@article{6091, abstract = {Cortical networks are characterized by sparse connectivity, with synapses found at only a subset of axo-dendritic contacts. Yet within these networks, neurons can exhibit high connection probabilities, suggesting that cell-intrinsic factors, not proximity, determine connectivity. Here, we identify ephrin-B3 (eB3) as a factor that determines synapse density by mediating a cell-cell competition that requires ephrin-B-EphB signaling. In a microisland culture system designed to isolate cell-cell competition, we find that eB3 determines winning and losing neurons in a contest for synapses. In a Mosaic Analysis with Double Markers (MADM) genetic mouse model system in vivo the relative levels of eB3 control spine density in layer 5 and 6 neurons. MADM cortical neurons in vitro reveal that eB3 controls synapse density independently of action potential-driven activity. Our findings illustrate a new class of competitive mechanism mediated by trans-synaptic organizing proteins which control the number of synapses neurons receive relative to neighboring neurons.}, author = {Henderson, Nathan T. and Le Marchand, Sylvain J. and Hruska, Martin and Hippenmeyer, Simon and Luo, Liqun and Dalva, Matthew B.}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{Ephrin-B3 controls excitatory synapse density through cell-cell competition for EphBs}}, doi = {10.7554/eLife.41563}, volume = {8}, year = {2019}, } @article{6046, abstract = {Sudden stress often triggers diverse, temporally structured gene expression responses in microbes, but it is largely unknown how variable in time such responses are and if genes respond in the same temporal order in every single cell. Here, we quantified timing variability of individual promoters responding to sublethal antibiotic stress using fluorescent reporters, microfluidics, and time‐lapse microscopy. We identified lower and upper bounds that put definite constraints on timing variability, which varies strongly among promoters and conditions. Timing variability can be interpreted using results from statistical kinetics, which enable us to estimate the number of rate‐limiting molecular steps underlying different responses. We found that just a few critical steps control some responses while others rely on dozens of steps. To probe connections between different stress responses, we then tracked the temporal order and response time correlations of promoter pairs in individual cells. Our results support that, when bacteria are exposed to the antibiotic nitrofurantoin, the ensuing oxidative stress and SOS responses are part of the same causal chain of molecular events. In contrast, under trimethoprim, the acid stress response and the SOS response are part of different chains of events running in parallel. Our approach reveals fundamental constraints on gene expression timing and provides new insights into the molecular events that underlie the timing of stress responses.}, author = {Mitosch, Karin and Rieckh, Georg and Bollenbach, Mark Tobias}, journal = {Molecular systems biology}, number = {2}, publisher = {Embo Press}, title = {{Temporal order and precision of complex stress responses in individual bacteria}}, doi = {10.15252/msb.20188470}, volume = {15}, year = {2019}, } @article{6105, abstract = { Hosts can alter their strategy towards pathogens during their lifetime; that is, they can show phenotypic plasticity in immunity or life history. Immune priming is one such example, where a previous encounter with a pathogen confers enhanced protection upon secondary challenge, resulting in reduced pathogen load (i.e., resistance) and improved host survival. However, an initial encounter might also enhance tolerance, particularly to less virulent opportunistic pathogens that establish persistent infections. In this scenario, individuals are better able to reduce the negative fecundity consequences that result from a high pathogen burden. Finally, previous exposure may also lead to life‐history adjustments, such as terminal investment into reproduction. Using different Drosophila melanogaster host genotypes and two bacterial pathogens, Lactococcus lactis and Pseudomonas entomophila, we tested whether previous exposure results in resistance or tolerance and whether it modifies immune gene expression during an acute‐phase infection (one day post‐challenge). We then asked whether previous pathogen exposure affects chronic‐phase pathogen persistence and longer‐term survival (28 days post‐challenge). We predicted that previous exposure would increase host resistance to an early stage bacterial infection while it might come at a cost to host fecundity tolerance. We reasoned that resistance would be due in part to stronger immune gene expression after challenge. We expected that previous exposure would improve long‐term survival, that it would reduce