@article{159, abstract = {L-type Ca2+ channels (LTCCs) play a crucial role in excitation-contraction coupling and release of hormones from secretory cells. They are targets of antihypertensive and antiarrhythmic drugs such as diltiazem. Here, we present a photoswitchable diltiazem, FHU-779, which can be used to reversibly block endogenous LTCCs by light. FHU-779 is as potent as diltiazem and can be used to place pancreatic β-cell function and cardiac activity under optical control.}, author = {Fehrentz, Timm and Huber, Florian and Hartrampf, Nina and Bruegmann, Tobias and Frank, James and Fine, Nicholas and Malan, Daniela and Danzl, Johann G and Tikhonov, Denis and Sumser, Maritn and Sasse, Philipp and Hodson, David and Zhorov, Boris and Klocker, Nikolaj and Trauner, Dirk}, journal = {Nature Chemical Biology}, number = {8}, pages = {764 -- 767}, publisher = {Nature Publishing Group}, title = {{Optical control of L-type Ca2+ channels using a diltiazem photoswitch}}, doi = {10.1038/s41589-018-0090-8}, volume = {14}, year = {2018}, } @article{16, abstract = {We report quantitative evidence of mixing-layer elastic instability in a viscoelastic fluid flow between two widely spaced obstacles hindering a channel flow at Re 1 and Wi 1. Two mixing layers with nonuniform shear velocity profiles are formed in the region between the obstacles. The mixing-layer instability arises in the vicinity of an inflection point on the shear velocity profile with a steep variation in the elastic stress. The instability results in an intermittent appearance of small vortices in the mixing layers and an amplification of spatiotemporal averaged vorticity in the elastic turbulence regime. The latter is characterized through scaling of friction factor with Wi and both pressure and velocity spectra. Furthermore, the observations reported provide improved understanding of the stability of the mixing layer in a viscoelastic fluid at large elasticity, i.e., Wi 1 and Re 1 and oppose the current view of suppression of vorticity solely by polymer additives.}, author = {Varshney, Atul and Steinberg, Victor}, journal = {Physical Review Fluids}, number = {10}, publisher = {American Physical Society}, title = {{Mixing layer instability and vorticity amplification in a creeping viscoelastic flow}}, doi = {10.1103/PhysRevFluids.3.103303}, volume = {3}, year = {2018}, } @article{161, abstract = {Which properties of metabolic networks can be derived solely from stoichiometry? Predictive results have been obtained by flux balance analysis (FBA), by postulating that cells set metabolic fluxes to maximize growth rate. Here we consider a generalization of FBA to single-cell level using maximum entropy modeling, which we extend and test experimentally. Specifically, we define for Escherichia coli metabolism a flux distribution that yields the experimental growth rate: the model, containing FBA as a limit, provides a better match to measured fluxes and it makes a wide range of predictions: on flux variability, regulation, and correlations; on the relative importance of stoichiometry vs. optimization; on scaling relations for growth rate distributions. We validate the latter here with single-cell data at different sub-inhibitory antibiotic concentrations. The model quantifies growth optimization as emerging from the interplay of competitive dynamics in the population and regulation of metabolism at the level of single cells.}, author = {De Martino, Daniele and Mc, Andersson Anna and Bergmiller, Tobias and Guet, Calin C and Tkacik, Gasper}, journal = {Nature Communications}, number = {1}, publisher = {Springer Nature}, title = {{Statistical mechanics for metabolic networks during steady state growth}}, doi = {10.1038/s41467-018-05417-9}, volume = {9}, year = {2018}, } @article{162, abstract = {Facial shape is the basis for facial recognition and categorization. Facial features reflect the underlying geometry of the skeletal structures. Here, we reveal that cartilaginous nasal capsule (corresponding to upper jaw and face) is shaped by signals generated by neural structures: brain and olfactory epithelium. Brain-derived Sonic Hedgehog (SHH) enables the induction of nasal septum and posterior nasal capsule, whereas the formation of a capsule roof is controlled by signals from the olfactory epithelium. Unexpectedly, the cartilage of the nasal capsule turned out to be important for shaping membranous facial bones during development. This suggests that conserved neurosensory structures could benefit from protection and have evolved signals inducing cranial cartilages encasing them. Experiments with mutant mice revealed that the genomic regulatory regions controlling production of SHH in the nervous system contribute to facial cartilage morphogenesis, which might be a mechanism responsible for the adaptive evolution of animal faces and snouts.