TY - JOUR
AB - The rare socially parasitic butterfly Maculinea alcon occurs in two forms, which are characteristic of hygric or xeric habitats and which exploit different host plants and host ants. The status of these two forms has been the subject of considerable controversy. Populations of the two forms are usually spatially distinct, but at Răscruci in Romania both forms occur on the same site (syntopically). We examined the genetic differentiation between the two forms using eight microsatellite markers, and compared with a nearby hygric site, Şardu. Our results showed that while the two forms are strongly differentiated at Răscruci, it is the xeric form there that is most similar to the hygric form at Şardu, and Bayesian clustering algorithms suggest that these two populations have exchanged genes relatively recently. We found strong evidence for population substructuring, caused by high within host ant nest relatedness, indicating very limited dispersal of most ovipositing females, but not association with particular host ant species. Our results are consistent with the results of larger scale phylogeographic studies that suggest that the two forms represent local ecotypes specialising on different host plants, each with a distinct flowering phenology, providing a temporal rather than spatial barrier to gene flow.
AU - Tartally, András
AU - Kelager, Andreas
AU - Fürst, Matthias
AU - Nash, David
ID - 1431
IS - 3
JF - PeerJ
TI - Host plant use drives genetic differentiation in syntopic populations of Maculinea alcon
VL - 2016
ER -
TY - JOUR
AB - We prove that the system of subordination equations, defining the free additive convolution of two probability measures, is stable away from the edges of the support and blow-up singularities by showing that the recent smoothness condition of Kargin is always satisfied. As an application, we consider the local spectral statistics of the random matrix ensemble A+UBU⁎A+UBU⁎, where U is a Haar distributed random unitary or orthogonal matrix, and A and B are deterministic matrices. In the bulk regime, we prove that the empirical spectral distribution of A+UBU⁎A+UBU⁎ concentrates around the free additive convolution of the spectral distributions of A and B on scales down to N−2/3N−2/3.
AU - Bao, Zhigang
AU - Erdös, László
AU - Schnelli, Kevin
ID - 1434
IS - 3
JF - Journal of Functional Analysis
TI - Local stability of the free additive convolution
VL - 271
ER -
TY - JOUR
AB - ATP released from neurons and astrocytes during neuronal activity or under pathophysiological circumstances is able to influence information flow in neuronal circuits by activation of ionotropic P2X and metabotropic P2Y receptors and subsequent modulation of cellular excitability, synaptic strength, and plasticity. In the present paper we review cellular and network effects of P2Y receptors in the brain. We show that P2Y receptors inhibit the release of neurotransmitters, modulate voltage- and ligand-gated ion channels, and differentially influence the induction of synaptic plasticity in the prefrontal cortex, hippocampus, and cerebellum. The findings discussed here may explain how P2Y1 receptor activation during brain injury, hypoxia, inflammation, schizophrenia, or Alzheimer's disease leads to an impairment of cognitive processes. Hence, it is suggested that the blockade of P2Y1 receptors may have therapeutic potential against cognitive disturbances in these states.
AU - Guzmán, José
AU - Gerevich, Zoltan
ID - 1435
JF - Neural Plasticity
TI - P2Y receptors in synaptic transmission and plasticity: Therapeutic potential in cognitive dysfunction
VL - 2016
ER -
TY - JOUR
AB - We study the time evolution of a system of N spinless fermions in R3 which interact through a pair potential, e.g., the Coulomb potential. We compare the dynamics given by the solution to Schrödinger's equation with the time-dependent Hartree-Fock approximation, and we give an estimate for the accuracy of this approximation in terms of the kinetic energy of the system. This leads, in turn, to bounds in terms of the initial total energy of the system.
AU - Bach, Volker
AU - Breteaux, Sébastien
AU - Petrat, Sören P
AU - Pickl, Peter
AU - Tzaneteas, Tim
ID - 1436
IS - 1
JF - Journal de Mathématiques Pures et Appliquées
TI - Kinetic energy estimates for the accuracy of the time-dependent Hartree-Fock approximation with Coulomb interaction
VL - 105
ER -
TY - CONF
AB - In this paper, we consider termination of probabilistic programs with real-valued variables. The questions concerned are: (a) qualitative ones that ask (i) whether the program terminates with probability 1 (almost-sure termination) and (ii) whether the expected termination time is finite (finite termination); (b) quantitative ones that ask (i) to approximate the expected termination time (expectation problem) and (ii) to compute a bound B such that the probability to terminate after B steps decreases exponentially (concentration problem). To solve these questions, we utilize the notion of ranking supermartingales which is a powerful approach for proving termination of probabilistic programs. In detail, we focus on algorithmic synthesis of linear ranking-supermartingales over affine probabilistic programs (APP's) with both angelic and demonic non-determinism. An important subclass of APP's is LRAPP which is defined as the class of all APP's over which a linear ranking-supermartingale exists. Our main contributions are as follows. Firstly, we show that the membership problem of LRAPP (i) can be decided in polynomial time for APP's with at most demonic non-determinism, and (ii) is NP-hard and in PSPACE for APP's with angelic non-determinism; moreover, the NP-hardness result holds already for APP's without probability and demonic non-determinism. Secondly, we show that the concentration problem over LRAPP can be solved in the same complexity as for the membership problem of LRAPP. Finally, we show that the expectation problem over LRAPP can be solved in 2EXPTIME and is PSPACE-hard even for APP's without probability and non-determinism (i.e., deterministic programs). Our experimental results demonstrate the effectiveness of our approach to answer the qualitative and quantitative questions over APP's with at most demonic non-determinism.
AU - Chatterjee, Krishnendu
AU - Fu, Hongfei
AU - Novotny, Petr
AU - Hasheminezhad, Rouzbeh
ID - 1438
TI - Algorithmic analysis of qualitative and quantitative termination problems for affine probabilistic programs
VL - 20-22
ER -
TY - CONF
AB - Fault-tolerant distributed algorithms play an important role in many critical/high-availability applications. These algorithms are notoriously difficult to implement correctly, due to asynchronous communication and the occurrence of faults, such as the network dropping messages or computers crashing. We introduce PSYNC, a domain specific language based on the Heard-Of model, which views asynchronous faulty systems as synchronous ones with an adversarial environment that simulates asynchrony and faults by dropping messages. We define a runtime system for PSYNC that efficiently executes on asynchronous networks. We formalize the relation between the runtime system and PSYNC in terms of observational refinement. The high-level lockstep abstraction introduced by PSYNC simplifies the design and implementation of fault-tolerant distributed algorithms and enables automated formal verification. We have implemented an embedding of PSYNC in the SCALA programming language with a runtime system for asynchronous networks. We show the applicability of PSYNC by implementing several important fault-tolerant distributed algorithms and we compare the implementation of consensus algorithms in PSYNC against implementations in other languages in terms of code size, runtime efficiency, and verification.
AU - Dragoi, Cezara
AU - Henzinger, Thomas A
AU - Zufferey, Damien
ID - 1439
TI - PSYNC: A partially synchronous language for fault-tolerant distributed algorithms
VL - 20-22
ER -
TY - JOUR
AU - Janovjak, Harald L
ID - 1440
IS - 2
JF - Structure
TI - Light at the end of the protein: Crystal structure of a C-terminal light-sensing domain
VL - 24
ER -
TY - JOUR
AB - Optogenetics and photopharmacology enable the spatio-temporal control of cell and animal behavior by light. Although red light offers deep-tissue penetration and minimal phototoxicity, very few red-light-sensitive optogenetic methods are currently available. We have now developed a red-light-induced homodimerization domain. We first showed that an optimized sensory domain of the cyanobacterial phytochrome 1 can be expressed robustly and without cytotoxicity in human cells. We then applied this domain to induce the dimerization of two receptor tyrosine kinases—the fibroblast growth factor receptor 1 and the neurotrophin receptor trkB. This new optogenetic method was then used to activate the MAPK/ERK pathway non-invasively in mammalian tissue and in multicolor cell-signaling experiments. The light-controlled dimerizer and red-light-activated receptor tyrosine kinases will prove useful to regulate a variety of cellular processes with light. Go deep with red: The sensory domain (S) of the cyanobacterial phytochrome 1 (CPH1) was repurposed to induce the homodimerization of proteins in living cells by red light. By using this domain, light-activated protein kinases were engineered that can be activated orthogonally from many fluorescent proteins and through mammalian tissue. Pr/Pfr=red-/far-red-absorbing state of CPH1.
AU - Gschaider-Reichhart, Eva
AU - Inglés Prieto, Álvaro
AU - Tichy, Alexandra-Madelaine
AU - Mckenzie, Catherine
AU - Janovjak, Harald L
ID - 1441
IS - 21
JF - Angewandte Chemie - International Edition
TI - A phytochrome sensory domain permits receptor activation by red light
VL - 55
ER -
TY - JOUR
AU - Calatrava Moreno, Maria
AU - Auzinger, Thomas
AU - Werthner, Hannes
ID - 1445
IS - 1
JF - Scientometrics
TI - Erratum to: On the uncertainty of interdisciplinarity measurements due to incomplete bibliographic data
VL - 107
ER -
TY - JOUR
AB - The accuracy of interdisciplinarity measurements is directly related to the quality of the underlying bibliographic data. Existing indicators of interdisciplinarity are not capable of reflecting the inaccuracies introduced by incorrect and incomplete records because correct and complete bibliographic data can rarely be obtained. This is the case for the Rao–Stirling index, which cannot handle references that are not categorized into disciplinary fields. We introduce a method that addresses this problem. It extends the Rao–Stirling index to acknowledge missing data by calculating its interval of uncertainty using computational optimization. The evaluation of our method indicates that the uncertainty interval is not only useful for estimating the inaccuracy of interdisciplinarity measurements, but it also delivers slightly more accurate aggregated interdisciplinarity measurements than the Rao–Stirling index.
AU - Calatrava Moreno, Maria
AU - Auzinger, Thomas
AU - Werthner, Hannes
ID - 1446
IS - 1
JF - Scientometrics
TI - On the uncertainty of interdisciplinarity measurements due to incomplete bibliographic data
VL - 107
ER -
TY - JOUR
AB - We develop a new and systematic method for proving entropic Ricci curvature lower bounds for Markov chains on discrete sets. Using different methods, such bounds have recently been obtained in several examples (e.g., 1-dimensional birth and death chains, product chains, Bernoulli–Laplace models, and random transposition models). However, a general method to obtain discrete Ricci bounds had been lacking. Our method covers all of the examples above. In addition we obtain new Ricci curvature bounds for zero-range processes on the complete graph. The method is inspired by recent work of Caputo, Dai Pra and Posta on discrete functional inequalities.
AU - Fathi, Max
AU - Maas, Jan
ID - 1448
IS - 3
JF - The Annals of Applied Probability
TI - Entropic Ricci curvature bounds for discrete interacting systems
VL - 26
ER -
TY - JOUR
AB - The actin cytoskeleton plays important roles in the formation and internalization of endocytic vesicles. In yeast, endocytic vesicles move towards early endosomes along actin cables, however, the molecular machinery regulating interaction between endocytic vesicles and actin cables is poorly understood. The Eps15-like protein Pan1p plays a key role in actin-mediated endocytosis and is negatively regulated by Ark1 and Prk1 kinases. Here we show that pan1 mutated to prevent phosphorylation at all 18 threonines, pan1-18TA, displayed almost the same endocytic defect as ark1Δ prk1Δ cells, and contained abnormal actin concentrations including several endocytic compartments. Early endosomes were highly localized in the actin concentrations and displayed movement along actin cables. The dephosphorylated form of Pan1p also caused stable associations between endocytic vesicles and actin cables, and between endocytic vesicles and endosomes. Thus Pan1 phosphorylation is part of a novel mechanism that regulates endocytic compartment interactions with each other and with actin cables.
AU - Toshima, Junko
AU - Furuya, Eri
AU - Nagano, Makoto
AU - Kanno, Chisa
AU - Sakamoto, Yuta
AU - Ebihara, Masashi
AU - Siekhaus, Daria E
AU - Toshima, Jiro
ID - 1475
IS - February 2016
JF - eLife
TI - Yeast Eps15-like endocytic protein Pan1p regulates the interaction between endocytic vesicles, endosomes and the actin cytoskeleton
VL - 5
ER -
TY - JOUR
AB - The dynamic assembly and disassembly of actin filaments is essential for the formation and transport of vesicles during endocytosis. In yeast, two types of actin structures, namely cortical patches and cytoplasmic cables, play a direct role in endocytosis, but how their interaction is regulated remains unclear. Here, we show that Srv2/CAP, an evolutionarily conserved actin regulator, is required for efficient endocytosis owing to its role in the formation of the actin patches that aid initial vesicle invagination and of the actin cables that these move along. Deletion of the SRV2 gene resulted in the appearance of aberrant fragmented actin cables that frequently moved past actin patches, the sites of endocytosis. We find that the C-terminal CARP domain of Srv2p is vitally important for the proper assembly of actin patches and cables; we also demonstrate that the N-terminal helical folded domain of Srv2 is required for its localization to actin patches, specifically to the ADP-actin rich region through an interaction with cofilin. These results demonstrate the in vivo roles of Srv2p in the regulation of the actin cytoskeleton during clathrin-mediated endocytosis
AU - Toshima, Junko
AU - Horikomi, Chika
AU - Okada, Asuka
AU - Hatori, Makiko
AU - Nagano, Makoto
AU - Masuda, Atsushi
AU - Yamamoto, Wataru
AU - Siekhaus, Daria E
AU - Toshima, Jiro
ID - 1476
IS - 2
JF - Journal of Cell Science
TI - Srv2/CAP is required for polarized actin cable assembly and patch internalization during clathrin-mediated endocytosis
VL - 129
ER -
TY - JOUR
AB - We consider partially observable Markov decision processes (POMDPs) with ω-regular conditions specified as parity objectives. The class of ω-regular languages provides a robust specification language to express properties in verification, and parity objectives are canonical forms to express them. The qualitative analysis problem given a POMDP and a parity objective asks whether there is a strategy to ensure that the objective is satisfied with probability 1 (resp. positive probability). While the qualitative analysis problems are undecidable even for special cases of parity objectives, we establish decidability (with optimal complexity) for POMDPs with all parity objectives under finite-memory strategies. We establish optimal (exponential) memory bounds and EXPTIME-completeness of the qualitative analysis problems under finite-memory strategies for POMDPs with parity objectives. We also present a practical approach, where we design heuristics to deal with the exponential complexity, and have applied our implementation on a number of POMDP examples.
