@inproceedings{7808, abstract = {Quantization converts neural networks into low-bit fixed-point computations which can be carried out by efficient integer-only hardware, and is standard practice for the deployment of neural networks on real-time embedded devices. However, like their real-numbered counterpart, quantized networks are not immune to malicious misclassification caused by adversarial attacks. We investigate how quantization affects a network’s robustness to adversarial attacks, which is a formal verification question. We show that neither robustness nor non-robustness are monotonic with changing the number of bits for the representation and, also, neither are preserved by quantization from a real-numbered network. For this reason, we introduce a verification method for quantized neural networks which, using SMT solving over bit-vectors, accounts for their exact, bit-precise semantics. We built a tool and analyzed the effect of quantization on a classifier for the MNIST dataset. We demonstrate that, compared to our method, existing methods for the analysis of real-numbered networks often derive false conclusions about their quantizations, both when determining robustness and when detecting attacks, and that existing methods for quantized networks often miss attacks. Furthermore, we applied our method beyond robustness, showing how the number of bits in quantization enlarges the gender bias of a predictor for students’ grades.}, author = {Giacobbe, Mirco and Henzinger, Thomas A and Lechner, Mathias}, booktitle = {International Conference on Tools and Algorithms for the Construction and Analysis of Systems}, isbn = {9783030452360}, issn = {1611-3349}, location = {Dublin, Ireland}, pages = {79--97}, publisher = {Springer Nature}, title = {{How many bits does it take to quantize your neural network?}}, doi = {10.1007/978-3-030-45237-7_5}, volume = {12079}, year = {2020}, } @article{7586, abstract = {CLC chloride/proton exchangers may support acidification of endolysosomes and raise their luminal Cl− concentration. Disruption of endosomal ClC‐3 causes severe neurodegeneration. To assess the importance of ClC‐3 Cl−/H+ exchange, we now generate Clcn3unc/unc mice in which ClC‐3 is converted into a Cl− channel. Unlike Clcn3−/− mice, Clcn3unc/unc mice appear normal owing to compensation by ClC‐4 with which ClC‐3 forms heteromers. ClC‐4 protein levels are strongly reduced in Clcn3−/−, but not in Clcn3unc/unc mice because ClC‐3unc binds and stabilizes ClC‐4 like wild‐type ClC‐3. Although mice lacking ClC‐4 appear healthy, its absence in Clcn3unc/unc/Clcn4−/− mice entails even stronger neurodegeneration than observed in Clcn3−/− mice. A fraction of ClC‐3 is found on synaptic vesicles, but miniature postsynaptic currents and synaptic vesicle acidification are not affected in Clcn3unc/unc or Clcn3−/− mice before neurodegeneration sets in. Both, Cl−/H+‐exchange activity and the stabilizing effect on ClC‐4, are central to the biological function of ClC‐3.}, author = {Weinert, Stefanie and Gimber, Niclas and Deuschel, Dorothea and Stuhlmann, Till and Puchkov, Dmytro and Farsi, Zohreh and Ludwig, Carmen F. and Novarino, Gaia and López-Cayuqueo, Karen I. and Planells-Cases, Rosa and Jentsch, Thomas J.}, issn = {1460-2075}, journal = {EMBO Journal}, publisher = {EMBO Press}, title = {{Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration}}, doi = {10.15252/embj.2019103358}, volume = {39}, year = {2020}, } @article{6761, abstract = {In resource allocation games, selfish players share resources that are needed in order to fulfill their objectives. The cost of using a resource depends on the load on it. In the traditional setting, the players make their choices concurrently and in one-shot. That is, a strategy for a player is a subset of the resources. We introduce and study dynamic resource allocation games. In this setting, the game proceeds in phases. In each phase each player chooses one resource. A scheduler dictates the order in which the players proceed in a phase, possibly scheduling several players to proceed concurrently. The game ends when each player has collected a set of resources that fulfills his objective. The cost for each player then depends on this set as well as on the load on the resources in it – we consider both congestion and cost-sharing games. We argue that the dynamic setting is the suitable setting for many applications in practice. We study the stability of dynamic resource allocation games, where the appropriate notion of stability is that of subgame perfect equilibrium, study the inefficiency incurred due to selfish behavior, and also study problems that are particular to the dynamic setting, like constraints on the order in which resources can be chosen or the problem of finding a scheduler that achieves stability.