@article{943, abstract = {Like many developing tissues, the vertebrate neural tube is patterned by antiparallel morphogen gradients. To understand how these inputs are interpreted, we measured morphogen signaling and target gene expression in mouse embryos and chick ex vivo assays. From these data, we derived and validated a characteristic decoding map that relates morphogen input to the positional identity of neural progenitors. Analysis of the observed responses indicates that the underlying interpretation strategy minimizes patterning errors in response to the joint input of noisy opposing gradients. We reverse-engineered a transcriptional network that provides a mechanistic basis for the observed cell fate decisions and accounts for the precision and dynamics of pattern formation. Together, our data link opposing gradient dynamics in a growing tissue to precise pattern formation.}, author = {Zagórski, Marcin P and Tabata, Yoji and Brandenberg, Nathalie and Lutolf, Matthias and Tkacik, Gasper and Bollenbach, Tobias and Briscoe, James and Kicheva, Anna}, issn = {00368075}, journal = {Science}, number = {6345}, pages = {1379 -- 1383}, publisher = {American Association for the Advancement of Science}, title = {{Decoding of position in the developing neural tube from antiparallel morphogen gradients}}, doi = {10.1126/science.aam5887}, volume = {356}, year = {2017}, } @article{944, abstract = {The concerted production of neurons and glia by neural stem cells (NSCs) is essential for neural circuit assembly. In the developing cerebral cortex, radial glia progenitors (RGPs) generate nearly all neocortical neurons and certain glia lineages. RGP proliferation behavior shows a high degree of non-stochasticity, thus a deterministic characteristic of neuron and glia production. However, the cellular and molecular mechanisms controlling RGP behavior and proliferation dynamics in neurogenesis and glia generation remain unknown. By using mosaic analysis with double markers (MADM)-based genetic paradigms enabling the sparse and global knockout with unprecedented single-cell resolution, we identified Lgl1 as a critical regulatory component. We uncover Lgl1-dependent tissue-wide community effects required for embryonic cortical neurogenesis and novel cell-autonomous Lgl1 functions controlling RGP-mediated glia genesis and postnatal NSC behavior. These results suggest that NSC-mediated neuron and glia production is tightly regulated through the concerted interplay of sequential Lgl1-dependent global and cell intrinsic mechanisms.}, author = {Beattie, Robert J and Postiglione, Maria P and Burnett, Laura and Laukoter, Susanne and Streicher, Carmen and Pauler, Florian and Xiao, Guanxi and Klezovitch, Olga and Vasioukhin, Valeri and Ghashghaei, Troy and Hippenmeyer, Simon}, issn = {08966273}, journal = {Neuron}, number = {3}, pages = {517 -- 533.e3}, publisher = {Cell Press}, title = {{Mosaic analysis with double markers reveals distinct sequential functions of Lgl1 in neural stem cells}}, doi = {10.1016/j.neuron.2017.04.012}, volume = {94}, year = {2017}, } @inproceedings{942, abstract = {A notable class of techniques for automatic program repair is known as semantics-based. Such techniques, e.g., Angelix, infer semantic specifications via symbolic execution, and then use program synthesis to construct new code that satisfies those inferred specifications. However, the obtained specifications are naturally incomplete, leaving the synthesis engine with a difficult task of synthesizing a general solution from a sparse space of many possible solutions that are consistent with the provided specifications but that do not necessarily generalize. We present S3, a new repair synthesis engine that leverages programming-by-examples methodology to synthesize high-quality bug repairs. The novelty in S3 that allows it to tackle the sparse search space to create more general repairs is three-fold: (1) A systematic way to customize and constrain the syntactic search space via a domain-specific language, (2) An efficient enumeration-based search strategy over the constrained search space, and (3) A number of ranking features based on measures of the syntactic and semantic distances between candidate solutions and the original buggy program. We compare S3’s repair effectiveness with state-of-the-art synthesis engines Angelix, Enumerative, and CVC4. S3 can successfully and correctly fix at least three times more bugs than the best baseline