AU - Chatterjee, Krishnendu
AU - Chmelik, Martin
AU - Tracol, Mathieu
ID - 1477
IS - 5
JF - Journal of Computer and System Sciences
TI - What is decidable about partially observable Markov decision processes with ω-regular objectives
VL - 82
ER -
TY - JOUR
AB - We consider the Tonks-Girardeau gas subject to a random external potential. If the disorder is such that the underlying one-particle Hamiltonian displays localization (which is known to be generically the case), we show that there is exponential decay of correlations in the many-body eigenstates. Moreover, there is no Bose-Einstein condensation and no superfluidity, even at zero temperature.
AU - Seiringer, Robert
AU - Warzel, Simone
ID - 1478
IS - 3
JF - New Journal of Physics
TI - Decay of correlations and absence of superfluidity in the disordered Tonks-Girardeau gas
VL - 18
ER -
TY - JOUR
AB - Most entropy notions H(.) like Shannon or min-entropy satisfy a chain rule stating that for random variables X,Z, and A we have H(X|Z,A)≥H(X|Z)−|A|. That is, by conditioning on A the entropy of X can decrease by at most the bitlength |A| of A. Such chain rules are known to hold for some computational entropy notions like Yao’s and unpredictability-entropy. For HILL entropy, the computational analogue of min-entropy, the chain rule is of special interest and has found many applications, including leakage-resilient cryptography, deterministic encryption, and memory delegation. These applications rely on restricted special cases of the chain rule. Whether the chain rule for conditional HILL entropy holds in general was an open problem for which we give a strong negative answer: we construct joint distributions (X,Z,A), where A is a distribution over a single bit, such that the HILL entropy H HILL (X|Z) is large but H HILL (X|Z,A) is basically zero.
Our counterexample just makes the minimal assumption that NP⊈P/poly. Under the stronger assumption that injective one-way function exist, we can make all the distributions efficiently samplable.
Finally, we show that some more sophisticated cryptographic objects like lossy functions can be used to sample a distribution constituting a counterexample to the chain rule making only a single invocation to the underlying object.
AU - Krenn, Stephan
AU - Pietrzak, Krzysztof Z
AU - Wadia, Akshay
AU - Wichs, Daniel
ID - 1479
IS - 3
JF - Computational Complexity
TI - A counterexample to the chain rule for conditional HILL entropy
VL - 25
ER -
TY - JOUR
AB - Exponential varieties arise from exponential families in statistics. These real algebraic varieties have strong positivity and convexity properties, familiar from toric varieties and their moment maps. Among them are varieties of inverses of symmetric matrices satisfying linear constraints. This class includes Gaussian graphical models. We develop a general theory of exponential varieties. These are derived from hyperbolic polynomials and their integral representations. We compare the multidegrees and ML degrees of the gradient map for hyperbolic polynomials.
AU - Michałek, Mateusz
AU - Sturmfels, Bernd
AU - Uhler, Caroline
AU - Zwiernik, Piotr
ID - 1480
IS - 1
JF - Proceedings of the London Mathematical Society
TI - Exponential varieties
VL - 112
ER -
TY - JOUR
AB - Plants have the ability to continously generate new organs by maintaining populations of stem cells throught their lives. The shoot apical meristem (SAM) provides a stable environment for the maintenance of stem cells. All cells inside the SAM divide, yet boundaries and patterns are maintained. Experimental evidence indicates that patterning is independent of cell lineage, thus a dynamic self-regulatory mechanism is required. A pivotal role in the organization of the SAM is played by the WUSCHEL gene (WUS). An important question in this regard is that how WUS expression is positioned in the SAM via a cell-lineage independent signaling mechanism. In this study we demonstrate via mathematical modeling that a combination of an inhibitor of the Cytokinin (CK) receptor, Arabidopsis histidine kinase 4 (AHK4) and two morphogens originating from the top cell layer, can plausibly account for the cell lineage-independent centering of WUS expression within SAM. Furthermore, our laser ablation and microsurgical experiments support the hypothesis that patterning in SAM occurs at the level of CK reception and signaling. The model suggests that the interplay between CK signaling, WUS/CLV feedback loop and boundary signals can account for positioning of the WUS expression, and provides directions for further experimental investigation.
AU - Adibi, Milad
AU - Yoshida, Saiko
AU - Weijers, Dolf
AU - Fleck, Christian
ID - 1482
IS - 2
JF - PLoS One
TI - Centering the organizing center in the Arabidopsis thaliana shoot apical meristem by a combination of cytokinin signaling and self-organization
VL - 11
ER -
TY - JOUR
AU - Chen, Xu
AU - Wu, Shuang
AU - Liu, Zengyu
AU - Friml, Jiřĺ
ID - 1484
IS - 6
JF - Trends in Cell Biology
TI - Environmental and endogenous control of cortical microtubule orientation
VL - 26
ER -
TY - JOUR
AB - In this article the notion of metabolic turnover is revisited in the light of recent results of out-of-equilibrium thermodynamics. By means of Monte Carlo methods we perform an exact sampling of the enzymatic fluxes in a genome scale metabolic network of E. Coli in stationary growth conditions from which we infer the metabolites turnover times. However the latter are inferred from net fluxes, and we argue that this approximation is not valid for enzymes working nearby thermodynamic equilibrium. We recalculate turnover times from total fluxes by performing an energy balance analysis of the network and recurring to the fluctuation theorem. We find in many cases values one of order of magnitude lower, implying a faster picture of intermediate metabolism.
AU - De Martino, Daniele
ID - 1485
IS - 1
JF - Physical Biology
TI - Genome-scale estimate of the metabolic turnover of E. Coli from the energy balance analysis
VL - 13
ER -
TY - JOUR
AB - We review recent results concerning the mathematical properties of the Bardeen-Cooper-Schrieffer (BCS) functional of superconductivity, which were obtained in a series of papers, partly in collaboration with R. Frank, E. Hamza, S. Naboko, and J. P. Solovej. Our discussion includes, in particular, an investigation of the critical temperature for a general class of interaction potentials, as well as a study of its dependence on external fields. We shall explain how the Ginzburg-Landau model can be derived from the BCS theory in a suitable parameter regime.
AU - Hainzl, Christian
AU - Seiringer, Robert
ID - 1486
IS - 2
JF - Journal of Mathematical Physics
TI - The Bardeen–Cooper–Schrieffer functional of superconductivity and its mathematical properties
VL - 57
ER -
TY - JOUR
AB - Rhythms with time scales of multiple cycles per second permeate the mammalian brain, yet neuroscientists are not certain of their functional roles. One leading idea is that coherent oscillation between two brain regions facilitates the exchange of information between them. In rats, the hippocampus and the vibrissal sensorimotor system both are characterized by rhythmic oscillation in the theta range, 5–12 Hz. Previous work has been divided as to whether the two rhythms are independent or coherent. To resolve this question, we acquired three measures from rats—whisker motion, hippocampal local field potential (LFP), and barrel cortex unit firing—during a whisker-mediated texture discrimination task and during control conditions (not engaged in a whisker-mediated memory task). Compared to control conditions, the theta band of hippocampal LFP showed a marked increase in power as the rats approached and then palpated the texture. Phase synchronization between whisking and hippocampal LFP increased by almost 50% during approach and texture palpation. In addition, a greater proportion of barrel cortex neurons showed firing that was phase-locked to hippocampal theta while rats were engaged in the discrimination task. Consistent with a behavioral consequence of phase synchronization, the rats identified the texture more rapidly and with lower error likelihood on trials in which there was an increase in theta-whisking coherence at the moment of texture palpation. These results suggest that coherence between the whisking rhythm, barrel cortex firing, and hippocampal LFP is augmented selectively during epochs in which the rat collects sensory information and that such coherence enhances the efficiency of integration of stimulus information into memory and decision-making centers.
AU - Grion, Natalia
AU - Akrami, Athena
AU - Zuo, Yangfang
AU - Stella, Federico
AU - Diamond, Mathew
ID - 1487
IS - 2
JF - PLoS Biology
TI - Coherence between rat sensorimotor system and hippocampus is enhanced during tactile discrimination
VL - 14
ER -
TY - JOUR
AB - Branching morphogenesis of the epithelial ureteric bud forms the renal collecting duct system and is critical for normal nephron number, while low nephron number is implicated in hypertension and renal disease. Ureteric bud growth and branching requires GDNF signaling from the surrounding mesenchyme to cells at the ureteric bud tips, via the Ret receptor tyrosine kinase and coreceptor Gfrα1; Ret signaling up-regulates transcription factors Etv4 and Etv5, which are also critical for branching. Despite extensive knowledge of the genetic control of these events, it is not understood, at the cellular level, how renal branching morphogenesis is achieved or how Ret signaling influences epithelial cell behaviors to promote this process. Analysis of chimeric embryos previously suggested a role for Ret signaling in promoting cell rearrangements in the nephric duct, but this method was unsuited to study individual cell behaviors during ureteric bud branching. Here, we use Mosaic Analysis with Double Markers (MADM), combined with organ culture and time-lapse imaging, to trace the movements and divisions of individual ureteric bud tip cells. We first examine wild-type clones and then Ret or Etv4 mutant/wild-type clones in which the mutant and wild-type sister cells are differentially and heritably marked by green and red fluorescent proteins. We find that, in normal kidneys, most individual tip cells behave as self-renewing progenitors, some of whose progeny remain at the tips while others populate the growing UB trunks. In Ret or Etv4 MADM clones, the wild-type cells generated at a UB tip are much more likely to remain at, or move to, the new tips during branching and elongation, while their Ret−/− or Etv4−/− sister cells tend to lag behind and contribute only to the trunks. By tracking successive mitoses in a cell lineage, we find that Ret signaling has little effect on proliferation, in contrast to its effects on cell movement. Our results show that Ret/Etv4 signaling promotes directed cell movements in the ureteric bud tips, and suggest a model in which these cell movements mediate branching morphogenesis.
AU - Riccio, Paul
AU - Cebrián, Cristina
AU - Zong, Hui
AU - Hippenmeyer, Simon
AU - Costantini, Frank
ID - 1488
IS - 2
JF - PLoS Biology
TI - Ret and Etv4 promote directed movements of progenitor cells during renal branching morphogenesis
VL - 14
ER -
TY - JOUR
AB - We prove optimal local law, bulk universality and non-trivial decay for the off-diagonal elements of the resolvent for a class of translation invariant Gaussian random matrix ensembles with correlated entries.
AU - Ajanki, Oskari H
AU - Erdös, László
AU - Krüger, Torben H
ID - 1489
IS - 2
JF - Journal of Statistical Physics
TI - Local spectral statistics of Gaussian matrices with correlated entries
VL - 163
ER -
TY - JOUR
AB - To induce adaptive immunity, dendritic cells (DCs) migrate through afferent lymphatic vessels (LVs) to draining lymph nodes (dLNs). This process occurs in several consecutive steps. Upon entry into lymphatic capillaries, DCs first actively crawl into downstream collecting vessels. From there, they are next passively and rapidly transported to the dLN by lymph flow. Here, we describe a role for the chemokine CCL21 in intralymphatic DC crawling. Performing time-lapse imaging in murine skin, we found that blockade of CCL21-but not the absence of lymph flow-completely abolished DC migration from capillaries toward collecting vessels and reduced the ability of intralymphatic DCs to emigrate from skin. Moreover, we found that in vitro low laminar flow established a CCL21 gradient along lymphatic endothelial monolayers, thereby inducing downstream-directed DC migration. These findings reveal a role for intralymphatic CCL21 in promoting DC trafficking to dLNs, through the formation of a flow-induced gradient.
AU - Russo, Erica
AU - Teijeira, Alvaro
AU - Vaahtomeri, Kari
AU - Willrodt, Ann
AU - Bloch, Joël
AU - Nitschké, Maximilian
AU - Santambrogio, Laura
AU - Kerjaschki, Dontscho
AU - Sixt, Michael K
AU - Halin, Cornelia
ID - 1490
IS - 7
JF - Cell Reports
TI - Intralymphatic CCL21 promotes tissue egress of dendritic cells through afferent lymphatic vessels
VL - 14
ER -
TY - JOUR
AB - We study the ground state of a trapped Bose gas, starting from the full many-body Schrödinger Hamiltonian, and derive the non-linear Schrödinger energy functional in the limit of a large particle number, when the interaction potential converges slowly to a Dirac delta function. Our method is based on quantitative estimates on the discrepancy between the full many-body energy and its mean-field approximation using Hartree states. These are proved using finite dimensional localization and a quantitative version of the quantum de Finetti theorem. Our approach covers the case of attractive interactions in the regime of stability. In particular, our main new result is a derivation of the 2D attractive non-linear Schrödinger ground state.
AU - Lewin, Mathieu
AU - Nam, Phan
AU - Rougerie, Nicolas
ID - 1491
IS - 9
JF - Transactions of the American Mathematical Society
TI - The mean-field approximation and the non-linear Schrödinger functional for trapped Bose gases
VL - 368
ER -
TY - JOUR
AB - To sustain a lifelong ability to initiate organs, plants retain pools of undifferentiated cells with a preserved prolif eration capacity. The root pericycle represents a unique tissue with conditional meristematic activity, and its tight control determines initiation of lateral organs. Here we show that the meristematic activity of the pericycle is constrained by the interaction with the adjacent endodermis. Release of these restraints by elimination of endo dermal cells by single-cell ablation triggers the pericycle to re-enter the cell cycle. We found that endodermis removal substitutes for the phytohormone auxin-dependent initiation of the pericycle meristematic activity. However, auxin is indispensable to steer the cell division plane orientation of new organ-defining divisions. We propose a dual, spatiotemporally distinct role for auxin during lateral root initiation. In the endodermis, auxin releases constraints arising from cell-to-cell interactions that compromise the pericycle meristematic activity, whereas, in the pericycle, auxin defines the orientation of the cell division plane to initiate lateral roots.
AU - Marhavy, Peter
AU - Montesinos López, Juan C
AU - Abuzeineh, Anas
AU - Van Damme, Daniël
AU - Vermeer, Joop
AU - Duclercq, Jérôme
AU - Rakusova, Hana
AU - Marhavá, Petra
AU - Friml, Jirí
AU - Geldner, Niko
AU - Benková, Eva
ID - 1492
IS - 4
JF - Genes and Development
TI - Targeted cell elimination reveals an auxin-guided biphasic mode of lateral root initiation
VL - 30
ER -
TY - JOUR
AB - We introduce a new method for deriving the time-dependent Hartree or Hartree-Fock equations as an effective mean-field dynamics from the microscopic Schrödinger equation for fermionic many-particle systems in quantum mechanics. The method is an adaption of the method used in Pickl (Lett. Math. Phys. 97 (2) 151–164 2011) for bosonic systems to fermionic systems. It is based on a Gronwall type estimate for a suitable measure of distance between the microscopic solution and an antisymmetrized product state. We use this method to treat a new mean-field limit for fermions with long-range interactions in a large volume. Some of our results hold for singular attractive or repulsive interactions. We can also treat Coulomb interaction assuming either a mild singularity cutoff or certain regularity conditions on the solutions to the Hartree(-Fock) equations. In the considered limit, the kinetic and interaction energy are of the same order, while the average force is subleading. For some interactions, we prove that the Hartree(-Fock) dynamics is a more accurate approximation than a simpler dynamics that one would expect from the subleading force. With our method we also treat the mean-field limit coupled to a semiclassical limit, which was discussed in the literature before, and we recover some of the previous results. All results hold for initial data close (but not necessarily equal) to antisymmetrized product states and we always provide explicit rates of convergence.
