TY - JOUR
AB - Oriented mitosis is essential during tissue morphogenesis. The Wnt/planar cell polarity (Wnt/PCP) pathway orients mitosis in a number of developmental systems, including dorsal epiblast cell divisions along the animal-vegetal (A-V) axis during zebrafish gastrulation. How Wnt signalling orients the mitotic plane is, however, unknown. Here we show that, in dorsal epiblast cells, anthrax toxin receptor 2a (Antxr2a) accumulates in a polarized cortical cap, which is aligned with the embryonic A-V axis and forecasts the division plane. Filamentous actin (F-actin) also forms an A-V polarized cap, which depends on Wnt/PCP and its effectors RhoA and Rock2. Antxr2a is recruited to the cap by interacting with actin. Antxr2a also interacts with RhoA and together they activate the diaphanous-related formin zDia2. Mechanistically, Antxr2a functions as a Wnt-dependent polarized determinant, which, through the action of RhoA and zDia2, exerts torque on the spindle to align it with the A-V axis.
AU - Castanon, Irinka
AU - Abrami, Laurence
AU - Holtzer, Laurent
AU - Heisenberg, Carl-Philipp J
AU - Van Der Goot, Françoise
AU - González Gaitán, Marcos
ID - 2918
IS - 1
JF - Nature Cell Biology
TI - Anthrax toxin receptor 2a controls mitotic spindle positioning
VL - 15
ER -
TY - JOUR
AB - The distribution of the phytohormone auxin regulates many aspects of plant development including growth response to gravity. Gravitropic root curvature involves coordinated and asymmetric cell elongation between the lower and upper side of the root, mediated by differential cellular auxin levels. The asymmetry in the auxin distribution is established and maintained by a spatio-temporal regulation of the PIN-FORMED (PIN) auxin transporter activity. We provide novel insights into the complex regulation of PIN abundance and activity during root gravitropism. We show that PIN2 turnover is differentially regulated on the upper and lower side of gravistimulated roots by distinct but partially overlapping auxin feedback mechanisms. In addition to regulating transcription and clathrin-mediated internalization, auxin also controls PIN abundance at the plasma membrane by promoting their vacuolar targeting and degradation. This effect of elevated auxin levels requires the activity of SKP-Cullin-F-box TIR1/AFB (SCF TIR1/AFB)-dependent pathway. Importantly, also suboptimal auxin levels mediate PIN degradation utilizing the same signalling pathway. These feedback mechanisms are functionally important during gravitropic response and ensure fine-tuning of auxin fluxes for maintaining as well as terminating asymmetric growth.
AU - Baster, Pawel
AU - Robert, Stéphanie
AU - Kleine Vehn, Jürgen
AU - Vanneste, Steffen
AU - Kania, Urszula
AU - Grunewald, Wim
AU - De Rybel, Bert
AU - Beeckman, Tom
AU - Friml, Jirí
ID - 2919
IS - 2
JF - EMBO Journal
TI - SCF^TIR1 AFB-auxin signalling regulates PIN vacuolar trafficking and auxin fluxes during root gravitropism
VL - 32
ER -
TY - JOUR
AB - Cell polarisation in development is a common and fundamental process underlying embryo patterning and morphogenesis, and has been extensively studied over the past years. Our current knowledge of cell polarisation in development is predominantly based on studies that have analysed polarisation of single cells, such as eggs, or cellular aggregates with a stable polarising interface, such as cultured epithelial cells (St Johnston and Ahringer, 2010). However, in embryonic development, particularly of vertebrates, cell polarisation processes often encompass large numbers of cells that are placed within moving and proliferating tissues, and undergo mesenchymal-to-epithelial transitions with a highly complex spatiotemporal choreography. How such intricate cell polarisation processes in embryonic development are achieved has only started to be analysed. By using live imaging of neurulation in the transparent zebrafish embryo, Buckley et al (2012) now describe a novel polarisation strategy by which cells assemble an apical domain in the part of their cell body that intersects with the midline of the forming neural rod. This mechanism, along with the previously described mirror-symmetric divisions (Tawk et al, 2007), is thought to trigger formation of both neural rod midline and lumen.