}, author = {Kaucka, Marketa and Petersen, Julian and Tesarova, Marketa and Szarowska, Bara and Kastriti, Maria and Xie, Meng and Kicheva, Anna and Annusver, Karl and Kasper, Maria and Symmons, Orsolya and Pan, Leslie and Spitz, Francois and Kaiser, Jozef and Hovorakova, Maria and Zikmund, Tomas and Sunadome, Kazunori and Matise, Michael P and Wang, Hui and Marklund, Ulrika and Abdo, Hind and Ernfors, Patrik and Maire, Pascal and Wurmser, Maud and Chagin, Andrei S and Fried, Kaj and Adameyko, Igor}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{Signals from the brain and olfactory epithelium control shaping of the mammalian nasal capsule cartilage}}, doi = {10.7554/eLife.34465}, volume = {7}, year = {2018}, } @article{163, abstract = {For ultrafast fixation of biological samples to avoid artifacts, high-pressure freezing (HPF) followed by freeze substitution (FS) is preferred over chemical fixation at room temperature. After HPF, samples are maintained at low temperature during dehydration and fixation, while avoiding damaging recrystallization. This is a notoriously slow process. McDonald and Webb demonstrated, in 2011, that sample agitation during FS dramatically reduces the necessary time. Then, in 2015, we (H.G. and S.R.) introduced an agitation module into the cryochamber of an automated FS unit and demonstrated that the preparation of algae could be shortened from days to a couple of hours. We argued that variability in the processing, reproducibility, and safety issues are better addressed using automated FS units. For dissemination, we started low-cost manufacturing of agitation modules for two of the most widely used FS units, the Automatic Freeze Substitution Systems, AFS(1) and AFS2, from Leica Microsystems, using three dimensional (3D)-printing of the major components. To test them, several labs independently used the modules on a wide variety of specimens that had previously been processed by manual agitation, or without agitation. We demonstrate that automated processing with sample agitation saves time, increases flexibility with respect to sample requirements and protocols, and produces data of at least as good quality as other approaches.}, author = {Reipert, Siegfried and Goldammer, Helmuth and Richardson, Christine and Goldberg, Martin and Hawkins, Timothy and Hollergschwandtner, Elena and Kaufmann, Walter and Antreich, Sebastian and Stierhof, York}, issn = {0022-1554}, journal = {Journal of Histochemistry and Cytochemistry}, number = {12}, pages = {903--921}, publisher = {SAGE Publications}, title = {{Agitation modules: Flexible means to accelerate automated freeze substitution}}, doi = {10.1369/0022155418786698}, volume = {66}, year = {2018}, } @article{17, abstract = {Creeping flow of polymeric fluid without inertia exhibits elastic instabilities and elastic turbulence accompanied by drag enhancement due to elastic stress produced by flow-stretched polymers. However, in inertia-dominated flow at high Re and low fluid elasticity El, a reduction in turbulent frictional drag is caused by an intricate competition between inertial and elastic stresses. Here we explore the effect of inertia on the stability of viscoelastic flow in a broad range of control parameters El and (Re,Wi). We present the stability diagram of observed flow regimes in Wi-Re coordinates and find that the instabilities' onsets show an unexpectedly nonmonotonic dependence on El. Further, three distinct regions in the diagram are identified based on El. Strikingly, for high-elasticity fluids we discover a complete relaminarization of flow at Reynolds number in the range of 1 to 10, different from a well-known turbulent drag reduction. These counterintuitive effects may be explained by a finite polymer extensibility and a suppression of vorticity at high Wi. Our results call for further theoretical and numerical development to uncover the role of inertial effect on elastic turbulence in a viscoelastic flow.