}, author = {Avni, Guy and Henzinger, Thomas A and Kupferman, Orna}, issn = {0304-3975}, journal = {Theoretical Computer Science}, pages = {42--55}, publisher = {Elsevier}, title = {{Dynamic resource allocation games}}, doi = {10.1016/j.tcs.2019.06.031}, volume = {807}, year = {2020}, } @article{7623, abstract = {A two-dimensional mathematical model for cells migrating without adhesion capabilities is presented and analyzed. Cells are represented by their cortex, which is modeled as an elastic curve, subject to an internal pressure force. Net polymerization or depolymerization in the cortex is modeled via local addition or removal of material, driving a cortical flow. The model takes the form of a fully nonlinear degenerate parabolic system. An existence analysis is carried out by adapting ideas from the theory of gradient flows. Numerical simulations show that these simple rules can account for the behavior observed in experiments, suggesting a possible mechanical mechanism for adhesion-independent motility.}, author = {Jankowiak, Gaspard and Peurichard, Diane and Reversat, Anne and Schmeiser, Christian and Sixt, Michael K}, issn = {0218-2025}, journal = {Mathematical Models and Methods in Applied Sciences}, number = {3}, pages = {513--537}, publisher = {World Scientific Publishing}, title = {{Modeling adhesion-independent cell migration}}, doi = {10.1142/S021820252050013X}, volume = {30}, year = {2020}, } @phdthesis{8386, abstract = {Form versus function is a long-standing debate in various design-related fields, such as architecture as well as graphic and industrial design. A good design that balances form and function often requires considerable human effort and collaboration among experts from different professional fields. Computational design tools provide a new paradigm for designing functional objects. In computational design, form and function are represented as mathematical quantities, with the help of numerical and combinatorial algorithms, they can assist even novice users in designing versatile models that exhibit their desired functionality. This thesis presents three disparate research studies on the computational design of functional objects: The appearance of 3d print—we optimize the volumetric material distribution for faithfully replicating colored surface texture in 3d printing; the dynamic motion of mechanical structures— our design system helps the novice user to retarget various mechanical templates with different functionality to complex 3d shapes; and a more abstract functionality, multistability—our algorithm automatically generates models that exhibit multiple stable target poses. For each of these cases, our computational design tools not only ensure the functionality of the results but also permit the user aesthetic freedom over the form. Moreover, fabrication constraints were taken into account, which allow for the immediate creation of physical realization via 3D printing or laser cutting.}, author = {Zhang, Ran}, issn = {2663-337X}, pages = {148}, publisher = {Institute of Science and Technology Austria}, title = {{Structure-aware computational design and its application to 3D printable volume scattering, mechanism, and multistability}}, doi = {10.15479/AT:ISTA:8386}, year = {2020}, } @inproceedings{7966, abstract = {For 1≤m≤n, we consider a natural m-out-of-n multi-instance scenario for a public-key encryption (PKE) scheme. An adversary, given n independent instances of PKE, wins if he breaks at least m out of the n instances. In this work, we are interested in the scaling factor of PKE schemes, SF, which measures how well the difficulty of breaking m out of the n instances scales in m. That is, a scaling factor SF=ℓ indicates that breaking m out of n instances is at least ℓ times more difficult than breaking one single instance. A PKE scheme with small scaling factor hence provides an ideal target for mass surveillance. In fact, the Logjam attack (CCS 2015) implicitly exploited, among other things, an almost constant scaling factor of ElGamal over finite fields (with shared group parameters). For Hashed ElGamal over elliptic curves, we use the generic group model to argue that the scaling factor depends on