AU - Petrat, Sören P
AU - Pickl, Peter
ID - 1493
IS - 1
JF - Mathematical Physics, Analysis and Geometry
TI - A new method and a new scaling for deriving fermionic mean-field dynamics
VL - 19
ER -
TY - JOUR
AB - Turbulence is one of the most frequently encountered non-equilibrium phenomena in nature, yet characterizing the transition that gives rise to turbulence in basic shear flows has remained an elusive task. Although, in recent studies, critical points marking the onset of sustained turbulence have been determined for several such flows, the physical nature of the transition could not be fully explained. In extensive experimental and computational studies we show for the example of Couette flow that the onset of turbulence is a second-order phase transition and falls into the directed percolation universality class. Consequently, the complex laminar–turbulent patterns distinctive for the onset of turbulence in shear flows result from short-range interactions of turbulent domains and are characterized by universal critical exponents. More generally, our study demonstrates that even high-dimensional systems far from equilibrium such as turbulence exhibit universality at onset and that here the collective dynamics obeys simple rules.
AU - Lemoult, Grégoire M
AU - Shi, Liang
AU - Avila, Kerstin
AU - Jalikop, Shreyas V
AU - Avila, Marc
AU - Hof, Björn
ID - 1494
IS - 3
JF - Nature Physics
TI - Directed percolation phase transition to sustained turbulence in Couette flow
VL - 12
ER -
TY - JOUR
AB - The two-photon 1s2 2s 2p 3P0 1s22s2 1S0 transition in berylliumlike ions is theoretically investigated within a fully relativistic framework and a second-order perturbation theory. We focus our analysis on how electron correlation, as well as the negative-energy spectrum, can affect the forbidden E1M1 decay rate. For this purpose, we include the electronic correlation via an effective local potential and within a single configuration-state model. Due to its experimental interest, evaluations of decay rates are performed for berylliumlike xenon and uranium. We find that the negative-energy contribution can be neglected at the present level of accuracy in the evaluation of the decay rate. On the other hand, if contributions of electronic correlation are not carefully taken into account, it may change the lifetime of the metastable state by up to 20%. By performing a full-relativistic jj-coupling calculation, we found a decrease of the decay rate by two orders of magnitude compared to non-relativistic LS-coupling calculations, for the selected heavy ions.
AU - Amaro, Pedro
AU - Fratini, Filippo
AU - Safari, Laleh
AU - Machado, Jorge
AU - Guerra, Mauro
AU - Indelicato, Paul
AU - Santos, José
ID - 1496
IS - 3
JF - Physical Review A - Atomic, Molecular, and Optical Physics
TI - Relativistic evaluation of the two-photon decay of the metastable 1s22s2p3P0 state in berylliumlike ions with an effective-potential model
VL - 93
ER -
TY - JOUR
AB - The inference of demographic history from genome data is hindered by a lack of efficient computational approaches. In particular, it has proved difficult to exploit the information contained in the distribution of genealogies across the genome. We have previously shown that the generating function (GF) of genealogies can be used to analytically compute likelihoods of demographic models from configurations of mutations in short sequence blocks (Lohse et al. 2011). Although the GF has a simple, recursive form, the size of such likelihood calculations explodes quickly with the number of individuals and applications of this framework have so far been mainly limited to small samples (pairs and triplets) for which the GF can be written by hand. Here we investigate several strategies for exploiting the inherent symmetries of the coalescent. In particular, we show that the GF of genealogies can be decomposed into a set of equivalence classes that allows likelihood calculations from nontrivial samples. Using this strategy, we automated blockwise likelihood calculations for a general set of demographic scenarios in Mathematica. These histories may involve population size changes, continuous migration, discrete divergence, and admixture between multiple populations. To give a concrete example, we calculate the likelihood for a model of isolation with migration (IM), assuming two diploid samples without phase and outgroup information. We demonstrate the new inference scheme with an analysis of two individual butterfly genomes from the sister species Heliconius melpomene rosina and H. cydno.
AU - Lohse, Konrad
AU - Chmelik, Martin
AU - Martin, Simon
AU - Barton, Nicholas H
ID - 1518
IS - 2
JF - Genetics
TI - Efficient strategies for calculating blockwise likelihoods under the coalescent
VL - 202
ER -
TY - JOUR
AB - Complex I (NADH:ubiquinone oxidoreductase) plays a central role in cellular energy production, coupling electron transfer between NADH and quinone to proton translocation. It is the largest protein assembly of respiratory chains and one of the most elaborate redox membrane proteins known. Bacterial enzyme is about half the size of mitochondrial and thus provides its important "minimal" model. Dysfunction of mitochondrial complex I is implicated in many human neurodegenerative diseases. The L-shaped complex consists of a hydrophilic arm, where electron transfer occurs, and a membrane arm, where proton translocation takes place. We have solved the crystal structures of the hydrophilic domain of complex I from Thermus thermophilus, the membrane domain from Escherichia coli and recently of the intact, entire complex I from T. thermophilus (536. kDa, 16 subunits, 9 iron-sulphur clusters, 64 transmembrane helices). The 95. Å long electron transfer pathway through the enzyme proceeds from the primary electron acceptor flavin mononucleotide through seven conserved Fe-S clusters to the unusual elongated quinone-binding site at the interface with the membrane domain. Four putative proton translocation channels are found in the membrane domain, all linked by the central flexible axis containing charged residues. The redox energy of electron transfer is coupled to proton translocation by the as yet undefined mechanism proposed to involve long-range conformational changes. This article is part of a Special Issue entitled Respiratory complex I, edited by Volker Zickermann and Ulrich Brandt.
AU - Berrisford, John
AU - Baradaran, Rozbeh
AU - Sazanov, Leonid A
ID - 1521
IS - 7
JF - Biochimica et Biophysica Acta - Bioenergetics
TI - Structure of bacterial respiratory complex I
VL - 1857
ER -
TY - JOUR
AB - We classify smooth Brunnian (i.e., unknotted on both components) embeddings (S2 × S1) ⊔ S3 → ℝ6. Any Brunnian embedding (S2 × S1) ⊔ S3 → ℝ6 is isotopic to an explicitly constructed embedding fk,m,n for some integers k, m, n such that m ≡ n (mod 2). Two embeddings fk,m,n and fk′ ,m′,n′ are isotopic if and only if k = k′, m ≡ m′ (mod 2k) and n ≡ n′ (mod 2k). We use Haefliger’s classification of embeddings S3 ⊔ S3 → ℝ6 in our proof. The relation between the embeddings (S2 × S1) ⊔ S3 → ℝ6 and S3 ⊔ S3 → ℝ6 is not trivial, however. For example, we show that there exist embeddings f: (S2 ×S1) ⊔ S3 → ℝ6 and g, g′ : S3 ⊔ S3 → ℝ6 such that the componentwise embedded connected sum f # g is isotopic to f # g′ but g is not isotopic to g′.
AU - Avvakumov, Serhii
ID - 1522
IS - 1
JF - Moscow Mathematical Journal
TI - The classification of certain linked 3-manifolds in 6-space
VL - 16
ER -
TY - JOUR
AB - For random graphs, the containment problem considers the probability that a binomial random graph G(n, p) contains a given graph as a substructure. When asking for the graph as a topological minor, i.e., for a copy of a subdivision of the given graph, it is well known that the (sharp) threshold is at p = 1/n. We consider a natural analogue of this question for higher-dimensional random complexes Xk(n, p), first studied by Cohen, Costa, Farber and Kappeler for k = 2. Improving previous results, we show that p = Θ(1/ √n) is the (coarse) threshold for containing a subdivision of any fixed complete 2-complex. For higher dimensions k > 2, we get that p = O(n−1/k) is an upper bound for the threshold probability of containing a subdivision of a fixed k-dimensional complex.
AU - Gundert, Anna
AU - Wagner, Uli
ID - 1523
IS - 4
JF - Proceedings of the American Mathematical Society
TI - On topological minors in random simplicial complexes
VL - 144
ER -
TY - CONF
AB - When designing genetic circuits, the typical primitives used in major existing modelling formalisms are gene interaction graphs, where edges between genes denote either an activation or inhibition relation. However, when designing experiments, it is important to be precise about the low-level mechanistic details as to how each such relation is implemented. The rule-based modelling language Kappa allows to unambiguously specify mechanistic details such as DNA binding sites, dimerisation of transcription factors, or co-operative interactions. Such a detailed description comes with complexity and computationally costly executions. We propose a general method for automatically transforming a rule-based program, by eliminating intermediate species and adjusting the rate constants accordingly. To the best of our knowledge, we show the first automated reduction of rule-based models based on equilibrium approximations.
Our algorithm is an adaptation of an existing algorithm, which was designed for reducing reaction-based programs; our version of the algorithm scans the rule-based Kappa model in search for those interaction patterns known to be amenable to equilibrium approximations (e.g. Michaelis-Menten scheme). Additional checks are then performed in order to verify if the reduction is meaningful in the context of the full model. The reduced model is efficiently obtained by static inspection over the rule-set. The tool is tested on a detailed rule-based model of a λ-phage switch, which lists 92 rules and 13 agents. The reduced model has 11 rules and 5 agents, and provides a dramatic reduction in simulation time of several orders of magnitude.
AU - Beica, Andreea
AU - Guet, Calin C
AU - Petrov, Tatjana
ID - 1524
TI - Efficient reduction of kappa models by static inspection of the rule-set
VL - 9271
ER -
TY - CONF
AB - We present the first study of robustness of systems that are both timed as well as reactive (I/O). We study the behavior of such timed I/O systems in the presence of uncertain inputs and formalize their robustness using the analytic notion of Lipschitz continuity: a timed I/O system is K-(Lipschitz) robust if the perturbation in its output is at most K times the perturbation in its input. We quantify input and output perturbation using similarity functions over timed words such as the timed version of the Manhattan distance and the Skorokhod distance. We consider two models of timed I/O systems — timed transducers and asynchronous sequential circuits. We show that K-robustness of timed transducers can be decided in polynomial space under certain conditions. For asynchronous sequential circuits, we reduce K-robustness w.r.t. timed Manhattan distances to K-robustness of discrete letter-to-letter transducers and show PSpace-completeness of the problem.
AU - Henzinger, Thomas A
AU - Otop, Jan
AU - Samanta, Roopsha
ID - 1526
TI - Lipschitz robustness of timed I/O systems
VL - 9583
ER -
TY - JOUR
AB - We consider partially observable Markov decision processes (POMDPs) with a set of target states and an integer cost associated with every transition. The optimization objective we study asks to minimize the expected total cost of reaching a state in the target set, while ensuring that the target set is reached almost surely (with probability 1). We show that for integer costs approximating the optimal cost is undecidable. For positive costs, our results are as follows: (i) we establish matching lower and upper bounds for the optimal cost, both double exponential in the POMDP state space size; (ii) we show that the problem of approximating the optimal cost is decidable and present approximation algorithms developing on the existing algorithms for POMDPs with finite-horizon objectives. While the worst-case running time of our algorithm is double exponential, we also present efficient stopping criteria for the algorithm and show experimentally that it performs well in many examples of interest.
AU - Chatterjee, Krishnendu
AU - Chmelik, Martin
AU - Gupta, Raghav
AU - Kanodia, Ayush
ID - 1529
JF - Artificial Intelligence
TI - Optimal cost almost-sure reachability in POMDPs
VL - 234
ER -
TY - JOUR
AB - We provide general conditions for which bosonic quadratic Hamiltonians on Fock spaces can be diagonalized by Bogoliubov transformations. Our results cover the case when quantum systems have infinite degrees of freedom and the associated one-body kinetic and paring operators are unbounded. Our sufficient conditions are optimal in the sense that they become necessary when the relevant one-body operators commute.
AU - Nam, Phan
AU - Napiórkowski, Marcin M
AU - Solovej, Jan
ID - 1545
IS - 11
JF - Journal of Functional Analysis
TI - Diagonalization of bosonic quadratic Hamiltonians by Bogoliubov transformations
VL - 270
ER -
TY - JOUR
AB - Antibiotic resistance carries a fitness cost that must be overcome in order for resistance to persist over the long term. Compensatory mutations that recover the functional defects associated with resistance mutations have been argued to play a key role in overcoming the cost of resistance, but compensatory mutations are expected to be rare relative to generally beneficial mutations that increase fitness, irrespective of antibiotic resistance. Given this asymmetry, population genetics theory predicts that populations should adapt by compensatory mutations when the cost of resistance is large, whereas generally beneficial mutations should drive adaptation when the cost of resistance is small. We tested this prediction by determining the genomic mechanisms underpinning adaptation to antibiotic-free conditions in populations of the pathogenic bacterium Pseudomonas aeruginosa that carry costly antibiotic resistance mutations. Whole-genome sequencing revealed that populations founded by high-cost rifampicin-resistant mutants adapted via compensatory mutations in three genes of the RNA polymerase core enzyme, whereas populations founded by low-cost mutants adapted by generally beneficial mutations, predominantly in the quorum-sensing transcriptional regulator gene lasR. Even though the importance of compensatory evolution in maintaining resistance has been widely recognized, our study shows that the roles of general adaptation in maintaining resistance should not be underestimated and highlights the need to understand how selection at other sites in the genome influences the dynamics of resistance alleles in clinical settings.
AU - Qi, Qin
AU - Toll Riera, Macarena
AU - Heilbron, Karl
AU - Preston, Gail
AU - Maclean, R Craig
ID - 1552
IS - 1822
JF - Proceedings of the Royal Society of London Series B Biological Sciences
TI - The genomic basis of adaptation to the fitness cost of rifampicin resistance in Pseudomonas aeruginosa
VL - 283
ER -
TY - JOUR
AB - A modular approach to constructing cryptographic protocols leads to simple designs but often inefficient instantiations. On the other hand, ad hoc constructions may yield efficient protocols at the cost of losing conceptual simplicity. We suggest a new design paradigm, structure-preserving cryptography, that provides a way to construct modular protocols with reasonable efficiency while retaining conceptual simplicity. A cryptographic scheme over a bilinear group is called structure-preserving if its public inputs and outputs consist of elements from the bilinear groups and their consistency can be verified by evaluating pairing-product equations. As structure-preserving schemes smoothly interoperate with each other, they are useful as building blocks in modular design of cryptographic applications. This paper introduces structure-preserving commitment and signature schemes over bilinear groups with several desirable properties. The commitment schemes include homomorphic, trapdoor and length-reducing commitments to group elements, and the structure-preserving signature schemes are the first ones that yield constant-size signatures on multiple group elements. A structure-preserving signature scheme is called automorphic if the public keys lie in the message space, which cannot be achieved by compressing inputs via a cryptographic hash function, as this would destroy the mathematical structure we are trying to preserve. Automorphic signatures can be used for building certification chains underlying privacy-preserving protocols. Among a vast number of applications of structure-preserving protocols, we present an efficient round-optimal blind-signature scheme and a group signature scheme with an efficient and concurrently secure protocol for enrolling new members.
