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- ItemWhole-Cell Analysis of Low-Density Lipoprotein Uptake by Macrophages Using STEM Tomography(San Francisco, CA : Public Library of Science, 2013) Baudoin, J.-P.; Jerome, W.G.; Kübel, C.; de Jonge, N.Nanoparticles of heavy materials such as gold can be used as markers in quantitative electron microscopic studies of protein distributions in cells with nanometer spatial resolution. Studying nanoparticles within the context of cells is also relevant for nanotoxicological research. Here, we report a method to quantify the locations and the number of nanoparticles, and of clusters of nanoparticles inside whole eukaryotic cells in three dimensions using scanning transmission electron microscopy (STEM) tomography. Whole-mount fixed cellular samples were prepared, avoiding sectioning or slicing. The level of membrane staining was kept much lower than is common practice in transmission electron microscopy (TEM), such that the nanoparticles could be detected throughout the entire cellular thickness. Tilt-series were recorded with a limited tilt-range of 80° thereby preventing excessive beam broadening occurring at higher tilt angles. The 3D locations of the nanoparticles were nevertheless determined with high precision using computation. The obtained information differed from that obtained with conventional TEM tomography data since the nanoparticles were highlighted while only faint contrast was obtained on the cellular material. Similar as in fluorescence microscopy, a particular set of labels can be studied. This method was applied to study the fate of sequentially up-taken low-density lipoprotein (LDL) conjugated to gold nanoparticles in macrophages. Analysis of a 3D reconstruction revealed that newly up-taken LDL-gold was delivered to lysosomes containing previously up-taken LDL-gold thereby forming onion-like clusters.
- ItemRolled-up magnetic microdrillers: Towards remotely controlled minimally invasive surgery(Cambridge [u.a.] : Royal Society of Chemistry, 2013) Xi, W.; Solovev, A.A.; Ananth, A.N.; Gracias, D.H.; Sanchez, S.; Schmidt, O.G.Self-folded magnetic microtools with sharp ends are directed at enabling drilling and related incision operations of tissues, ex vivo, in a fluid with a viscosity similar to that of blood. These microtools change their rotation from a horizontal to a vertical one when they are immersed into a rotational magnetic field. Novel self-assembly paradigms with magnetic materials can enable the creation of remotely controlled and mass-produced tools for potential applications in minimally invasive surgery.
- ItemProjections of temperature-related excess mortality under climate change scenarios(Amsterdam : Elsevier B.V., 2017) Gasparrini, A.; Guo, Y.; Sera, F.; Vicedo-Cabrera, A.M.; Huber, V.; Tong, S.; de Sousa Zanotti Stagliorio Coelho, M.; Nascimento Saldiva, P.H.; Lavigne, E.; Matus Correa, P.; Valdes Ortega, N.; Kan, H.; Osorio, S.; Kyselý, J.; Urban, A.; Jaakkola, J.J.K.; Ryti, N.R.I.; Pascal, M.; Goodman, P.G.; Zeka, A.; Michelozzi, P.; Scortichini, M.; Hashizume, M.; Honda, Y.; Hurtado-Diaz, M.; Cesar Cruz, J.; Seposo, X.; Kim, H.; Tobias, A.; Iñiguez, C.; Forsberg, B.; Åström, D.O.; Ragettli, M.S.; Guo, Y.L.; Wu, C.-F.; Zanobetti, A.; Schwartz, J.; Bell, M.L.; Dang, T.N.; Van, D.D.; Heaviside, C.; Vardoulakis, S.; Hajat, S.; Haines, A.; Armstrong, B.Background: Climate change can directly affect human health by varying exposure to non-optimal outdoor temperature. However, evidence on this direct impact at a global scale is limited, mainly due to issues in modelling and projecting complex and highly heterogeneous epidemiological relationships across different populations and climates. Methods: We collected observed daily time series of mean temperature and mortality counts for all causes or non-external causes only, in periods ranging from Jan 1, 1984, to Dec 31, 2015, from various locations across the globe through the Multi-Country Multi-City Collaborative Research Network. We estimated temperature–mortality relationships through a two-stage time series design. We generated current and future daily mean temperature series under four scenarios of climate change, determined by varying trajectories of greenhouse gas emissions, using five general circulation models. We projected excess mortality for cold and heat and their