@article{3788, abstract = {Cell sorting is a widespread phenomenon pivotal to the early development of multicellular organisms. In vitro cell sorting studies have been instrumental in revealing the cellular properties driving this process. However, these studies have as yet been limited to two-dimensional analysis of three-dimensional cell sorting events. Here we describe a method to record the sorting of primary zebrafish ectoderm and mesoderm germ layer progenitor cells in three dimensions over time, and quantitatively analyze their sorting behavior using an order parameter related to heterotypic interface length. We investigate the cell population size dependence of sorted aggregates and find that the germ layer progenitor cells engulfed in the final configuration display a relationship between total interfacial length and system size according to a simple geometrical argument, subject to a finite-size effect.}, author = {Klopper, Abigail and Krens, Gabriel and Grill, Stephan and Heisenberg, Carl-Philipp J}, journal = {The European Physical Journal E: Soft Matter and Biological Physics}, number = {2}, pages = {99 -- 103}, publisher = {Springer}, title = {{Finite-size corrections to scaling behavior in sorted cell aggregates}}, doi = {10.1140/epje/i2010-10642-y}, volume = {33}, year = {2010}, } @article{3789, abstract = {The development of multicellular organisms is dependent on the tight coordination between tissue growth and morphogenesis. The stereotypical orientation of cell divisions has been proposed to be a fundamental mechanism by which proliferating and growing tissues take shape. However, the actual contribution of stereotypical division orientation (SDO) to tissue morphogenesis is unclear. In zebrafish, cell divisions with stereotypical orientation have been implicated in both body-axis elongation and neural rod formation [1, 2], although there is little direct evidence for a critical function of SDO in either of these processes. Here we show that SDO is required for formation of the neural rod midline during neurulation but dispensable for elongation of the body axis during gastrulation. Our data indicate that SDO during both gastrulation and neurulation is dependent on the noncanonical Wnt receptor Frizzled 7 (Fz7) and that interfering with cell division orientation leads to severe defects in neural rod midline formation but not body-axis elongation. These findings suggest a novel function for Fz7-controlled cell division orientation in neural rod midline formation during neurulation. }, author = {Quesada-Hernández, Elena and Caneparo, Luca and Schneider, Sylvia and Winkler, Sylke and Liebling, Michael and Fraser, Scott and Heisenberg, Carl-Philipp J}, journal = {Current Biology}, number = {21}, pages = {1966 -- 1972}, publisher = {Cell Press}, title = {{Stereotypical cell division orientation controls neural rod midline formation in zebrafish}}, doi = {10.1016/j.cub.2010.10.009}, volume = {20}, year = {2010}, } @article{3790, abstract = {Cell shape and motility are primarily controlled by cellular mechanics. The attachment of the plasma membrane to the underlying actomyosin cortex has been proposed to be important for cellular processes involving membrane deformation. However, little is known about the actual function of membrane-to-cortex attachment (MCA) in cell protrusion formation and migration, in particular in the context of the developing embryo. Here, we use a multidisciplinary approach to study MCA in zebrafish mesoderm and endoderm (mesendoderm) germ layer progenitor cells, which migrate using a combination of different protrusion types, namely, lamellipodia, filopodia, and blebs, during zebrafish gastrulation. By interfering with the activity of molecules linking the cortex to the membrane and measuring resulting changes in MCA by atomic force microscopy, we show that reducing MCA in mesendoderm progenitors increases the proportion of cellular blebs and reduces the directionality of cell migration. We propose that MCA is a key parameter controlling the relative proportions of different cell protrusion types in mesendoderm progenitors, and thus is key in controlling directed migration during gastrulation.