infection persistence, and we expected to find genetic variation in these responses. We found that previous exposure to P. entomophila weakened host resistance to a second infection independent of genotype and had no effect on immune gene expression. Fecundity tolerance showed genotypic variation but was not influenced by previous exposure. However, L. lactis persisted as a chronic infection, whereas survivors cleared the more pathogenic P. entomophila infection. To our knowledge, this is the first study that addresses host tolerance to bacteria in relation to previous exposure, taking a multi‐faceted approach to address the topic. Our results suggest that previous exposure comes with transient costs to resistance during the early stage of infection in this host–pathogen system and that infection persistence may be bacterium‐specific. }, author = {Kutzer, Megan and Kurtz, Joachim and Armitage, Sophie A.O.}, issn = {13652656}, journal = {Journal of Animal Ecology}, number = {4}, pages = {566--578}, publisher = {Wiley}, title = {{A multi-faceted approach testing the effects of previous bacterial exposure on resistance and tolerance}}, doi = {10.1111/1365-2656.12953}, volume = {88}, year = {2019}, } @article{6088, abstract = {P-Glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) are two efflux transporters at the blood–brain barrier (BBB), which effectively restrict brain distribution of diverse drugs, such as tyrosine kinase inhibitors. There is a crucial need for pharmacological ABCB1 and ABCG2 inhibition protocols for a more effective treatment of brain diseases. In the present study, seven marketed drugs (osimertinib, erlotinib, nilotinib, imatinib, lapatinib, pazopanib, and cyclosporine A) and one nonmarketed drug (tariquidar), with known in vitro ABCB1/ABCG2 inhibitory properties, were screened for their inhibitory potency at the BBB in vivo. Positron emission tomography (PET) using the model ABCB1/ABCG2 substrate [11C]erlotinib was performed in mice. Tested inhibitors were administered as i.v. bolus injections at 30 min before the start of the PET scan, followed by a continuous i.v. infusion for the duration of the PET scan. Five of the tested drugs increased total distribution volume of [11C]erlotinib in the brain (VT,brain) compared to vehicle-treated animals (tariquidar, + 69%; erlotinib, + 19% and +23% for the 21.5 mg/kg and the 43 mg/kg dose, respectively; imatinib, + 22%; lapatinib, + 25%; and cyclosporine A, + 49%). For all drugs, increases in [11C]erlotinib brain distribution were lower than in Abcb1a/b(−/−)Abcg2(−/−) mice (+149%), which suggested that only partial ABCB1/ABCG2 inhibition was reached at the mouse BBB. The plasma concentrations of the tested drugs at the time of the PET scan were higher than clinically achievable plasma concentrations. Some of the tested drugs led to significant increases in blood radioactivity concentrations measured at the end of the PET scan (erlotinib, + 103% and +113% for the 21.5 mg/kg and the 43 mg/kg dose, respectively; imatinib, + 125%; and cyclosporine A, + 101%), which was most likely caused by decreased hepatobiliary excretion of radioactivity. Taken together, our data suggest that some marketed tyrosine kinase inhibitors may be repurposed to inhibit ABCB1 and ABCG2 at the BBB. From a clinical perspective, moderate increases in brain delivery despite the administration of high i.v. doses as well as peripheral drug–drug interactions due to transporter inhibition in clearance organs question the translatability of this concept.}, author = {Traxl, Alexander and Mairinger, Severin and Filip, Thomas and Sauberer, Michael and Stanek, Johann and Poschner, Stefan and Jäger, Walter and Zoufal, Viktoria and Novarino, Gaia and Tournier, Nicolas and Bauer, Martin and Wanek, Thomas and Langer, Oliver}, journal = {Molecular Pharmaceutics}, number = {3}, pages = {1282--1293}, publisher = {American Chemical Society}, title = {{Inhibition of ABCB1 and ABCG2 at the mouse blood-brain barrier with marketed drugs to improve brain delivery of the model ABCB1/ABCG2 substrate [11C]erlotinib}}, doi = {10.1021/acs.molpharmaceut.8b01217}, volume = {16}, year = {2019}, } @article{6087, abstract = {Cell fate specification by lateral inhibition typically involves contact signaling through the Delta-Notch signaling pathway. However, whether this is the only signaling mode mediating lateral inhibition remains unclear. Here we show that in zebrafish oogenesis, a group of cells within the granulosa cell layer at the oocyte animal pole acquire elevated levels of the transcriptional coactivator TAZ in their nuclei. One of these cells, the future micropyle precursor cell (MPC), accumulates increasingly high levels of nuclear TAZ and grows faster than its surrounding cells, mechanically compressing those cells, which ultimately lose TAZ from their nuclei. Strikingly, relieving neighbor-cell compression by MPC ablation or aspiration restores nuclear TAZ accumulation in neighboring cells, eventually leading to MPC re-specification from these cells. Conversely, MPC specification is defective in taz−/− follicles. These findings uncover a novel mode of lateral inhibition in cell fate specification based on mechanical signals controlling TAZ activity.