@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}, } @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}, } @unpublished{7800, abstract = {De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3 (CUL3) lead to autism spectrum disorder (ASD). Here, we used Cul3 mouse models to evaluate the consequences of Cul3 mutations in vivo. Our results show that Cul3 haploinsufficient mice exhibit deficits in motor coordination as well as ASD-relevant social and cognitive impairments. Cul3 mutant brain displays cortical lamination abnormalities due to defective neuronal migration and reduced numbers of excitatory and inhibitory neurons. In line with the observed abnormal columnar organization, Cul3 haploinsufficiency is associated with decreased spontaneous excitatory and inhibitory activity in the cortex. At the molecular level, employing a quantitative proteomic approach, we show that Cul3 regulates cytoskeletal and adhesion protein abundance in mouse embryos. Abnormal regulation of cytoskeletal proteins in Cul3 mutant neuronal cells results in atypical organization of the actin mesh at the cell leading edge, likely causing the observed migration deficits. In contrast to these important functions early in development, Cul3 deficiency appears less relevant at adult stages. In fact, induction of Cul3 haploinsufficiency in adult mice does not result in the behavioral defects observed in constitutive Cul3 haploinsufficient animals. Taken together, our data indicate that Cul3 has a critical role in the regulation of cytoskeletal proteins and neuronal migration and that ASD-associated defects and behavioral abnormalities are primarily due to Cul3 functions at early developmental stages.}, author = {Morandell, Jasmin and Schwarz, Lena A and Basilico, Bernadette and Tasciyan, Saren and Nicolas, Armel and Sommer, Christoph M and Kreuzinger, Caroline and Knaus, Lisa and Dobler, Zoe and Cacci, Emanuele and Danzl, Johann G and Novarino, Gaia}, booktitle = {bioRxiv}, publisher = {Cold Spring Harbor Laboratory}, title = {{Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development}}, doi = {10.1101/2020.01.10.902064 }, year = {2020}, } @article{8131, abstract = {The possibility to generate construct valid animal models enabled the development and testing of therapeutic strategies targeting the core features of autism spectrum disorders (ASDs). At the same time, these studies highlighted the necessity of identifying sensitive developmental time windows for successful therapeutic interventions. Animal and human studies also uncovered the possibility to stratify the variety of ASDs in molecularly distinct subgroups, potentially facilitating effective treatment design. Here, we focus on the molecular pathways emerging as commonly affected by mutations in diverse ASD-risk genes, on their role during critical windows of brain development and the potential treatments targeting these biological processes.}, author = {Basilico, Bernadette and Morandell, Jasmin and Novarino, Gaia}, issn = {18790380}, journal = {Current Opinion in Genetics and Development}, number = {12}, pages = {126--137}, publisher = {Elsevier}, title = {{Molecular mechanisms for targeted ASD treatments}}, doi = {10.1016/j.gde.2020.06.004}, volume = {65}, 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{7889, abstract = {Autoluminescent plants engineered to express a bacterial bioluminescence gene cluster in plastids have not been widely adopted because of low light output. We engineered tobacco plants with a fungal bioluminescence system that converts caffeic acid (present in all plants) into luciferin and report self-sustained luminescence that is visible to the naked eye. Our findings could underpin development of a suite of imaging tools for plants.}, author = {Mitiouchkina, Tatiana and Mishin, Alexander S. and Gonzalez Somermeyer, Louisa and Markina, Nadezhda M. and Chepurnyh, Tatiana V. and Guglya, Elena B. and Karataeva, Tatiana A. and Palkina, Kseniia A. and Shakhova, Ekaterina S. and Fakhranurova, Liliia I. and Chekova, Sofia V. and Tsarkova, Aleksandra S. and Golubev, Yaroslav V. and Negrebetsky, Vadim V. and Dolgushin, Sergey A. and Shalaev, Pavel V. and Shlykov, Dmitry and Melnik, Olesya A. and Shipunova, Victoria O. and Deyev, Sergey M. and Bubyrev, Andrey I. and Pushin, Alexander S. and Choob, Vladimir V. and Dolgov, Sergey V. and Kondrashov, Fyodor and Yampolsky, Ilia V. and Sarkisyan, Karen S.}, issn = {1546-1696}, journal = {Nature Biotechnology}, pages = {944--946}, publisher = {Springer Nature}, title = {{Plants with genetically encoded autoluminescence}}, doi = {10.1038/s41587-020-0500-9}, volume = {38}, year = {2020}, } @unpublished{9750, abstract = {Tension of the actomyosin cell cortex plays a key role in determining cell-cell contact growth and size. The level of cortical tension outside of the cell-cell contact, when pulling at the contact edge, scales with the total size to which a cell-cell contact can grow1,2. Here we show in zebrafish primary germ layer progenitor cells that this monotonic relationship only applies to a narrow range of cortical tension increase, and that above a critical threshold, contact size inversely scales with cortical tension. This switch from cortical tension increasing to decreasing progenitor cell-cell contact size is caused by cortical tension promoting E-cadherin anchoring to the actomyosin cytoskeleton, thereby increasing clustering and stability of E-cadherin at the contact. Once tension-mediated E-cadherin stabilization at the contact exceeds a critical threshold level, the rate by which the contact expands in response to pulling forces from the cortex sharply drops, leading to smaller contacts at physiologically relevant timescales of contact formation. Thus, the activity of cortical tension in expanding cell-cell contact size is limited by tension stabilizing E-cadherin-actin complexes at the contact.