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- ItemA New PqsR Inverse Agonist Potentiates Tobramycin Efficacy to Eradicate Pseudomonas aeruginosa Biofilms(2021) Schütz, Christian; Ho, Duy-Khiet; Hamed, Mostafa Mohamed; Abdelsamie, Ahmed Saad; Röhrig, Teresa; Herr, Christian; Kany, Andreas Martin; Rox, Katharina; Schmelz, Stefan; Siebenbürger, Lorenz; Wirth, Marius; Börger, Carsten; Yahiaoui, Samir; Bals, Robert; Scrima, Andrea; Blankenfeldt, Wulf; Horstmann, Justus Constantin; Christmann, Rebekka; Murgia, Xabier; Koch, Marcus; Berwanger, Aylin; Loretz, Brigitta; Hirsch, Anna Katharina Herta; Hartmann, Rolf Wolfgang; Lehr, Claus-Michael; Empting, MartinPseudomonas aeruginosa (PA) infections can be notoriously difficult to treat and are often accompanied by the development of antimicrobial resistance (AMR). Quorum sensing inhibitors (QSI) acting on PqsR (MvfR) – a crucial transcriptional regulator serving major functions in PA virulence – can enhance antibiotic efficacy and eventually prevent the AMR. An integrated drug discovery campaign including design, medicinal chemistry-driven hit-to-lead optimization and in-depth biological profiling of a new QSI generation is reported. The QSI possess excellent activity in inhibiting pyocyanin production and PqsR reporter-gene with IC50 values as low as 200 and 11 × 10−9 m, respectively. Drug metabolism and pharmacokinetics (DMPK) as well as safety pharmacology studies especially highlight the promising translational properties of the lead QSI for pulmonary applications. Moreover, target engagement of the lead QSI is shown in a PA mucoid lung infection mouse model. Beyond that, a significant synergistic effect of a QSI-tobramycin (Tob) combination against PA biofilms using a tailor-made squalene-derived nanoparticle (NP) formulation, which enhance the minimum biofilm eradicating concentration (MBEC) of Tob more than 32-fold is demonstrated. The novel lead QSI and the accompanying NP formulation highlight the potential of adjunctive pathoblocker-mediated therapy against PA infections opening up avenues for preclinical development.
- ItemA physicochemical perspective of aging from single-cell analysis of ph, macromolecular and organellar crowding in yeast(Cambridge : eLife Sciences Publications, 2020) Mouton, Sara N.; Thaller, David J.; Crane, Matthew M.; Rempel, Irina L.; Terpstra, Owen T.; Steen, Anton; Kaeberlein, Matt; Lusk, C. Patrick; Boersma, Arnold J.; Veenhoff, Liesbeth M.Cellular aging is a multifactorial process that is characterized by a decline in homeostatic capacity, best described at the molecular level. Physicochemical properties such as pH and macromolecular crowding are essential to all molecular processes in cells and require maintenance. Whether a drift in physicochemical properties contributes to the overall decline of homeostasis in aging is not known. Here we show that the cytosol of yeast cells acidifies modestly in early aging and sharply after senescence. Using a macromolecular crowding sensor optimized for long-term FRET measurements, we show that crowding is rather stable and that the stability of crowding is a stronger predictor for lifespan than the absolute crowding levels. Additionally, in aged cells we observe drastic changes in organellar volume, leading to crowding on the µm scale, which we term organellar crowding. Our measurements provide an initial framework of physicochemical parameters of replicatively aged yeast cells. © 2020, eLife Sciences Publications Ltd. All rights reserved.