AU - Compagnon, Julien
AU - Heisenberg, Carl-Philipp J
ID - 2920
IS - 1
JF - EMBO Journal
TI - Neurulation coordinating cell polarisation and lumen formation
VL - 32
ER -
TY - JOUR
AB - In this paper, we present the first output-sensitive algorithm to compute the persistence diagram of a filtered simplicial complex. For any Γ > 0, it returns only those homology classes with persistence at least Γ. Instead of the classical reduction via column operations, our algorithm performs rank computations on submatrices of the boundary matrix. For an arbitrary constant δ ∈ (0, 1), the running time is O (C (1 - δ) Γ R d (n) log n), where C (1 - δ) Γ is the number of homology classes with persistence at least (1 - δ) Γ, n is the total number of simplices in the complex, d its dimension, and R d (n) is the complexity of computing the rank of an n × n matrix with O (d n) nonzero entries. Depending on the choice of the rank algorithm, this yields a deterministic O (C (1 - δ) Γ n 2.376) algorithm, an O (C (1 - δ) Γ n 2.28) Las-Vegas algorithm, or an O (C (1 - δ) Γ n 2 + ε{lunate}) Monte-Carlo algorithm for an arbitrary ε{lunate} > 0. The space complexity of the Monte-Carlo version is bounded by O (d n) = O (n log n).
AU - Chen, Chao
AU - Kerber, Michael
ID - 2939
IS - 4
JF - Computational Geometry: Theory and Applications
TI - An output sensitive algorithm for persistent homology
VL - 46
ER -
TY - CONF
AB - A chain rule for an entropy notion H(.) states that the entropy H(X) of a variable X decreases by at most l if conditioned on an l-bit string A, i.e., H(X|A)>= H(X)-l. More generally, it satisfies a chain rule for conditional entropy if H(X|Y,A)>= H(X|Y)-l.
All natural information theoretic entropy notions we are aware of (like Shannon or min-entropy) satisfy some kind of chain rule for conditional entropy. Moreover, many computational entropy notions (like Yao entropy, unpredictability entropy and several variants of HILL entropy) satisfy the chain rule for conditional entropy, though here not only the quantity decreases by l, but also the quality of the entropy decreases exponentially in l. However, for
the standard notion of conditional HILL entropy (the computational equivalent of min-entropy) the existence of such a rule was unknown so far.
In this paper, we prove that for conditional HILL entropy no meaningful chain rule exists, assuming the existence of one-way permutations: there exist distributions X,Y,A, where A is a distribution over a single bit, but $H(X|Y)>>H(X|Y,A)$, even if we simultaneously allow for a massive degradation in the quality of the entropy.
The idea underlying our construction is based on a surprising connection between the chain rule for HILL entropy and deniable encryption.
AU - Krenn, Stephan
AU - Pietrzak, Krzysztof Z
AU - Wadia, Akshay
ED - Sahai, Amit
ID - 2940
TI - A counterexample to the chain rule for conditional HILL entropy, and what deniable encryption has to do with it
VL - 7785
ER -
TY - CONF
AB - Many visual datasets are traditionally used to analyze the performance of different learning techniques. The evaluation is usually done within each dataset, therefore it is questionable if such results are a reliable indicator of true generalization ability. We propose here an algorithm to exploit the existing data resources when learning on a new multiclass problem. Our main idea is to identify an image representation that decomposes orthogonally into two subspaces: a part specific to each dataset, and a part generic to, and therefore shared between, all the considered source sets. This allows us to use the generic representation as un-biased reference knowledge for a novel classification task. By casting the method in the multi-view setting, we also make it possible to use different features for different databases. We call the algorithm MUST, Multitask Unaligned Shared knowledge Transfer. Through extensive experiments on five public datasets, we show that MUST consistently improves the cross-datasets generalization performance.
AU - Tommasi, Tatiana
AU - Quadrianto, Novi
AU - Caputo, Barbara
AU - Lampert, Christoph
ID - 2948
TI - Beyond dataset bias: Multi-task unaligned shared knowledge transfer
VL - 7724
ER -
TY - JOUR
AB - Background: Monoclonal antibodies (mAb), such as trastuzumab are a valuable addition to breast cancer therapy.