}, author = {Slovakova, Jana and Sikora, Mateusz K and Caballero Mancebo, Silvia and Krens, Gabriel and Kaufmann, Walter and Huljev, Karla and Heisenberg, Carl-Philipp J}, booktitle = {bioRxiv}, pages = {41}, publisher = {Cold Spring Harbor Laboratory}, title = {{Tension-dependent stabilization of E-cadherin limits cell-cell contact expansion}}, doi = {10.1101/2020.11.20.391284}, year = {2020}, } @article{7885, abstract = {Eukaryotic cells migrate by coupling the intracellular force of the actin cytoskeleton to the environment. While force coupling is usually mediated by transmembrane adhesion receptors, especially those of the integrin family, amoeboid cells such as leukocytes can migrate extremely fast despite very low adhesive forces1. Here we show that leukocytes cannot only migrate under low adhesion but can also transmit forces in the complete absence of transmembrane force coupling. When confined within three-dimensional environments, they use the topographical features of the substrate to propel themselves. Here the retrograde flow of the actin cytoskeleton follows the texture of the substrate, creating retrograde shear forces that are sufficient to drive the cell body forwards. Notably, adhesion-dependent and adhesion-independent migration are not mutually exclusive, but rather are variants of the same principle of coupling retrograde actin flow to the environment and thus can potentially operate interchangeably and simultaneously. As adhesion-free migration is independent of the chemical composition of the environment, it renders cells completely autonomous in their locomotive behaviour.}, author = {Reversat, Anne and Gärtner, Florian R and Merrin, Jack and Stopp, Julian A and Tasciyan, Saren and Aguilera Servin, Juan L and De Vries, Ingrid and Hauschild, Robert and Hons, Miroslav and Piel, Matthieu and Callan-Jones, Andrew and Voituriez, Raphael and Sixt, Michael K}, issn = {14764687}, journal = {Nature}, pages = {582–585}, publisher = {Springer Nature}, title = {{Cellular locomotion using environmental topography}}, doi = {10.1038/s41586-020-2283-z}, volume = {582}, year = {2020}, } @article{7426, abstract = {This paper presents a novel abstraction technique for analyzing Lyapunov and asymptotic stability of polyhedral switched systems. A polyhedral switched system is a hybrid system in which the continuous dynamics is specified by polyhedral differential inclusions, the invariants and guards are specified by polyhedral sets and the switching between the modes do not involve reset of variables. A finite state weighted graph abstracting the polyhedral switched system is constructed from a finite partition of the state–space, such that the satisfaction of certain graph conditions, such as the absence of cycles with product of weights on the edges greater than (or equal) to 1, implies the stability of the system. However, the graph is in general conservative and hence, the violation of the graph conditions does not imply instability. If the analysis fails to establish stability due to the conservativeness in the approximation, a counterexample (cycle with product of edge weights greater than or equal to 1) indicating a potential reason for the failure is returned. Further, a more precise approximation of the switched system can be constructed by considering a finer partition of the state–space in the construction of the finite weighted graph. We present experimental results on analyzing stability of switched systems using the above method.}, author = {Garcia Soto, Miriam and Prabhakar, Pavithra}, issn = {1751-570X}, journal = {Nonlinear Analysis: Hybrid Systems}, number = {5}, publisher = {Elsevier}, title = {{Abstraction based verification of stability of polyhedral switched systems}}, doi = {10.1016/j.nahs.2020.100856}, volume = {36}, year = {2020}, } @phdthesis{8983, abstract = {Metabolic adaptation is a critical feature of migrating cells. It tunes the metabolic programs of migrating cells to allow them to efficiently exert their crucial roles in development, inflammatory responses and tumor metastasis. Cell migration through physically challenging contexts requires energy. However, how the metabolic reprogramming that underlies in vivo cell invasion is controlled is still unanswered. In my PhD project, I identify a novel conserved metabolic shift in Drosophila melanogaster immune cells that by modulating their bioenergetic potential controls developmentally programmed tissue invasion. We show that this regulation requires a novel conserved nuclear protein, named Atossa. Atossa enhances the transcription of a set of proteins, including an RNA helicase Porthos and two metabolic enzymes, each of which increases the tissue invasion of leading Drosophila macrophages and can rescue the atossa mutant