}, author = {Diz Muñoz, Alba and Krieg, Michael and Bergert, Martin and Ibarlucea Benitez, Itziar and Müller, Daniel and Paluch, Ewa and Heisenberg, Carl-Philipp J}, journal = {PLoS Biology}, number = {11}, publisher = {Public Library of Science}, title = {{Control of directed cell migration in vivo by membrane-to-cortex attachment}}, doi = {10.1371/journal.pbio.1000544}, volume = {8}, year = {2010}, } @article{3792, abstract = {The yolk syncytial layer (YSL) plays crucial roles in early zebrafish development. The YSL is a transient extra-embryonic syncytial tissue that forms during early cleavage stages and persists until larval stages. During gastrulation, the YSL undergoes highly dynamic movements, which are tightly coordinated with the movements of the overlying germ layer progenitor cells, and has critical functions in cell fate specification and morphogenesis of the early germ layers. Movement coordination between the YSL and blastoderm cells is dependent on contact between these tissues, and is probably required for the patterning and morphogenetic function of the YSL. In this review, we will discuss recent advances in elucidating the molecular and cellular mechanisms underlying the YSL morphogenesis and movement coordination between the YSL and blastoderm during early development.}, author = {Carvalho, Lara and Heisenberg, Carl-Philipp J}, journal = {Trends in Cell Biology}, number = {10}, pages = {586 -- 592}, publisher = {Cell Press}, title = {{The yolk syncytial layer in early, zebrafish development}}, doi = {10.1016/j.tcb.2010.06.009}, volume = {20}, year = {2010}, } @inproceedings{3793, abstract = {Recent progress in per-pixel object class labeling of natural images can be attributed to the use of multiple types of image features and sound statistical learning approaches. Within the latter, Conditional Random Fields (CRF) are prominently used for their ability to represent interactions between random variables. Despite their popularity in computer vision, parameter learning for CRFs has remained difficult, popular approaches being cross-validation and piecewise training. In this work, we propose a simple yet expressive tree-structured CRF based on a recent hierarchical image segmentation method. Our model combines and weights multiple image features within a hierarchical representation and allows simple and efficient globally-optimal learning of ≈ 105 parameters. The tractability of our model allows us to pose and answer some of the open questions regarding parameter learning applying to CRF-based approaches. The key findings for learning CRF models are, from the obvious to the surprising, i) multiple image features always help, ii) the limiting dimension with respect to current models is the amount of training data, iii) piecewise training is competitive, iv) current methods for max-margin training fail for models with many parameters. }, author = {Nowozin, Sebastian and Gehler, Peter and Lampert, Christoph}, location = {Heraklion, Crete, Greece}, pages = {98 -- 111}, publisher = {Springer}, title = {{On parameter learning in CRF-based approaches to object class image segmentation}}, doi = {10.1007/978-3-642-15567-3_8}, volume = {6316}, year = {2010}, } @inproceedings{3794, abstract = {We study the problem of multimodal dimensionality reduction assuming that data samples can be missing at training time, and not all data modalities may be present at application time. Maximum covariance analysis, as a generalization of PCA, has many desirable properties, but its application to practical problems is limited by its need for perfectly paired data. We overcome this limitation by a latent variable approach that allows working with weakly paired data and is still able to efficiently process large datasets using standard numerical routines. The resulting weakly paired maximum covariance analysis often finds better representations than alternative methods, as we show in two exemplary tasks: texture discrimination and transfer learning.}, author = {Lampert, Christoph and Krömer, Oliver}, location = {Heraklion, Crete, Greece}, pages = {566 -- 579}, publisher = {Springer}, title = {{Weakly-paired maximum covariance analysis for multimodal dimensionality reduction and transfer learning}}, doi = {10.1007/978-3-642-15552-9_41}, volume = {6312}, year = {2010}, } @inbook{3795, abstract = {The (apparent) contour of a smooth mapping from a 2-manifold to the plane, f: M → R2 , is the set of critical values, that is, the image of the points at which the gradients of the two component functions are linearly dependent. Assuming M is compact and orientable and measuring difference with the erosion distance, we prove that the contour is stable.