Data obtained from neoadjuvant settings revealed that antibody-dependent cell-mediated cytotoxicity (ADCC) is a
major mechanism of action for the mAb trastuzumab. Conflicting results still call into question whether disease
progression, prolonged treatment or concomitant chemotherapy influences ADCC and related immunological
phenomena.
Methods: We analyzed the activity of ADCC and antibody-dependent cell-mediated phagocytosis (ADCP) of
peripheral blood mononuclear cells (PBMCs) from human epidermal growth factor receptor 2 (HER2/neu) positive
breast cancer patients receiving trastuzumab therapy either in an adjuvant (n = 13) or metastatic (n = 15) setting as
well as from trastuzumab treatment-naive (t-naive) HER2/neu negative patients (n = 15). PBMCs from healthy volunteers
(n = 24) were used as controls. ADCC and ADCP activity was correlated with the expression of antibody binding
Fc-gamma receptor (FcγR)I (CD64), FcγRII (CD32) and FcγRIII (CD16) on CD14+ (monocytes) and CD56+ (NK) cells, as well as the expression of CD107a+ (LAMP-1) on CD56+ cells and the total amount of CD4+CD25+FOXP3+ (Treg) cells. In metastatic patients, markers were correlated with progression-free survival (PFS).
Results: ADCC activity was significantly down regulated in metastatic, adjuvant and t-naive patient cohorts as compared to healthy controls. Reduced ADCC activity was inversely correlated with the expression of CD107a on CD56+
cells in adjuvant patients. ADCC and ADCP activity of the patient cohorts were similar, regardless of treatment duration
or additional chemotherapy. PFS in metastatic patients inversely correlated with the number of peripheral Treg cells.
Conclusion: The reduction of ADCC in patients as compared to healthy controls calls for adjuvant strategies, such as
immune-enhancing agents, to improve the activity of trastuzumab. However, efficacy of trastuzumab-specific ADCC
and ADCP appears not to be affected by treatment duration, disease progression or concomitant chemotherapy. This
finding supports the application of trastuzumab at any stage of the disease.
AU - Petricevic, Branka
AU - Laengle, Johannes
AU - Singer, Josef
AU - Sachet, Monika
AU - Fazekas, Judit
AU - Steger, Guenther
AU - Bartsch, Rupert
AU - Jensen-Jarolim, Erika
AU - Bergmann, Michael
ID - 8245
JF - Journal of Translational Medicine
SN - 1479-5876
TI - Trastuzumab mediates antibody-dependent cell-mediated cytotoxicity and phagocytosis to the same extent in both adjuvant and metastatic HER2/neu breast cancer patients
VL - 11
ER -
TY - JOUR
AB - As sessile organisms, plants have to be able to adapt to a continuously changing environment. Plants that perceive some of these changes as stress signals activate signaling pathways to modulate their development and to enable them to survive. The complex responses to environmental cues are to a large extent mediated by plant hormones that together orchestrate the final plant response. The phytohormone cytokinin is involved in many plant developmental processes. Recently, it has been established that cytokinin plays an important role in stress responses, but does not act alone. Indeed, the hormonal control of plant development and stress adaptation is the outcome of a complex network of multiple synergistic and antagonistic interactions between various hormones. Here, we review the recent findings on the cytokinin function as part of this hormonal network. We focus on the importance of the crosstalk between cytokinin and other hormones, such as abscisic acid, jasmonate, salicylic acid, ethylene, and auxin in the modulation of plant development and stress adaptation. Finally, the impact of the current research in the biotechnological industry will be discussed.
AU - O'Brien, José
AU - Benková, Eva
ID - 827
JF - Frontiers in Plant Science
TI - Cytokinin cross talking during biotic and abiotic stress responses
VL - 4
ER -
TY - JOUR
AB - The plant root system is essential for providing anchorage to the soil, supplying minerals and water, and synthesizing metabolites. It is a dynamic organ modulated by external cues such as environmental signals, water and nutrients availability, salinity and others. Lateral roots (LRs) are initiated from the primary root post-embryonically, after which they progress through discrete developmental stages which can be independently controlled, providing a high level of plasticity during root system formation. Within this review, main contributions are presented, from the classical forward genetic screens to the more recent high-throughput approaches, combined with computer model predictions, dissecting how LRs and thereby root system architecture is established and developed.
