@inproceedings{8339, abstract = {Discrete Gaussian distributions over lattices are central to lattice-based cryptography, and to the computational and mathematical aspects of lattices more broadly. The literature contains a wealth of useful theorems about the behavior of discrete Gaussians under convolutions and related operations. Yet despite their structural similarities, most of these theorems are formally incomparable, and their proofs tend to be monolithic and written nearly “from scratch,” making them unnecessarily hard to verify, understand, and extend. In this work we present a modular framework for analyzing linear operations on discrete Gaussian distributions. The framework abstracts away the particulars of Gaussians, and usually reduces proofs to the choice of appropriate linear transformations and elementary linear algebra. To showcase the approach, we establish several general properties of discrete Gaussians, and show how to obtain all prior convolution theorems (along with some new ones) as straightforward corollaries. As another application, we describe a self-reduction for Learning With Errors (LWE) that uses a fixed number of samples to generate an unlimited number of additional ones (having somewhat larger error). The distinguishing features of our reduction are its simple analysis in our framework, and its exclusive use of discrete Gaussians without any loss in parameters relative to a prior mixed discrete-and-continuous approach. As a contribution of independent interest, for subgaussian random matrices we prove a singular value concentration bound with explicitly stated constants, and we give tighter heuristics for specific distributions that are commonly used for generating lattice trapdoors. These bounds yield improvements in the concrete bit-security estimates for trapdoor lattice cryptosystems.}, author = {Genise, Nicholas and Micciancio, Daniele and Peikert, Chris and Walter, Michael}, booktitle = {23rd IACR International Conference on the Practice and Theory of Public-Key Cryptography}, isbn = {9783030453732}, issn = {1611-3349}, location = {Edinburgh, United Kingdom}, pages = {623--651}, publisher = {Springer Nature}, title = {{Improved discrete Gaussian and subgaussian analysis for lattice cryptography}}, doi = {10.1007/978-3-030-45374-9_21}, volume = {12110}, year = {2020}, } @inproceedings{8987, abstract = {Currently several projects aim at designing and implementing protocols for privacy preserving automated contact tracing to help fight the current pandemic. Those proposal are quite similar, and in their most basic form basically propose an app for mobile phones which broadcasts frequently changing pseudorandom identifiers via (low energy) Bluetooth, and at the same time, the app stores IDs broadcast by phones in its proximity. Only if a user is tested positive, they upload either the beacons they did broadcast (which is the case in decentralized proposals as DP-3T, east and west coast PACT or Covid watch) or received (as in Popp-PT or ROBERT) during the last two weeks or so. Vaudenay [eprint 2020/399] observes that this basic scheme (he considers the DP-3T proposal) succumbs to relay and even replay attacks, and proposes more complex interactive schemes which prevent those attacks without giving up too many privacy aspects. Unfortunately interaction is problematic for this application for efficiency and security reasons. The countermeasures that have been suggested so far are either not practical or give up on key privacy aspects. We propose a simple non-interactive variant of the basic protocol that (security) Provably prevents replay and (if location data is available) relay attacks. (privacy) The data of all parties (even jointly) reveals no information on the location or time where encounters happened. (efficiency) The broadcasted message can fit into 128 bits and uses only basic crypto (commitments and secret key authentication). Towards this end we introduce the concept of “delayed authentication”, which basically is a message authentication code where verification can be done in two steps, where the first doesn’t require the key, and the second doesn’t require the message.