the scheme's granularity. In low granularity, meaning each public key contains its independent group parameter, the scheme has optimal scaling factor SF=m; In medium and high granularity, meaning all public keys share the same group parameter, the scheme still has a reasonable scaling factor SF=√m. Our findings underline that instantiating ElGamal over elliptic curves should be preferred to finite fields in a multi-instance scenario. As our main technical contribution, we derive new generic-group lower bounds of Ω(√(mp)) on the difficulty of solving both the m-out-of-n Gap Discrete Logarithm and the m-out-of-n Gap Computational Diffie-Hellman problem over groups of prime order p, extending a recent result by Yun (EUROCRYPT 2015). We establish the lower bound by studying the hardness of a related computational problem which we call the search-by-hypersurface problem.}, author = {Auerbach, Benedikt and Giacon, Federico and Kiltz, Eike}, booktitle = {Advances in Cryptology – EUROCRYPT 2020}, isbn = {9783030457266}, issn = {1611-3349}, pages = {475--506}, publisher = {Springer Nature}, title = {{Everybody’s a target: Scalability in public-key encryption}}, doi = {10.1007/978-3-030-45727-3_16}, volume = {12107}, year = {2020}, } @inproceedings{8623, abstract = {We introduce the monitoring of trace properties under assumptions. An assumption limits the space of possible traces that the monitor may encounter. An assumption may result from knowledge about the system that is being monitored, about the environment, or about another, connected monitor. We define monitorability under assumptions and study its theoretical properties. In particular, we show that for every assumption A, the boolean combinations of properties that are safe or co-safe relative to A are monitorable under A. We give several examples and constructions on how an assumption can make a non-monitorable property monitorable, and how an assumption can make a monitorable property monitorable with fewer resources, such as integer registers.}, author = {Henzinger, Thomas A and Sarac, Naci E}, booktitle = {Runtime Verification}, isbn = {9783030605070}, issn = {1611-3349}, location = {Los Angeles, CA, United States}, pages = {3--18}, publisher = {Springer Nature}, title = {{Monitorability under assumptions}}, doi = {10.1007/978-3-030-60508-7_1}, volume = {12399}, year = {2020}, } @inproceedings{8732, abstract = {A simple drawing D(G) of a graph G is one where each pair of edges share at most one point: either a common endpoint or a proper crossing. An edge e in the complement of G can be inserted into D(G) if there exists a simple drawing of G+e extending D(G). As a result of Levi’s Enlargement Lemma, if a drawing is rectilinear (pseudolinear), that is, the edges can be extended into an arrangement of lines (pseudolines), then any edge in the complement of G can be inserted. In contrast, we show that it is NP -complete to decide whether one edge can be inserted into a simple drawing. This remains true even if we assume that the drawing is pseudocircular, that is, the edges can be extended to an arrangement of pseudocircles. On the positive side, we show that, given an arrangement of pseudocircles A and a pseudosegment σ , it can be decided in polynomial time whether there exists a pseudocircle Φσ extending σ for which A∪{Φσ} is again an arrangement of pseudocircles.}, author = {Arroyo Guevara, Alan M and Klute, Fabian and Parada, Irene and Seidel, Raimund and Vogtenhuber, Birgit and Wiedera, Tilo}, booktitle = {Graph-Theoretic Concepts in Computer Science}, isbn = {9783030604394}, issn = {1611-3349}, location = {Leeds, United Kingdom}, pages = {325--338}, publisher = {Springer Nature}, title = {{Inserting one edge into a simple drawing is hard}}, doi = {10.1007/978-3-030-60440-0_26}, volume = {12301}, year = {2020}, } @inbook{10865, abstract = {We introduce the notion of Witness Maps as a cryptographic notion of a proof system. A Unique Witness Map (UWM) deterministically maps all witnesses for an NP statement to a single representative witness, resulting in a computationally sound, deterministic-prover, non-interactive witness independent proof system. A relaxation of UWM, called Compact Witness Map (CWM), maps all the witnesses to a small number of witnesses, resulting in a “lossy” deterministic-prover, non-interactive proof-system. We also define a Dual Mode Witness Map (DMWM) which adds an “extractable” mode to a CWM. Our main construction is a DMWM for all NP relations, assuming