AU - Abe, Masayuki
AU - Fuchsbauer, Georg
AU - Groth, Jens
AU - Haralambiev, Kristiyan
AU - Ohkubo, Miyako
ID - 1592
IS - 2
JF - Journal of Cryptology
TI - Structure preserving signatures and commitments to group elements
VL - 29
ER -
TY - JOUR
AB - Chemokines are the main guidance cues directing leukocyte migration. Opposed to early assumptions, chemokines do not necessarily act as soluble cues but are often immobilized within tissues, e.g., dendritic cell migration toward lymphatic vessels is guided by a haptotactic gradient of the chemokine CCL21. Controlled assay systems to quantitatively study haptotaxis in vitro are still missing. In this chapter, we describe an in vitro haptotaxis assay optimized for the unique properties of dendritic cells. The chemokine CCL21 is immobilized in a bioactive state, using laser-assisted protein adsorption by photobleaching. The cells follow this immobilized CCL21 gradient in a haptotaxis chamber, which provides three dimensionally confined migration conditions.
AU - Schwarz, Jan
AU - Sixt, Michael K
ID - 1597
JF - Methods in Enzymology
TI - Quantitative analysis of dendritic cell haptotaxis
VL - 570
ER -
TY - JOUR
AB - The addition of polysialic acid to N- and/or O-linked glycans, referred to as polysialylation, is a rare posttranslational modification that is mainly known to control the developmental plasticity of the nervous system. Here we show that CCR7, the central chemokine receptor controlling immune cell trafficking to secondary lymphatic organs, carries polysialic acid. This modification is essential for the recognition of the CCR7 ligand CCL21. As a consequence, dendritic cell trafficking is abrogated in polysialyltransferase-deficient mice, manifesting as disturbed lymph node homeostasis and unresponsiveness to inflammatory stimuli. Structure-function analysis of chemokine-receptor interactions reveals that CCL21 adopts an autoinhibited conformation, which is released upon interaction with polysialic acid. Thus, we describe a glycosylation-mediated immune cell trafficking disorder and its mechanistic basis.
AU - Kiermaier, Eva
AU - Moussion, Christine
AU - Veldkamp, Christopher
AU - Gerardy Schahn, Rita
AU - De Vries, Ingrid
AU - Williams, Larry
AU - Chaffee, Gary
AU - Phillips, Andrew
AU - Freiberger, Friedrich
AU - Imre, Richard
AU - Taleski, Deni
AU - Payne, Richard
AU - Braun, Asolina
AU - Förster, Reinhold
AU - Mechtler, Karl
AU - Mühlenhoff, Martina
AU - Volkman, Brian
AU - Sixt, Michael K
ID - 1599
IS - 6269
JF - Science
TI - Polysialylation controls dendritic cell trafficking by regulating chemokine recognition
VL - 351
ER -
TY - JOUR
AB - We show that the Anderson model has a transition from localization to delocalization at exactly 2 dimensional growth rate on antitrees with normalized edge weights which are certain discrete graphs. The kinetic part has a one-dimensional structure allowing a description through transfer matrices which involve some Schur complement. For such operators we introduce the notion of having one propagating channel and extend theorems from the theory of one-dimensional Jacobi operators that relate the behavior of transfer matrices with the spectrum. These theorems are then applied to the considered model. In essence, in a certain energy region the kinetic part averages the random potentials along shells and the transfer matrices behave similar as for a one-dimensional operator with random potential of decaying variance. At d dimensional growth for d>2 this effective decay is strong enough to obtain absolutely continuous spectrum, whereas for some uniform d dimensional growth with d<2 one has pure point spectrum in this energy region. At exactly uniform 2 dimensional growth also some singular continuous spectrum appears, at least at small disorder. As a corollary we also obtain a change from singular spectrum (d≤2) to absolutely continuous spectrum (d≥3) for random operators of the type rΔdr+λ on ℤd, where r is an orthogonal radial projection, Δd the discrete adjacency operator (Laplacian) on ℤd and λ a random potential.
AU - Sadel, Christian
ID - 1608
IS - 7
JF - Annales Henri Poincare
TI - Anderson transition at 2 dimensional growth rate on antitrees and spectral theory for operators with one propagating channel
VL - 17
ER -
TY - JOUR
AB - We prove that whenever A is a 3-conservative relational structure with only binary and unary relations,then the algebra of polymorphisms of A either has no Taylor operation (i.e.,CSP(A)is NP-complete),or it generates an SD(∧) variety (i.e.,CSP(A)has bounded width).
AU - Kazda, Alexandr
ID - 1612
IS - 1
JF - Algebra Universalis
TI - CSP for binary conservative relational structures
VL - 75
ER -
TY - JOUR
AB - In the last decade, induced pluripotent stem (iPS) cells have revolutionized the utility of human in vitro models of neurological disease. The iPS-derived and differentiated cells allow researchers to study the impact of a distinct cell type in health and disease as well as performing therapeutic drug screens on a human genetic background. In particular, clinical trials for Alzheimer's disease (AD) have been often failing. Two of the potential reasons are first, the species gap involved in proceeding from initial discoveries in rodent models to human studies, and second, an unsatisfying patient stratification, meaning subgrouping patients based on the disease severity due to the lack of phenotypic and genetic markers. iPS cells overcome this obstacles and will improve our understanding of disease subtypes in AD. They allow researchers conducting in depth characterization of neural cells from both familial and sporadic AD patients as well as preclinical screens on human cells.
In this review, we briefly outline the status quo of iPS cell research in neurological diseases along with the general advantages and pitfalls of these models. We summarize how genome-editing techniques such as CRISPR/Cas will allow researchers to reduce the problem of genomic variability inherent to human studies, followed by recent iPS cell studies relevant to AD. We then focus on current techniques for the differentiation of iPS cells into neural cell types that are relevant to AD research. Finally, we discuss how the generation of three-dimensional cell culture systems will be important for understanding AD phenotypes in a complex cellular milieu, and how both two- and three-dimensional iPS cell models can provide platforms for drug discovery and translational studies into the treatment of AD.
AU - Mungenast, Alison
AU - Siegert, Sandra
AU - Tsai, Li
ID - 1613
JF - Molecular and Cellular Neuroscience
TI - Modeling Alzheimer's disease with human induced pluripotent stem (iPS) cells
VL - 73
ER -
TY - JOUR
AB - The hippocampus plays a key role in learning and memory. Previous studies suggested that the main types of principal neurons, dentate gyrus granule cells (GCs), CA3 pyramidal neurons, and CA1 pyramidal neurons, differ in their activity pattern, with sparse firing in GCs and more frequent firing in CA3 and CA1 pyramidal neurons. It has been assumed but never shown that such different activity may be caused by differential synaptic excitation. To test this hypothesis, we performed high-resolution whole-cell patch-clamp recordings in anesthetized rats in vivo. In contrast to previous in vitro data, both CA3 and CA1 pyramidal neurons fired action potentials spontaneously, with a frequency of ∼3–6 Hz, whereas GCs were silent. Furthermore, both CA3 and CA1 cells primarily fired in bursts. To determine the underlying mechanisms, we quantitatively assessed the frequency of spontaneous excitatory synaptic input, the passive membrane properties, and the active membrane characteristics. Surprisingly, GCs showed comparable synaptic excitation to CA3 and CA1 cells and the highest ratio of excitation versus hyperpolarizing inhibition. Thus, differential synaptic excitation is not responsible for differences in firing. Moreover, the three types of hippocampal neurons markedly differed in their passive properties. While GCs showed the most negative membrane potential, CA3 pyramidal neurons had the highest input resistance and the slowest membrane time constant. The three types of neurons also differed in the active membrane characteristics. GCs showed the highest action potential threshold, but displayed the largest gain of the input-output curves. In conclusion, our results reveal that differential firing of the three main types of hippocampal principal neurons in vivo is not primarily caused by differences in the characteristics of the synaptic input, but by the distinct properties of synaptic integration and input-output transformation.
AU - Kowalski, Janina
AU - Gan, Jian
AU - Jonas, Peter M
AU - Pernia-Andrade, Alejandro
ID - 1616
IS - 5
JF - Hippocampus
TI - Intrinsic membrane properties determine hippocampal differential firing pattern in vivo in anesthetized rats
VL - 26
ER -
TY - JOUR
AB - We study the discrepancy of jittered sampling sets: such a set P⊂ [0,1]d is generated for fixed m∈ℕ by partitioning [0,1]d into md axis aligned cubes of equal measure and placing a random point inside each of the N=md cubes. We prove that, for N sufficiently large, 1/10 d/N1/2+1/2d ≤EDN∗(P)≤ √d(log N) 1/2/N1/2+1/2d, where the upper bound with an unspecified constant Cd was proven earlier by Beck. Our proof makes crucial use of the sharp Dvoretzky-Kiefer-Wolfowitz inequality and a suitably taylored Bernstein inequality; we have reasons to believe that the upper bound has the sharp scaling in N. Additional heuristics suggest that jittered sampling should be able to improve known bounds on the inverse of the star-discrepancy in the regime N≳dd. We also prove a partition principle showing that every partition of [0,1]d combined with a jittered sampling construction gives rise to a set whose expected squared L2-discrepancy is smaller than that of purely random points.
AU - Pausinger, Florian
AU - Steinerberger, Stefan
ID - 1617
JF - Journal of Complexity
TI - On the discrepancy of jittered sampling
VL - 33
ER -
TY - JOUR
AB - We consider the Bardeen–Cooper–Schrieffer free energy functional for particles interacting via a two-body potential on a microscopic scale and in the presence of weak external fields varying on a macroscopic scale. We study the influence of the external fields on the critical temperature. We show that in the limit where the ratio between the microscopic and macroscopic scale tends to zero, the next to leading order of the critical temperature is determined by the lowest eigenvalue of the linearization of the Ginzburg–Landau equation.
AU - Frank, Rupert
AU - Hainzl, Christian
AU - Seiringer, Robert
AU - Solovej, Jan
ID - 1620
IS - 1
JF - Communications in Mathematical Physics
TI - The external field dependence of the BCS critical temperature
VL - 342
ER -
TY - JOUR
AB - We prove analogues of the Lieb–Thirring and Hardy–Lieb–Thirring inequalities for many-body quantum systems with fractional kinetic operators and homogeneous interaction potentials, where no anti-symmetry on the wave functions is assumed. These many-body inequalities imply interesting one-body interpolation inequalities, and we show that the corresponding one- and many-body inequalities are actually equivalent in certain cases.
AU - Lundholm, Douglas
AU - Nam, Phan
AU - Portmann, Fabian
ID - 1622
IS - 3
JF - Archive for Rational Mechanics and Analysis
TI - Fractional Hardy–Lieb–Thirring and related Inequalities for interacting systems
VL - 219
ER -
TY - JOUR
AB - Ancestral processes are fundamental to modern population genetics and spatial structure has been the subject of intense interest for many years. Despite this interest, almost nothing is known about the distribution of the locations of pedigree or genetic ancestors. Using both spatially continuous and stepping-stone models, we show that the distribution of pedigree ancestors approaches a travelling wave, for which we develop two alternative approximations. The speed and width of the wave are sensitive to the local details of the model. After a short time, genetic ancestors spread far more slowly than pedigree ancestors, ultimately diffusing out with radius ## rather than spreading at constant speed. In contrast to the wave of pedigree ancestors, the spread of genetic ancestry is insensitive to the local details of the models.
AU - Kelleher, Jerome
AU - Etheridge, Alison
AU - Véber, Amandine
AU - Barton, Nicholas H
ID - 1631
JF - Theoretical Population Biology
TI - Spread of pedigree versus genetic ancestry in spatially distributed populations
VL - 108
ER -
TY - JOUR
AB - The plant hormone auxin (indole-3-acetic acid) is a major regulator of plant growth and development including embryo and root patterning, lateral organ formation and growth responses to environmental stimuli. Auxin is directionally transported from cell to cell by the action of specific auxin influx [AUXIN-RESISTANT1 (AUX1)] and efflux [PIN-FORMED (PIN)] transport regulators, whose polar, subcellular localizations are aligned with the direction of the auxin flow. Auxin itself regulates its own transport by modulation of the expression and subcellular localization of the auxin transporters. Increased auxin levels promote the transcription of PIN2 and AUX1 genes as well as stabilize PIN proteins at the plasma membrane, whereas prolonged auxin exposure increases the turnover of PIN proteins and their degradation in the vacuole. In this study, we applied a forward genetic approach, to identify molecular components playing a role in the auxin-mediated degradation. We generated EMS-mutagenized Arabidopsis PIN2::PIN2:GFP, AUX1::AUX1:YFP eir1aux1 populations and designed a screen for mutants with persistently strong fluorescent signals of the tagged PIN2 and AUX1 after prolonged treatment with the synthetic auxin 2,4-dichlorophenoxyacetic acid (2,4-D). This approach yielded novel auxin degradation mutants defective in trafficking and degradation of PIN2 and AUX1 proteins and established a role for auxin-mediated degradation in plant development.
AU - Zemová, Radka
AU - Zwiewka, Marta
AU - Bielach, Agnieszka
AU - Robert, Hélène
AU - Friml, Jirí
ID - 1641
IS - 2
JF - Journal of Plant Growth Regulation
TI - A forward genetic screen for new regulators of auxin mediated degradation of auxin transport proteins in Arabidopsis thaliana
VL - 35
ER -
TY - CONF
AB - A somewhere statistically binding (SSB) hash, introduced by Hubáček and Wichs (ITCS ’15), can be used to hash a long string x to a short digest y = H hk (x) using a public hashing-key hk. Furthermore, there is a way to set up the hash key hk to make it statistically binding on some arbitrary hidden position i, meaning that: (1) the digest y completely determines the i’th bit (or symbol) of x so that all pre-images of y have the same value in the i’th position, (2) it is computationally infeasible to distinguish the position i on which hk is statistically binding from any other position i’. Lastly, the hash should have a local opening property analogous to Merkle-Tree hashing, meaning that given x and y = H hk (x) it should be possible to create a short proof π that certifies the value of the i’th bit (or symbol) of x without having to provide the entire input x. A similar primitive called a positional accumulator, introduced by Koppula, Lewko and Waters (STOC ’15) further supports dynamic updates of the hashed value. These tools, which are interesting in their own right, also serve as one of the main technical components in several recent works building advanced applications from indistinguishability obfuscation (iO).