on datasets of 52 bugs in small programs, and 100 bugs in real-world large programs. }, author = {Le, Xuan and Chu, Duc Hiep and Lo, David and Le Goues, Claire and Visser, Willem}, isbn = {978-145035105-8}, location = {Paderborn, Germany}, pages = {593 -- 604}, publisher = {ACM}, title = {{S3: Syntax- and semantic-guided repair synthesis via programming by examples}}, doi = {10.1145/3106237.3106309}, volume = {F130154}, year = {2017}, } @article{939, abstract = {We reveal the existence of continuous families of guided single-mode solitons in planar waveguides with weakly nonlinear active core and absorbing boundaries. Stable propagation of TE and TM-polarized solitons is accompanied by attenuation of all other modes, i.e., the waveguide features properties of conservative and dissipative systems. If the linear spectrum of the waveguide possesses exceptional points, which occurs in the case of TM polarization, an originally focusing (defocusing) material nonlinearity may become effectively defocusing (focusing). This occurs due to the geometric phase of the carried eigenmode when the surface impedance encircles the exceptional point. In its turn, the change of the effective nonlinearity ensures the existence of dark (bright) solitons in spite of focusing (defocusing) Kerr nonlinearity of the core. The existence of an exceptional point can also result in anomalous enhancement of the effective nonlinearity. In terms of practical applications, the nonlinearity of the reported waveguide can be manipulated by controlling the properties of the absorbing cladding.}, author = {Midya, Bikashkali and Konotop, Vladimir}, issn = {00319007}, journal = {Physical Review Letters}, number = {3}, publisher = {American Physical Society}, title = {{Waveguides with absorbing boundaries: Nonlinearity controlled by an exceptional point and solitons}}, doi = {10.1103/PhysRevLett.119.033905}, volume = {119}, year = {2017}, } @misc{9853, abstract = {Egg laying rates and infection loads of C. obscurior queens}, author = {Giehr, Julia and Grasse, Anna V and Cremer, Sylvia and Heinze, Jürgen and Schrempf, Alexandra}, publisher = {The Royal Society}, title = {{Raw data from ant queens increase their reproductive efforts after pathogen infection}}, doi = {10.6084/m9.figshare.5117788.v1}, year = {2017}, } @article{822, abstract = {Polymicrobial infections constitute small ecosystems that accommodate several bacterial species. Commonly, these bacteria are investigated in isolation. However, it is unknown to what extent the isolates interact and whether their interactions alter bacterial growth and ecosystem resilience in the presence and absence of antibiotics. We quantified the complete ecological interaction network for 72 bacterial isolates collected from 23 individuals diagnosed with polymicrobial urinary tract infections and found that most interactions cluster based on evolutionary relatedness. Statistical network analysis revealed that competitive and cooperative reciprocal interactions are enriched in the global network, while cooperative interactions are depleted in the individual host community networks. A population dynamics model parameterized by our measurements suggests that interactions restrict community stability, explaining the observed species diversity of these communities. We further show that the clinical isolates frequently protect each other from clinically relevant antibiotics. Together, these results highlight that ecological interactions are crucial for the growth and survival of bacteria in polymicrobial infection communities and affect their assembly and resilience. }, author = {De Vos, Marjon and Zagórski, Marcin P and Mcnally, Alan and Bollenbach, Mark Tobias}, issn = {00278424}, journal = {PNAS}, number = {40}, pages = {10666 -- 10671}, publisher = {National Academy of Sciences}, title = {{Interaction networks, ecological stability, and collective antibiotic tolerance in polymicrobial infections}}, doi = {10.1073/pnas.1713372114}, volume = {114}, year = {2017}, } @inproceedings{833, abstract = {We present an efficient algorithm to compute Euler characteristic curves of gray scale images of arbitrary dimension. In various applications the Euler characteristic curve is used as a descriptor of an image. Our algorithm is the first streaming algorithm for Euler characteristic curves. The usage of streaming removes the necessity to store the entire image in RAM. Experiments show that our implementation handles terabyte scale images on commodity hardware. Due to lock-free parallelism, it scales well with the number of processor cores. Additionally, we put the concept of the Euler characteristic curve in the wider context of computational topology. In particular, we explain the connection with persistence diagrams.