}, author = {Varshney, Atul and Steinberg, Victor}, journal = {Physical Review Fluids}, number = {10}, publisher = {American Physical Society}, title = {{Drag enhancement and drag reduction in viscoelastic flow}}, doi = {10.1103/PhysRevFluids.3.103302}, volume = {3}, year = {2018}, } @inproceedings{78, abstract = {We provide a procedure for detecting the sub-segments of an incrementally observed Boolean signal ω that match a given temporal pattern ϕ. As a pattern specification language, we use timed regular expressions, a formalism well-suited for expressing properties of concurrent asynchronous behaviors embedded in metric time. We construct a timed automaton accepting the timed language denoted by ϕ and modify it slightly for the purpose of matching. We then apply zone-based reachability computation to this automaton while it reads ω, and retrieve all the matching segments from the results. Since the procedure is automaton based, it can be applied to patterns specified by other formalisms such as timed temporal logics reducible to timed automata or directly encoded as timed automata. The procedure has been implemented and its performance on synthetic examples is demonstrated.}, author = {Bakhirkin, Alexey and Ferrere, Thomas and Nickovic, Dejan and Maler, Oded and Asarin, Eugene}, isbn = {978-3-030-00150-6}, location = {Bejing, China}, pages = {215 -- 232}, publisher = {Springer}, title = {{Online timed pattern matching using automata}}, doi = {10.1007/978-3-030-00151-3_13}, volume = {11022}, year = {2018}, } @inproceedings{7812, abstract = {Deep neural networks (DNNs) continue to make significant advances, solving tasks from image classification to translation or reinforcement learning. One aspect of the field receiving considerable attention is efficiently executing deep models in resource-constrained environments, such as mobile or embedded devices. This paper focuses on this problem, and proposes two new compression methods, which jointly leverage weight quantization and distillation of larger teacher networks into smaller student networks. The first method we propose is called quantized distillation and leverages distillation during the training process, by incorporating distillation loss, expressed with respect to the teacher, into the training of a student network whose weights are quantized to a limited set of levels. The second method, differentiable quantization, optimizes the location of quantization points through stochastic gradient descent, to better fit the behavior of the teacher model. We validate both methods through experiments on convolutional and recurrent architectures. We show that quantized shallow students can reach similar accuracy levels to full-precision teacher models, while providing order of magnitude compression, and inference speedup that is linear in the depth reduction. In sum, our results enable DNNs for resource-constrained environments to leverage architecture and accuracy advances developed on more powerful devices.}, author = {Polino, Antonio and Pascanu, Razvan and Alistarh, Dan-Adrian}, booktitle = {6th International Conference on Learning Representations}, location = {Vancouver, Canada}, title = {{Model compression via distillation and quantization}}, year = {2018}, } @inproceedings{79, abstract = {Markov Decision Processes (MDPs) are a popular class of models suitable for solving control decision problems in probabilistic reactive systems. We consider parametric MDPs (pMDPs) that include parameters in some of the transition probabilities to account for stochastic uncertainties of the environment such as noise or input disturbances. We study pMDPs with reachability objectives where the parameter values are unknown and impossible to measure directly during execution, but there is a probability distribution known over the parameter values. We study for the first time computing parameter-independent strategies that are expectation optimal, i.e., optimize the expected reachability probability under the probability distribution over the parameters. We present an encoding of our problem to partially observable MDPs (POMDPs), i.e., a reduction of our problem to computing optimal strategies in POMDPs. We evaluate our method experimentally on several benchmarks: a motivating (repeated) learner model; a series of benchmarks of varying configurations of a robot moving on a grid; and a consensus protocol.