The prior constructions of SSB hashing and positional accumulators required fully homomorphic encryption (FHE) and iO respectively. In this work, we give new constructions of these tools based on well studied number-theoretic assumptions such as DDH, Phi-Hiding and DCR, as well as a general construction from lossy/injective functions.
AU - Okamoto, Tatsuaki
AU - Pietrzak, Krzysztof Z
AU - Waters, Brent
AU - Wichs, Daniel
ID - 1653
TI - New realizations of somewhere statistically binding hashing and positional accumulators
VL - 9452
ER -
TY - JOUR
AB - We introduce a modification of the classic notion of intrinsic volume using persistence moments of height functions. Evaluating the modified first intrinsic volume on digital approximations of a compact body with smoothly embedded boundary in Rn, we prove convergence to the first intrinsic volume of the body as the resolution of the approximation improves. We have weaker results for the other modified intrinsic volumes, proving they converge to the corresponding intrinsic volumes of the n-dimensional unit ball.
AU - Edelsbrunner, Herbert
AU - Pausinger, Florian
ID - 1662
JF - Advances in Mathematics
TI - Approximation and convergence of the intrinsic volume
VL - 287
ER -
TY - JOUR
AB - We introduce a scheme for preparation, manipulation, and read out of Majorana zero modes in semiconducting wires with mesoscopic superconducting islands. Our approach synthesizes recent advances in materials growth with tools commonly used in quantum-dot experiments, including gate control of tunnel barriers and Coulomb effects, charge sensing, and charge pumping. We outline a sequence of milestones interpolating between zero-mode detection and quantum computing that includes (1) detection of fusion rules for non-Abelian anyons using either proximal charge sensors or pumped current, (2) validation of a prototype topological qubit, and (3) demonstration of non-Abelian statistics by braiding in a branched geometry. The first two milestones require only a single wire with two islands, and additionally enable sensitive measurements of the system\'s excitation gap, quasiparticle poisoning rates, residual Majorana zero-mode splittings, and topological-qubit coherence times. These pre-braiding experiments can be adapted to other manipulation and read out schemes as well.
AU - Aasen, David
AU - Hell, Michael
AU - Mishmash, Ryan
AU - Higginbotham, Andrew P
AU - Danon, Jeroen
AU - Leijnse, Martin
AU - Jespersen, Thomas
AU - Folk, Joshua
AU - Marcs, Charles
AU - Flensberg, Karsten
AU - Alicea, Jason
ID - 100
IS - 3
JF - Physical Review X
TI - Milestones toward Majorana-based quantum computing
VL - 6
ER -
TY - JOUR
AB - Feedback loops in biological networks, among others, enable differentiation and cell cycle progression, and increase robustness in signal transduction. In natural networks, feedback loops are often complex and intertwined, making it challenging to identify which loops are mainly responsible for an observed behavior. However, minimal synthetic replicas could allow for such identification. Here, we engineered a synthetic permease-inducer-repressor system in Saccharomyces cerevisiae to analyze if a transport-mediated positive feedback loop could be a core mechanism for the switch-like behavior in the regulation of metabolic gene networks such as the S. cerevisiae GAL system or the Escherichia coli lac operon. We characterized the synthetic circuit using deterministic and stochastic mathematical models. Similar to its natural counterparts, our synthetic system shows bistable and hysteretic behavior, and the inducer concentration range for bistability as well as the switching rates between the two stable states depend on the repressor concentration. Our results indicate that a generic permease–inducer–repressor circuit with a single feedback loop is sufficient to explain the experimentally observed bistable behavior of the natural systems. We anticipate that the approach of reimplementing natural systems with orthogonal parts to identify crucial network components is applicable to other natural systems such as signaling pathways.
AU - Gnügge, Robert
AU - Dharmarajan, Lekshmi
AU - Lang, Moritz
AU - Stelling, Jörg
ID - 1008
IS - 10
JF - ACS Synthetic Biology
TI - An orthogonal permease–inducer–repressor feedback loop shows bistability
VL - 5
ER -
TY - JOUR
AB - Majorana zero modes are quasiparticle excitations in condensed matter systems that have been proposed as building blocks of fault-tolerant quantum computers. They are expected to exhibit non-Abelian particle statistics, in contrast to the usual statistics of fermions and bosons, enabling quantum operations to be performed by braiding isolated modes around one another. Quantum braiding operations are topologically protected insofar as these modes are pinned near zero energy, with the departure from zero expected to be exponentially small as the modes become spatially separated. Following theoretical proposals, several experiments have identified signatures of Majorana modes in nanowires with proximity-induced superconductivity and atomic chains, with small amounts of mode splitting potentially explained by hybridization of Majorana modes. Here, we use Coulomb-blockade spectroscopy in an InAs nanowire segment with epitaxial aluminium, which forms a proximity-induced superconducting Coulomb island (a â ∼ Majorana islandâ (tm)) that is isolated from normal-metal leads by tunnel barriers, to measure the splitting of near-zero-energy Majorana modes. We observe exponential suppression of energy splitting with increasing wire length. For short devices of a few hundred nanometres, sub-gap state energies oscillate as the magnetic field is varied, as is expected for hybridized Majorana modes. Splitting decreases by a factor of about ten for each half a micrometre of increased wire length. For devices longer than about one micrometre, transport in strong magnetic fields occurs through a zero-energy state that is energetically isolated from a continuum, yielding uniformly spaced Coulomb-blockade conductance peaks, consistent with teleportation via Majorana modes. Our results help to explain the trivial-to-topological transition in finite systems and to quantify the scaling of topological protection with end-mode separation.
AU - Albrecht, S M
AU - Higginbotham, Andrew P
AU - Jespersen, Thomas
AU - Madsen, Morten
AU - Kuemmeth, Ferdinand
AU - Nygård, Jesper
AU - Krogstrup, Peter
AU - Marcus, Charles
ID - 101
IS - 7593
JF - Nature
TI - Exponential protection of zero modes in Majorana islands
VL - 531
ER -
TY - JOUR
AB - Recent experiments have produced mounting evidence of Majorana zero modes in nanowire-superconductor hybrids. Signatures of an expected topological phase transition accompanying the onset of these modes nevertheless remain elusive. We investigate a fundamental question concerning this issue: Do well-formed Majorana modes necessarily entail a sharp phase transition in these setups? Assuming reasonable parameters, we argue that finite-size effects can dramatically smooth this putative transition into a crossover, even in systems large enough to support well-localized Majorana modes. We propose overcoming such finite-size effects by examining the behavior of low-lying excited states through tunneling spectroscopy. In particular, the excited-state energies exhibit characteristic field and density dependence, and scaling with system size, that expose an approaching topological phase transition. We suggest several experiments for extracting the predicted behavior. As a useful byproduct, the protocols also allow one to measure the wire's spin-orbit coupling directly in its superconducting environment.
AU - Mishmash, Ryan
AU - Aasen, David
AU - Higginbotham, Andrew P
AU - Alicea, Jason
ID - 102
IS - 24
JF - Physical Review B
TI - Approaching a topological phase transition in Majorana nanowires
VL - 93
ER -
TY - JOUR
AB - Far-field super-resolution fluorescence microscopy discerns fluorophores residing closer than the diffraction barrier by briefly transferring them in different (typically ON and OFF) states before detection. In coordinate-targeted super-resolution variants, such as stimulated emission depletion (STED) microscopy, this state difference is created by the intensity minima and maxima of an optical pattern, causing all fluorophores to assume the off state, for instance, except at the minima. Although strong spatial confinement of the on state enables high resolution, it also subjects the fluorophores to excess intensities and state cycles at the maxima. Here, we address these issues by driving the fluorophores into a second off state that is inert to the excess light. By using reversibly switchable fluorescent proteins as labels, our approach reduces bleaching and enhances resolution and contrast in live-cell STED microscopy. Using two or more transitions to off states is a useful strategy for augmenting the power of coordinate-targeted super-resolution microscopy.
AU - Danzl, Johann G
AU - Sidenstein, Sven
AU - Gregor, Carola
AU - Urban, Nicolai
AU - Ilgen, Peter
AU - Jakobs, Stefan
AU - Hell, Stefan
ID - 1057
IS - 2
JF - Nature Photonics
TI - Coordinate-targeted fluorescence nanoscopy with multiple off states
VL - 10
ER -
TY - JOUR
AB - A range of bright and photostable rhodamines and carbopyronines with absorption maxima in the range of λ=500-630 nm were prepared, and enabled the specific labeling of cytoskeletal filaments using HaloTag technology followed by staining with 1 μm solutions of the dye-ligand conjugates. The synthesis, photophysical parameters, fluorogenic behavior, and structure-property relationships of the new dyes are discussed. Light microscopy with stimulated emission depletion (STED) provided one- and two-color images of living cells with an optical resolution of 40-60 nm.
AU - Butkevich, Alexey
AU - Mitronova, Gyuzel
AU - Sidenstein, Sven
AU - Klocke, Jessica
AU - Kamin, Dirk
AU - Meineke, Dirk
AU - D'Este, Elisa
AU - Kraemer, Philip
AU - Danzl, Johann G
AU - Belov, Vladimir
AU - Hell, Stefan
ID - 1059
IS - 10
JF - Angewandte Chemie - International Edition
TI - Fluorescent rhodamines and fluorogenic carbopyronines for super-resolution STED microscopy in living cells
VL - 55
ER -
TY - JOUR
AB - Superresolution fluorescence microscopy of multiple fluorophores still requires development. Here we present simultaneous three-colour stimulated emission depletion (STED) nanoscopy relying on a single STED beam at 620 nm. Toggling the STED beam between two or more power levels ("multilevelSTEDv) optimizes resolution and contrast in all colour channels, which are intrinsically co-aligned and well separated. Three-colour recording is demonstrated by imaging the nanoscale cytoskeletal organization in cultured hippocampal neurons. The down to ∼35 nm resolution identified periodic actin/betaII spectrin lattices along dendrites and spines; however, at presynaptic and postsynaptic sites, these patterns were found to be absent. Both our multicolour scheme and the 620 nm STED line should be attractive for routine STED microscopy applications.
AU - Sidenstein, Sven
AU - D'Este, Elisa
AU - Böhm, Marvin
AU - Danzl, Johann G
AU - Belov, Vladimir
AU - Hell, Stefan
ID - 1060
JF - Scientific Reports
TI - Multicolour multilevel STED nanoscopy of actin/spectrin organization at synapses
VL - 6
ER -
TY - CONF
AB - Games on graphs provide the appropriate framework to study several central problems in computer science, such as verification and synthesis of reactive systems. One of the most basic objectives for games on graphs is the liveness (or Büchi) objective that given a target set of vertices requires that some vertex in the target set is visited infinitely often. We study generalized Büchi objectives (i.e., conjunction of liveness objectives), and implications between two generalized Büchi objectives (known as GR(1) objectives), that arise in numerous applications in computer-aided verification. We present improved algorithms and conditional super-linear lower bounds based on widely believed assumptions about the complexity of (A1) combinatorial Boolean matrix multiplication and (A2) CNF-SAT. We consider graph games with n vertices, m edges, and generalized Büchi objectives with k conjunctions. First, we present an algorithm with running time O(k*n^2), improving the previously known O(k*n*m) and O(k^2*n^2) worst-case bounds. Our algorithm is optimal for dense graphs under (A1). Second, we show that the basic algorithm for the problem is optimal for sparse graphs when the target sets have constant size under (A2). Finally, we consider GR(1) objectives, with k_1 conjunctions in the antecedent and k_2 conjunctions in the consequent, and present an O(k_1 k_2 n^{2.5})-time algorithm, improving the previously known O(k_1*k_2*n*m)-time algorithm for m > n^{1.5}.
AU - Chatterjee, Krishnendu
AU - Dvorák, Wolfgang
AU - Henzinger, Monika
AU - Loitzenbauer, Veronika
ID - 1068
TI - Conditionally optimal algorithms for generalized Büchi Games
VL - 58
ER -
TY - CONF
AB - The Continuous Skolem Problem asks whether a real-valued function satisfying a linear differen-
tial equation has a zero in a given interval of real numbers. This is a fundamental reachability
problem for continuous linear dynamical systems, such as linear hybrid automata and continuous-
time Markov chains. Decidability of the problem is currently open – indeed decidability is open
even for the sub-problem in which a zero is sought in a bounded interval. In this paper we show
decidability of the bounded problem subject to Schanuel’s Conjecture, a unifying conjecture in
transcendental number theory. We furthermore analyse the unbounded problem in terms of the
frequencies of the differential equation, that is, the imaginary parts of the characteristic roots.
We show that the unbounded problem can be reduced to the bounded problem if there is at most
one rationally linearly independent frequency, or if there are two rationally linearly independent
frequencies and all characteristic roots are simple. We complete the picture by showing that de-
cidability of the unbounded problem in the case of two (or more) rationally linearly independent
frequencies would entail a major new effectiveness result in Diophantine approximation, namely
computability of the Diophantine-approximation types of all real algebraic numbers.
AU - Chonev, Ventsislav K
AU - Ouaknine, Joël
AU - Worrell, James
ID - 1069
TI - On the skolem problem for continuous linear dynamical systems
VL - 55
ER -
TY - CONF
AB - We present a logic that extends CTL (Computation Tree Logic) with operators that express synchronization properties. A property is synchronized in a system if it holds in all paths of a certain length. The new logic is obtained by using the same path quantifiers and temporal operators as in CTL, but allowing a different order of the quantifiers. This small syntactic variation induces a logic that can express non-regular properties for which known extensions of MSO with equality of path length are undecidable. We show that our variant of CTL is decidable and that the model-checking problem is in Delta_3^P = P^{NP^NP}, and is DP-hard. We analogously consider quantifier exchange in extensions of CTL, and we present operators defined using basic operators of CTL* that express the occurrence of infinitely many synchronization points. We show that the model-checking problem remains in Delta_3^P. The distinguishing power of CTL and of our new logic coincide if the Next operator is allowed in the logics, thus the classical bisimulation quotient can be used for state-space reduction before model checking.