}, author = {Heiss, Teresa and Wagner, Hubert}, editor = {Felsberg, Michael and Heyden, Anders and Krüger, Norbert}, issn = {03029743}, location = {Ystad, Sweden}, pages = {397 -- 409}, publisher = {Springer}, title = {{Streaming algorithm for Euler characteristic curves of multidimensional images}}, doi = {10.1007/978-3-319-64689-3_32}, volume = {10424}, year = {2017}, } @article{805, abstract = {During corticogenesis, distinct classes of neurons are born from progenitor cells located in the ventricular and subventricular zones, from where they migrate towards the pial surface to assemble into highly organized layer-specific circuits. However, the precise and coordinated transcriptional network activity defining neuronal identity is still not understood. Here, we show that genetic depletion of the basic helix-loop-helix (bHLH) transcription factor E2A splice variant E47 increased the number of Tbr1-positive deep layer and Satb2-positive upper layer neurons at E14.5, while depletion of the alternatively spliced E12 variant did not affect layer-specific neurogenesis. While ChIP-Seq identified a big overlap for E12- and E47-specific binding sites in embryonic NSCs, including sites at the cyclin-dependent kinase inhibitor (CDKI) Cdkn1c gene locus, RNA-Seq revealed a unique transcriptional regulation by each splice variant. E47 activated the expression of the CDKI Cdkn1c through binding to a distal enhancer. Finally, overexpression of E47 in embryonic NSCs in vitro impaired neurite outgrowth and E47 overexpression in vivo by in utero electroporation disturbed proper layer-specific neurogenesis and upregulated p57(KIP2) expression. Overall, this study identified E2A target genes in embryonic NSCs and demonstrates that E47 regulates neuronal differentiation via p57(KIP2).}, author = {Pfurr, Sabrina and Chu, Yu and Bohrer, Christian and Greulich, Franziska and Beattie, Robert J and Mammadzada, Könül and Hils, Miriam and Arnold, Sebastian and Taylor, Verdon and Schachtrup, Kristina and Uhlenhaut, N Henriette and Schachtrup, Christian}, journal = {Development}, pages = {3917 -- 3931}, publisher = {Company of Biologists}, title = {{The E2A splice variant E47 regulates the differentiation of projection neurons via p57(KIP2) during cortical development}}, doi = {10.1242/dev.145698}, volume = {144}, year = {2017}, } @article{834, abstract = {Thermal and many-body localized phases are separated by a dynamical phase transition of a new kind. We analyze the distribution of off-diagonal matrix elements of local operators across this transition in two different models of disordered spin chains. We show that the behavior of matrix elements can be used to characterize the breakdown of thermalization and to extract the many-body Thouless energy. We find that upon increasing the disorder strength the system enters a critical region around the many-body localization transition. The properties of the system in this region are: (i) the Thouless energy becomes smaller than the level spacing, (ii) the matrix elements show critical dependence on the energy difference, and (iii) the matrix elements, viewed as amplitudes of a fictitious wave function, exhibit strong multifractality. This critical region decreases with the system size, which we interpret as evidence for a diverging correlation length at the many-body localization transition. Our findings show that the correlation length becomes larger than the accessible system sizes in a broad range of disorder strength values and shed light on the critical behavior near the many-body localization transition.}, author = {Serbyn, Maksym and Zlatko, Papic and Abanin, Dmitry}, issn = {24699950}, journal = {Physical Review B - Condensed Matter and Materials Physics}, number = {10}, publisher = {American Physical Society}, title = {{Thouless energy and multifractality across the many-body localization transition}}, doi = {10.1103/PhysRevB.96.104201}, volume = {96}, year = {2017}, } @article{823, abstract = {The resolution of a linear system with positive integer variables is a basic yet difficult computational problem with many applications. We consider sparse uncorrelated random systems parametrised by the density c and the ratio α=N/M between number of variables N and number of constraints M. By means of ensemble calculations we show that the space of feasible solutions endows a Van-Der-Waals phase diagram in the plane (c, α). We give numerical evidence that the associated computational problems become more difficult across the critical point and in particular in the coexistence region.