic but neglect the network topology. Network topology is crucial in IoT as devices are not evenly distributed. Therefore, we present new techniques for collaboration between routing, application, and machine learning. Our approach, which pushes the operators as close as possible to the data source, minimizes the produced network traffic by 10%. Additionally, the model can reduce the number of intermediate results by a factor of 100 in comparison to other state-of-the-art approaches.
Iron is one of the most abundant elements on earth and essential for life. However, Fe
ions are rather insoluble and microorganisms such as fungi may use siderophores as strong chelators for uptake. ...In addition, free cytoplasmic iron is rather toxic and intracellular siderophores are used to control the toxicity. Siderophores are also important for iron storage. We studied two siderophore systems in the plant necrotrophic fungus Alternaria alternata and show that the non-ribosomal peptide synthase, Nps2, is required for the biosynthesis of intracellular ferricrocin, whereas Nps6 is needed for the formation of extracellular coprogen and coprogen B. Whereas nps2 was dispensable for growth on iron-depleted medium, nps6 was essential under those conditions. nps2 deletion caused an increase in spore formation and reduced pathogenicity on tomato. Our results suggest that A. alternata employs an external and an internal siderophore system to adapt to low iron conditions.
Macrophages are versatile immune cells capable of polarizing into functional subsets depending on environmental stimulation. In atherosclerotic lesions, proinflammatory polarized macrophages are ...associated with symptomatic plaques, whereas Th2 (T-helper cell type 2) cytokine-polarized macrophages are inversely related with disease progression. To establish a functional cause for these observations, we analyzed extracellular matrix degradation phenotypes in polarized macrophages.
We provide evidence that proinflammatory polarized macrophages rely on membrane-bound proteases including MMP-14 (matrix metalloproteinase-14) and the serine protease uPA (urokinase plasminogen activator) together with its receptor uPAR for extracellular matrix degradation. In contrast, Th2 cytokine alternatively primed macrophages do not show different proteolytic activity in comparison to unpolarized macrophages and lack increased localization of MMP-14 and uPA receptor to the cell membrane. Nonetheless, they express the highest amount of the serine protease uPA. However, uPA activity is blocked by similarly increased expression of its inhibitor PAI-1 (plasminogen activator inhibitor 1). When inhibiting PAI-1 or when analyzing macrophages deficient in PAI-1, Th2 cytokine-polarized macrophages display the same matrix degradation capability as proinflammatory-primed macrophages. Within atherosclerotic lesions, macrophages positive for the alternative activation marker CD206 express high levels of PAI-1. In addition, to test changed tissue remodeling capacities of alternatively activated macrophages, we used a bleomycin lung injury model in mice reconstituted with PAI-1
bone marrow. These results supported an enhanced remodeling phenotype displayed by increased fibrosis and elevated MMP activity in the lung after PAI-1 loss.
We were able to demonstrate matrix degradation dependent on membrane-bound proteases in proinflammatory stimulated macrophages and a forced proteolytical quiescence in alternatively polarized macrophages by the expression of PAI-1.
Lymphatic filariasis (LF) is a neglected tropical disease that can cause hydrocele and its associated stigma, loss of economic productivity, and depression. Hydrocele surgery is an essential part of ...LF morbidity management but can be difficult for national programs to implement. To improve access to hydrocele surgeries in Côte d'Ivoire, we provided a WHO-certified surgical training for six surgical teams from five health districts in Côte d'Ivoire. We then evaluated the surgical outcomes and assessed the impact of hydrocele surgery on quality of life of hydrocelectomy patients. Preoperative and operative records were reviewed to describe baseline hydrocele characteristics and operative details. Postoperative interviews were conducted 4 to 6 months after surgical correction using a standardized questionnaire. Seventeen men underwent surgery during the training and were available for an interview at the 6-month visit. At the time of 6-month follow-up, 11/17 (64.7%) reported improvement in activities of daily living and reduction in difficulties with work, 8/17 (47.1%) reported an improved economic situation, 15/17 (88.2%) reported improved social interactions, and 15/16 (93.8%) reported improved sex life after surgical correction. Three patients (17.6%) had minor postoperative complications, but none required hospitalization. All 17 patients who were available for an interview were satisfied with their surgery. Surgical hydrocelectomy training in Côte d'Ivoire was well received and provided life-altering health improvements for participating patients across multiple domains of life. Support to scale up surgical capacity for this neglected problem is needed.
PDF