- ItemNitrosylation vs. oxidation – How to modulate cold physical plasmas for biological applications(San Francisco, California, US : PLOS, 2019) Lackmann, Jan-Wilm; Bruno, Giuliana; Jablonowski, Helena; Kogelheide, Friederike; Offerhaus, Björn; Held, Julian; Schulz-von der Gathen, Volker; Stapelmann, Katharina; von Woedtke, Thomas; Wende, KristianThiol moieties are major targets for cold plasma-derived nitrogen and oxygen species, making CAPs convenient tools to modulate redox-signaling pathways in cells and tissues. The underlying biochemical pathways are currently under investigation but especially the role of CAP derived RNS is barely understood. Their potential role in protein thiol nitrosylation would be relevant in inflammatory processes such as wound healing and improving their specific production by CAP would allow for enhanced treatment options beyond the current application. The impact of a modified kINPen 09 argon plasma jet with nitrogen shielding on cysteine as a thiol-carrying model substance was investigated by FTIR spectroscopy and high-resolution mass spectrometry. The deposition of short-lived radical species was measured by electron paramagnetic resonance spectroscopy, long-lived species were quantified by ion chromatography (NO2-, NO3-) and xylenol orange assay (H2O2). Product profiles were compared to samples treated with the so-called COST jet, being introduced by a European COST initiative as a reference device, using both reference conditions as well as conditions adjusted to kINPen gas mixtures. While thiol oxidation was dominant under all tested conditions, an Ar + N2/O2 gas compositions combined with a nitrogen curtain fostered nitric oxide deposition and the desired generation of S-nitrosocysteine. Interestingly, the COST-jet revealed significant differences in its chemical properties in comparison to the kINPen by showing a more stable production of RNS with different gas admixtures, indicating a different •NO production pathway. Taken together, results indicate various chemical properties of kINPen and COST-jet as well as highlight the potential of plasma tuning not only by gas admixtures alone but by adjusting the surrounding atmosphere as well.
- ItemA Gini approach to spatial CO2 emissions(San Francisco, California, US : PLOS, 2020) Zhou, Bin; Thies, Stephan; Gudipudi, Ramana; Lüdeke, Matthias K.B.; Kropp, Jürgen P.; Rybski, DiegoCombining global gridded population and fossil fuel based CO2 emission data at 1 km scale, we investigate the spatial origin of CO2 emissions in relation to the population distribution within countries. We depict the correlations between these two datasets by a quasi-Lorenz curve which enables us to discern the individual contributions of densely and sparsely populated regions to the national CO2 emissions. We observe pronounced country-specific characteristics and quantify them using an indicator resembling the Gini-index. As demonstrated by a robustness test, the Gini-index for each country arise from a compound distribution between the population and emissions which differs among countries. Relating these indices with the degree of socio-economic development measured by per capita Gross Domestic Product (GDP) at purchase power parity, we find a strong negative correlation between the two quantities with a Pearson correlation coefficient of -0.71. More specifically, this implies that in developing countries locations with large population tend to emit relatively more CO2, and in developed countries the opposite tends to be the case. Based on the relation to urban scaling, we discuss the implications for CO2 emissions from cities. Our results show that general statements with regard to the (in)efficiency of large cities should be avoided as it is subject to the socio-economic development of respective countries. Concerning the political relevance, our results suggest a differentiated spatial prioritization in deploying climate change mitigation measures in cities for developed and developing countries.
- ItemOptoregulated force application to cellular receptors using molecular motors(London : Nature Publishing Group, 2021) Zheng, Yijun; Han, Mitchell K.L.; Zhao, Renping; Blass, Johanna; Zhang, Jingnan; Zhou, Dennis W.; Colard-Itté, Jean-Rémy; Dattler, Damien; Çolak, Arzu; Hoth, Markus; García, Andrés J.; Qu, Bin; Bennewitz, Roland; Giuseppone, Nicolas; del Campo, AránzazuProgress in our understanding of mechanotransduction events requires noninvasive methods for the manipulation of forces at molecular scale in physiological environments. Inspired by cellular mechanisms for force application (i.e. motor proteins pulling on cytoskeletal fibers), we present a unique molecular machine that can apply forces at cell-matrix and cell-cell junctions using light as an energy source. The key actuator is a light-driven rotatory molecular motor linked to polymer chains, which is intercalated between a membrane receptor and an engineered biointerface. The light-driven actuation of the molecular motor is converted in mechanical twisting of the entangled polymer chains, which will in turn effectively “pull” on engaged cell membrane receptors (e.g., integrins, T cell receptors) within the illuminated area. Applied forces have physiologically-relevant magnitude and occur at time scales within the relevant ranges for mechanotransduction at cell-friendly exposure conditions, as demonstrated in force-dependent focal adhesion maturation and T cell activation experiments. Our results reveal the potential of nanomotors for the manipulation of living cells at the molecular scale and demonstrate a functionality which at the moment cannot be achieved by other technologies for force application.