}, author = {Colabrese, Simona and De Martino, Daniele and Leuzzi, Luca and Marinari, Enzo}, issn = {17425468}, journal = { Journal of Statistical Mechanics: Theory and Experiment}, number = {9}, publisher = {IOPscience}, title = {{Phase transitions in integer linear problems}}, doi = {10.1088/1742-5468/aa85c3}, volume = {2017}, year = {2017}, } @article{824, abstract = {In shear flows at transitional Reynolds numbers, localized patches of turbulence, known as puffs, coexist with the laminar flow. Recently, Avila et al. (Phys. Rev. Lett., vol. 110, 2013, 224502) discovered two spatially localized relative periodic solutions for pipe flow, which appeared in a saddle-node bifurcation at low Reynolds number. Combining slicing methods for continuous symmetry reduction with Poincaré sections for the first time in a shear flow setting, we compute and visualize the unstable manifold of the lower-branch solution and show that it extends towards the neighbourhood of the upper-branch solution. Surprisingly, this connection even persists far above the bifurcation point and appears to mediate the first stage of the puff generation: amplification of streamwise localized fluctuations. When the state-space trajectories on the unstable manifold reach the vicinity of the upper branch, corresponding fluctuations expand in space and eventually take the usual shape of a puff.}, author = {Budanur, Nazmi B and Hof, Björn}, issn = {00221120}, journal = {Journal of Fluid Mechanics}, publisher = {Cambridge University Press}, title = {{Heteroclinic path to spatially localized chaos in pipe flow}}, doi = {10.1017/jfm.2017.516}, volume = {827}, year = {2017}, } @article{799, abstract = {Membrane traffic at the trans-Golgi network (TGN) is crucial for correctly distributing various membrane proteins to their destination. Polarly localized auxin efflux proteins, including PIN-FORMED1 (PIN1), are dynamically transported between the endosomes and the plasma membrane (PM) in the plant cells. The intracellular trafficking of PIN1 protein is sensitive to a fungal toxin brefeldin A (BFA), which is known to inhibit guanine-nucleotide exchange factors for ADP ribosylation factors (ARF GEFs) such as GNOM. However, the molecular details of the BFA-sensitive trafficking pathway have not been revealed fully. In a previous study, we have identified an Arabidopsis mutant BFA-visualized endocytic trafficking defective 3 (ben3) which exhibited reduced sensitivity to BFA in terms of BFA-induced intracellular PIN1 agglomeration. Here, we show that BEN3 encodes a member of BIG family ARF GEFs, BIG2. Fluorescent proteins tagged BEN3/BIG2 co-localized with markers for TGN / early endosome (EE). Inspection of conditionally induced de novo synthesized PIN1 confirmed that its secretion to the PM is BFA-sensitive and established BEN3/BIG2 as a crucial component of this BFA action at the level of TGN/EE. Furthermore, ben3 mutation alleviated BFA-induced agglomeration of another TGN-localized ARF GEF BEN1/MIN7. Taken together our results suggest that BEN3/BIG2 is an ARF GEF component, which confers BFA sensitivity to the TGN/EE in Arabidopsis.}, author = {Kitakura, Saeko and Adamowski, Maciek and Matsuura, Yuki and Santuari, Luca and Kouno, Hirotaka and Arima, Kohei and Hardtke, Christian and Friml, Jirí and Kakimoto, Tatsuo and Tanaka, Hirokazu}, issn = {00320781}, journal = {Plant and Cell Physiology}, number = {10}, publisher = {Oxford University Press}, title = {{BEN3/BIG2 ARF GEF is involved in brefeldin a-sensitive trafficking at the trans-Golgi network/early endosome in Arabidopsis thaliana}}, doi = {10.1093/pcp/pcx118}, volume = {58}, year = {2017}, } @article{800, abstract = {Gamma oscillations (30–150 Hz) in neuronal networks are associated with the processing and recall of information. We measured local field potentials in the dentate gyrus of freely moving mice and found that gamma activity occurs in bursts, which are highly heterogeneous in their spatial extensions, ranging from focal to global coherent events. Synaptic communication among