phenotype. Porthos selectively regulates the translational efficiency of a subset of mRNAs containing a 5’-UTR cis-regulatory TOP-like sequence. These 5’TOPL mRNA targets encode mitochondrial-related proteins, including subunits of mitochondrial oxidative phosphorylation (OXPHOS) components III and V and other metabolic-related proteins. Porthos powers up mitochondrial OXPHOS to engender a sufficient ATP supply, which is required for tissue invasion of leading macrophages. Atossa’s two vertebrate orthologs rescue the invasion defect. In my PhD project, I elucidate that Atossa displays a conserved developmental metabolic control to modulate metabolic capacities and the cellular energy state, through altered transcription and translation, to aid the tissue infiltration of leading cells into energy demanding barriers.}, author = {Emtenani, Shamsi}, issn = {2663-337X}, pages = {141}, publisher = {Institute of Science and Technology Austria}, title = {{Metabolic regulation of Drosophila macrophage tissue invasion}}, doi = {10.15479/AT:ISTA:8983}, year = {2020}, } @unpublished{8557, abstract = {The infiltration of immune cells into tissues underlies the establishment of tissue resident macrophages, and responses to infections and tumors. Yet the mechanisms immune cells utilize to negotiate tissue barriers in living organisms are not well understood, and a role for cortical actin has not been examined. Here we find that the tissue invasion of Drosophila macrophages, also known as plasmatocytes or hemocytes, utilizes enhanced cortical F-actin levels stimulated by the Drosophila member of the fos proto oncogene transcription factor family (Dfos, Kayak). RNA sequencing analysis and live imaging show that Dfos enhances F-actin levels around the entire macrophage surface by increasing mRNA levels of the membrane spanning molecular scaffold tetraspanin TM4SF, and the actin cross-linking filamin Cheerio which are themselves required for invasion. Cortical F-actin levels are critical as expressing a dominant active form of Diaphanous, a actin polymerizing Formin, can rescue the Dfos Dominant Negative macrophage invasion defect. In vivo imaging shows that Dfos is required to enhance the efficiency of the initial phases of macrophage tissue entry. Genetic evidence argues that this Dfos-induced program in macrophages counteracts the constraint produced by the tension of surrounding tissues and buffers the mechanical properties of the macrophage nucleus from affecting tissue entry. We thus identify tuning the cortical actin cytoskeleton through Dfos as a key process allowing efficient forward movement of an immune cell into surrounding tissues.}, author = {Belyaeva, Vera and Wachner, Stephanie and Gridchyn, Igor and Linder, Markus and Emtenani, Shamsi and György, Attila and Sibilia, Maria and Siekhaus, Daria E}, booktitle = {bioRxiv}, title = {{Cortical actin properties controlled by Drosophila Fos aid macrophage infiltration against surrounding tissue resistance}}, doi = {10.1101/2020.09.18.301481}, year = {2020}, } @unpublished{8831, abstract = {Holes in planar Ge have high mobilities, strong spin-orbit interaction and electrically tunable g-factors, and are therefore emerging as a promising candidate for hybrid superconductorsemiconductor devices. This is further motivated by the observation of supercurrent transport in planar Ge Josephson Field effect transistors (JoFETs). A key challenge towards hybrid germanium quantum technology is the design of high quality interfaces and superconducting contacts that are robust against magnetic fields. By combining the assets of Al, which has a long superconducting coherence, and Nb, which has a significant superconducting gap, we form low-disordered JoFETs with large ICRN products that are capable of withstanding high magnetic fields. We furthermore demonstrate the ability of phase-biasing individual JoFETs opening up an avenue to explore topological superconductivity in planar Ge. The persistence of superconductivity in the reported hybrid devices beyond 1.8 T paves the way towards integrating spin qubits and proximity-induced superconductivity on the same chip.}, author = {Aggarwal, Kushagra and Hofmann, Andrea C and Jirovec, Daniel and Prieto Gonzalez, Ivan and Sammak, Amir and Botifoll, Marc and Marti-Sanchez, Sara and Veldhorst, Menno and Arbiol, Jordi and Scappucci, Giordano and Katsaros, Georgios}, booktitle = {arXiv}, title = {{Enhancement of proximity induced superconductivity in planar Germanium}}, 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 = {14220067}, 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}, } @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 = {16113349}, 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{8089, abstract = {We consider the classical problem of invariant generation for programs with polynomial assignments and focus on synthesizing invariants that are a conjunction of strict polynomial inequalities. We present a sound and semi-complete method based on positivstellensaetze, i.e. theorems in semi-algebraic geometry that characterize positive polynomials over a semi-algebraic set. On the theoretical side, the worst-case complexity of our approach is subexponential, whereas the worst-case complexity of the previous complete method (Kapur, ACA 2004) is doubly-exponential. Even when restricted to linear invariants, the best previous complexity for complete invariant generation is exponential (Colon et al, CAV 2003). On the practical side, we reduce the invariant generation problem to quadratic programming (QCLP), which is a classical optimization problem with many industrial solvers. We demonstrate the applicability of our approach by providing experimental results on several academic benchmarks. To the best of our knowledge, the only previous invariant generation method that provides completeness guarantees for invariants consisting of polynomial inequalities is (Kapur, ACA 2004), which relies on quantifier elimination and cannot even handle toy programs such as our running example.