}, author = {Arming, Sebastian and Bartocci, Ezio and Chatterjee, Krishnendu and Katoen, Joost P and Sokolova, Ana}, location = {Beijing, China}, pages = {53--70}, publisher = {Springer}, title = {{Parameter-independent strategies for pMDPs via POMDPs}}, doi = {10.1007/978-3-319-99154-2_4}, volume = {11024}, year = {2018}, } @inproceedings{81, abstract = {We solve the offline monitoring problem for timed propositional temporal logic (TPTL), interpreted over dense-time Boolean signals. The variant of TPTL we consider extends linear temporal logic (LTL) with clock variables and reset quantifiers, providing a mechanism to specify real-time constraints. We first describe a general monitoring algorithm based on an exhaustive computation of the set of satisfying clock assignments as a finite union of zones. We then propose a specialized monitoring algorithm for the one-variable case using a partition of the time domain based on the notion of region equivalence, whose complexity is linear in the length of the signal, thereby generalizing a known result regarding the monitoring of metric temporal logic (MTL). The region and zone representations of time constraints are known from timed automata verification and can also be used in the discrete-time case. Our prototype implementation appears to outperform previous discrete-time implementations of TPTL monitoring,}, author = {Elgyütt, Adrian and Ferrere, Thomas and Henzinger, Thomas A}, location = {Beijing, China}, pages = {53 -- 70}, publisher = {Springer}, title = {{Monitoring temporal logic with clock variables}}, doi = {10.1007/978-3-030-00151-3_4}, volume = {11022}, year = {2018}, } @article{82, abstract = {In experimental cultures, when bacteria are mixed with lytic (virulent) bacteriophage, bacterial cells resistant to the phage commonly emerge and become the dominant population of bacteria. Following the ascent of resistant mutants, the densities of bacteria in these simple communities become limited by resources rather than the phage. Despite the evolution of resistant hosts, upon which the phage cannot replicate, the lytic phage population is most commonly maintained in an apparently stable state with the resistant bacteria. Several mechanisms have been put forward to account for this result. Here we report the results of population dynamic/evolution experiments with a virulent mutant of phage Lambda, λVIR, and Escherichia coli in serial transfer cultures. We show that, following the ascent of λVIR-resistant bacteria, λVIRis maintained in the majority of cases in maltose-limited minimal media and in all cases in nutrient-rich broth. Using mathematical models and experiments, we show that the dominant mechanism responsible for maintenance of λVIRin these resource-limited populations dominated by resistant E. coli is a high rate of either phenotypic or genetic transition from resistance to susceptibility—a hitherto undemonstrated mechanism we term "leaky resistance." We discuss the implications of leaky resistance to our understanding of the conditions for the maintenance of phage in populations of bacteria—their “existence conditions.”.}, author = {Chaudhry, Waqas and Pleska, Maros and Shah, Nilang and Weiss, Howard and Mccall, Ingrid and Meyer, Justin and Gupta, Animesh and Guet, Calin C and Levin, Bruce}, journal = {PLoS Biology}, number = {8}, publisher = {Public Library of Science}, title = {{Leaky resistance and the conditions for the existence of lytic bacteriophage}}, doi = {10.1371/journal.pbio.2005971}, volume = {16}, year = {2018}, } @unpublished{8547, abstract = {The cerebral cortex contains multiple hierarchically organized areas with distinctive cytoarchitectonical patterns, but the cellular mechanisms underlying the emergence of this diversity remain unclear. Here, we have quantitatively investigated the neuronal output of individual progenitor cells in the ventricular zone of the developing mouse neocortex using a combination of methods that together circumvent the biases and limitations of individual approaches. We found that individual cortical progenitor cells show a high degree of stochasticity and generate pyramidal cell lineages that adopt a wide range of laminar configurations. Mathematical modelling these lineage data suggests that a small number of progenitor cell populations, each generating pyramidal cells following different stochastic developmental programs, suffice to generate the heterogenous complement of pyramidal cell lineages that collectively build the complex cytoarchitecture of the neocortex.