perisomatic-inhibitory interneurons (PIIs) is thought to play an important role in the generation of hippocampal gamma patterns. However, how neuronal circuits can generate synchronous oscillations at different spatial scales is unknown. We analyzed paired recordings in dentate gyrus slices and show that synaptic signaling at interneuron-interneuron synapses is distance dependent. Synaptic strength declines whereas the duration of inhibitory signals increases with axonal distance among interconnected PIIs. Using neuronal network modeling, we show that distance-dependent inhibition generates multiple highly synchronous focal gamma bursts allowing the network to process complex inputs in parallel in flexibly organized neuronal centers.}, author = {Strüber, Michael and Sauer, Jonas and Jonas, Peter M and Bartos, Marlene}, issn = {20411723}, journal = {Nature Communications}, number = {1}, publisher = {Nature Publishing Group}, title = {{Distance-dependent inhibition facilitates focality of gamma oscillations in the dentate gyrus}}, doi = {10.1038/s41467-017-00936-3}, volume = {8}, year = {2017}, } @article{803, abstract = {Eukaryotic cells store their chromosomes in a single nucleus. This is important to maintain genomic integrity, as chromosomes packaged into separate nuclei (micronuclei) are prone to massive DNA damage. During mitosis, higher eukaryotes disassemble their nucleus and release individualized chromosomes for segregation. How numerous chromosomes subsequently reform a single nucleus has remained unclear. Using image-based screening of human cells, we identified barrier-to-autointegration factor (BAF) as a key factor guiding membranes to form a single nucleus. Unexpectedly, nuclear assembly does not require BAF?s association with inner nuclear membrane proteins but instead relies on BAF?s ability to bridge distant DNA sites. Live-cell imaging and in vitro reconstitution showed that BAF enriches around the mitotic chromosome ensemble to induce a densely cross-bridged chromatin layer that is mechanically stiff and limits membranes to the surface. Our study reveals that BAF-mediated changes in chromosome mechanics underlie nuclear assembly with broad implications for proper genome function.}, author = {Samwer, Matthias and Schneider, Maximilian and Hoefler, Rudolf and Schmalhorst, Philipp S and Jude, Julian and Zuber, Johannes and Gerlic, Daniel}, issn = {00928674}, journal = {Cell}, number = {5}, pages = {956 -- 972}, publisher = {Cell Press}, title = {{DNA cross-bridging shapes a single nucleus from a set of mitotic chromosomes}}, doi = {10.1016/j.cell.2017.07.038}, volume = {170}, year = {2017}, } @article{804, abstract = {Polysaccharides (carbohydrates) are key regulators of a large number of cell biological processes. However, precise biochemical or genetic manipulation of these often complex structures is laborious and hampers experimental structure–function studies. Molecular Dynamics (MD) simulations provide a valuable alternative tool to generate and test hypotheses on saccharide function. Yet, currently used MD force fields often overestimate the aggregation propensity of polysaccharides, affecting the usability of those simulations. Here we tested MARTINI, a popular coarse-grained (CG) force field for biological macromolecules, for its ability to accurately represent molecular forces between saccharides. To this end, we calculated a thermodynamic solution property, the second virial coefficient of the osmotic pressure (B22). Comparison with light scattering experiments revealed a nonphysical aggregation of a prototypical polysaccharide in MARTINI, pointing at an imbalance of the nonbonded solute–solute, solute–water, and water–water interactions. This finding also applies to smaller oligosaccharides which were all found to aggregate in simulations even at moderate concentrations, well below their solubility limit. Finally, we explored the influence of the Lennard-Jones (LJ) interaction between saccharide molecules and propose a simple scaling of the LJ interaction strength that makes MARTINI more reliable for the simulation of saccharides.