net change in 1990–2099 under each scenario of climate change, assuming no adaptation or population changes. Findings: Our dataset comprised 451 locations in 23 countries across nine regions of the world, including 85 879 895 deaths. Results indicate, on average, a net increase in temperature-related excess mortality under high-emission scenarios, although with important geographical differences. In temperate areas such as northern Europe, east Asia, and Australia, the less intense warming and large decrease in cold-related excess would induce a null or marginally negative net effect, with the net change in 2090–99 compared with 2010–19 ranging from −1·2% (empirical 95% CI −3·6 to 1·4) in Australia to −0·1% (−2·1 to 1·6) in east Asia under the highest emission scenario, although the decreasing trends would reverse during the course of the century. Conversely, warmer regions, such as the central and southern parts of America or Europe, and especially southeast Asia, would experience a sharp surge in heat-related impacts and extremely large net increases, with the net change at the end of the century ranging from 3·0% (−3·0 to 9·3) in Central America to 12·7% (−4·7 to 28·1) in southeast Asia under the highest emission scenario. Most of the health effects directly due to temperature increase could be avoided under scenarios involving mitigation strategies to limit emissions and further warming of the planet. Interpretation: This study shows the negative health impacts of climate change that, under high-emission scenarios, would disproportionately affect warmer and poorer regions of the world. Comparison with lower emission scenarios emphasises the importance of mitigation policies for limiting global warming and reducing the associated health risks. Funding: UK Medical Research Council.
- ItemLiver Dysfunction and Phosphatidylinositol-3-Kinase Signalling in Early Sepsis: Experimental Studies in Rodent Models of Peritonitis(San Francisco, CA : Public Library of Science, 2012) Recknagel, P.; Gonnert, F.A.; Westermann, M.; Lambeck, S.; Lupp, A.; Rudiger, A.; Dyson, A.; Carré, J.E.; Kortgen, A.; Krafft, C.; Popp, J.; Sponholz, C.; Fuhrmann, V.; Hilger, I.; Claus, R.A.; Riedemann, N.C.; Wetzker, R.; Singer, M.; Trauner, M.; Bauer, M.Background: Hepatic dysfunction and jaundice are traditionally viewed as late features of sepsis and portend poor outcomes. We hypothesized that changes in liver function occur early in the onset of sepsis, yet pass undetected by standard laboratory tests. Methods and Findings: In a long-term rat model of faecal peritonitis, biotransformation and hepatobiliary transport were impaired, depending on subsequent disease severity, as early as 6 h after peritoneal contamination. Phosphatidylinositol-3-kinase (PI3K) signalling was simultaneously induced at this time point. At 15 h there was hepatocellular accumulation of bilirubin, bile acids, and xenobiotics, with disturbed bile acid conjugation and drug metabolism. Cholestasis was preceded by disruption of the bile acid and organic anion transport machinery at the canalicular pole. Inhibitors of PI3K partially prevented cytokine-induced loss of villi in cultured HepG2 cells. Notably, mice lacking the PI3Kγ gene were protected against cholestasis and impaired bile acid conjugation. This was partially confirmed by an increase in plasma bile acids (e.g., chenodeoxycholic acid [CDCA] and taurodeoxycholic acid [TDCA]) observed in 48 patients on the day severe sepsis was diagnosed; unlike bilirubin (area under the receiver-operating curve: 0.59), these bile acids predicted 28-d mortality with high sensitivity and specificity (area under the receiver-operating curve: CDCA: 0.77; TDCA: 0.72; CDCA+TDCA: 0.87). Conclusions: Liver dysfunction is an early and commonplace event in the rat model of sepsis studied here; PI3K signalling seems to play a crucial role. All aspects of hepatic biotransformation are affected, with severity relating to subsequent prognosis. Detected changes significantly precede conventional markers and are reflected by early alterations in plasma bile acids. These observations carry important implications for the diagnosis of liver dysfunction and pharmacotherapy in the critically ill. Further clinical work is necessary to extend these concepts into clinical practice. Please see later in the article for the Editors' Summary.