}, author = {Llorca, Alfredo and Ciceri, Gabriele and Beattie, Robert J and Wong, Fong K. and Diana, Giovanni and Serafeimidou, Eleni and Fernández-Otero, Marian and Streicher, Carmen and Arnold, Sebastian J. and Meyer, Martin and Hippenmeyer, Simon and Maravall, Miguel and Marín, Oscar}, booktitle = {bioRxiv}, publisher = {Cold Spring Harbor Laboratory}, title = {{Heterogeneous progenitor cell behaviors underlie the assembly of neocortical cytoarchitecture}}, doi = {10.1101/494088}, year = {2018}, } @inbook{86, abstract = {Responsiveness—the requirement that every request to a system be eventually handled—is one of the fundamental liveness properties of a reactive system. Average response time is a quantitative measure for the responsiveness requirement used commonly in performance evaluation. We show how average response time can be computed on state-transition graphs, on Markov chains, and on game graphs. In all three cases, we give polynomial-time algorithms.}, author = {Chatterjee, Krishnendu and Henzinger, Thomas A and Otop, Jan}, booktitle = {Principles of Modeling}, editor = {Lohstroh, Marten and Derler, Patricia and Sirjani, Marjan}, pages = {143 -- 161}, publisher = {Springer}, title = {{Computing average response time}}, doi = {10.1007/978-3-319-95246-8_9}, volume = {10760}, year = {2018}, } @article{8618, abstract = {The reversibly switchable fluorescent proteins (RSFPs) commonly used for RESOLFT nanoscopy have been developed from fluorescent proteins of the GFP superfamily. These proteins are bright, but exhibit several drawbacks such as relatively large size, oxygen-dependence, sensitivity to low pH, and limited switching speed. Therefore, RSFPs from other origins with improved properties need to be explored. Here, we report the development of two RSFPs based on the LOV domain of the photoreceptor protein YtvA from Bacillus subtilis. LOV domains obtain their fluorescence by association with the abundant cellular cofactor flavin mononucleotide (FMN). Under illumination with blue and ultraviolet light, they undergo a photocycle, making these proteins inherently photoswitchable. Our first improved variant, rsLOV1, can be used for RESOLFT imaging, whereas rsLOV2 proved useful for STED nanoscopy of living cells with a resolution of down to 50 nm. In addition to their smaller size compared to GFP-related proteins (17 kDa instead of 27 kDa) and their usability at low pH, rsLOV1 and rsLOV2 exhibit faster switching kinetics, switching on and off 3 times faster than rsEGFP2, the fastest-switching RSFP reported to date. Therefore, LOV-domain-based RSFPs have potential for applications where the switching speed of GFP-based proteins is limiting.}, author = {Gregor, Carola and Sidenstein, Sven C. and Andresen, Martin and Sahl, Steffen J. and Danzl, Johann G and Hell, Stefan W.}, issn = {2045-2322}, journal = {Scientific Reports}, keywords = {Multidisciplinary}, publisher = {Springer Nature}, title = {{Novel reversibly switchable fluorescent proteins for RESOLFT and STED nanoscopy engineered from the bacterial photoreceptor YtvA}}, doi = {10.1038/s41598-018-19947-1}, volume = {8}, year = {2018}, } @article{913, abstract = {Coordinated cell polarization in developing tissues is a recurrent theme in multicellular organisms. In plants, a directional distribution of the plant hormone auxin is at the core of many developmental programs. A feedback regulation of auxin on the polarized localization of PIN auxin transporters in individual cells has been proposed as a self-organizing mechanism for coordinated tissue polarization, but the molecular mechanisms linking auxin signalling to PIN-dependent auxin transport remain unknown. We performed a microarray-based approach to find regulators of the auxin-induced PIN relocation in the Arabidopsis thaliana root. We identified a subset of a family of phosphatidylinositol transfer proteins (PITP), the PATELLINs (PATL). Here, we show that PATLs are expressed in partially overlapping cells types in different tissues going through mitosis or initiating differentiation programs. PATLs are plasma membrane-associated proteins accumulated in Arabidopsis embryos, primary roots, lateral root primordia, and developing stomata. Higher order patl mutants display reduced PIN1 repolarization in response to auxin, shorter root apical meristem, and drastic defects in embryo and seedling development. This suggests PATLs redundantly play a crucial role in polarity and patterning in Arabidopsis.