sub-exponentially secure indistinguishability obfuscation ( iO ), along with standard cryptographic assumptions. The DMWM construction relies on a CWM and a new primitive called Cumulative All-Lossy-But-One Trapdoor Functions (C-ALBO-TDF), both of which are in turn instantiated based on iO and other primitives. Our instantiation of a CWM is in fact a UWM; in turn, we show that a UWM implies Witness Encryption. Along the way to constructing UWM and C-ALBO-TDF, we also construct, from standard assumptions, Puncturable Digital Signatures and a new primitive called Cumulative Lossy Trapdoor Functions (C-LTDF). The former improves up on a construction of Bellare et al. (Eurocrypt 2016), who relied on sub-exponentially secure iO and sub-exponentially secure OWF. As an application of our constructions, we show how to use a DMWM to construct the first leakage and tamper-resilient signatures with a deterministic signer, thereby solving a decade old open problem posed by Katz and Vaikunthanathan (Asiacrypt 2009), by Boyle, Segev and Wichs (Eurocrypt 2011), as well as by Faonio and Venturi (Asiacrypt 2016). Our construction achieves the optimal leakage rate of 1−o(1) .}, author = {Chakraborty, Suvradip and Prabhakaran, Manoj and Wichs, Daniel}, booktitle = {Public-Key Cryptography}, editor = {Kiayias, A}, isbn = {9783030453732}, issn = {1611-3349}, pages = {220--246}, publisher = {Springer Nature}, title = {{Witness maps and applications}}, doi = {10.1007/978-3-030-45374-9_8}, volume = {12110}, year = {2020}, } @inbook{9123, abstract = {Inversions are chromosomal rearrangements where the order of genes is reversed. Inversions originate by mutation and can be under positive, negative or balancing selection. Selective effects result from potential disruptive effects on meiosis, gene disruption at inversion breakpoints and, importantly, the effects of inversions as modifiers of recombination rate: Recombination is strongly reduced in individuals heterozygous for an inversion, allowing for alleles at different loci to be inherited as a ‘block’. This may lead to a selective advantage whenever it is favourable to keep certain combinations of alleles associated, for example under local adaptation with gene flow. Inversions can cover a considerable part of a chromosome and contain numerous loci under different selection pressures, so that the resulting overall effects may be complex. Empirical data from various systems show that inversions may have a prominent role in local adaptation, speciation, parallel evolution, the maintenance of polymorphism and sex chromosome evolution.}, author = {Westram, Anja M and Faria, Rui and Butlin, Roger and Johannesson, Kerstin}, booktitle = {eLS}, isbn = {9780470016176}, issn = {9780470015902}, publisher = {Wiley}, title = {{Inversions and Evolution}}, doi = {10.1002/9780470015902.a0029007}, year = {2020}, } @article{6649, abstract = {While Hartree–Fock theory is well established as a fundamental approximation for interacting fermions, it has been unclear how to describe corrections to it due to many-body correlations. In this paper we start from the Hartree–Fock state given by plane waves and introduce collective particle–hole pair excitations. These pairs can be approximately described by a bosonic quadratic Hamiltonian. We use Bogoliubov theory to construct a trial state yielding a rigorous Gell-Mann–Brueckner–type upper bound to the ground state energy. Our result justifies the random-phase approximation in the mean-field scaling regime, for repulsive, regular interaction potentials. }, author = {Benedikter, Niels P and Nam, Phan Thành and Porta, Marcello and Schlein, Benjamin and Seiringer, Robert}, issn = {1432-0916}, journal = {Communications in Mathematical Physics}, pages = {2097–2150}, publisher = {Springer Nature}, title = {{Optimal upper bound for the correlation energy of a Fermi gas in the mean-field regime}}, doi = {10.1007/s00220-019-03505-5}, volume = {374}, year = {2020}, } @article{7866, abstract = {In this paper, we establish convergence to equilibrium for a drift–diffusion–recombination system modelling the charge transport within certain semiconductor devices. More precisely, we consider a two-level system for electrons and holes which is augmented by an intermediate energy level for electrons in so-called trapped states. The recombination dynamics use the mass action principle by taking into account this additional trap level. The main part of the paper is concerned with the derivation of an entropy–entropy production inequality, which entails exponential convergence to the equilibrium via the so-called entropy method. The novelty of our approach lies in the fact that the entropy method is applied uniformly in a fast-reaction parameter which governs the lifetime of electrons on the trap level. Thus, the resulting decay estimate for the densities of electrons and holes extends to the corresponding quasi-steady-state approximation.