}, author = {Xia, Peng and Gütl, Daniel J and Zheden, Vanessa and Heisenberg, Carl-Philipp J}, journal = {Cell}, number = {6}, pages = {1379--1392.e14}, publisher = {Elsevier}, title = {{Lateral inhibition in cell specification mediated by mechanical signals modulating TAZ activity}}, doi = {10.1016/j.cell.2019.01.019}, volume = {176}, year = {2019}, } @misc{9806, abstract = {1. Hosts can alter their strategy towards pathogens during their lifetime, i.e., they can show phenotypic plasticity in immunity or life history. Immune priming is one such example, where a previous encounter with a pathogen confers enhanced protection upon secondary challenge, resulting in reduced pathogen load (i.e. resistance) and improved host survival. However, an initial encounter might also enhance tolerance, particularly to less virulent opportunistic pathogens that establish persistent infections. In this scenario, individuals are better able to reduce the negative fitness consequences that result from a high pathogen load. Finally, previous exposure may also lead to life history adjustments, such as terminal investment into reproduction. 2. Using different Drosophila melanogaster host genotypes and two bacterial pathogens, Lactococcus lactis and Pseudomonas entomophila, we tested if previous exposure results in resistance or tolerance and whether it modifies immune gene expression during an acute-phase infection (one day post-challenge). We then asked if previous pathogen exposure affects chronic-phase pathogen persistence and longer-term survival (28 days post-challenge). 3. We predicted that previous exposure would increase host resistance to an early stage bacterial infection while it might come at a cost to host fecundity tolerance. We reasoned that resistance would be due in part to stronger immune gene expression after challenge. We expected that previous exposure would improve long-term survival, that it would reduce infection persistence, and we expected to find genetic variation in these responses. 4. We found that previous exposure to P. entomophila weakened host resistance to a second infection independent of genotype and had no effect on immune gene expression. Fecundity tolerance showed genotypic variation but was not influenced by previous exposure. However, L. lactis persisted as a chronic infection, whereas survivors cleared the more pathogenic P. entomophila infection. 5. To our knowledge, this is the first study that addresses host tolerance to bacteria in relation to previous exposure, taking a multi-faceted approach to address the topic. Our results suggest that previous exposure comes with transient costs to resistance during the early stage of infection in this host-pathogen system and that infection persistence may be bacterium-specific.}, author = {Kutzer, Megan and Kurtz, Joachim and Armitage, Sophie A.O.}, publisher = {Dryad}, title = {{Data from: A multi-faceted approach testing the effects of previous bacterial exposure on resistance and tolerance}}, doi = {10.5061/dryad.9kj41f0}, year = {2019}, } @article{6086, abstract = {We show that linear analytic cocycles where all Lyapunov exponents are negative infinite are nilpotent. For such one-frequency cocycles we show that they can be analytically conjugated to an upper triangular cocycle or a Jordan normal form. As a consequence, an arbitrarily small analytic perturbation leads to distinct Lyapunov exponents. Moreover, in the one-frequency case where the th Lyapunov exponent is finite and the st negative infinite, we obtain a simple criterion for domination in which case there is a splitting into a nilpotent part and an invertible part.}, author = {Sadel, Christian and Xu, Disheng}, journal = {Ergodic Theory and Dynamical Systems}, number = {4}, pages = {1082--1098}, publisher = {Cambridge University Press}, title = {{Singular analytic linear cocycles with negative infinite Lyapunov exponents}}, doi = {10.1017/etds.2017.52}, volume = {39}, year = {2019}, } @article{6102, abstract = {Light is a union of electric and magnetic fields, and nowhere is the complex relationship between these fields more evident than in the near fields of nanophotonic structures. There, complicated electric and magnetic fields varying over subwavelength scales are generally present, which results in photonic phenomena such as extraordinary optical momentum, superchiral fields, and a complex spatial evolution of optical singularities. An understanding