}, author = {Pietrzak, Krzysztof Z}, booktitle = {Progress in Cryptology}, isbn = {9783030652760}, issn = {1611-3349}, location = {Bangalore, India}, pages = {3--15}, publisher = {Springer Nature}, title = {{Delayed authentication: Preventing replay and relay attacks in private contact tracing}}, doi = {10.1007/978-3-030-65277-7_1}, volume = {12578}, year = {2020}, } @inproceedings{8322, abstract = {Reverse firewalls were introduced at Eurocrypt 2015 by Miro-nov and Stephens-Davidowitz, as a method for protecting cryptographic protocols against attacks on the devices of the honest parties. In a nutshell: a reverse firewall is placed outside of a device and its goal is to “sanitize” the messages sent by it, in such a way that a malicious device cannot leak its secrets to the outside world. It is typically assumed that the cryptographic devices are attacked in a “functionality-preserving way” (i.e. informally speaking, the functionality of the protocol remains unchanged under this attacks). In their paper, Mironov and Stephens-Davidowitz construct a protocol for passively-secure two-party computations with firewalls, leaving extension of this result to stronger models as an open question. In this paper, we address this problem by constructing a protocol for secure computation with firewalls that has two main advantages over the original protocol from Eurocrypt 2015. Firstly, it is a multiparty computation protocol (i.e. it works for an arbitrary number n of the parties, and not just for 2). Secondly, it is secure in much stronger corruption settings, namely in the active corruption model. More precisely: we consider an adversary that can fully corrupt up to 𝑛−1 parties, while the remaining parties are corrupt in a functionality-preserving way. Our core techniques are: malleable commitments and malleable non-interactive zero-knowledge, which in particular allow us to create a novel protocol for multiparty augmented coin-tossing into the well with reverse firewalls (that is based on a protocol of Lindell from Crypto 2001).}, author = {Chakraborty, Suvradip and Dziembowski, Stefan and Nielsen, Jesper Buus}, booktitle = {Advances in Cryptology – CRYPTO 2020}, isbn = {9783030568795}, issn = {1611-3349}, location = {Santa Barbara, CA, United States}, pages = {732--762}, publisher = {Springer Nature}, title = {{Reverse firewalls for actively secure MPCs}}, doi = {10.1007/978-3-030-56880-1_26}, volume = {12171}, year = {2020}, } @inproceedings{8194, abstract = {Fixed-point arithmetic is a popular alternative to floating-point arithmetic on embedded systems. Existing work on the verification of fixed-point programs relies on custom formalizations of fixed-point arithmetic, which makes it hard to compare the described techniques or reuse the implementations. In this paper, we address this issue by proposing and formalizing an SMT theory of fixed-point arithmetic. We present an intuitive yet comprehensive syntax of the fixed-point theory, and provide formal semantics for it based on rational arithmetic. We also describe two decision procedures for this theory: one based on the theory of bit-vectors and the other on the theory of reals. We implement the two decision procedures, and evaluate our implementations using existing mature SMT solvers on a benchmark suite we created. Finally, we perform a case study of using the theory we propose to verify properties of quantized neural networks.}, author = {Baranowski, Marek and He, Shaobo and Lechner, Mathias and Nguyen, Thanh Son and Rakamarić, Zvonimir}, booktitle = {Automated Reasoning}, isbn = {9783030510732}, issn = {1611-3349}, location = {Paris, France}, pages = {13--31}, publisher = {Springer Nature}, title = {{An SMT theory of fixed-point arithmetic}}, doi = {10.1007/978-3-030-51074-9_2}, volume = {12166}, year = {2020}, } @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}, } @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}, } @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}, } @article{8707, abstract = {Dynamic changes in the three-dimensional (3D) organization of chromatin are associated with central biological processes, such as transcription, replication and development. Therefore, the comprehensive identification and quantification of these changes is fundamental to understanding of evolutionary and regulatory mechanisms. Here, we present Comparison of Hi-C Experiments using Structural Similarity (CHESS), an algorithm for the comparison of chromatin contact maps and automatic differential feature extraction. We demonstrate the robustness of CHESS to experimental variability and showcase its biological applications on (1) interspecies comparisons of syntenic regions in human and mouse models; (2) intraspecies identification of conformational changes in Zelda-depleted Drosophila embryos; (3) patient-specific aberrant chromatin conformation in a diffuse large B-cell lymphoma sample; and (4) the systematic identification of chromatin contact differences in high-resolution Capture-C data. In summary, CHESS is a computationally efficient method for the comparison and classification of changes in chromatin contact data.