}, author = {Fellner, Klemens and Kniely, Michael}, issn = {2296-9039}, journal = {Journal of Elliptic and Parabolic Equations}, pages = {529--598}, publisher = {Springer Nature}, title = {{Uniform convergence to equilibrium for a family of drift–diffusion models with trap-assisted recombination and the limiting Shockley–Read–Hall model}}, doi = {10.1007/s41808-020-00068-8}, volume = {6}, year = {2020}, } @article{21640, abstract = {Conventional computing architectures have no known efficient algorithms for combinatorial optimization tasks such as the Ising problem, which requires finding the ground state spin configuration of an arbitrary Ising graph. Physical Ising machines have recently been developed as an alternative to conventional exact and heuristic solvers; however, these machines typically suffer from decreased ground state convergence probability or universality for high edge- density graphs or arbitrary graph weights, respectively. We experimentally demonstrate a proof-of-principle integrated nanophotonic recurrent Ising sampler (INPRIS), using a hybrid scheme combining electronics and silicon-on-insulator photonics, that is capable of converging to the ground state of various four-spin graphs with high probability. The INPRIS results indicate that noise may be used as a resource to speed up the ground state search and to explore larger regions of the phase space, thus allowing one to probe noise-dependent physical observables. Since the recurrent pho- tonic transformation that our machine imparts is a fixed function of the graph problem and therefore compatible with optoelectronic architectures that support GHz clock rates (such as passive or non-volatile photonic circuits that do not require reprogramming at each iteration), this work suggests the potential for future systems that could achieve orders- of-magnitude speedups in exploring the solution space of combinatorially hard problems. }, author = {Prabhu, Mihika and Roques-Carmes, Charles and Shen, Yichen and Harris, Nicholas and Jing, Li and Carolan, Jacques and Hamerly, Ryan and Baehr-Jones, Tom and Hochberg, Michael and Čeperić, Vladimir and Joannopoulos, John D. and Englund, Dirk R. and Soljačić, Marin}, issn = {2334-2536}, journal = {Optica}, number = {5}, pages = {551--558}, publisher = {Optica Publishing Group}, title = {{Accelerating recurrent Ising machines in photonic integrated circuits}}, doi = {10.1364/optica.386613}, volume = {7}, year = {2020}, } @article{21637, abstract = {We demonstrate new axisymmetric inverse-design techniques that can solve problems radically different from traditional lenses, including reconfigurable lenses (that shift a multi-frequency focal spot in response to refractive-index changes) and widely separated multi-wavelength lenses (λ = 1 µm and 10 µm). We also present experimental validation for an axisymmetric inverse-designed monochrome lens in the near-infrared fabricated via two-photon polymerization. Axisymmetry allows fullwave Maxwell solvers to be scaled up to structures hundreds or even thousands of wavelengths in diameter before requiring domain-decomposition approximations, while multilayer topology optimization with ∼105 degrees of freedom can tackle challenging design problems even when restricted to axisymmetric structures.}, author = {Christiansen, Rasmus E. and Lin, Zin and Roques-Carmes, Charles and Salamin, Yannick and Kooi, Steven E. and Joannopoulos, John D. and Soljačić, Marin and Johnson, Steven G.