}, author = {Edelsbrunner, Herbert and Morozov, Dmitriy and Patel, Amit}, booktitle = {Topological Data Analysis and Visualization: Theory, Algorithms and Applications}, pages = {27 -- 42}, publisher = {Springer}, title = {{The stability of the apparent contour of an orientable 2-manifold}}, doi = {10.1007/978-3-642-15014-2_3}, year = {2010}, } @article{3829, abstract = {To determine the number of open Ca(2+) channels necessary for transmitter release at the inhibitory basket cell-granule cell synapse in rat hippocampus, we combined presynaptic Ca(2+) imaging, recording of postsynaptic currents and modeling. We found that that the opening of three or fewer Ca(2+) channels triggered transmitter release. Furthermore, a small number of Ca(2+) channels were able to evoke release with high temporal precision, despite stochastic Ca(2+) channel opening.}, author = {Bucurenciu, Iancu and Bischofberger, Josef and Peter Jonas}, journal = {Nature Neuroscience}, number = {1}, pages = {19 -- 21}, publisher = {Nature Publishing Group}, title = {{A small number of open Ca(2+) channels trigger transmitter release at a central GABAergic synapse}}, doi = {10.1038/nn.2461 }, volume = {13}, year = {2010}, } @article{3830, abstract = {Fast-spiking, parvalbumin-expressing basket cells (BCs) are important for feedforward and feedback inhibition. During network activity, BCs respond with short latency and high temporal precision. It is thought that the specific properties of input synapses are responsible for rapid recruitment. However, a potential contribution of active dendritic conductances has not been addressed. We combined confocal imaging and patch-clamp techniques to obtain simultaneous somatodendritic recordings from BCs. Action potentials were initiated in the BC axon and backpropagated into the dendrites with reduced amplitude and little activity dependence. These properties were explained by a high K+ to Na+ conductance ratio in BC dendrites. Computational analysis indicated that dendritic K+ channels convey unique integration properties to BCs, leading to the rapid and temporally precise activation by excitatory inputs.}, author = {Hua Hu and Martina, Marco and Peter Jonas}, journal = {Science}, number = {5961}, pages = {52 -- 8}, publisher = {American Association for the Advancement of Science}, title = {{Dendritic mechanisms underlying rapid synaptic activation of fast-spiking hippocampal interneurons}}, doi = {10.1126/science.1177876}, volume = {327}, year = {2010}, } @article{3831, abstract = {Fast-spiking, parvalbumin-expressing basket cells (BCs) play a key role in feedforward and feedback inhibition in the hippocampus. However, the dendritic mechanisms underlying rapid interneuron recruitment have remained unclear. To quantitatively address this question, we developed detailed passive cable models of BCs in the dentate gyrus based on dual somatic or somatodendritic recordings and complete morphologic reconstructions. Both specific membrane capacitance and axial resistivity were comparable to those of pyramidal neurons, but the average somatodendritic specific membrane resistance (R(m)) was substantially lower in BCs. Furthermore, R(m) was markedly nonuniform, being lowest in soma and proximal dendrites, intermediate in distal dendrites, and highest in the axon. Thus, the somatodendritic gradient of R(m) was the reverse of that in pyramidal neurons. Further computational analysis revealed that these unique cable properties accelerate the time course of synaptic potentials at the soma in response to fast inputs, while boosting the efficacy of slow distal inputs. These properties will facilitate both rapid phasic and efficient tonic activation of BCs in hippocampal microcircuits.}, author = {Norenberg, Anja and Hua Hu and Vida, Imre and Bartos, Marlene and Peter Jonas}, journal = {PNAS}, number = {2}, pages = {894 -- 9}, publisher = {National Academy of Sciences}, title = {{Distinct nonuniform cable properties optimize rapid and efficient activation of fast-spiking GABAergic interneurons}}, doi = {10.1073/pnas.0910716107}, volume = {107}, year = {2010}, } @article{3832, abstract = {A recent paper by von Engelhardt et al. identifies a novel auxiliary subunit of native AMPARs, termedCKAMP44. Unlike other auxiliary subunits, CKAMP44 accelerates desensitization and prolongs recovery from desensitization. CKAMP44 is highly expressed in hippocampal dentate gyrus granule cells and decreases the paired-pulse ratio at perforant path input synapses. Thus, both principal and auxiliary AMPAR subunits control the time course of signaling at glutamatergic synapses.