}, author = { Galan, Silvia and Machnik, Nick N and Kruse, Kai and Díaz, Noelia and Marti-Renom, Marc A and Vaquerizas, Juan M}, issn = {1546-1718}, journal = {Nature Genetics}, pages = {1247--1255}, publisher = {Springer Nature}, title = {{CHESS enables quantitative comparison of chromatin contact data and automatic feature extraction}}, doi = {10.1038/s41588-020-00712-y}, volume = {52}, year = {2020}, } @article{8532, abstract = {The molecular anatomy of synapses defines their characteristics in transmission and plasticity. Precise measurements of the number and distribution of synaptic proteins are important for our understanding of synapse heterogeneity within and between brain regions. Freeze–fracture replica immunogold electron microscopy enables us to analyze them quantitatively on a two-dimensional membrane surface. Here, we introduce Darea software, which utilizes deep learning for analysis of replica images and demonstrate its usefulness for quick measurements of the pre- and postsynaptic areas, density and distribution of gold particles at synapses in a reproducible manner. We used Darea for comparing glutamate receptor and calcium channel distributions between hippocampal CA3-CA1 spine synapses on apical and basal dendrites, which differ in signaling pathways involved in synaptic plasticity. We found that apical synapses express a higher density of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and a stronger increase of AMPA receptors with synaptic size, while basal synapses show a larger increase in N-methyl-D-aspartate (NMDA) receptors with size. Interestingly, AMPA and NMDA receptors are segregated within postsynaptic sites and negatively correlated in density among both apical and basal synapses. In the presynaptic sites, Cav2.1 voltage-gated calcium channels show similar densities in apical and basal synapses with distributions consistent with an exclusion zone model of calcium channel-release site topography.}, author = {Kleindienst, David and Montanaro-Punzengruber, Jacqueline-Claire and Bhandari, Pradeep and Case, Matthew J and Fukazawa, Yugo and Shigemoto, Ryuichi}, issn = {1422-0067}, journal = {International Journal of Molecular Sciences}, number = {18}, publisher = {MDPI}, title = {{Deep learning-assisted high-throughput analysis of freeze-fracture replica images applied to glutamate receptors and calcium channels at hippocampal synapses}}, doi = {10.3390/ijms21186737}, volume = {21}, year = {2020}, } @phdthesis{8657, abstract = {Synthesis of proteins – translation – is a fundamental process of life. Quantitative studies anchor translation into the context of bacterial physiology and reveal several mathematical relationships, called “growth laws,” which capture physiological feedbacks between protein synthesis and cell growth. Growth laws describe the dependency of the ribosome abundance as a function of growth rate, which can change depending on the growth conditions. Perturbations of translation reveal that bacteria employ a compensatory strategy in which the reduced translation capability results in increased expression of the translation machinery. Perturbations of translation are achieved in various ways; clinically interesting is the application of translation-targeting antibiotics – translation inhibitors. The antibiotic effects on bacterial physiology are often poorly understood. Bacterial responses to two or more simultaneously applied antibiotics are even more puzzling. The combined antibiotic effect determines the type of drug interaction, which ranges from synergy (the effect is stronger than expected) to antagonism (the effect is weaker) and suppression (one of the drugs loses its potency). In the first part of this work, we systematically measure the pairwise interaction network for translation inhibitors that interfere with different steps in translation. We find that the interactions are surprisingly diverse and tend to be more antagonistic. To explore the underlying mechanisms, we begin with a minimal biophysical model of combined antibiotic action. We base this model on the kinetics of antibiotic uptake and binding together with the physiological response described by the growth laws. The biophysical model explains some drug interactions, but not all; it specifically fails to predict suppression. In the second part of this work, we hypothesize that elusive suppressive drug interactions result from the interplay between ribosomes halted in different stages of translation. To elucidate this putative mechanism of drug interactions between translation inhibitors, we generate translation bottlenecks genetically using in- ducible control of translation factors that regulate well-defined translation cycle steps. These perturbations