}, issn = {1094-4087}, journal = {Optics Express}, number = {23}, pages = {33854--33868}, publisher = {Optica Publishing Group}, title = {{Fullwave Maxwell inverse design of axisymmetric, tunable, and multi-scale multi-wavelength metalenses}}, doi = {10.1364/oe.403192}, volume = {28}, year = {2020}, } @article{21642, abstract = {By codesigning a metaoptical front end in conjunction with an image‐processing back end, we demonstrate noise sensitivity and compactness substantially superior to either an optics‐only or a computation‐only approach, illustrated by two examples: subwavelength imaging and reconstruction of the full polarization coherence matrices of multiple light sources. Our end‐to‐end inverse designs couple the solution of the full Maxwell equations—exploiting all aspects of wave physics arising in subwavelength scatterers—with inverse‐scattering algorithms in a single large‐scale optimization involving degrees of freedom. The resulting structures scatter light in a way that is radically different from either a conventional lens or a random microstructure, and suppress the noise sensitivity of the inverse‐scattering computation by several orders of magnitude. Incorporating the full wave physics is especially crucial for detecting spectral and polarization information that is discarded by geometric optics and scalar diffraction theory.}, author = {Lin, Zin and Roques-Carmes, Charles and Pestourie, Raphaël and Soljačić, Marin and Majumdar, Arka and Johnson, Steven G.}, issn = {2192-8614}, journal = {Nanophotonics}, keywords = {computational imaging, end-to-end photonic inverse design, inverse scattering, meta-optics, polarimetry}, number = {3}, pages = {1177--1187}, publisher = {Wiley}, title = {{End‐to‐end nanophotonic inverse design for imaging and polarimetry}}, doi = {10.1515/nanoph-2020-0579}, volume = {10}, year = {2020}, } @inproceedings{9198, abstract = {The optimization of multilayer neural networks typically leads to a solution with zero training error, yet the landscape can exhibit spurious local minima and the minima can be disconnected. In this paper, we shed light on this phenomenon: we show that the combination of stochastic gradient descent (SGD) and over-parameterization makes the landscape of multilayer neural networks approximately connected and thus more favorable to optimization. More specifically, we prove that SGD solutions are connected via a piecewise linear path, and the increase in loss along this path vanishes as the number of neurons grows large. This result is a consequence of the fact that the parameters found by SGD are increasingly dropout stable as the network becomes wider. We show that, if we remove part of the neurons (and suitably rescale the remaining ones), the change in loss is independent of the total number of neurons, and it depends only on how many neurons are left. Our results exhibit a mild dependence on the input dimension: they are dimension-free for two-layer networks and depend linearly on the dimension for multilayer networks. We validate our theoretical findings with numerical experiments for different architectures and classification tasks.}, author = {Shevchenko, Aleksandr and Mondelli, Marco}, booktitle = {Proceedings of the 37th International Conference on Machine Learning}, pages = {8773--8784}, publisher = {ML Research Press}, title = {{Landscape connectivity and dropout stability of SGD solutions for over-parameterized neural networks}}, volume = {119}, year = {2020}, } @phdthesis{8350, abstract = {Cytoplasm is a gel-like crowded environment composed of tens of thousands of macromolecules, organelles, cytoskeletal networks and cytosol. The structure of the cytoplasm is thought to be highly organized and heterogeneous due to the crowding of its constituents and their effective compartmentalization. In such an environment, the diffusive dynamics of the molecules is very restricted, an effect that is further amplified by clustering and anchoring of molecules. Despite the jammed nature of the cytoplasm at the microscopic scale, large-scale reorganization of cytoplasm is essential for important cellular functions, such as nuclear positioning and cell division. How such mesoscale reorganization of the cytoplasm is achieved, especially for very large cells such as oocytes or syncytial tissues that can span hundreds of micrometers in size, has only begun to be understood. In this thesis, I focus on the recent advances in elucidating the molecular, cellular and biophysical principles underlying cytoplasmic organization across different scales, structures and species. First, I outline which of these principles have been identified by reductionist approaches, such as in vitro reconstitution assays, where boundary conditions and components can be modulated at ease. I then describe how the theoretical and experimental framework established in these reduced systems have been applied to their more complex in vivo counterparts, in particular oocytes and embryonic syncytial structures, and discuss how such complex biological systems can initiate symmetry breaking and establish