- ItemUnsplit superconducting and time reversal symmetry breaking transitions in Sr2RuO4 under hydrostatic pressure and disorder([London] : Nature Publishing Group UK, 2021) Grinenko, Vadim; Das, Debarchan; Gupta, Ritu; Zinkl, Bastian; Kikugawa, Naoki; Maeno, Yoshiteru; Hicks, Clifford W.; Klauss, Hans-Henning; Sigrist, Manfred; Khasanov, RustemThere is considerable evidence that the superconducting state of Sr2RuO4 breaks time reversal symmetry. In the experiments showing time reversal symmetry breaking, its onset temperature, TTRSB, is generally found to match the critical temperature, Tc, within resolution. In combination with evidence for even parity, this result has led to consideration of a dxz ± idyz order parameter. The degeneracy of the two components of this order parameter is protected by symmetry, yielding TTRSB = Tc, but it has a hard-to-explain horizontal line node at kz = 0. Therefore, s ± id and d ± ig order parameters are also under consideration. These avoid the horizontal line node, but require tuning to obtain TTRSB ≈ Tc. To obtain evidence distinguishing these two possible scenarios (of symmetry-protected versus accidental degeneracy), we employ zero-field muon spin rotation/relaxation to study pure Sr2RuO4 under hydrostatic pressure, and Sr1.98La0.02RuO4 at zero pressure. Both hydrostatic pressure and La substitution alter Tc without lifting the tetragonal lattice symmetry, so if the degeneracy is symmetry-protected, TTRSB should track changes in Tc, while if it is accidental, these transition temperatures should generally separate. We observe TTRSB to track Tc, supporting the hypothesis of dxz ± idyz order.
- ItemNano-biosupercapacitors enable autarkic sensor operation in blood([London] : Nature Publishing Group UK, 2021) Lee, Yeji; Bandari, Vineeth Kumar; Li, Zhe; Medina-Sánchez, Mariana; Maitz, Manfred F.; Karnaushenko, Daniil; Tsurkan, Mikhail V; Karnaushenko, Dmitriy D.; Schmidt, Oliver G.Today’s smallest energy storage devices for in-vivo applications are larger than 3 mm3 and lack the ability to continuously drive the complex functions of smart dust electronic and microrobotic systems. Here, we create a tubular biosupercapacitor occupying a mere volume of 1/1000 mm3 (=1 nanoliter), yet delivering up to 1.6 V in blood. The tubular geometry of this nano-biosupercapacitor provides efficient self-protection against external forces from pulsating blood or muscle contraction. Redox enzymes and living cells, naturally present in blood boost the performance of the device by 40% and help to solve the self-discharging problem persistently encountered by miniaturized supercapacitors. At full capacity, the nano-biosupercapacitors drive a complex integrated sensor system to measure the pH-value in blood. This demonstration opens up opportunities for next generation intravascular implants and microrobotic systems operating in hard-to-reach small spaces deep inside the human body.