of such phenomena requires nanoscale measurements of the complete optical field vector. Although the sensitivity of near- field scanning optical microscopy to the complete electromagnetic field was recently demonstrated, a separation of different components required a priori knowledge of the sample. Here, we introduce a robust algorithm that can disentangle all six electric and magnetic field components from a single near-field measurement without any numerical modeling of the structure. As examples, we unravel the fields of two prototypical nanophotonic structures: a photonic crystal waveguide and a plasmonic nanowire. These results pave the way for new studies of complex photonic phenomena at the nanoscale and for the design of structures that optimize their optical behavior.}, author = {Le Feber, B. and Sipe, J. E. and Wulf, Matthias and Kuipers, L. and Rotenberg, N.}, issn = {20477538}, journal = {Light: Science and Applications}, number = {1}, publisher = {Springer Nature}, title = {{A full vectorial mapping of nanophotonic light fields}}, doi = {10.1038/s41377-019-0124-3}, volume = {8}, year = {2019}, } @article{6104, abstract = {Abiotic stress poses constant challenges for plant survival and is a serious problem for global agricultural productivity. On a molecular level, stress conditions result in elevation of reactive oxygen species (ROS) production causing oxidative stress associated with oxidation of proteins and nucleic acids as well as impairment of membrane functions. Adaptation of root growth to ROS accumulation is facilitated through modification of auxin and cytokinin hormone homeostasis. Here, we report that in Arabidopsis root meristem, ROS-induced changes of auxin levels correspond to decreased abundance of PIN auxin efflux carriers at the plasma membrane (PM). Specifically, increase in H2O2 levels affects PIN2 endocytic recycling. We show that the PIN2 intracellular trafficking during adaptation to oxidative stress requires the function of the ADP-ribosylation factor (ARF)-guanine-nucleotide exchange factor (GEF) BEN1, an actin-associated regulator of the trafficking from the PM to early endosomes and, presumably, indirectly, trafficking to the vacuoles. We propose that H2O2 levels affect the actin dynamics thus modulating ARF-GEF-dependent trafficking of PIN2. This mechanism provides a way how root growth acclimates to stress and adapts to a changing environment.}, author = {Zwiewka, Marta and Bielach, Agnieszka and Tamizhselvan, Prashanth and Madhavan, Sharmila and Ryad, Eman Elrefaay and Tan, Shutang and Hrtyan, Mónika and Dobrev, Petre and Vanková, Radomira and Friml, Jiří and Tognetti, Vanesa B.}, issn = {1471-9053}, journal = {Plant and Cell Physiology}, number = {2}, pages = {255--273}, publisher = {Oxford University Press}, title = {{Root adaptation to H2O2-induced oxidative stress by ARF-GEF BEN1- and cytoskeleton-mediated PIN2 trafficking}}, doi = {10.1093/pcp/pcz001}, volume = {60}, year = {2019}, } @article{6191, abstract = {The formation of self-organized patterns is key to the morphogenesis of multicellular organisms, although a comprehensive theory of biological pattern formation is still lacking. Here, we propose a minimal model combining tissue mechanics with morphogen turnover and transport to explore routes to patterning. Our active description couples morphogen reaction and diffusion, which impact cell differentiation and tissue mechanics, to a two-phase poroelastic rheology, where one tissue phase consists of a poroelastic cell network and the other one of a permeating extracellular fluid, which provides a feedback by actively transporting morphogens. While this model encompasses previous theories approximating tissues to inert monophasic media, such as Turing’s reaction–diffusion model, it overcomes some of their key limitations permitting pattern formation via any two-species biochemical kinetics due to mechanically induced cross-diffusion flows. Moreover, we describe a qualitatively different advection-driven Keller–Segel instability which allows for the formation of patterns with a single morphogen and whose fundamental mode pattern robustly scales with tissue size. We discuss the potential relevance of these findings for tissue morphogenesis.