}, author = {Schmalhorst, Philipp S and Deluweit, Felix and Scherrers, Roger and Heisenberg, Carl-Philipp J and Sikora, Mateusz K}, issn = {15499618}, journal = {Journal of Chemical Theory and Computation}, number = {10}, pages = {5039 -- 5053}, publisher = {American Chemical Society}, title = {{Overcoming the limitations of the MARTINI force field in simulations of polysaccharides}}, doi = {10.1021/acs.jctc.7b00374}, volume = {13}, year = {2017}, } @article{746, abstract = {Metabotropic glutamate receptor subtype 5 (mGluR5) is crucially implicated in the pathophysiology of Fragile X Syndrome (FXS); however, its dysfunction at the sub-cellular level, and related synaptic and cognitive phenotypes are unexplored. Here, we probed the consequences of mGluR5/Homer scaffold disruption for mGluR5 cell-surface mobility, synaptic N-methyl-D-Aspartate receptor (NMDAR) function, and behavioral phenotypes in the second-generation Fmr1 knockout (KO) mouse. Using single-molecule tracking, we found that mGluR5 was significantly more mobile at synapses in hippocampal Fmr1 KO neurons, causing an increased synaptic surface co-clustering of mGluR5 and NMDAR. This correlated with a reduced amplitude of synaptic NMDAR currents, a lack of their mGluR5-Activated long-Term depression, and NMDAR/hippocampus dependent cognitive deficits. These synaptic and behavioral phenomena were reversed by knocking down Homer1a in Fmr1 KO mice. Our study provides a mechanistic link between changes of mGluR5 dynamics and pathological phenotypes of FXS, unveiling novel targets for mGluR5-based therapeutics.}, author = {Aloisi, Elisabetta and Le Corf, Katy and Dupuis, Julien and Zhang, Pei and Ginger, Melanie and Labrousse, Virginie and Spatuzza, Michela and Georg Haberl, Matthias and Costa, Lara and Shigemoto, Ryuichi and Tappe Theodor, Anke and Drago, Fillippo and Vincenzo Piazza, Pier and Mulle, Christophe and Groc, Laurent and Ciranna, Lucia and Catania, Maria and Frick, Andreas}, issn = {20411723}, journal = {Nature Communications}, number = {1}, publisher = {Nature Publishing Group}, title = {{Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice}}, doi = {10.1038/s41467-017-01191-2}, volume = {8}, year = {2017}, } @article{749, abstract = {Synaptotagmin 7 (Syt7) is thought to be a Ca2+ sensor that mediates asynchronous transmitter release and facilitation at synapses. However, Syt7 is strongly expressed in fast-spiking, parvalbumin-expressing GABAergic interneurons, and the output synapses of these neurons produce only minimal asynchronous release and show depression rather than facilitation. To resolve this apparent contradiction, we examined the effects of genetic elimination of Syt7 on synaptic transmission at the GABAergic basket cell (BC)-Purkinje cell (PC) synapse in cerebellum. Our results indicate that at the BC-PC synapse, Syt7 contributes to asynchronous release, pool replenishment, and facilitation. In combination, these three effects ensure efficient transmitter release during high-frequency activity and guarantee frequency independence of inhibition. Our results identify a distinct function of Syt7: ensuring the efficiency of high-frequency inhibitory synaptic transmission}, author = {Chen, Chong and Satterfield, Rachel and Young, Samuel and Jonas, Peter M}, issn = {22111247}, journal = {Cell Reports}, number = {8}, pages = {2082 -- 2089}, publisher = {Cell Press}, title = {{Triple function of Synaptotagmin 7 ensures efficiency of high-frequency transmission at central GABAergic synapses}}, doi = {10.1016/j.celrep.2017.10.122}, volume = {21}, year = {2017}, } @article{744, abstract = {In evolutionary game theory interactions between individuals are often assumed obligatory. However, in many real-life situations, individuals can decide to opt out of an interaction depending on the information they have about the opponent. We consider a simple evolutionary game theoretic model to study such a scenario, where at each encounter between two individuals the type of the opponent (cooperator/defector) is known with some probability, and where each individual either accepts or opts out of the interaction. If the type of the opponent is unknown, a trustful individual accepts the interaction, whereas a suspicious individual opts out of the interaction. If either of the two individuals opt out both individuals remain without an interaction. We show that in the prisoners dilemma optional interactions along with suspicious behaviour facilitates the emergence of trustful cooperation.