- ItemSocial tipping dynamics for stabilizing Earth's climate by 2050(2020) Otto, Ilona M.; Donges, Jonathan F.; Cremades, Roger; Bhowmik, Avit; Hewitt, Richard J.; Lucht, Wolfgang; Rockström, Johan; Allerberger, Franziska; McCaffrey, Mark; Doe, Sylvanus S.P.; Lenferna, Alex; Morán, Nerea; van Vuuren, Detlef P.; Schellnhuber, Hans JoachimSafely achieving the goals of the Paris Climate Agreement requires a worldwide transformation to carbon-neutral societies within the next 30 y. Accelerated technological progress and policy implementations are required to deliver emissions reductions at rates sufficiently fast to avoid crossing dangerous tipping points in the Earth's climate system. Here, we discuss and evaluate the potential of social tipping interventions (STIs) that can activate contagious processes of rapidly spreading technologies, behaviors, social norms, and structural reorganization within their functional domains that we refer to as social tipping elements (STEs). STEs are subdomains of the planetary socioeconomic system where the required disruptive change may take place and lead to a sufficiently fast reduction in anthropogenic greenhouse gas emissions. The results are based on online expert elicitation, a subsequent expert workshop, and a literature review. The STIs that could trigger the tipping of STE subsystems include 1) removing fossil-fuel subsidies and incentivizing decentralized energy generation (STE1, energy production and storage systems), 2) building carbon-neutral cities (STE2, human settlements), 3) divesting from assets linked to fossil fuels (STE3, financial markets), 4) revealing the moral implications of fossil fuels (STE4, norms and value systems), 5) strengthening climate education and engagement (STE5, education system), and 6) disclosing information on greenhouse gas emissions (STE6, information feedbacks). Our research reveals important areas of focus for larger-scale empirical and modeling efforts to better understand the potentials of harnessing social tipping dynamics for climate change mitigation.
- ItemCommunicating sentiment and outlook reverses inaction against collective risks(Washington, DC : National Acad. of Sciences, 2020) Wang, Zhen; Jusup, Marko; Guo, Hao; Shi, Lei; Geček, Sunčana; Anand, Madhur; Perc, Matjaž; Bauch, Chris T.; Kurths, Jürgen; Boccaletti, Stefano; Schellnhuber, Hans JoachimCollective risks permeate society, triggering social dilemmas in which working toward a common goal is impeded by selfish interests. One such dilemma is mitigating runaway climate change. To study the social aspects of climate-change mitigation, we organized an experimental game and asked volunteer groups of three different sizes to invest toward a common mitigation goal. If investments reached a preset target, volunteers would avoid all consequences and convert their remaining capital into monetary payouts. In the opposite case, however, volunteers would lose all their capital with 50% probability. The dilemma was, therefore, whether to invest one's own capital or wait for others to step in. We find that communicating sentiment and outlook helps to resolve the dilemma by a fundamental shift in investment patterns. Groups in which communication is allowed invest persistently and hardly ever give up, even when their current investment deficits are substantial. The improved investment patterns are robust to group size, although larger groups are harder to coordinate, as evidenced by their overall lower success frequencies. A clustering algorithm reveals three behavioral types and shows that communication reduces the abundance of the free-riding type. Climate-change mitigation, however, is achieved mainly by cooperator and altruist types stepping up and increasing contributions as the failure looms. Meanwhile, contributions from free riders remain flat throughout the game. This reveals that the mechanisms behind avoiding collective risks depend on an interaction between behavioral type, communication, and timing.
- ItemEvidence of two-dimensional flat band at the surface of antiferromagnetic kagome metal FeSn([London] : Nature Publishing Group UK, 2021) Han, Minyong; Inoue, Hisashi; Fang, Shiang; John, Caolan; Ye, Linda; Chan, Mun K.; Graf, David; Suzuki, Takehito; Ghimire, Madhav Prasad; Cho, Won Joon; Kaxiras, Efthimios; Checkelsky, Joseph G.The kagome lattice has long been regarded as a theoretical framework that connects lattice geometry to unusual singularities in electronic structure. Transition metal kagome compounds have been recently identified as a promising material platform to investigate the long-sought electronic flat band. Here we report the signature of a two-dimensional flat band at the surface of antiferromagnetic kagome metal FeSn by means of planar tunneling spectroscopy. Employing a Schottky heterointerface of FeSn and an n-type semiconductor Nb-doped SrTiO3, we observe an anomalous enhancement in tunneling conductance within a finite energy range of FeSn. Our first-principles calculations show this is consistent with a spin-polarized flat band localized at the ferromagnetic kagome layer at the Schottky interface. The spectroscopic capability to characterize the electronic structure of a kagome compound at a thin film heterointerface will provide a unique opportunity to probe flat band induced phenomena in an energy-resolved fashion with simultaneous electrical tuning of its properties. Furthermore, the exotic surface state discussed herein is expected to manifest as peculiar spin-orbit torque signals in heterostructure-based spintronic devices.