accurately mimic antibiotic action and drug interactions, supporting that the interplay of different translation bottlenecks partially causes these interactions. We extend this approach by varying two translation bottlenecks simultaneously. This approach reveals the suppression of translocation inhibition by inhibited translation. We rationalize this effect by modeling dense traffic of ribosomes that move on transcripts in a translation factor-mediated manner. This model predicts a dissolution of traffic jams caused by inhibited translocation when the density of ribosome traffic is reduced by lowered initiation. We base this model on the growth laws and quantitative relationships between different translation and growth parameters. In the final part of this work, we describe a set of tools aimed at quantification of physiological and translation parameters. We further develop a simple model that directly connects the abundance of a translation factor with the growth rate, which allows us to extract physiological parameters describing initiation. We demonstrate the development of tools for measuring translation rate. This thesis showcases how a combination of high-throughput growth rate mea- surements, genetics, and modeling can reveal mechanisms of drug interactions. Furthermore, by a gradual transition from combinations of antibiotics to precise genetic interventions, we demonstrated the equivalency between genetic and chemi- cal perturbations of translation. These findings tile the path for quantitative studies of antibiotic combinations and illustrate future approaches towards the quantitative description of translation.}, author = {Kavcic, Bor}, isbn = {978-3-99078-011-4}, issn = {2663-337X}, pages = {271}, publisher = {Institute of Science and Technology Austria}, title = {{Perturbations of protein synthesis: from antibiotics to genetics and physiology}}, doi = {10.15479/AT:ISTA:8657}, year = {2020}, } @article{8569, abstract = {Concerted radial migration of newly born cortical projection neurons, from their birthplace to their final target lamina, is a key step in the assembly of the cerebral cortex. The cellular and molecular mechanisms regulating the specific sequential steps of radial neuronal migration in vivo are however still unclear, let alone the effects and interactions with the extracellular environment. In any in vivo context, cells will always be exposed to a complex extracellular environment consisting of (1) secreted factors acting as potential signaling cues, (2) the extracellular matrix, and (3) other cells providing cell–cell interaction through receptors and/or direct physical stimuli. Most studies so far have described and focused mainly on intrinsic cell-autonomous gene functions in neuronal migration but there is accumulating evidence that non-cell-autonomous-, local-, systemic-, and/or whole tissue-wide effects substantially contribute to the regulation of radial neuronal migration. These non-cell-autonomous effects may differentially affect cortical neuron migration in distinct cellular environments. However, the cellular and molecular natures of such non-cell-autonomous mechanisms are mostly unknown. Furthermore, physical forces due to collective migration and/or community effects (i.e., interactions with surrounding cells) may play important roles in neocortical projection neuron migration. In this concise review, we first outline distinct models of non-cell-autonomous interactions of cortical projection neurons along their radial migration trajectory during development. We then summarize experimental assays and platforms that can be utilized to visualize and potentially probe non-cell-autonomous mechanisms. Lastly, we define key questions to address in the future.}, author = {Hansen, Andi H and Hippenmeyer, Simon}, issn = {2296-634X}, journal = {Frontiers in Cell and Developmental Biology}, number = {9}, publisher = {Frontiers}, title = {{Non-cell-autonomous mechanisms in radial projection neuron migration in the developing cerebral cortex}}, doi = {10.3389/fcell.2020.574382}, volume = {8}, year = {2020}, } @phdthesis{8340, abstract = {Mitochondria are sites of oxidative phosphorylation in eukaryotic cells. Oxidative phosphorylation operates by a chemiosmotic mechanism made possible by redox-driven proton pumping machines which establish a proton motive force across the inner mitochondrial membrane. This electrochemical proton gradient is used to drive ATP synthesis, which powers the majority of cellular processes such as protein synthesis, locomotion and signalling. In this thesis I investigate the structures and molecular mechanisms of two inner mitochondrial proton pumping enzymes, respiratory