AU - Cuesta, Candela
AU - Wabnik, Krzysztof T
AU - Benková, Eva
ID - 828
JF - Frontiers in Plant Science
TI - Systems approaches to study root architecture dynamics
VL - 4
ER -
TY - JOUR
AB - The transition of proteins from their soluble functional state to amyloid fibrils and aggregates is associated with the onset of several human diseases. Protein aggregation often requires some structural reshaping and the subsequent formation of intermolecular contacts. Therefore, the study of the conformation of excited protein states and their ability to form oligomers is of primary importance for understanding the molecular basis of amyloid fibril formation. Here, we investigated the oligomerization processes that occur along the folding of the amyloidogenic human protein β2-microglobulin. The combination of real-time two-dimensional NMR data with real-time small-angle X-ray scattering measurements allowed us to derive thermodynamic and kinetic information on protein oligomerization of different conformational states populated along the folding pathways. In particular, we could demonstrate that a long-lived folding intermediate (I-state) has a higher propensity to oligomerize compared to the native state. Our data agree well with a simple five-state kinetic model that involves only monomeric and dimeric species. The dimers have an elongated shape with the dimerization interface located at the apical side of β2-microglobulin close to Pro32, the residue that has a trans conformation in the I-state and a cis conformation in the native (N) state. Our experimental data suggest that partial unfolding in the apical half of the protein close to Pro32 leads to an excited state conformation with enhanced propensity for oligomerization. This excited state becomes more populated in the transient I-state due to the destabilization of the native conformation by the trans-Pro32 configuration.
AU - Rennella, E.
AU - Cutuil, T.
AU - Schanda, Paul
AU - Ayala, I.
AU - Gabel, F.
AU - Forge, V.
AU - Corazza, A.
AU - Esposito, G.
AU - Brutscher, B.
ID - 8462
IS - 15
JF - Journal of Molecular Biology
KW - Molecular Biology
SN - 0022-2836
TI - Oligomeric states along the folding pathways of β2-microglobulin: Kinetics, thermodynamics, and structure
VL - 425
ER -
TY - CONF
AB - In this work we present a flexible tool for tumor progression, which simulates the evolutionary dynamics of cancer. Tumor progression implements a multi-type branching process where the key parameters are the fitness landscape, the mutation rate, and the average time of cell division. The fitness of a cancer cell depends on the mutations it has accumulated. The input to our tool could be any fitness landscape, mutation rate, and cell division time, and the tool produces the growth dynamics and all relevant statistics.
AU - Reiter, Johannes
AU - Božić, Ivana
AU - Chatterjee, Krishnendu
AU - Nowak, Martin
ID - 2000
T2 - Proceedings of 25th Int. Conf. on Computer Aided Verification
TI - TTP: Tool for tumor progression
VL - 8044
ER -
TY - JOUR
AB - Traditional statistical methods for confidentiality protection of statistical databases do not scale well to deal with GWAS databases especially in terms of guarantees regarding protection from linkage to external information. The more recent concept of differential privacy, introduced by the cryptographic community, is an approach which provides a rigorous definition of privacy with meaningful privacy guarantees in the presence of arbitrary external information, although the guarantees may come at a serious price in terms of data utility. Building on such notions, we propose new methods to release aggregate GWAS data without compromising an individual’s privacy. We present methods for releasing differentially private minor allele frequencies, chi-square statistics and p-values. We compare these approaches on simulated data and on a GWAS study of canine hair length involving 685 dogs. We also propose a privacy-preserving method for finding genome-wide associations based on a differentially-private approach to penalized logistic regression.