}, author = {Guzmán, José and Jonas, Peter M}, journal = {Neuron}, number = {1}, pages = {8 -- 10}, publisher = {Elsevier}, title = {{Beyond TARPs: The growing list of auxiliary AMPAR subunits}}, doi = {10.1016/j.neuron.2010.04.003}, volume = {66}, year = {2010}, } @article{3833, author = {Jonas, Peter M and Hefft, Stefan}, journal = {The European Journal of Neuroscience}, number = {7}, pages = {1194 -- 1195}, publisher = {Wiley-Blackwell}, title = {{GABA release at terminals of CCK-interneurons: synchrony, asynchrony and modulation by cannabinoid receptors (commentary on Ali & Todorova)}}, doi = {10.1111/j.1460-9568.2010.07189.x}, volume = {31}, year = {2010}, } @article{3834, abstract = {Background The chemical master equation (CME) is a system of ordinary differential equations that describes the evolution of a network of chemical reactions as a stochastic process. Its solution yields the probability density vector of the system at each point in time. Solving the CME numerically is in many cases computationally expensive or even infeasible as the number of reachable states can be very large or infinite. We introduce the sliding window method, which computes an approximate solution of the CME by performing a sequence of local analysis steps. In each step, only a manageable subset of states is considered, representing a "window" into the state space. In subsequent steps, the window follows the direction in which the probability mass moves, until the time period of interest has elapsed. We construct the window based on a deterministic approximation of the future behavior of the system by estimating upper and lower bounds on the populations of the chemical species. Results In order to show the effectiveness of our approach, we apply it to several examples previously described in the literature. The experimental results show that the proposed method speeds up the analysis considerably, compared to a global analysis, while still providing high accuracy. Conclusions The sliding window method is a novel approach to address the performance problems of numerical algorithms for the solution of the chemical master equation. The method efficiently approximates the probability distributions at the time points of interest for a variety of chemically reacting systems, including systems for which no upper bound on the population sizes of the chemical species is known a priori.}, author = {Wolf, Verena and Goel, Rushil and Mateescu, Maria and Henzinger, Thomas A}, journal = {BMC Systems Biology}, number = {42}, pages = {1 -- 19}, publisher = {BioMed Central}, title = {{Solving the chemical master equation using sliding windows}}, doi = {10.1186/1752-0509-4-42}, volume = {4}, year = {2010}, } @inproceedings{3838, abstract = {We present a numerical approximation technique for the analysis of continuous-time Markov chains that describe net- works of biochemical reactions and play an important role in the stochastic modeling of biological systems. Our approach is based on the construction of a stochastic hybrid model in which certain discrete random variables of the original Markov chain are approximated by continuous deterministic variables. We compute the solution of the stochastic hybrid model using a numerical algorithm that discretizes time and in each step performs a mutual update of the transient prob- ability distribution of the discrete stochastic variables and the values of the continuous deterministic variables. We im- plemented the algorithm and we demonstrate its usefulness and efficiency on several case studies from systems biology.}, author = {Henzinger, Thomas A and Mateescu, Maria and Mikeev, Linar and Wolf, Verena}, location = {Trento, Italy}, pages = {55 -- 65}, publisher = {Springer}, title = {{Hybrid numerical solution of the chemical master equation}}, doi = {10.1145/1839764.1839772}, year = {2010}, } @inproceedings{3839, abstract = {We present a loop property generation method for loops iterating over multi-dimensional arrays. When used on matrices, our method is able to infer their shapes (also called types), such as upper-triangular, diagonal, etc. To gen- erate loop properties, we first transform a nested loop iterating over a multi- dimensional array into an equivalent collection of unnested loops. Then, we in- fer quantified loop invariants for each unnested loop using a generalization of a recurrence-based invariant generation technique. These loop invariants give us conditions on matrices from which we can derive matrix types automatically us- ing theorem provers. Invariant generation is implemented in the software package Aligator and types are derived by theorem provers and SMT solvers, including Vampire and Z3. When run on the Java matrix package JAMA, our tool was able to infer automatically all matrix types describing the matrix shapes guaranteed by JAMA’s API.