}, author = {Tejos, Ricardo and Rodríguez Furlán, Cecilia and Adamowski, Maciek and Sauer, Michael and Norambuena, Lorena and Friml, Jirí}, issn = {0021-9533}, journal = {Journal of Cell Science}, number = {2}, publisher = {Company of Biologists}, title = {{PATELLINS are regulators of auxin mediated PIN1 relocation and plant development in Arabidopsis thaliana}}, doi = {10.1242/jcs.204198}, volume = {131}, year = {2018}, } @article{9229, author = {Danzl, Johann G}, issn = {2500-2295}, journal = {Opera Medica et Physiologica}, number = {S1}, pages = {11}, publisher = {Lobachevsky State University of Nizhny Novgorod}, title = {{Diffraction-unlimited optical imaging for synaptic physiology}}, doi = {10.20388/omp2018.00s1.001}, volume = {4}, year = {2018}, } @article{9471, abstract = {The DEMETER (DME) DNA glycosylase catalyzes genome-wide DNA demethylation and is required for endosperm genomic imprinting and embryo viability. Targets of DME-mediated DNA demethylation reside in small, euchromatic, AT-rich transposons and at the boundaries of large transposons, but how DME interacts with these diverse chromatin states is unknown. The STRUCTURE SPECIFIC RECOGNITION PROTEIN 1 (SSRP1) subunit of the chromatin remodeler FACT (facilitates chromatin transactions), was previously shown to be involved in the DME-dependent regulation of genomic imprinting in Arabidopsis endosperm. Therefore, to investigate the interaction between DME and chromatin, we focused on the activity of the two FACT subunits, SSRP1 and SUPPRESSOR of TY16 (SPT16), during reproduction in Arabidopsis. We found that FACT colocalizes with nuclear DME in vivo, and that DME has two classes of target sites, the first being euchromatic and accessible to DME, but the second, representing over half of DME targets, requiring the action of FACT for DME-mediated DNA demethylation genome-wide. Our results show that the FACT-dependent DME targets are GC-rich heterochromatin domains with high nucleosome occupancy enriched with H3K9me2 and H3K27me1. Further, we demonstrate that heterochromatin-associated linker histone H1 specifically mediates the requirement for FACT at a subset of DME-target loci. Overall, our results demonstrate that FACT is required for DME targeting by facilitating its access to heterochromatin.}, author = {Frost, Jennifer M. and Kim, M. Yvonne and Park, Guen Tae and Hsieh, Ping-Hung and Nakamura, Miyuki and Lin, Samuel J. H. and Yoo, Hyunjin and Choi, Jaemyung and Ikeda, Yoko and Kinoshita, Tetsu and Choi, Yeonhee and Zilberman, Daniel and Fischer, Robert L.}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences}, keywords = {Multidisciplinary}, number = {20}, pages = {E4720--E4729}, publisher = {National Academy of Sciences}, title = {{FACT complex is required for DNA demethylation at heterochromatin during reproduction in Arabidopsis}}, doi = {10.1073/pnas.1713333115}, volume = {115}, year = {2018}, } @misc{9807, abstract = {Table S1. Genes with highest betweenness. Table S2. Local and Master regulators up-regulated. Table S3. Local and Master regulators down-regulated (XLSX 23 kb).}, author = {Higareda Almaraz, Juan and Karbiener, Michael and Giroud, Maude and Pauler, Florian and Gerhalter, Teresa and Herzig, Stephan and Scheideler, Marcel}, publisher = {Springer Nature}, title = {{Additional file 1: Of Norepinephrine triggers an immediate-early regulatory network response in primary human white adipocytes}}, doi = {10.6084/m9.figshare.7295339.v1}, year = {2018}, } @misc{9808, abstract = {Table S4. Counts per Gene per Million Reads Mapped. (XLSX 2751 kb).}, author = {Higareda Almaraz, Juan and Karbiener, Michael and Giroud, Maude and Pauler, Florian and Gerhalter, Teresa and Herzig, Stephan and Scheideler, Marcel}, publisher = {Springer Nature}, title = {{Additional file 3: Of Norepinephrine triggers an immediate-early regulatory network response in primary human white adipocytes}}, doi = {10.6084/m9.figshare.7295369.v1}, year = {2018}, } @misc{9810, author = {Chaudhry, Waqas and Pleska, Maros and Shah, Nilang and Weiss, Howard and Mccall, Ingrid and Meyer, Justin and Gupta, Animesh and Guet, Calin C and Levin, Bruce}, publisher = {Public Library of Science}, title = {{Numerical data used in figures}}, doi = {10.1371/journal.pbio.2005971.s008}, year = {2018}, }