patterning. Specifically, I examine an example of large-scale reorganizations taking place in zebrafish embryos, where extensive cytoplasmic streaming leads to the segregation of cytoplasm from yolk granules along the animal-vegetal axis of the embryo. Using biophysical experimentation and theory, I investigate the forces underlying this process, to show that this process does not rely on cortical actin reorganization, as previously thought, but instead on a cell-cycle-dependent bulk actin polymerization wave traveling from the animal to the vegetal pole of the embryo. This wave functions in segregation by both pulling cytoplasm animally and pushing yolk granules vegetally. Cytoplasm pulling is mediated by bulk actin network flows exerting friction forces on the cytoplasm, while yolk granule pushing is achieved by a mechanism closely resembling actin comet formation on yolk granules. This study defines a novel role of bulk actin polymerization waves in embryo polarization via cytoplasmic segregation. Lastly, I describe the cytoplasmic reorganizations taking place during zebrafish oocyte maturation, where the initial segregation of the cytoplasm and yolk granules occurs. Here, I demonstrate a previously uncharacterized wave of microtubule aster formation, traveling the oocyte along the animal-vegetal axis. Further research is required to determine the role of such microtubule structures in cytoplasmic reorganizations therein. Collectively, these studies provide further evidence for the coupling between cell cytoskeleton and cell cycle machinery, which can underlie a core self-organizing mechanism for orchestrating large-scale reorganizations in a cell-cycle-tunable manner, where the modulations of the force-generating machinery and cytoplasmic mechanics can be harbored to fulfill cellular functions.}, author = {Shamipour, Shayan}, issn = {2663-337X}, pages = {107}, publisher = {Institute of Science and Technology Austria}, title = {{Bulk actin dynamics drive phase segregation in zebrafish oocytes }}, doi = {10.15479/AT:ISTA:8350}, year = {2020}, } @article{7888, abstract = {Embryonic stem cell cultures are thought to self-organize into embryoid bodies, able to undergo symmetry-breaking, germ layer specification and even morphogenesis. Yet, it is unclear how to reconcile this remarkable self-organization capacity with classical experiments demonstrating key roles for extrinsic biases by maternal factors and/or extraembryonic tissues in embryogenesis. Here, we show that zebrafish embryonic tissue explants, prepared prior to germ layer induction and lacking extraembryonic tissues, can specify all germ layers and form a seemingly complete mesendoderm anlage. Importantly, explant organization requires polarized inheritance of maternal factors from dorsal-marginal regions of the blastoderm. Moreover, induction of endoderm and head-mesoderm, which require peak Nodal-signaling levels, is highly variable in explants, reminiscent of embryos with reduced Nodal signals from the extraembryonic tissues. Together, these data suggest that zebrafish explants do not undergo bona fide self-organization, but rather display features of genetically encoded self-assembly, where intrinsic genetic programs control the emergence of order.}, author = {Schauer, Alexandra and Nunes Pinheiro, Diana C and Hauschild, Robert and Heisenberg, Carl-Philipp J}, issn = {2050-084X}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{Zebrafish embryonic explants undergo genetically encoded self-assembly}}, doi = {10.7554/elife.55190}, volume = {9}, year = {2020}, } @phdthesis{7680, abstract = {Proteins and their complex dynamic interactions regulate cellular mechanisms from sensing and transducing extracellular signals, to mediating genetic responses, and sustaining or changing cell morphology. To manipulate these protein-protein interactions (PPIs) that govern the behavior and fate of cells, synthetically constructed, genetically encoded tools provide the means to precisely target proteins of interest (POIs), and control their subcellular localization and activity in vitro and in vivo. Ideal synthetic tools react to an orthogonal cue, i.e. a trigger that does not activate any other endogenous process, thereby allowing manipulation of the POI alone. In optogenetics, naturally occurring photosensory domain from plants, algae and bacteria are re-purposed and genetically fused to POIs. Illumination with light of a specific wavelength triggers a conformational change that can mediate