AU - Uhler, Caroline
AU - Slavkovic, Aleksandra
AU - Fienberg, Stephen
ID - 2009
IS - 1
JF - Journal of Privacy and Confidentiality
TI - Privacy-preserving data sharing for genome-wide association studies
VL - 5
ER -
TY - JOUR
AB - Many algorithms for inferring causality rely heavily on the faithfulness assumption. The main justification for imposing this assumption is that the set of unfaithful distributions has Lebesgue measure zero, since it can be seen as a collection of hypersurfaces in a hypercube. However, due to sampling error the faithfulness condition alone is not sufficient for statistical estimation, and strong-faithfulness has been proposed and assumed to achieve uniform or high-dimensional consistency. In contrast to the plain faithfulness assumption, the set of distributions that is not strong-faithful has nonzero Lebesgue measure and in fact, can be surprisingly large as we show in this paper. We study the strong-faithfulness condition from a geometric and combinatorial point of view and give upper and lower bounds on the Lebesgue measure of strong-faithful distributions for various classes of directed acyclic graphs. Our results imply fundamental limitations for the PC-algorithm and potentially also for other algorithms based on partial correlation testing in the Gaussian case.
AU - Uhler, Caroline
AU - Raskutti, Garvesh
AU - Bühlmann, Peter
AU - Yu, Bin
ID - 2010
IS - 2
JF - The Annals of Statistics
TI - Geometry of the faithfulness assumption in causal inference
VL - 41
ER -
TY - CONF
AB - There is a trade-off between performance and correctness in implementing concurrent data structures. Better performance may be achieved at the expense of relaxing correctness, by redefining the semantics of data structures. We address such a redefinition of data structure semantics and present a systematic and formal framework for obtaining new data structures by quantitatively relaxing existing ones. We view a data structure as a sequential specification S containing all "legal" sequences over an alphabet of method calls. Relaxing the data structure corresponds to defining a distance from any sequence over the alphabet to the sequential specification: the k-relaxed sequential specification contains all sequences over the alphabet within distance k from the original specification. In contrast to other existing work, our relaxations are semantic (distance in terms of data structure states). As an instantiation of our framework, we present two simple yet generic relaxation schemes, called out-of-order and stuttering relaxation, along with several ways of computing distances. We show that the out-of-order relaxation, when further instantiated to stacks, queues, and priority queues, amounts to tolerating bounded out-of-order behavior, which cannot be captured by a purely syntactic relaxation (distance in terms of sequence manipulation, e.g. edit distance). We give concurrent implementations of relaxed data structures and demonstrate that bounded relaxations provide the means for trading correctness for performance in a controlled way. The relaxations are monotonic which further highlights the trade-off: increasing k increases the number of permitted sequences, which as we demonstrate can lead to better performance. Finally, since a relaxed stack or queue also implements a pool, we actually have new concurrent pool implementations that outperform the state-of-the-art ones.
AU - Henzinger, Thomas A
AU - Kirsch, Christoph
AU - Payer, Hannes
AU - Sezgin, Ali
AU - Sokolova, Ana
ID - 2181
SN - 978-1-4503-1832-7
T2 - Proceedings of the 40th annual ACM SIGPLAN-SIGACT symposium on Principles of programming language
TI - Quantitative relaxation of concurrent data structures
ER -
TY - CONF
AB - We propose a general framework for abstraction with respect to quantitative properties, such as worst-case execution time, or power consumption. Our framework provides a systematic way for counter-example guided abstraction refinement for quantitative properties. The salient aspect of the framework is that it allows anytime verification, that is, verification algorithms that can be stopped at any time (for example, due to exhaustion of memory), and report approximations that improve monotonically when the algorithms are given more time. We instantiate the framework with a number of quantitative abstractions and refinement schemes, which differ in terms of how much quantitative information they keep from the original system. We introduce both state-based and trace-based quantitative abstractions, and we describe conditions that define classes of quantitative properties for which the abstractions provide over-approximations. We give algorithms for evaluating the quantitative properties on the abstract systems. We present algorithms for counter-example based refinements for quantitative properties for both state-based and segment-based abstractions. We perform a case study on worst-case execution time of executables to evaluate the anytime verification aspect and the quantitative abstractions we proposed.