complex I and transhydrogenase. I present the first high-resolution structure of the full transhydrogenase from any species, and a significantly improved structure of complex I. Improving the resolution from 3.3 Å available previously to up to 2.3 Å in this thesis allowed us to model bound water molecules, crucial in the proton pumping mechanism. For both enzymes, up to five cryo-EM datasets with different substrates and inhibitors bound were solved to delineate the catalytic cycle and understand the proton pumping mechanism. In transhydrogenase, the proton channel is gated by reversible detachment of the NADP(H)-binding domain which opens the proton channel to the opposite sites of the membrane. In complex I, the proton channels are gated by reversible protonation of key glutamate and lysine residues and breaking of the water wire connecting the proton pumps with the quinone reduction site. The tight coupling between the redox and the proton pumping reactions in transhydrogenase is achieved by controlling the NADP(H) exchange which can only happen when the NADP(H)-binding domain interacts with the membrane domain. In complex I, coupling is achieved by cycling of the whole complex between the closed state, in which quinone can get reduced, and the open state, in which NADH can induce quinol ejection from the binding pocket. On the basis of these results I propose detailed mechanisms for catalytic cycles of transhydrogenase and complex I that are consistent with a large amount of previous work. In both enzymes, conformational and electrostatic mechanisms contribute to the overall catalytic process. Results presented here could be used for better understanding of the human pathologies arising from deficiencies of complex I or transhydrogenase and could be used to develop novel therapies.}, author = {Kampjut, Domen}, isbn = {978-3-99078-008-4}, issn = {2663-337X}, pages = {242}, publisher = {Institute of Science and Technology Austria}, title = {{Molecular mechanisms of mitochondrial redox-coupled proton pumping enzymes}}, doi = {10.15479/AT:ISTA:8340}, year = {2020}, } @phdthesis{8620, abstract = {The development of the human brain occurs through a tightly regulated series of dynamic and adaptive processes during prenatal and postnatal life. A disruption of this strictly orchestrated series of events can lead to a number of neurodevelopmental conditions, including Autism Spectrum Disorders (ASDs). ASDs are a very common, etiologically and phenotypically heterogeneous group of disorders sharing the core symptoms of social interaction and communication deficits and restrictive and repetitive interests and behaviors. They are estimated to affect one in 59 individuals in the U.S. and, over the last three decades, mutations in more than a hundred genetic loci have been convincingly linked to ASD pathogenesis. Yet, for the vast majority of these ASD-risk genes their role during brain development and precise molecular function still remain elusive. De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin 3 (CUL3) lead to ASD. In the study described here, we used Cul3 mouse models to evaluate the consequences of Cul3 mutations in vivo. Our results show that Cul3 heterozygous knockout mice exhibit deficits in motor coordination as well as ASD-relevant social and cognitive impairments. Cul3+/-, Cul3+/fl Emx1-Cre and Cul3fl/fl Emx1-Cre mutant brains display cortical lamination abnormalities due to defective migration of post-mitotic excitatory neurons, as well as reduced numbers of excitatory and inhibitory neurons. In line with the observed abnormal cortical organization, Cul3 heterozygous deletion is associated with decreased spontaneous excitatory and inhibitory activity in the cortex. At the molecular level we show that Cul3 regulates cytoskeletal and adhesion protein abundance in the mouse embryonic cortex. Abnormal regulation of cytoskeletal proteins in Cul3 mutant neural cells results in atypical organization of the actin mesh at the cell leading edge. Of note, heterozygous deletion of Cul3 in adult mice does not induce the majority of the behavioral defects observed in constitutive Cul3 haploinsufficient animals, pointing to a critical time-window for Cul3 deficiency. In conclusion, our data indicate that Cul3 plays a critical role in the regulation of cytoskeletal proteins and neuronal migration. ASD-associated defects and behavioral abnormalities are primarily due to dosage sensitive Cul3 functions at early brain developmental stages.