}, author = {Henzinger, Thomas A and Hottelier, Thibaud and Kovács, Laura and Voronkov, Andrei}, location = {Madrid, Spain}, pages = {163 -- 179}, publisher = {Springer}, title = {{Invariant and type inference for matrices}}, doi = {10.1007/978-3-642-11319-2_14}, volume = {5944}, year = {2010}, } @inproceedings{3840, abstract = {Classical formalizations of systems and properties are boolean: given a system and a property, the property is either true or false of the system. Correspondingly, classical methods for system analysis determine the truth value of a property, preferably giving a proof if the property is true, and a counterexample if the property is false; classical methods for system synthesis construct a system for which a property is true; classical methods for system transformation, composition, and abstraction aim to preserve the truth of properties. The boolean view is prevalent even if the system, the property, or both refer to numerical quantities, such as the times or probabilities of events. For example, a timed automaton either satisfies or violates a formula of a real-time logic; a stochastic process either satisfies or violates a formula of a probabilistic logic. The classical black-and-white view partitions the world into "correct" and "incorrect" systems, offering few nuances. In reality, of several systems that satisfy a property in the boolean sense, often some are more desirable than others, and of the many systems that violate a property, usually some are less objectionable than others. For instance, among the systems that satisfy the response property that every request be granted, we may prefer systems that grant requests quickly (the quicker, the better), or we may prefer systems that issue few unnecessary grants (the fewer, the better); and among the systems that violate the response property, we may prefer systems that serve many initial requests (the more, the better), or we may prefer systems that serve many requests in the long run (the greater the fraction of served to unserved requests, the better). Formally, while a boolean notion of correctness is given by a preorder on systems and properties, a quantitative notion of correctness is defined by a directed metric on systems and properties, where the distance between a system and a property provides a measure of "fit" or "desirability." There are many ways how such distances can be defined. In a linear-time framework, one assigns numerical values to individual behaviors before assigning values to systems and properties, which are sets of behaviors. For example, the value of a single behavior may be a discounted value, which is largely determined by a prefix of the behavior, e.g., by the number of requests that are granted before the first request that is not granted; or a limit value, which is independent of any finite prefix. A limit value may be an average, such as the average response time over an infinite sequence of requests and grants, or a supremum, such as the worst-case response time. Similarly, the value of a set of behaviors may be an extremum or an average across the values of all behaviors in the set: in this way one can measure the worst of all possible average-case response times, or the average of all possible worst-case response times, etc. Accordingly, the distance between two sets of behaviors may be defined as the worst or average difference between the values of corresponding behaviors. In summary, we propagate replacing boolean specifications for the correctness of systems with quantitative measures for the desirability of systems. In quantitative analysis, the aim is to compute the distance between a system and a property (or between two systems, or two properties); in quantitative synthesis, the objective is to construct a system that has minimal distance from a given property. Multiple quantitative measures can be prioritized (e.g., combined lexicographically into a single measure) or studied along the Pareto curve. Quantitative transformations, compositions, and abstractions of systems are useful if they allow us to bound the induced change in distance from a property. We present some initial results in some of these directions. We also give some potential applications, which not only generalize tradiditional correctness concerns in the functional, timed, and probabilistic domains, but also capture such system measures as resource use, performance, cost, reliability, and robustness.