AU - Chatterjee, Krishnendu
AU - Doyen, Laurent
ID - 1070
TI - Computation tree logic for synchronization properties
VL - 55
ER -
TY - CONF
AB - We consider data-structures for answering reachability and distance queries on constant-treewidth graphs with n nodes, on the standard RAM computational model with wordsize W=Theta(log n). Our first contribution is a data-structure that after O(n) preprocessing time, allows (1) pair reachability queries in O(1) time; and (2) single-source reachability queries in O(n/log n) time. This is (asymptotically) optimal and is faster than DFS/BFS when answering more than a constant number of single-source queries. The data-structure uses at all times O(n) space. Our second contribution is a space-time tradeoff data-structure for distance queries. For any epsilon in [1/2,1], we provide a data-structure with polynomial preprocessing time that allows pair queries in O(n^{1-\epsilon} alpha(n)) time, where alpha is the inverse of the Ackermann function, and at all times uses O(n^epsilon) space. The input graph G is not considered in the space complexity.
AU - Chatterjee, Krishnendu
AU - Ibsen-Jensen, Rasmus
AU - Pavlogiannis, Andreas
ID - 1071
TI - Optimal reachability and a space time tradeoff for distance queries in constant treewidth graphs
VL - 57
ER -
TY - JOUR
AB - The asymmetric localization of proteins in the plasma membrane domains of eukaryotic cells is a fundamental manifestation of cell polarity that is central to multicellular organization and developmental patterning. In plants, the mechanisms underlying the polar localization of cargo proteins are still largely unknown and appear to be fundamentally distinct from those operating in mammals. Here, we present a systematic, quantitative comparative analysis of the polar delivery and subcellular localization of proteins that characterize distinct polar plasma membrane domains in plant cells. The combination of microscopic analyses and computational modeling revealed a mechanistic framework common to diverse polar cargos and underlying the establishment and maintenance of apical, basal, and lateral polar domains in plant cells. This mechanism depends on the polar secretion, constitutive endocytic recycling, and restricted lateral diffusion of cargos within the plasma membrane. Moreover, our observations suggest that polar cargo distribution involves the individual protein potential to form clusters within the plasma membrane and interact with the extracellular matrix. Our observations provide insights into the shared cellular mechanisms of polar cargo delivery and polarity maintenance in plant cells.
AU - Łangowski, Łukasz
AU - Wabnik, Krzysztof T
AU - Li, Hongjiang
AU - Vanneste, Steffen
AU - Naramoto, Satoshi
AU - Tanaka, Hirokazu
AU - Friml, Jirí
ID - 1081
JF - Cell Discovery
TI - Cellular mechanisms for cargo delivery and polarity maintenance at different polar domains in plant cells
VL - 2
ER -
TY - CONF
AB - In many applications, it is desirable to extract only the relevant aspects of data. A principled way to do this is the information bottleneck (IB) method, where one seeks a code that maximises information about a relevance variable, Y, while constraining the information encoded about the original data, X. Unfortunately however, the IB method is computationally demanding when data are high-dimensional and/or non-gaussian. Here we propose an approximate variational scheme for maximising a lower bound on the IB objective, analogous to variational EM. Using this method, we derive an IB algorithm to recover features that are both relevant and sparse. Finally, we demonstrate how kernelised versions of the algorithm can be used to address a broad range of problems with non-linear relation between X and Y.
AU - Chalk, Matthew J
AU - Marre, Olivier
AU - Tkacik, Gasper
ID - 1082
TI - Relevant sparse codes with variational information bottleneck
VL - 29
ER -
TY - JOUR
AB - Cholecystokinin-expressing interneurons (CCK-INs) mediate behavior state-dependent inhibition in cortical circuits and themselves receive strong GABAergic input. However, it remains unclear to what extent GABABreceptors (GABABRs) contribute to their inhibitory control. Using immunoelectron microscopy, we found that CCK-INs in the rat hippocampus possessed high levels of dendritic GABABRs and KCTD12 auxiliary proteins, whereas postsynaptic effector Kir3 channels were present at lower levels. Consistently, whole-cell recordings revealed slow GABABR-mediated inhibitory postsynaptic currents (IPSCs) in most CCK-INs. In spite of the higher surface density of GABABRs in CCK-INs than in CA1 principal cells, the amplitudes of IPSCs were comparable, suggesting that the expression of Kir3 channels is the limiting factor for the GABABR currents in these INs. Morphological analysis showed that CCK-INs were diverse, comprising perisomatic-targeting basket cells (BCs), as well as dendrite-targeting (DT) interneurons, including a previously undescribed DT type. GABABR-mediated IPSCs in CCK-INs were large in BCs, but small in DT subtypes. In response to prolonged activation, GABABR-mediated currents displayed strong desensitization, which was absent in KCTD12-deficient mice. This study highlights that GABABRs differentially control CCK-IN subtypes, and the kinetics and desensitization of GABABR-mediated currents are modulated by KCTD12 proteins.
AU - Booker, Sam
AU - Althof, Daniel
AU - Gross, Anna
AU - Loreth, Desiree
AU - Müller, Johanna
AU - Unger, Andreas
AU - Fakler, Bernd
AU - Varro, Andrea
AU - Watanabe, Masahiko
AU - Gassmann, Martin
AU - Bettler, Bernhard
AU - Shigemoto, Ryuichi
AU - Vida, Imre
AU - Kulik, Ákos
ID - 1083
IS - 3
JF - Cerebral Cortex
TI - KCTD12 auxiliary proteins modulate kinetics of GABAB receptor-mediated inhibition in Cholecystokinin-containing interneurons
VL - 27
ER -
TY - JOUR
AB - Cell geometry is tightly coupled to gene expression patterns within the tissue microenvironment. This perspective synthesizes evidence that the 3D organization of chromosomes is a critical intermediate for geometric control of genomic programs. Using a combination of experiments and modeling we outline approaches to decipher the mechano-genomic code that governs cellular homeostasis and reprogramming.
AU - Uhler, Caroline
AU - Shivashankar, G V
ID - 1088
IS - 4
JF - BioArchitecture
TI - Geometric control and modeling of genome reprogramming
VL - 6
ER -
TY - CONF
AB - While weighted automata provide a natural framework to express quantitative properties, many basic properties like average response time cannot be expressed with weighted automata. Nested weighted automata extend weighted automata and consist of a master automaton and a set of slave automata that are invoked by the master automaton. Nested weighted automata are strictly more expressive than weighted automata (e.g., average response time can be expressed with nested weighted automata), but the basic decision questions have higher complexity (e.g., for deterministic automata, the emptiness question for nested weighted automata is PSPACE-hard, whereas the corresponding complexity for weighted automata is PTIME). We consider a natural subclass of nested weighted automata where at any point at most a bounded number k of slave automata can be active. We focus on automata whose master value function is the limit average. We show that these nested weighted automata with bounded width are strictly more expressive than weighted automata (e.g., average response time with no overlapping requests can be expressed with bound k=1, but not with non-nested weighted automata). We show that the complexity of the basic decision problems (i.e., emptiness and universality) for the subclass with k constant matches the complexity for weighted automata. Moreover, when k is part of the input given in unary we establish PSPACE-completeness.
AU - Chatterjee, Krishnendu
AU - Henzinger, Thomas A
AU - Otop, Jan
ID - 1090
TI - Nested weighted limit-average automata of bounded width
VL - 58
ER -
TY - CONF
AB - We introduce a general class of distances (metrics) between Markov chains, which are based on linear behaviour. This class encompasses distances given topologically (such as the total variation distance or trace distance) as well as by temporal logics or automata. We investigate which of the distances can be approximated by observing the systems, i.e. by black-box testing or simulation, and we provide both negative and positive results.
AU - Daca, Przemyslaw
AU - Henzinger, Thomas A
AU - Kretinsky, Jan
AU - Petrov, Tatjana
ID - 1093
TI - Linear distances between Markov chains
VL - 59
ER -
TY - CHAP
AB - Immunogold labeling of freeze-fracture replicas has recently been used for high-resolution visualization of protein localization in electron microscopy. This method has higher labeling efficiency than conventional immunogold methods for membrane molecules allowing precise quantitative measurements. However, one of the limitations of freeze-fracture replica immunolabeling is difficulty in keeping structural orientation and identifying labeled profiles in complex tissues like brain. The difficulty is partly due to fragmentation of freeze-fracture replica preparations during labeling procedures and limited morphological clues on the replica surface. To overcome these issues, we introduce here a grid-glued replica method combined with SEM observation. This method allows histological staining before dissolving the tissue and easy handling of replicas during immunogold labeling, and keeps the whole replica surface intact without fragmentation. The procedure described here is also useful for matched double-replica analysis allowing further identification of labeled profiles in corresponding P-face and E-face.
AU - Harada, Harumi
AU - Shigemoto, Ryuichi
ID - 1094
T2 - High-Resolution Imaging of Cellular Proteins
TI - Immunogold protein localization on grid-glued freeze-fracture replicas
VL - 1474
ER -
TY - CONF
AB - The semantics of concurrent data structures is usually given by a sequential specification and a consistency condition. Linearizability is the most popular consistency condition due to its simplicity and general applicability. Nevertheless, for applications that do not require all guarantees offered by linearizability, recent research has focused on improving performance and scalability of concurrent data structures by relaxing their semantics. In this paper, we present local linearizability, a relaxed consistency condition that is applicable to container-type concurrent data structures like pools, queues, and stacks. While linearizability requires that the effect of each operation is observed by all threads at the same time, local linearizability only requires that for each thread T, the effects of its local insertion operations and the effects of those removal operations that remove values inserted by T are observed by all threads at the same time. We investigate theoretical and practical properties of local linearizability and its relationship to many existing consistency conditions. We present a generic implementation method for locally linearizable data structures that uses existing linearizable data structures as building blocks. Our implementations show performance and scalability improvements over the original building blocks and outperform the fastest existing container-type implementations.
AU - Haas, Andreas
AU - Henzinger, Thomas A
AU - Holzer, Andreas
AU - Kirsch, Christoph
AU - Lippautz, Michael
AU - Payer, Hannes
AU - Sezgin, Ali
AU - Sokolova, Ana
AU - Veith, Helmut
ID - 1095
T2 - Leibniz International Proceedings in Informatics
TI - Local linearizability for concurrent container-type data structures
VL - 59
ER -
TY - JOUR
AU - Schwayer, Cornelia
AU - Sikora, Mateusz K
AU - Slovakova, Jana
AU - Kardos, Roland
AU - Heisenberg, Carl-Philipp J
ID - 1096
IS - 6
JF - Developmental Cell
TI - Actin rings of power
VL - 37
ER -
TY - CONF
AB - We present an interactive system for computational design, optimization, and fabrication of multicopters. Our computational approach allows non-experts to design, explore, and evaluate a wide range of different multicopters. We provide users with an intuitive interface for assembling a multicopter from a collection of components (e.g., propellers, motors, and carbon fiber rods). Our algorithm interactively optimizes shape and controller parameters of the current design to ensure its proper operation. In addition, we allow incorporating a variety of other metrics (such as payload, battery usage, size, and cost) into the design process and exploring tradeoffs between them. We show the efficacy of our method and system by designing, optimizing, fabricating, and operating multicopters with complex geometries and propeller configurations. We also demonstrate the ability of our optimization algorithm to improve the multicopter performance under different metrics.
AU - Du, Tao
AU - Schulz, Adriana
AU - Zhu, Bo
AU - Bickel, Bernd
AU - Matusik, Wojciech
ID - 1097
IS - 6
TI - Computational multicopter design
VL - 35
ER -
TY - CONF
AB - Better understanding of the potential benefits of information transfer and representation learning is an important step towards the goal of building intelligent systems that are able to persist in the world and learn over time. In this work, we consider a setting where the learner encounters a stream of tasks but is able to retain only limited information from each encountered task, such as a learned predictor. In contrast to most previous works analyzing this scenario, we do not make any distributional assumptions on the task generating process. Instead, we formulate a complexity measure that captures the diversity of the observed tasks. We provide a lifelong learning algorithm with error guarantees for every observed task (rather than on average). We show sample complexity reductions in comparison to solving every task in isolation in terms of our task complexity measure. Further, our algorithmic framework can naturally be viewed as learning a representation from encountered tasks with a neural network.
AU - Pentina, Anastasia
AU - Urner, Ruth
ID - 1098
TI - Lifelong learning with weighted majority votes
VL - 29
ER -
TY - CONF
AB - We present FlexMolds, a novel computational approach to automatically design flexible, reusable molds that, once 3D printed, allow us to physically fabricate, by means of liquid casting, multiple copies of complex shapes with rich surface details and complex topology. The approach to design such flexible molds is based on a greedy bottom-up search of possible cuts over an object, evaluating for each possible cut the feasibility of the resulting mold. We use a dynamic simulation approach to evaluate candidate molds, providing a heuristic to generate forces that are able to open, detach, and remove a complex mold from the object it surrounds. We have tested the approach with a number of objects with nontrivial shapes and topologies.
AU - Malomo, Luigi
AU - Pietroni, Nico
AU - Bickel, Bernd
AU - Cignoni, Paolo
ID - 1099
IS - 6
TI - FlexMolds: Automatic design of flexible shells for molding
VL - 35
ER -
TY - JOUR
AB - Optical sensors based on the phenomenon of Förster resonance energy transfer (FRET) are powerful tools that have advanced the study of small molecules in biological systems. However, sensor construction is not trivial and often requires multiple rounds of engineering or an ability to screen large numbers of variants. A method that would allow the accurate rational design of FRET sensors would expedite the production of biologically useful sensors. Here, we present Rangefinder, a computational algorithm that allows rapid in silico screening of dye attachment sites in a ligand-binding protein for the conjugation of a dye molecule to act as a Förster acceptor for a fused fluorescent protein. We present three ratiometric fluorescent sensors designed with Rangefinder, including a maltose sensor with a dynamic range of >300% and the first sensors for the most abundant sialic acid in human cells, N-acetylneuraminic acid. Provided a ligand-binding protein exists, it is our expectation that this model will facilitate the design of an optical sensor for any small molecule of interest.
AU - Mitchell, Joshua
AU - Whitfield, Jason
AU - Zhang, William
AU - Henneberger, Christian
AU - Janovjak, Harald L
AU - O'Mara, Megan
AU - Jackson, Colin
ID - 1101
IS - 11
JF - ACS SENSORS
TI - Rangefinder: A semisynthetic FRET sensor design algorithm
VL - 1
ER -
TY - CONF
AB - Weakly-supervised object localization methods tend to fail for object classes that consistently co-occur with the same background elements, e.g. trains on tracks. We propose a method to overcome these failures by adding a very small amount of model-specific additional annotation. The main idea is to cluster a deep network\'s mid-level representations and assign object or distractor labels to each cluster. Experiments show substantially improved localization results on the challenging ILSVC2014 dataset for bounding box detection and the PASCAL VOC2012 dataset for semantic segmentation.