}, author = {Recho, Pierre and Hallou, Adrien and Hannezo, Edouard B}, issn = {10916490}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, number = {12}, pages = {5344--5349}, publisher = {National Academy of Sciences}, title = {{Theory of mechanochemical patterning in biphasic biological tissues}}, doi = {10.1073/pnas.1813255116}, volume = {116}, year = {2019}, } @article{6190, abstract = {Increased levels of the chemokine CCL2 in cancer patients are associated with poor prognosis. Experimental evidence suggests that CCL2 correlates with inflammatory monocyte recruitment and induction of vascular activation, but the functionality remains open. Here, we show that endothelial Ccr2 facilitates pulmonary metastasis using an endothelial-specific Ccr2-deficient mouse model (Ccr2ecKO). Similar levels of circulating monocytes and equal leukocyte recruitment to metastatic lesions of Ccr2ecKO and Ccr2fl/fl littermates were observed. The absence of endothelial Ccr2 strongly reduced pulmonary metastasis, while the primary tumor growth was unaffected. Despite a comparable cytokine milieu in Ccr2ecKO and Ccr2fl/fl littermates the absence of vascular permeability induction was observed only in Ccr2ecKO mice. CCL2 stimulation of pulmonary endothelial cells resulted in increased phosphorylation of MLC2, endothelial cell retraction, and vascular leakiness that was blocked by an addition of a CCR2 inhibitor. These data demonstrate that endothelial CCR2 expression is required for tumor cell extravasation and pulmonary metastasis. Implications: The findings provide mechanistic insight into how CCL2–CCR2 signaling in endothelial cells promotes their activation through myosin light chain phosphorylation, resulting in endothelial retraction and enhanced tumor cell migration and metastasis.}, author = {Roblek, Marko and Protsyuk, Darya and Becker, Paul F. and Stefanescu, Cristina and Gorzelanny, Christian and Glaus Garzon, Jesus F. and Knopfova, Lucia and Heikenwalder, Mathias and Luckow, Bruno and Schneider, Stefan W. and Borsig, Lubor}, issn = {15573125}, journal = {Molecular Cancer Research}, number = {3}, pages = {783--793}, publisher = {AACR}, title = {{CCL2 is a vascular permeability factor inducing CCR2-dependent endothelial retraction during lung metastasis}}, doi = {10.1158/1541-7786.MCR-18-0530}, volume = {17}, year = {2019}, } @article{6230, abstract = {Great care is needed when interpreting claims about the genetic basis of human variation based on data from genome-wide association studies.}, author = {Barton, Nicholas H and Hermisson, Joachim and Nordborg, Magnus}, issn = {2050084X}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{Why structure matters}}, doi = {10.7554/eLife.45380}, volume = {8}, year = {2019}, } @article{6232, abstract = {The boundary behaviour of solutions of stochastic PDEs with Dirichlet boundary conditions can be surprisingly—and in a sense, arbitrarily—bad: as shown by Krylov[ SIAM J. Math. Anal.34(2003) 1167–1182], for any α>0 one can find a simple 1-dimensional constant coefficient linear equation whose solution at the boundary is not α-Hölder continuous.We obtain a positive counterpart of this: under some mild regularity assumptions on the coefficients, solutions of semilinear SPDEs on C1 domains are proved to be α-Hölder continuous up to the boundary with some α>0.}, author = {Gerencser, Mate}, issn = {00911798}, journal = {Annals of Probability}, number = {2}, pages = {804--834}, publisher = {Institute of Mathematical Statistics}, title = {{Boundary regularity of stochastic PDEs}}, doi = {10.1214/18-AOP1272}, volume = {47}, year = {2019}, } @article{6262, abstract = {Gravitropism is an adaptive response that orients plant growth parallel to the gravity vector. Asymmetric distribution of the phytohormone auxin is a necessary prerequisite to the tropic bending both in roots and shoots. During hypocotyl gravitropic response, the PIN3 auxin transporter polarizes within gravity-sensing cells to redirect intercellular auxin fluxes. First gravity-induced PIN3 polarization to the bottom cell mem- branes leads to the auxin accumulation at the lower side of the organ, initiating bending and, later, auxin feedback-mediated repolarization restores symmetric auxin distribution to terminate bending. Here, we per- formed a forward genetic screen to identify regulators of both PIN3 polarization events during gravitropic response. We searched for mutants with defective PIN3 polarizations based on easy-to-score morphological outputs of decreased or increased gravity-induced hypocotyl bending. We identified the number of hypocotyl reduced bending (hrb) and hypocotyl hyperbending (hhb) mutants, revealing that reduced bending corre- lated typically with defective gravity-induced PIN3 relocation whereas all analyzed hhb mutants showed defects in the second, auxin-mediated PIN3 relocation. Next-generation sequencing-aided mutation map- ping identified several candidate genes, including SCARECROW and ACTIN2, revealing roles of endodermis specification and actin cytoskeleton in the respective gravity- and auxin-induced PIN polarization events. The hypocotyl gravitropism screen thus promises to provide novel insights into mechanisms underlying cell polarity and plant adaptive development.