}, author = {Henzinger, Thomas A}, location = {Madrid, Spain}, number = {1}, pages = {157 -- 158}, publisher = {ACM}, title = {{From boolean to quantitative notions of correctness}}, doi = {10.1145/1706299.1706319}, volume = {45}, year = {2010}, } @article{3842, abstract = {Within systems biology there is an increasing interest in the stochastic behavior of biochemical reaction networks. An appropriate stochastic description is provided by the chemical master equation, which represents a continuous-time Markov chain (CTMC). The uniformization technique is an efficient method to compute probability distributions of a CTMC if the number of states is manageable. However, the size of a CTMC that represents a biochemical reaction network is usually far beyond what is feasible. In this paper we present an on-the-fly variant of uniformization, where we improve the original algorithm at the cost of a small approximation error. By means of several examples, we show that our approach is particularly well-suited for biochemical reaction networks.}, author = {Didier, Frédéric and Henzinger, Thomas A and Mateescu, Maria and Wolf, Verena}, journal = {IET Systems Biology}, number = {6}, pages = {441 -- 452}, publisher = {Institution of Engineering and Technology}, title = {{Fast adaptive uniformization of the chemical master equation}}, doi = {10.1049/iet-syb.2010.0005}, volume = {4}, year = {2010}, } @inproceedings{3845, abstract = {This paper presents Aligators, a tool for the generation of universally quantified array invariants. Aligators leverages recurrence solving and algebraic techniques to carry out inductive reasoning over array content. The Aligators’ loop extraction module allows treatment of multi-path loops by exploiting their commutativity and serializability properties. Our experience in applying Aligators on a collection of loops from open source software projects indicates the applicability of recurrence and algebraic solving techniques for reasoning about arrays.}, author = {Henzinger, Thomas A and Hottelier, Thibaud and Kovács, Laura and Rybalchenko, Andrey}, location = {Yogyakarta, Indonesia}, pages = {348 -- 356}, publisher = {Springer}, title = {{Aligators for arrays}}, doi = {10.1007/978-3-642-16242-8_25}, volume = {6397}, year = {2010}, } @inproceedings{3847, abstract = {The importance of stochasticity within biological systems has been shown repeatedly during the last years and has raised the need for efficient stochastic tools. We present SABRE, a tool for stochastic analysis of biochemical reaction networks. SABRE implements fast adaptive uniformization (FAU), a direct numerical approximation algorithm for computing transient solutions of biochemical reaction networks. Biochemical reactions networks represent biological systems studied at a molecular level and these reactions can be modeled as transitions of a Markov chain. SABRE accepts as input the formalism of guarded commands, which it interprets either as continuous-time or as discrete-time Markov chains. Besides operating in a stochastic mode, SABRE may also perform a deterministic analysis by directly computing a mean-field approximation of the system under study. We illustrate the different functionalities of SABRE by means of biological case studies.}, author = {Didier, Frédéric and Henzinger, Thomas A and Mateescu, Maria and Wolf, Verena}, location = {Williamsburg, USA}, pages = {193 -- 194}, publisher = {IEEE}, title = {{SABRE: A tool for the stochastic analysis of biochemical reaction networks}}, doi = {10.1109/QEST.2010.33}, year = {2010}, } @inproceedings{3848, abstract = {We define the robustness of a level set homology class of a function f:XR as the magnitude of a perturbation necessary to kill the class. Casting this notion into a group theoretic framework, we compute the robustness for each class, using a connection to extended persistent homology. The special case X=R3 has ramifications in medical imaging and scientific visualization.}, author = {Bendich, Paul and Edelsbrunner, Herbert and Morozov, Dmitriy and Patel, Amit}, location = {Liverpool, UK}, pages = {1 -- 10}, publisher = {Springer}, title = {{The robustness of level sets}}, doi = {10.1007/978-3-642-15775-2_1}, volume = {6346}, year = {2010}, }