AU - Kolesnikov, Alexander
AU - Lampert, Christoph
ID - 1102
T2 - Proceedings of the British Machine Vision Conference 2016
TI - Improving weakly-supervised object localization by micro-annotation
VL - 2016-September
ER -
TY - CONF
AB - We propose two parallel state-space-exploration algorithms for hybrid automaton (HA), with the goal of enhancing performance on multi-core shared-memory systems. The first uses the parallel, breadth-first-search algorithm (PBFS) of the SPIN model checker, when traversing the discrete modes of the HA, and enhances it with a parallel exploration of the continuous states within each mode. We show that this simple-minded extension of PBFS does not provide the desired load balancing in many HA benchmarks. The second algorithm is a task-parallel BFS algorithm (TP-BFS), which uses a cheap precomputation of the cost associated with the post operations (both continuous and discrete) in order to improve load balancing. We illustrate the TP-BFS and the cost precomputation of the post operators on a support-function-based algorithm for state-space exploration. The performance comparison of the two algorithms shows that, in general, TP-BFS provides a better utilization/load-balancing of the CPU. Both algorithms are implemented in the model checker XSpeed. Our experiments show a maximum speed-up of more than 2000 χ on a navigation benchmark, with respect to SpaceEx LGG scenario. In order to make the comparison fair, we employed an equal number of post operations in both tools. To the best of our knowledge, this paper represents the first attempt to provide parallel, reachability-analysis algorithms for HA.
AU - Gurung, Amit
AU - Deka, Arup
AU - Bartocci, Ezio
AU - Bogomolov, Sergiy
AU - Grosu, Radu
AU - Ray, Rajarshi
ID - 1103
TI - Parallel reachability analysis for hybrid systems
ER -
TY - CONF
AB - Jointly characterizing neural responses in terms of several external variables promises novel insights into circuit function, but remains computationally prohibitive in practice. Here we use gaussian process (GP) priors and exploit recent advances in fast GP inference and learning based on Kronecker methods, to efficiently estimate multidimensional nonlinear tuning functions. Our estimator require considerably less data than traditional methods and further provides principled uncertainty estimates. We apply these tools to hippocampal recordings during open field exploration and use them to characterize the joint dependence of CA1 responses on the position of the animal and several other variables, including the animal\'s speed, direction of motion, and network oscillations.Our results provide an unprecedentedly detailed quantification of the tuning of hippocampal neurons. The model\'s generality suggests that our approach can be used to estimate neural response properties in other brain regions.
AU - Savin, Cristina
AU - Tkacik, Gasper
ID - 1105
TI - Estimating nonlinear neural response functions using GP priors and Kronecker methods
VL - 29
ER -
TY - CONF
AB - We present a coherent microwave to telecom signal converter based on the electro-optical effect using a crystalline WGM-resonator coupled to a 3D microwave cavity, achieving high photon conversion efficiency of 0.1% with MHz bandwidth.
AU - Rueda, Alfredo
AU - Sedlmeir, Florian
AU - Collodo, Michele
AU - Vogl, Ulrich
AU - Stiller, Birgit
AU - Schunk, Georg
AU - Strekalov, Dimitry
AU - Marquardt, Christoph
AU - Fink, Johannes M
AU - Painter, Oskar
AU - Leuchs, Gerd
AU - Schwefel, Harald
ID - 1115
TI - Efficient single sideband microwave to optical conversion using a LiNbO inf 3 inf WGM-resonator
ER -
TY - THES
AB - Computer graphics is an extremely exciting field for two reasons. On the one hand,
there is a healthy injection of pragmatism coming from the visual effects industry
that want robust algorithms that work so they can produce results at an increasingly
frantic pace. On the other hand, they must always try to push the envelope and
achieve the impossible to wow their audiences in the next blockbuster, which means
that the industry has not succumb to conservatism, and there is plenty of room to
try out new and crazy ideas if there is a chance that it will pan into something
useful.
Water simulation has been in visual effects for decades, however it still remains
extremely challenging because of its high computational cost and difficult artdirectability.
The work in this thesis tries to address some of these difficulties.
Specifically, we make the following three novel contributions to the state-of-the-art
in water simulation for visual effects.
First, we develop the first algorithm that can convert any sequence of closed
surfaces in time into a moving triangle mesh. State-of-the-art methods at the time
could only handle surfaces with fixed connectivity, but we are the first to be able to
handle surfaces that merge and split apart. This is important for water simulation
practitioners, because it allows them to convert splashy water surfaces extracted
from particles or simulated using grid-based level sets into triangle meshes that can
be either textured and enhanced with extra surface dynamics as a post-process.
We also apply our algorithm to other phenomena that merge and split apart, such
as morphs and noisy reconstructions of human performances.
Second, we formulate a surface-based energy that measures the deviation of a
water surface froma physically valid state. Such discrepancies arise when there is a
mismatch in the degrees of freedom between the water surface and the underlying
physics solver. This commonly happens when practitioners use a moving triangle
mesh with a grid-based physics solver, or when high-resolution grid-based surfaces
are combined with low-resolution physics. Following the direction of steepest
descent on our surface-based energy, we can either smooth these artifacts or turn
them into high-resolution waves by interpreting the energy as a physical potential.
Third, we extend state-of-the-art techniques in non-reflecting boundaries to handle spatially and time-varying background flows. This allows a novel new
workflow where practitioners can re-simulate part of an existing simulation, such
as removing a solid obstacle, adding a new splash or locally changing the resolution.
Such changes can easily lead to new waves in the re-simulated region that would
reflect off of the new simulation boundary, effectively ruining the illusion of a
seamless simulation boundary between the existing and new simulations. Our
non-reflecting boundaries makes sure that such waves are absorbed.
AU - Bojsen-Hansen, Morten
ID - 1122
TI - Tracking, correcting and absorbing water surface waves
ER -
TY - THES
AB - Traditionally machine learning has been focusing on the problem of solving a single
task in isolation. While being quite well understood, this approach disregards an
important aspect of human learning: when facing a new problem, humans are able to
exploit knowledge acquired from previously learned tasks. Intuitively, access to several
problems simultaneously or sequentially could also be advantageous for a machine
learning system, especially if these tasks are closely related. Indeed, results of many
empirical studies have provided justification for this intuition. However, theoretical
justifications of this idea are rather limited.
The focus of this thesis is to expand the understanding of potential benefits of information
transfer between several related learning problems. We provide theoretical
analysis for three scenarios of multi-task learning - multiple kernel learning, sequential
learning and active task selection. We also provide a PAC-Bayesian perspective on
lifelong learning and investigate how the task generation process influences the generalization
guarantees in this scenario. In addition, we show how some of the obtained
theoretical results can be used to derive principled multi-task and lifelong learning
algorithms and illustrate their performance on various synthetic and real-world datasets.
AU - Pentina, Anastasia
ID - 1126
TI - Theoretical foundations of multi-task lifelong learning
ER -
TY - THES
AB - The process of gene expression is central to the modern understanding of how cellular systems
function. In this process, a special kind of regulatory proteins, called transcription factors,
are important to determine how much protein is produced from a given gene. As biological
information is transmitted from transcription factor concentration to mRNA levels to amounts of
protein, various sources of noise arise and pose limits to the fidelity of intracellular signaling.
This thesis concerns itself with several aspects of stochastic gene expression: (i) the mathematical
description of complex promoters responsible for the stochastic production of biomolecules,
(ii) fundamental limits to information processing the cell faces due to the interference from multiple
fluctuating signals, (iii) how the presence of gene expression noise influences the evolution
of regulatory sequences, (iv) and tools for the experimental study of origins and consequences
of cell-cell heterogeneity, including an application to bacterial stress response systems.
AU - Rieckh, Georg
ID - 1128
TI - Studying the complexities of transcriptional regulation
ER -
TY - CONF
AB - Hybrid systems have both continuous and discrete dynamics and are useful for modeling a variety of control systems, from air traffic control protocols to robotic maneuvers and beyond. Recently, numerous powerful and scalable tools for analyzing hybrid systems have emerged. Several of these tools implement automated formal methods for mathematically proving a system meets a specification. This tutorial session will present three recent hybrid systems tools: C2E2, HyST, and TuLiP. C2E2 is a simulated-based verification tool for hybrid systems, and uses validated numerical solvers and bloating of simulation traces to verify systems meet specifications. HyST is a hybrid systems model transformation and translation tool, and uses a canonical intermediate representation to support most of the recent verification tools, as well as automated sound abstractions that simplify verification of a given hybrid system. TuLiP is a controller synthesis tool for hybrid systems, where given a temporal logic specification to be satisfied for a system (plant) model, TuLiP will find a controller that meets a given specification. © 2016 IEEE.
AU - Duggirala, Parasara
AU - Fan, Chuchu
AU - Potok, Matthew
AU - Qi, Bolun
AU - Mitra, Sayan
AU - Viswanathan, Mahesh
AU - Bak, Stanley
AU - Bogomolov, Sergiy
AU - Johnson, Taylor
AU - Nguyen, Luan
AU - Schilling, Christian
AU - Sogokon, Andrew
AU - Tran, Hoang
AU - Xiang, Weiming
ID - 1134
T2 - 2016 IEEE Conference on Control Applications
TI - Tutorial: Software tools for hybrid systems verification transformation and synthesis C2E2 HyST and TuLiP
ER -
TY - CONF
AB - Time-triggered (TT) switched networks are a deterministic communication infrastructure used by real-time distributed embedded systems. These networks rely on the notion of globally discretized time (i.e. time slots) and a static TT schedule that prescribes which message is sent through which link at every time slot, such that all messages reach their destination before a global timeout. These schedules are generated offline, assuming a static network with fault-free links, and entrusting all error-handling functions to the end user. Assuming the network is static is an over-optimistic view, and indeed links tend to fail in practice. We study synthesis of TT schedules on a network in which links fail over time and we assume the switches run a very simple error-recovery protocol once they detect a crashed link. We address the problem of finding a pk; qresistant schedule; namely, one that, assuming the switches run a fixed error-recovery protocol, guarantees that the number of messages that arrive at their destination by the timeout is at least no matter what sequence of at most k links fail. Thus, we maintain the simplicity of the switches while giving a guarantee on the number of messages that meet the timeout. We show how a pk; q-resistant schedule can be obtained using a CEGAR-like approach: find a schedule, decide whether it is pk; q-resistant, and if it is not, use the witnessing fault sequence to generate a constraint that is added to the program. The newly added constraint disallows the schedule to be regenerated in a future iteration while also eliminating several other schedules that are not pk; q-resistant. We illustrate the applicability of our approach using an SMT-based implementation. © 2016 ACM.
AU - Avni, Guy
AU - Guha, Shibashis
AU - Rodríguez Navas, Guillermo
ID - 1135
T2 - Proceedings of the 13th International Conference on Embedded Software
TI - Synthesizing time triggered schedules for switched networks with faulty links
ER -
TY - CONF
AB - We propose an interactive sculpting system for seamlessly editing pre-computed animations of liquid, without the need for any resimulation. The input is a sequence of meshes without correspondences representing the liquid surface over time. Our method enables the efficient selection of consistent space-time parts of this animation, such as moving waves or droplets, which we call space-time features. Once selected, a feature can be copied, edited, or duplicated and then pasted back anywhere in space and time in the same or in another liquid animation sequence. Our method circumvents tedious user interactions by automatically computing the spatial and temporal ranges of the selected feature. We also provide space-time shape editing tools for non-uniform scaling, rotation, trajectory changes, and temporal editing to locally speed up or slow down motion. Using our tools, the user can edit and progressively refine any input simulation result, possibly using a library of precomputed space-time features extracted from other animations. In contrast to the trial-and-error loop usually required to edit animation results through the tuning of indirect simulation parameters, our method gives the user full control over the edited space-time behaviors. © 2016 Copyright held by the owner/author(s).
AU - Manteaux, Pierre
AU - Vimont, Ulysse
AU - Wojtan, Christopher J
AU - Rohmer, Damien
AU - Cani, Marie
ID - 1136
T2 - Proceedings of the 9th International Conference on Motion in Games
TI - Space-time sculpting of liquid animation
ER -
TY - JOUR
AB - RASGRP1 is an important guanine nucleotide exchange factor and activator of the RAS-MAPK pathway following T cell antigen receptor (TCR) signaling. The consequences of RASGRP1 mutations in humans are unknown. In a patient with recurrent bacterial and viral infections, born to healthy consanguineous parents, we used homozygosity mapping and exome sequencing to identify a biallelic stop-gain variant in RASGRP1. This variant segregated perfectly with the disease and has not been reported in genetic databases. RASGRP1 deficiency was associated in T cells and B cells with decreased phosphorylation of the extracellular-signal-regulated serine kinase ERK, which was restored following expression of wild-type RASGRP1. RASGRP1 deficiency also resulted in defective proliferation, activation and motility of T cells and B cells. RASGRP1-deficient natural killer (NK) cells exhibited impaired cytotoxicity with defective granule convergence and actin accumulation. Interaction proteomics identified the dynein light chain DYNLL1 as interacting with RASGRP1, which links RASGRP1 to cytoskeletal dynamics. RASGRP1-deficient cells showed decreased activation of the GTPase RhoA. Treatment with lenalidomide increased RhoA activity and reversed the migration and activation defects of RASGRP1-deficient lymphocytes.
AU - Salzer, Elisabeth
AU - Çaǧdaş, Deniz
AU - Hons, Miroslav
AU - Mace, Emily
AU - Garncarz, Wojciech
AU - Petronczki, Oezlem
AU - Platzer, René
AU - Pfajfer, Laurène
AU - Bilic, Ivan
AU - Ban, Sol
AU - Willmann, Katharina
AU - Mukherjee, Malini
AU - Supper, Verena
AU - Hsu, Hsiangting
AU - Banerjee, Pinaki
AU - Sinha, Papiya
AU - Mcclanahan, Fabienne
AU - Zlabinger, Gerhard
AU - Pickl, Winfried
AU - Gribben, John
AU - Stockinger, Hannes
AU - Bennett, Keiryn
AU - Huppa, Johannes
AU - Dupré, Loï̈C
AU - Sanal, Özden
AU - Jäger, Ulrich
AU - Sixt, Michael K
AU - Tezcan, Ilhan
AU - Orange, Jordan
AU - Boztug, Kaan
ID - 1137
IS - 12
JF - Nature Immunology
TI - RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics
VL - 17
ER -
TY - CONF
AB - Automata with monitor counters, where the transitions do not depend on counter values, and nested weighted automata are two expressive automata-theoretic frameworks for quantitative properties. For a well-studied and wide class of quantitative functions, we establish that automata with monitor counters and nested weighted automata are equivalent. We study for the first time such quantitative automata under probabilistic semantics. We show that several problems that are undecidable for the classical questions of emptiness and universality become decidable under the probabilistic semantics. We present a complete picture of decidability for such automata, and even an almost-complete picture of computational complexity, for the probabilistic questions we consider. © 2016 ACM.