- ItemAnti-Prion Drug mPPIg5 Inhibits PrPC Conversion to PrPSc(San Francisco, CA : Public Library of Science, 2013) McCarthy, J.M.; Franke, M.; Resenberger, U.K.; Waldron, S.; Simpson, J.C.; Tatzelt, J.; Appelhans, D.; Rogers, M.S.Prion diseases, also known as transmissible spongiform encephalopathies, are a group of fatal neurodegenerative diseases that include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle and Creutzfeldt-Jakob disease (CJD) in humans. The 'protein only hypothesis' advocates that PrPSc, an abnormal isoform of the cellular protein PrPC, is the main and possibly sole component of prion infectious agents. Currently, no effective therapy exists for these diseases at the symptomatic phase for either humans or animals, though a number of compounds have demonstrated the ability to eliminate PrPSc in cell culture models. Of particular interest are synthetic polymers known as dendrimers which possess the unique ability to eliminate PrPSc in both an intracellular and in vitro setting. The efficacy and mode of action of the novel anti-prion dendrimer mPPIg5 was investigated through the creation of a number of innovative bio-assays based upon the scrapie cell assay. These assays were used to demonstrate that mPPIg5 is a highly effective anti-prion drug which acts, at least in part, through the inhibition of PrPC to PrPSc conversion. Understanding how a drug works is a vital component in maximising its performance. By establishing the efficacy and method of action of mPPIg5, this study will help determine which drugs are most likely to enhance this effect and also aid the design of dendrimers with anti-prion capabilities for the future.
- ItemAntimicrobial Efficacy of Two Surface Barrier Discharges with Air Plasma against In Vitro Biofilms(San Francisco, CA : Public Library of Science, 2013) Matthes, R.; Bender, C.; Schlüter, R.; Koban, I.; Bussiahn, R.; Reuter, S.; Lademann, J.; Weltmann, K.-D.; Kramer, A.The treatment of infected wounds is one possible therapeutic aspect of plasma medicine. Chronic wounds are often associated with microbial biofilms which limit the efficacy of antiseptics. The present study investigates two different surface barrier discharges with air plasma to compare their efficacy against microbial biofilms with chlorhexidine digluconate solution (CHX) as representative of an important antibiofilm antiseptic. Pseudomonas aeruginosa SG81 and Staphylococcus epidermidis RP62A were cultivated on polycarbonate discs. The biofilms were treated for 30, 60, 150, 300 or 600 s with plasma or for 600 s with 0.1% CHX, respectively. After treatment, biofilms were dispensed by ultrasound and the antimicrobial effects were determined as difference in the number of the colony forming units by microbial culture. A high antimicrobial efficacy on biofilms of both plasma sources in comparison to CHX treatment was shown. The efficacy differs between the used strains and plasma sources. For illustration, the biofilms were examined under a scanning electron microscope before and after treatment. Additionally, cytotoxicity was determined by the MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay with L929 mouse fibroblast cell line. The cell toxicity of the used plasma limits its applicability on human tissue to maximally 150 s. The emitted UV irradiance was measured to estimate whether UV could limit the application on human tissue at the given parameters. It was found that the UV emission is negligibly low. In conclusion, the results support the assumption that air plasma could be an option for therapy of chronic wounds.
- ItemCharacterizing the sectoral development of cities(San Francisco, California, US : PLOS, 2021) Rybski, Diego; Pradhan, Prajal; Shutters, Shade T.; Butsic, Van; Kropp, Jürgen P.; Xue, BingPrevious research has identified a predictive model of how a nation’s distribution of gross domestic product (GDP) among agriculture (a), industry (i), and services (s) changes as a country develops. Here we use this national model to analyze the composition of GDP for US Metropolitan Statistical Areas (MSA) over time. To characterize the transfer of GDP shares between the sectors in the course of economic development we explore a simple system of differential equations proposed in the country-level model. Fitting the model to more than 120 MSAs we find that according to the obtained parameters MSAs can be classified into 6 groups (consecutive, high industry, re-industrializing; each of them also with reversed development direction). The consecutive transfer (a → i → s) is common but does not represent all MSAs examined. At the 95% confidence level, 40% of MSAs belong to types exhibiting an increasing share of GDP from agriculture. In California, such MSAs, which we classify as part of an agriculture renaissance, are found in the Central Valley.