AU - Cerny, Pavol
AU - Henzinger, Thomas A
AU - Radhakrishna, Arjun
ID - 2182
T2 - Proceedings of the 40th annual ACM SIGPLAN-SIGACT symposium on Principles of programming language
TI - Quantitative abstraction refinement
ER -
TY - CONF
AB - A straight skeleton is a well-known geometric structure, and several algorithms exist to construct the straight skeleton for a given polygon or planar straight-line graph. In this paper, we ask the reverse question: Given the straight skeleton (in form of a planar straight-line graph, with some rays to infinity), can we reconstruct a planar straight-line graph for which this was the straight skeleton? We show how to reduce this problem to the problem of finding a line that intersects a set of convex polygons. We can find these convex polygons and all such lines in $O(nlog n)$ time in the Real RAM computer model, where $n$ denotes the number of edges of the input graph. We also explain how our approach can be used for recognizing Voronoi diagrams of points, thereby completing a partial solution provided by Ash and Bolker in 1985.
AU - Biedl, Therese
AU - Held, Martin
AU - Huber, Stefan
ID - 2209
TI - Recognizing straight skeletons and Voronoi diagrams and reconstructing their input
ER -
TY - CONF
AB - A straight skeleton is a well-known geometric structure, and several algorithms exist to construct the straight skeleton for a given polygon. In this paper, we ask the reverse question: Given the straight skeleton (in form of a tree with a drawing in the plane, but with the exact position of the leaves unspecified), can we reconstruct the polygon? We show that in most cases there exists at most one polygon; in the remaining case there is an infinite number of polygons determined by one angle that can range in an interval. We can find this (set of) polygon(s) in linear time in the Real RAM computer model.
AU - Biedl, Therese
AU - Held, Martin
AU - Huber, Stefan
ID - 2210
T2 - 29th European Workshop on Computational Geometry
TI - Reconstructing polygons from embedded straight skeletons
ER -
TY - CONF
AB - We describe new extensions of the Vampire theorem prover for computing tree interpolants. These extensions generalize Craig interpolation in Vampire, and can also be used to derive sequence interpolants. We evaluated our implementation on a large number of examples over the theory of linear integer arithmetic and integer-indexed arrays, with and without quantifiers. When compared to other methods, our experiments show that some examples could only be solved by our implementation.
AU - Blanc, Régis
AU - Gupta, Ashutosh
AU - Kovács, Laura
AU - Kragl, Bernhard
ID - 2237
TI - Tree interpolation in Vampire
VL - 8312
ER -
TY - CONF
AB - We study the problem of achieving a given value in Markov decision processes (MDPs) with several independent discounted reward objectives. We consider a generalised version of discounted reward objectives, in which the amount of discounting depends on the states visited and on the objective. This definition extends the usual definition of discounted reward, and allows to capture the systems in which the value of different commodities diminish at different and variable rates.
We establish results for two prominent subclasses of the problem, namely state-discount models where the discount factors are only dependent on the state of the MDP (and independent of the objective), and reward-discount models where they are only dependent on the objective (but not on the state of the MDP). For the state-discount models we use a straightforward reduction to expected total reward and show that the problem whether a value is achievable can be solved in polynomial time. For the reward-discount model we show that memory and randomisation of the strategies are required, but nevertheless that the problem is decidable and it is sufficient to consider strategies which after a certain number of steps behave in a memoryless way.
For the general case, we show that when restricted to graphs (i.e. MDPs with no randomisation), pure strategies and discount factors of the form 1/n where n is an integer, the problem is in PSPACE and finite memory suffices for achieving a given value. We also show that when the discount factors are not of the form 1/n, the memory required by a strategy can be infinite.
AU - Chatterjee, Krishnendu
AU - Forejt, Vojtěch
AU - Wojtczak, Dominik
ID - 2238
TI - Multi-objective discounted reward verification in graphs and MDPs
VL - 8312
ER -
TY - CONF
AB - We show that modal logic over universally first-order definable classes of transitive frames is decidable. More precisely, let K be an arbitrary class of transitive Kripke frames definable by a universal first-order sentence. We show that the global and finite global satisfiability problems of modal logic over K are decidable in NP, regardless of choice of K. We also show that the local satisfiability and the finite local satisfiability problems of modal logic over K are decidable in NEXPTIME.
AU - Michaliszyn, Jakub
AU - Otop, Jan
ID - 2243
TI - Elementary modal logics over transitive structures
VL - 23
ER -