PPIs, such as dimerization or oligomerization. By using light as a trigger, these tools can be activated with high spatial and temporal precision, on subcellular and millisecond scales. Chemogenetic tools consist of protein domains that recognize and bind small molecules. By genetic fusion to POIs, these domains can mediate PPIs upon addition of their specific ligands, which are often synthetically designed to provide highly specific interactions and exhibit good bioavailability. Most optogenetic tools to mediate PPIs are based on well-studied photoreceptors responding to red, blue or near-UV light, leaving a striking gap in the green band of the visible light spectrum. Among both optogenetic and chemogenetic tools, there is an abundance of methods to induce PPIs, but tools to disrupt them require UV illumination, rely on covalent linkage and subsequent enzymatic cleavage or initially result in protein clustering of unknown stoichiometry. This work describes how the recently structurally and photochemically characterized green-light responsive cobalamin-binding domains (CBDs) from bacterial transcription factors were re-purposed to function as a green-light responsive optogenetic tool. In contrast to previously engineered optogenetic tools, CBDs do not induce PPI, but rather confer a PPI already upon expression, which can be rapidly disrupted by illumination. This was employed to mimic inhibition of constitutive activity of a growth factor receptor, and successfully implement for cell signalling in mammalian cells and in vivo to rescue development in zebrafish. This work further describes the development and application of a chemically induced de-dimerizer (CDD) based on a recently identified and structurally described bacterial oxyreductase. CDD forms a dimer upon expression in absence of its cofactor, the flavin derivative F420. Safety and of domain expression and ligand exposure are demonstrated in vitro and in vivo in zebrafish. The system is further applied to inhibit cell signalling output from a chimeric receptor upon F420 treatment. CBDs and CDD expand the repertoire of synthetic tools by providing novel mechanisms of mediating PPIs, and by recognizing previously not utilized cues. In the future, they can readily be combined with existing synthetic tools to functionally manipulate PPIs in vitro and in vivo.}, author = {Kainrath, Stephanie}, issn = {2663-337X}, pages = {98}, publisher = {Institute of Science and Technology Austria}, title = {{Synthetic tools for optogenetic and chemogenetic inhibition of cellular signals}}, doi = {10.15479/AT:ISTA:7680}, year = {2020}, } @article{8434, abstract = {Efficient migration on adhesive surfaces involves the protrusion of lamellipodial actin networks and their subsequent stabilization by nascent adhesions. The actin-binding protein lamellipodin (Lpd) is thought to play a critical role in lamellipodium protrusion, by delivering Ena/VASP proteins onto the growing plus ends of actin filaments and by interacting with the WAVE regulatory complex, an activator of the Arp2/3 complex, at the leading edge. Using B16-F1 melanoma cell lines, we demonstrate that genetic ablation of Lpd compromises protrusion efficiency and coincident cell migration without altering essential parameters of lamellipodia, including their maximal rate of forward advancement and actin polymerization. We also confirmed lamellipodia and migration phenotypes with CRISPR/Cas9-mediated Lpd knockout Rat2 fibroblasts, excluding cell type-specific effects. Moreover, computer-aided analysis of cell-edge morphodynamics on B16-F1 cell lamellipodia revealed that loss of Lpd correlates with reduced temporal protrusion maintenance as a prerequisite of nascent adhesion formation. We conclude that Lpd optimizes protrusion and nascent adhesion formation by counteracting frequent, chaotic retraction and membrane ruffling.This article has an associated First Person interview with the first author of the paper. }, author = {Dimchev, Georgi A and Amiri, Behnam and Humphries, Ashley C. and Schaks, Matthias and Dimchev, Vanessa and Stradal, Theresia E. B. and Faix, Jan and Krause, Matthias and Way, Michael and Falcke, Martin and Rottner, Klemens}, issn = {1477-9137}, journal = {Journal of Cell Science}, keywords = {Cell Biology}, number = {7}, publisher = {The Company of Biologists}, title = {{Lamellipodin tunes cell migration by stabilizing protrusions and promoting adhesion formation}}, doi = {10.1242/jcs.239020}, volume = {133}, year = {2020}, }