}, author = {Morandell, Jasmin}, issn = {2663-337X}, pages = {138}, publisher = {Institute of Science and Technology Austria}, title = {{Illuminating the role of Cul3 in autism spectrum disorder pathogenesis}}, doi = {10.15479/AT:ISTA:8620}, year = {2020}, } @inproceedings{7810, abstract = {Interprocedural data-flow analyses form an expressive and useful paradigm of numerous static analysis applications, such as live variables analysis, alias analysis and null pointers analysis. The most widely-used framework for interprocedural data-flow analysis is IFDS, which encompasses distributive data-flow functions over a finite domain. On-demand data-flow analyses restrict the focus of the analysis on specific program locations and data facts. This setting provides a natural split between (i) an offline (or preprocessing) phase, where the program is partially analyzed and analysis summaries are created, and (ii) an online (or query) phase, where analysis queries arrive on demand and the summaries are used to speed up answering queries. In this work, we consider on-demand IFDS analyses where the queries concern program locations of the same procedure (aka same-context queries). We exploit the fact that flow graphs of programs have low treewidth to develop faster algorithms that are space and time optimal for many common data-flow analyses, in both the preprocessing and the query phase. We also use treewidth to develop query solutions that are embarrassingly parallelizable, i.e. the total work for answering each query is split to a number of threads such that each thread performs only a constant amount of work. Finally, we implement a static analyzer based on our algorithms, and perform a series of on-demand analysis experiments on standard benchmarks. Our experimental results show a drastic speed-up of the queries after only a lightweight preprocessing phase, which significantly outperforms existing techniques.}, author = {Chatterjee, Krishnendu and Goharshady, Amir Kafshdar and Ibsen-Jensen, Rasmus and Pavlogiannis, Andreas}, booktitle = {European Symposium on Programming}, isbn = {9783030449131}, issn = {1611-3349}, location = {Dublin, Ireland}, pages = {112--140}, publisher = {Springer Nature}, title = {{Optimal and perfectly parallel algorithms for on-demand data-flow analysis}}, doi = {10.1007/978-3-030-44914-8_5}, volume = {12075}, year = {2020}, } @inproceedings{8728, abstract = {Discrete-time Markov Chains (MCs) and Markov Decision Processes (MDPs) are two standard formalisms in system analysis. Their main associated quantitative objectives are hitting probabilities, discounted sum, and mean payoff. Although there are many techniques for computing these objectives in general MCs/MDPs, they have not been thoroughly studied in terms of parameterized algorithms, particularly when treewidth is used as the parameter. This is in sharp contrast to qualitative objectives for MCs, MDPs and graph games, for which treewidth-based algorithms yield significant complexity improvements. In this work, we show that treewidth can also be used to obtain faster algorithms for the quantitative problems. For an MC with n states and m transitions, we show that each of the classical quantitative objectives can be computed in O((n+m)⋅t2) time, given a tree decomposition of the MC with width t. Our results also imply a bound of O(κ⋅(n+m)⋅t2) for each objective on MDPs, where κ is the number of strategy-iteration refinements required for the given input and objective. Finally, we make an experimental evaluation of our new algorithms on low-treewidth MCs and MDPs obtained from the DaCapo benchmark suite. Our experiments show that on low-treewidth MCs and MDPs, our algorithms outperform existing well-established methods by one or more orders of magnitude.}, author = {Asadi, Ali and Chatterjee, Krishnendu and Goharshady, Amir Kafshdar and Mohammadi, Kiarash and Pavlogiannis, Andreas}, booktitle = {Automated Technology for Verification and Analysis}, isbn = {9783030591519}, issn = {1611-3349}, location = {Hanoi, Vietnam}, pages = {253--270}, publisher = {Springer Nature}, title = {{Faster algorithms for quantitative analysis of MCs and MDPs with small treewidth}}, doi = {10.1007/978-3-030-59152-6_14}, volume = {12302}, year = {2020}, } @inproceedings{21621, abstract = {We show that nanophotonic structures enable the possibility of realizing lasers based on stimulated emission by free electrons. The associated threshold beam currents are in the nanoampere range, and could be realized in electron microscopes.}, author = {Rivera, Nicholas and Roques-Carmes, Charles and Kaminer, Ido and Soljačić, Marin}, booktitle = {Conference on Lasers and Electro-Optics}, location = {Washington, DC, United States}, publisher = {Optica Publishing Group}, title = {{Toward nanophotonic free-electron lasers}}, doi = {10.1364/cleo_qels.2020.fm2q.3}, year = {2020}, }