}, author = {Priklopil, Tadeas and Chatterjee, Krishnendu and Nowak, Martin}, issn = {00225193}, journal = { Journal of Theoretical Biology}, pages = {64 -- 72}, publisher = {Elsevier}, title = {{Optional interactions and suspicious behaviour facilitates trustful cooperation in prisoners dilemma}}, doi = {10.1016/j.jtbi.2017.08.025}, volume = {433}, year = {2017}, } @article{745, abstract = {Fluid flows in nature and applications are frequently subject to periodic velocity modulations. Surprisingly, even for the generic case of flow through a straight pipe, there is little consensus regarding the influence of pulsation on the transition threshold to turbulence: while most studies predict a monotonically increasing threshold with pulsation frequency (i.e. Womersley number, ), others observe a decreasing threshold for identical parameters and only observe an increasing threshold at low . In the present study we apply recent advances in the understanding of transition in steady shear flows to pulsating pipe flow. For moderate pulsation amplitudes we find that the first instability encountered is subcritical (i.e. requiring finite amplitude disturbances) and gives rise to localized patches of turbulence ('puffs') analogous to steady pipe flow. By monitoring the impact of pulsation on the lifetime of turbulence we map the onset of turbulence in parameter space. Transition in pulsatile flow can be separated into three regimes. At small Womersley numbers the dynamics is dominated by the decay turbulence suffers during the slower part of the cycle and hence transition is delayed significantly. As shown in this regime thresholds closely agree with estimates based on a quasi-steady flow assumption only taking puff decay rates into account. The transition point predicted in the zero limit equals to the critical point for steady pipe flow offset by the oscillation Reynolds number (i.e. the dimensionless oscillation amplitude). In the high frequency limit on the other hand, puff lifetimes are identical to those in steady pipe flow and hence the transition threshold appears to be unaffected by flow pulsation. In the intermediate frequency regime the transition threshold sharply drops (with increasing ) from the decay dominated (quasi-steady) threshold to the steady pipe flow level.}, author = {Xu, Duo and Warnecke, Sascha and Song, Baofang and Ma, Xingyu and Hof, Björn}, issn = {00221120}, journal = {Journal of Fluid Mechanics}, pages = {418 -- 432}, publisher = {Cambridge University Press}, title = {{Transition to turbulence in pulsating pipe flow}}, doi = {10.1017/jfm.2017.620}, volume = {831}, year = {2017}, } @article{747, abstract = {Bradykinin (BK), a component of the kallikrein-kininogen-kinin system exerts multiple effects via B1 and B2 receptor activation. In the cardiovascular system, bradykinin has cardioprotective and vasodilator properties. We investigated the effect of BK on cardiac-projecting neurons of nucleus ambiguus, a key site for the parasympathetic cardiac regulation. BK produced a dose-dependent increase in cytosolic Ca2+ concentration. Pretreatment with HOE140, a B2 receptor antagonist, but not with R715, a B1 receptor antagonist, abolished the response to BK. A selective B2 receptor agonist, but not a B1 receptor agonist, elicited an increase in cytosolic Ca2+ similarly to BK. Inhibition of N-type voltage-gated Ca2+ channels with ω-conotoxin GVIA had no effect on the Ca2+ signal produced by BK, while pretreatment with ω-conotoxin MVIIC, a blocker of P/Q-type of Ca2+ channels, significantly diminished the effect of BK. Pretreatment with xestospongin C and 2-aminoethoxydiphenyl borate, antagonists of inositol 1,4,5-trisphosphate receptors, abolished the response to BK. Inhibition of ryanodine receptors reduced the BK-induced Ca2+ increase, while disruption of lysosomal Ca2+ stores with bafilomycin A1 did not affect the response. BK produced a dose-dependent depolarization of nucleus ambiguus neurons, which was prevented by the B2 receptor antagonist. In vivo studies indicate that microinjection of BK into nucleus ambiguus elicited bradycardia in conscious rats via B2 receptors. In summary, in cardiac vagal neurons of nucleus ambiguus, BK activates B2 receptors promoting Ca2+ influx and Ca2+ release from endoplasmic reticulum, and membrane depolarization; these effects are translated in vivo by bradycardia.}, author = {Brǎiloiu, Eugen and Mcguire, Matthew and Shuler, Shadaria and Deliu, Elena and Barr, Jeffrey and Abood, Mary and Brailoiu, Gabriela}, issn = {03064522}, journal = {Neuroscience}, pages = {23 -- 32}, publisher = {Elsevier}, title = {{Modulation of cardiac vagal tone by bradykinin acting on nucleus ambiguus}}, doi = {10.1016/j.neuroscience.2017.09.034}, volume = {365}, year = {2017}, }