}, author = {Rakusová, Hana and Han, Huibin and Valošek, Petr and Friml, Jiří}, issn = {1365-313x}, journal = {The Plant Journal}, number = {6}, pages = {1048--1059}, publisher = {Wiley}, title = {{Genetic screen for factors mediating PIN polarization in gravistimulated Arabidopsis thaliana hypocotyls}}, doi = {10.1111/tpj.14301}, volume = {98}, year = {2019}, } @article{6297, abstract = {Cell-cell and cell-glycocalyx interactions under flow are important for the behaviour of circulating cells in blood and lymphatic vessels. However, such interactions are not well understood due in part to a lack of tools to study them in defined environments. Here, we develop a versatile in vitro platform for the study of cell-glycocalyx interactions in well-defined physical and chemical settings under flow. Our approach is demonstrated with the interaction between hyaluronan (HA, a key component of the endothelial glycocalyx) and its cell receptor CD44. We generate HA brushes in situ within a microfluidic device, and demonstrate the tuning of their physical (thickness and softness) and chemical (density of CD44 binding sites) properties using characterisation with reflection interference contrast microscopy (RICM) and application of polymer theory. We highlight the interactions of HA brushes with CD44-displaying beads and cells under flow. Observations of CD44+ beads on a HA brush with RICM enabled the 3-dimensional trajectories to be generated, and revealed interactions in the form of stop and go phases with reduced rolling velocity and reduced distance between the bead and the HA brush, compared to uncoated beads. Combined RICM and bright-field microscopy of CD44+ AKR1 T-lymphocytes revealed complementary information about the dynamics of cell rolling and cell morphology, and highlighted the formation of tethers and slings, as they interacted with a HA brush under flow. This platform can readily incorporate more complex models of the glycocalyx, and should permit the study of how mechanical and biochemical factors are orchestrated to enable highly selective blood cell-vessel wall interactions under flow.}, author = {Davies, Heather S. and Baranova, Natalia S. and El Amri, Nouha and Coche-Guérente, Liliane and Verdier, Claude and Bureau, Lionel and Richter, Ralf P. and Débarre, Delphine}, issn = {0945-053X}, journal = {Matrix Biology}, pages = {47--59}, publisher = {Elsevier}, title = {{An integrated assay to probe endothelial glycocalyx-blood cell interactions under flow in mechanically and biochemically well-defined environments}}, doi = {10.1016/j.matbio.2018.12.002}, volume = {78-79}, year = {2019}, } @article{6310, abstract = {An asymptotic formula is established for the number of rational points of bounded anticanonical height which lie on a certain Zariskiopen subset of an arbitrary smooth biquadratic hypersurface in sufficiently many variables. The proof uses the Hardy–Littlewood circle method.}, author = {Browning, Timothy D and Hu, L.Q.}, issn = {10902082}, journal = {Advances in Mathematics}, pages = {920--940}, publisher = {Elsevier}, title = {{Counting rational points on biquadratic hypersurfaces}}, doi = {10.1016/j.aim.2019.04.031}, volume = {349}, year = {2019}, } @article{6261, abstract = {Nitrate regulation of root stem cell activity is auxin-dependent.}, author = {Wang, Y and Gong, Z and Friml, Jiří and Zhang, J}, issn = {1532-2548}, journal = {Plant Physiology}, number = {1}, pages = {22--25}, publisher = {ASPB}, title = {{Nitrate modulates the differentiation of root distal stem cells}}, doi = {10.1104/pp.18.01305}, volume = {180}, year = {2019}, } @article{6352, abstract = {Chronic overuse of common pharmaceuticals, e.g. acetaminophen (paracetamol), often leads to the development of acute liver failure (ALF). This study aimed to elucidate the effect of cultured mesenchymal stem cells (MSCs) proteome on the onset of liver damage and regeneration dynamics in animals with ALF induced by acetaminophen, to test the liver protective efficacy of MSCs proteome depending on the oxygen tension in cell culture, and to blueprint protein components responsible for the effect. Protein compositions prepared from MSCs cultured in mild hypoxic (5% and 10% O2) and normal (21% O2) conditions were used to treat ALF induced in mice by injection of acetaminophen. To test the effect of reduced oxygen tension in cell culture on resulting MSCs proteome content we applied a combination of high performance liquid chromatography and mass-spectrometry (LC–MS/MS) for the identification of proteins in lysates of MSCs cultured at different O2 levels. The treatment of acetaminophen-administered animals with proteins released from cultured MSCs resulted in the inhibition of inflammatory reactions in damaged liver; the area of hepatocyte necrosis being reduced in the first 24 h. Compositions obtained from MSCs cultured at lower O2 level were shown to be more potent than a composition prepared from normoxic cells. A comparative characterization of protein pattern and identification of individual components done by a cytokine assay and proteomics analysis of protein compositions revealed that even moderate hypoxia produces discrete changes in the expression of various subsets of proteins responsible for intracellular respiration and cell signaling. The application of proteins prepared from MSCs grown in vitro at reduced oxygen tension significantly accelerates healing process in damaged liver tissue. The proteomics data obtained for different preparations offer new information about the potential candidates in the MSCs protein repertoire sensitive to oxygen tension in culture medium, which can be involved in the generalized mechanisms the cells use to respond to acute liver failure.