AU - Chatterjee, Krishnendu
AU - Henzinger, Thomas A
AU - Otop, Jan
ID - 1138
T2 - Proceedings of the 31st Annual ACM/IEEE Symposium
TI - Quantitative automata under probabilistic semantics
ER -
TY - JOUR
AB - Microtubules switch stochastically between phases of growth and shrinkage. The molecular mechanism responsible for the end of a growth phase, an event called catastrophe, is still not understood. The probability for a catastrophe to occur increases with microtubule age, putting constraints on the possible molecular mechanism of catastrophe induction. Here we used microfluidics-Assisted fast tubulin washout experiments to induce microtubule depolymerization in a controlled manner at different times after the start of growth. We found that aging can also be observed in this assay, providing valuable new constraints against which theoretical models of catastrophe induction can be tested. We found that the data can be quantitatively well explained by a simple kinetic threshold model that assumes an age-dependent broadening of the protective cap at the microtubule end as a result of an evolving tapered end structure; this leads to a decrease of the cap density and its stability. This analysis suggests an intuitive picture of the role of morphological changes of the protective cap for the age dependence of microtubule stability.
AU - Düllberg, Christian F
AU - Cade, Nicholas
AU - Surrey, Thomas
ID - 1139
IS - 22
JF - Molecular Biology and Evolution
TI - Microtubule aging probed by microfluidics assisted tubulin washout
VL - 27
ER -
TY - CONF
AB - Given a model of a system and an objective, the model-checking question asks whether the model satisfies the objective. We study polynomial-time problems in two classical models, graphs and Markov Decision Processes (MDPs), with respect to several fundamental -regular objectives, e.g., Rabin and Streett objectives. For many of these problems the best-known upper bounds are quadratic or cubic, yet no super-linear lower bounds are known. In this work our contributions are two-fold: First, we present several improved algorithms, and second, we present the first conditional super-linear lower bounds based on widely believed assumptions about the complexity of CNF-SAT and combinatorial Boolean matrix multiplication. A separation result for two models with respect to an objective means a conditional lower bound for one model that is strictly higher than the existing upper bound for the other model, and similarly for two objectives with respect to a model. Our results establish the following separation results: (1) A separation of models (graphs and MDPs) for disjunctive queries of reachability and Büchi objectives. (2) Two kinds of separations of objectives, both for graphs and MDPs, namely, (2a) the separation of dual objectives such as Streett/Rabin objectives, and (2b) the separation of conjunction and disjunction of multiple objectives of the same type such as safety, Büchi, and coBüchi. In summary, our results establish the first model and objective separation results for graphs and MDPs for various classical -regular objectives. Quite strikingly, we establish conditional lower bounds for the disjunction of objectives that are strictly higher than the existing upper bounds for the conjunction of the same objectives. © 2016 ACM.
AU - Chatterjee, Krishnendu
AU - Dvoák, Wolfgang
AU - Henzinger, Monika
AU - Loitzenbauer, Veronika
ID - 1140
T2 - Proceedings of the 31st Annual ACM/IEEE Symposium on Logic in Computer Science
TI - Model and objective separation with conditional lower bounds disjunction is harder than conjunction
ER -
TY - JOUR
AB - In this paper we introduce the Multiobjective Optimization Hierarchic Genetic Strategy with maturing (MO-mHGS), a meta-algorithm that performs evolutionary optimization in a hierarchy of populations. The maturing mechanism improves growth and reduces redundancy. The performance of MO-mHGS with selected state-of-the-art multiobjective evolutionary algorithms as internal algorithms is analysed on benchmark problems and their modifications for which single fitness evaluation time depends on the solution accuracy. We compare the proposed algorithm with the Island Model Genetic Algorithm as well as with single-deme methods, and discuss the impact of internal algorithms on the MO-mHGS meta-algorithm. © 2016 Elsevier B.V.
AU - Łazarz, Radosław
AU - Idzik, Michał
AU - Gądek, Konrad
AU - Gajda-Zagorska, Ewa P
ID - 1141
IS - 1
JF - Journal of Computational Science
TI - Hierarchic genetic strategy with maturing as a generic tool for multiobjective optimization
VL - 17
ER -
TY - JOUR
AB - Hemolysis drives susceptibility to bacterial infections and predicts poor outcome from sepsis. These detrimental effects are commonly considered to be a consequence of heme-iron serving as a nutrient for bacteria. We employed a Gram-negative sepsis model and found that elevated heme levels impaired the control of bacterial proliferation independently of heme-iron acquisition by pathogens. Heme strongly inhibited phagocytosis and the migration of human and mouse phagocytes by disrupting actin cytoskeletal dynamics via activation of the GTP-binding Rho family protein Cdc42 by the guanine nucleotide exchange factor DOCK8. A chemical screening approach revealed that quinine effectively prevented heme effects on the cytoskeleton, restored phagocytosis and improved survival in sepsis. These mechanistic insights provide potential therapeutic targets for patients with sepsis or hemolytic disorders.
AU - Martins, Rui
AU - Maier, Julia
AU - Gorki, Anna
AU - Huber, Kilian
AU - Sharif, Omar
AU - Starkl, Philipp
AU - Saluzzo, Simona
AU - Quattrone, Federica
AU - Gawish, Riem
AU - Lakovits, Karin
AU - Aichinger, Michael
AU - Radic Sarikas, Branka
AU - Lardeau, Charles
AU - Hladik, Anastasiya
AU - Korosec, Ana
AU - Brown, Markus
AU - Vaahtomeri, Kari
AU - Duggan, Michelle
AU - Kerjaschki, Dontscho
AU - Esterbauer, Harald
AU - Colinge, Jacques
AU - Eisenbarth, Stephanie
AU - Decker, Thomas
AU - Bennett, Keiryn
AU - Kubicek, Stefan
AU - Sixt, Michael K
AU - Superti Furga, Giulio
AU - Knapp, Sylvia
ID - 1142
IS - 12
JF - Nature Immunology
TI - Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions
VL - 17
ER -
TY - JOUR
AB - We study the ground state of a dilute Bose gas in a scaling limit where the Gross-Pitaevskii functional emerges. This is a repulsive nonlinear Schrödinger functional whose quartic term is proportional to the scattering length of the interparticle interaction potential. We propose a new derivation of this limit problem, with a method that bypasses some of the technical difficulties that previous derivations had to face. The new method is based on a combination of Dyson\'s lemma, the quantum de Finetti theorem and a second moment estimate for ground states of the effective Dyson Hamiltonian. It applies equally well to the case where magnetic fields or rotation are present.
AU - Nam, Phan
AU - Rougerie, Nicolas
AU - Seiringer, Robert
ID - 1143
IS - 2
JF - Analysis and PDE
TI - Ground states of large bosonic systems: The gross Pitaevskii limit revisited
VL - 9
ER -
TY - JOUR
AB - Auxin directs plant ontogenesis via differential accumulation within tissues depending largely on the activity of PIN proteins that mediate auxin efflux from cells and its directional cell-to-cell transport. Regardless of the developmental importance of PINs, the structure of these transporters is poorly characterized. Here, we present experimental data concerning protein topology of plasma membrane-localized PINs. Utilizing approaches based on pH-dependent quenching of fluorescent reporters combined with immunolocalization techniques, we mapped the membrane topology of PINs and further cross-validated our results using available topology modeling software. We delineated the topology of PIN1 with two transmembrane (TM) bundles of five α-helices linked by a large intracellular loop and a C-terminus positioned outside the cytoplasm. Using constraints derived from our experimental data, we also provide an updated position of helical regions generating a verisimilitude model of PIN1. Since the canonical long PINs show a high degree of conservation in TM domains and auxin transport capacity has been demonstrated for Arabidopsis representatives of this group, this empirically enhanced topological model of PIN1 will be an important starting point for further studies on PIN structure–function relationships. In addition, we have established protocols that can be used to probe the topology of other plasma membrane proteins in plants. © 2016 The Authors
AU - Nodzyński, Tomasz
AU - Vanneste, Steffen
AU - Zwiewka, Marta
AU - Pernisová, Markéta
AU - Hejátko, Jan
AU - Friml, Jirí
ID - 1145
IS - 11
JF - Molecular Plant
TI - Enquiry into the topology of plasma membrane localized PIN auxin transport components
VL - 9
ER -
TY - JOUR
AB - Apical dominance is one of the fundamental developmental phenomena in plant biology, which determines the overall architecture of aerial plant parts. Here we show apex decapitation activated competition for dominance in adjacent upper and lower axillary buds. A two-nodal-bud pea (Pisum sativum L.) was used as a model system to monitor and assess auxin flow, auxin transport channels, and dormancy and initiation status of axillary buds. Auxin flow was manipulated by lateral stem wounds or chemically by auxin efflux inhibitors 2,3,5-triiodobenzoic acid (TIBA), 1-N-naphtylphtalamic acid (NPA), or protein synthesis inhibitor cycloheximide (CHX) treatments, which served to interfere with axillary bud competition. Redirecting auxin flow to different points influenced which bud formed the outgrowing and dominant shoot. The obtained results proved that competition between upper and lower axillary buds as secondary auxin sources is based on the same auxin canalization principle that operates between the shoot apex and axillary bud. © The Author(s) 2016.
AU - Balla, Jozef
AU - Medved'Ová, Zuzana
AU - Kalousek, Petr
AU - Matiješčuková, Natálie
AU - Friml, Jirí
AU - Reinöhl, Vilém
AU - Procházka, Stanislav
ID - 1147
JF - Scientific Reports
TI - Auxin flow mediated competition between axillary buds to restore apical dominance
VL - 6
ER -
TY - JOUR
AB - Continuous-time Markov chain (CTMC) models have become a central tool for understanding the dynamics of complex reaction networks and the importance of stochasticity in the underlying biochemical processes. When such models are employed to answer questions in applications, in order to ensure that the model provides a sufficiently accurate representation of the real system, it is of vital importance that the model parameters are inferred from real measured data. This, however, is often a formidable task and all of the existing methods fail in one case or the other, usually because the underlying CTMC model is high-dimensional and computationally difficult to analyze. The parameter inference methods that tend to scale best in the dimension of the CTMC are based on so-called moment closure approximations. However, there exists a large number of different moment closure approximations and it is typically hard to say a priori which of the approximations is the most suitable for the inference procedure. Here, we propose a moment-based parameter inference method that automatically chooses the most appropriate moment closure method. Accordingly, contrary to existing methods, the user is not required to be experienced in moment closure techniques. In addition to that, our method adaptively changes the approximation during the parameter inference to ensure that always the best approximation is used, even in cases where different approximations are best in different regions of the parameter space. © 2016 Elsevier Ireland Ltd
AU - Schilling, Christian
AU - Bogomolov, Sergiy
AU - Henzinger, Thomas A
AU - Podelski, Andreas
AU - Ruess, Jakob
ID - 1148
JF - Biosystems
TI - Adaptive moment closure for parameter inference of biochemical reaction networks
VL - 149
ER -
TY - JOUR
AB - We study the usefulness of two most prominent publicly available rigorous ODE integrators: one provided by the CAPD group (capd.ii.uj.edu.pl), the other based on the COSY Infinity project (cosyinfinity.org). Both integrators are capable of handling entire sets of initial conditions and provide tight rigorous outer enclosures of the images under a time-T map. We conduct extensive benchmark computations using the well-known Lorenz system, and compare the computation time against the final accuracy achieved. We also discuss the effect of a few technical parameters, such as the order of the numerical integration method, the value of T, and the phase space resolution. We conclude that COSY may provide more precise results due to its ability of avoiding the variable dependency problem. However, the overall cost of computations conducted using CAPD is typically lower, especially when intervals of parameters are involved. Moreover, access to COSY is limited (registration required) and the rigorous ODE integrators are not publicly available, while CAPD is an open source free software project. Therefore, we recommend the latter integrator for this kind of computations. Nevertheless, proper choice of the various integration parameters turns out to be of even greater importance than the choice of the integrator itself. © 2016 IMACS. Published by Elsevier B.V. All rights reserved.
AU - Miyaji, Tomoyuki
AU - Pilarczyk, Pawel
AU - Gameiro, Marcio
AU - Kokubu, Hiroshi
AU - Mischaikow, Konstantin
ID - 1149
JF - Applied Numerical Mathematics
TI - A study of rigorous ODE integrators for multi scale set oriented computations
VL - 107
ER -
TY - JOUR
AB - When neutrophils infiltrate a site of inflammation, they have to stop at the right place to exert their effector function. In this issue of Developmental Cell, Wang et al. (2016) show that neutrophils sense reactive oxygen species via the TRPM2 channel to arrest migration at their target site. © 2016 Elsevier Inc.
AU - Renkawitz, Jörg
AU - Sixt, Michael K
ID - 1150
IS - 5
JF - Developmental Cell
TI - A Radical Break Restraining Neutrophil Migration
VL - 38
ER -
TY - JOUR
AB - Tissue patterning in multicellular organisms is the output of precise spatio–temporal regulation of gene expression coupled with changes in hormone dynamics. In plants, the hormone auxin regulates growth and development at every stage of a plant’s life cycle. Auxin signaling occurs through binding of the auxin molecule to a TIR1/AFB F-box ubiquitin ligase, allowing interaction with Aux/IAA transcriptional repressor proteins. These are subsequently ubiquitinated and degraded via the 26S proteasome, leading to derepression of auxin response factors (ARFs). How auxin is able to elicit such a diverse range of developmental responses through a single signaling module has not yet been resolved. Here we present an alternative auxin-sensing mechanism in which the ARF ARF3/ETTIN controls gene expression through interactions with process-specific transcription factors. This noncanonical hormonesensing mechanism exhibits strong preference for the naturally occurring auxin indole 3-acetic acid (IAA) and is important for coordinating growth and patterning in diverse developmental contexts such as gynoecium morphogenesis, lateral root emergence, ovule development, and primary branch formation. Disrupting this IAA-sensing ability induces morphological aberrations with consequences for plant fitness. Therefore, our findings introduce a novel transcription factor-based mechanism of hormone perception in plants. © 2016 Simonini et al.
AU - Simonini, Sara
AU - Deb, Joyita
AU - Moubayidin, Laila
AU - Stephenson, Pauline
AU - Valluru, Manoj
AU - Freire Rios, Alejandra
AU - Sorefan, Karim
AU - Weijers, Dolf
AU - Friml, Jirí
AU - Östergaard, Lars
ID - 1151
IS - 20
JF - Genes and Development
TI - A noncanonical auxin sensing mechanism is required for organ morphogenesis in arabidopsis
VL - 30
ER -