- ItemIn vitro model of metastasis to bone marrow mediates prostate cancer castration resistant growth through paracrine and extracellular matrix factors(San Francisco, CA : Public Library of Science, 2012) Lescarbeau, R.M.; Seib, F.P.; Prewitz, M.; Werner, C.; Kaplan, D.L.The spread of prostate cancer cells to the bone marrow microenvironment and castration resistant growth are key steps in disease progression and significant sources of morbidity. However, the biological significance of mesenchymal stem cells (MSCs) and bone marrow derived extracellular matrix (BM-ECM) in this process is not fully understood. We therefore established an in vitro engineered bone marrow tissue model that incorporates hMSCs and BM-ECM to facilitate mechanistic studies of prostate cancer cell survival in androgen-depleted media in response to paracrine factors and BM-ECM. hMSC-derived paracrine factors increased LNCaP cell survival, which was in part attributed to IGFR and IL6 signaling. In addition, BM-ECM increased LNCaP and MDA-PCa-2b cell survival in androgen-depleted conditions, and induced chemoresistance and morphological changes in LNCaPs. To determine the effect of BM-ECM on cell signaling, the phosphorylation status of 46 kinases was examined. Increases in the phosphorylation of MAPK pathway-related proteins as well as sustained Akt phosphorylation were observed in BM-ECM cultures when compared to cultures grown on plasma-treated polystyrene. Blocking MEK1/2 or the PI3K pathway led to a significant reduction in LNCaP survival when cultured on BM-ECM in androgen-depleted conditions. The clinical relevance of these observations was determined by analyzing Erk phosphorylation in human bone metastatic prostate cancer versus non-metastatic prostate cancer, and increased phosphorylation was seen in the metastatic samples. Here we describe an engineered bone marrow model that mimics many features observed in patients and provides a platform for mechanistic in vitro studies.
- ItemUltrafast vibrational control of organohalide perovskite optoelectronic devices using vibrationally promoted electronic resonance(Basingstoke : Nature Publishing Group, 2023) Gallop, Nathaniel. P.; Maslennikov, Dmitry R.; Mondal, Navendu; Goetz, Katelyn P.; Dai, Zhenbang; Schankler, Aaron M.; Sung, Woongmo; Nihonyanagi, Satoshi; Tahara, Tahei; Bodnarchuk, Maryna I.; Kovalenko, Maksym V.; Vaynzof, Yana; Rappe, Andrew M.; Bakulin, Artem A.Vibrational control (VC) of photochemistry through the optical stimulation of structural dynamics is a nascent concept only recently demonstrated for model molecules in solution. Extending VC to state-of-the-art materials may lead to new applications and improved performance for optoelectronic devices. Metal halide perovskites are promising targets for VC due to their mechanical softness and the rich array of vibrational motions of both their inorganic and organic sublattices. Here, we demonstrate the ultrafast VC of FAPbBr3 perovskite solar cells via intramolecular vibrations of the formamidinium cation using spectroscopic techniques based on vibrationally promoted electronic resonance. The observed short (~300 fs) time window of VC highlights the fast dynamics of coupling between the cation and inorganic sublattice. First-principles modelling reveals that this coupling is mediated by hydrogen bonds that modulate both lead halide lattice and electronic states. Cation dynamics modulating this coupling may suppress non-radiative recombination in perovskites, leading to photovoltaics with reduced voltage losses.
- ItemResearch data management in agricultural sciences in Germany: We are not yet where we want to be(San Francisco, California, US : PLOS, 2022) Senft, Matthias; Stahl, Ulrike; Svoboda, NikolaiTo meet the future challenges and foster integrated and holistic research approaches in agricultural sciences, new and sustainable methods in research data management (RDM) are needed. The involvement of scientific users is a critical success factor for their development. We conducted an online survey in 2020 among different user groups in agricultural sciences about their RDM practices and needs. In total, the questionnaire contained 52 questions on information about produced and (re-)used data, data quality aspects, information about the use of standards, publication practices and legal aspects of agricultural research data, the current situation in RDM in regards to awareness, consulting and curricula as well as needs of the agricultural community in respect to future developments. We received 196 (partially) completed questionnaires from data providers, data users, infrastructure and information service providers. In addition to the diversity in the research data landscape of agricultural sciences in Germany, the study reveals challenges, deficits and uncertainties in handling research data in agricultural sciences standing in the way of access and efficient reuse of valuable research data. However, the study also suggests and discusses potential solutions to enhance data publications, facilitate and secure data re-use, ensure data quality and develop services (i.e. training, support and bundling services). Therefore, our research article provides the basis for the development of common RDM, future infrastructures and services needed to foster the cultural change in handling research data across agricultural sciences in Germany and beyond.