}, author = {Temnov, Andrey Alexandrovich and Rogov, Konstantin Arkadevich and Sklifas, Alla Nikolaevna and Klychnikova, Elena Valerievna and Hartl, Markus and Djinovic-Carugo, Kristina and Charnagalov, Alexej}, issn = {15734978}, journal = {Molecular Biology Reports}, publisher = {Springer}, title = {{Protective properties of the cultured stem cell proteome studied in an animal model of acetaminophen-induced acute liver failure}}, doi = {10.1007/s11033-019-04765-z}, year = {2019}, } @article{6348, abstract = {High-speed optical telecommunication is enabled by wavelength-division multiplexing, whereby hundreds of individually stabilized lasers encode information within a single-mode optical fibre. Higher bandwidths require higher total optical power, but the power sent into the fibre is limited by optical nonlinearities within the fibre, and energy consumption by the light sources starts to become a substantial cost factor1. Optical frequency combs have been suggested to remedy this problem by generating numerous discrete, equidistant laser lines within a monolithic device; however, at present their stability and coherence allow them to operate only within small parameter ranges2,3,4. Here we show that a broadband frequency comb realized through the electro-optic effect within a high-quality whispering-gallery-mode resonator can operate at low microwave and optical powers. Unlike the usual third-order Kerr nonlinear optical frequency combs, our combs rely on the second-order nonlinear effect, which is much more efficient. Our result uses a fixed microwave signal that is mixed with an optical-pump signal to generate a coherent frequency comb with a precisely determined carrier separation. The resonant enhancement enables us to work with microwave powers that are three orders of magnitude lower than those in commercially available devices. We emphasize the practical relevance of our results to high rates of data communication. To circumvent the limitations imposed by nonlinear effects in optical communication fibres, one has to solve two problems: to provide a compact and fully integrated, yet high-quality and coherent, frequency comb generator; and to calculate nonlinear signal propagation in real time5. We report a solution to the first problem.}, author = {Rueda Sanchez, Alfredo R and Sedlmeir, Florian and Kumari, Madhuri and Leuchs, Gerd and Schwefel, Harald G.L.}, issn = {14764687}, journal = {Nature}, number = {7752}, pages = {378--381}, publisher = {Springer Nature}, title = {{Resonant electro-optic frequency comb}}, doi = {10.1038/s41586-019-1110-x}, volume = {568}, year = {2019}, } @article{6338, abstract = {Hippocampal activity patterns representing movement trajectories are reactivated in immobility and sleep periods, a process associated with memory recall, consolidation, and decision making. It is thought that only fixed, behaviorally relevant patterns can be reactivated, which are stored across hippocampal synaptic connections. To test whether some generalized rules govern reactivation, we examined trajectory reactivation following non-stereotypical exploration of familiar open-field environments. We found that random trajectories of varying lengths and timescales were reactivated, resembling that of Brownian motion of particles. The animals’ behavioral trajectory did not follow Brownian diffusion demonstrating that the exact behavioral experience is not reactivated. Therefore, hippocampal circuits are able to generate random trajectories of any recently active map by following diffusion dynamics. This ability of hippocampal circuits to generate representations of all behavioral outcome combinations, experienced or not, may underlie a wide variety of hippocampal-dependent cognitive functions such as learning, generalization, and planning.}, author = {Stella, Federico and Baracskay, Peter and O'Neill, Joseph and Csicsvari, Jozsef L}, journal = {Neuron}, pages = {450--461}, publisher = {Elsevier}, title = {{Hippocampal reactivation of random trajectories resembling Brownian diffusion}}, doi = {10.1016/j.neuron.2019.01.052}, volume = {102}, year = {2019}, }