}, author = {Chatterjee, Krishnendu and Fu, Hongfei and Goharshady, Amir Kafshdar and Goharshady, Ehsan Kafshdar}, booktitle = {Proceedings of the 41st ACM SIGPLAN Conference on Programming Language Design and Implementation}, isbn = {9781450376136}, location = {London, United Kingdom}, pages = {672--687}, publisher = {Association for Computing Machinery}, title = {{Polynomial invariant generation for non-deterministic recursive programs}}, doi = {10.1145/3385412.3385969}, year = {2020}, } @article{6918, abstract = {We consider the classic problem of Network Reliability. A network is given together with a source vertex, one or more target vertices, and probabilities assigned to each of the edges. Each edge of the network is operable with its associated probability and the problem is to determine the probability of having at least one source-to-target path that is entirely composed of operable edges. This problem is known to be NP-hard. We provide a novel scalable algorithm to solve the Network Reliability problem when the treewidth of the underlying network is small. We also show our algorithm’s applicability for real-world transit networks that have small treewidth, including the metro networks of major cities, such as London and Tokyo. Our algorithm leverages tree decompositions to shrink the original graph into much smaller graphs, for which reliability can be efficiently and exactly computed using a brute force method. To the best of our knowledge, this is the first exact algorithm for Network Reliability that can scale to handle real-world instances of the problem.}, author = {Goharshady, Amir Kafshdar and Mohammadi, Fatemeh}, issn = {09518320}, journal = {Reliability Engineering and System Safety}, publisher = {Elsevier}, title = {{An efficient algorithm for computing network reliability in small treewidth}}, doi = {10.1016/j.ress.2019.106665}, volume = {193}, year = {2020}, } @article{7161, abstract = {In this paper, we introduce an inertial projection-type method with different updating strategies for solving quasi-variational inequalities with strongly monotone and Lipschitz continuous operators in real Hilbert spaces. Under standard assumptions, we establish different strong convergence results for the proposed algorithm. Primary numerical experiments demonstrate the potential applicability of our scheme compared with some related methods in the literature.}, author = {Shehu, Yekini and Gibali, Aviv and Sagratella, Simone}, issn = {1573-2878}, journal = {Journal of Optimization Theory and Applications}, pages = {877–894}, publisher = {Springer Nature}, title = {{Inertial projection-type methods for solving quasi-variational inequalities in real Hilbert spaces}}, doi = {10.1007/s10957-019-01616-6}, volume = {184}, year = {2020}, } @article{7652, abstract = {Organisms cope with change by taking advantage of transcriptional regulators. However, when faced with rare environments, the evolution of transcriptional regulators and their promoters may be too slow. Here, we investigate whether the intrinsic instability of gene duplication and amplification provides a generic alternative to canonical gene regulation. Using real-time monitoring of gene-copy-number mutations in Escherichia coli, we show that gene duplications and amplifications enable adaptation to fluctuating environments by rapidly generating copy-number and, therefore, expression-level polymorphisms. This amplification-mediated gene expression tuning (AMGET) occurs on timescales that are similar to canonical gene regulation and can respond to rapid environmental changes. Mathematical modelling shows that amplifications also tune gene expression in stochastic environments in which transcription-factor-based schemes are hard to evolve or maintain. The fleeting nature of gene amplifications gives rise to a generic population-level mechanism that relies on genetic heterogeneity to rapidly tune the expression of any gene, without leaving any genomic signature.}, author = {Tomanek, Isabella and Grah, Rok and Lagator, M. and Andersson, A. M. C. and Bollback, Jonathan P and Tkačik, Gašper and Guet, Calin C}, issn = {2397-334X}, journal = {Nature Ecology & Evolution}, number = {4}, pages = {612--625}, publisher = {Springer Nature}, title = {{Gene amplification as a form of population-level gene expression regulation}}, doi = {10.1038/s41559-020-1132-7}, volume = {4}, year = {2020}, } @phdthesis{7258, abstract = {Many flows encountered in nature and applications are characterized by a chaotic motion known as turbulence. Turbulent flows generate intense friction with pipe walls and are responsible for considerable amounts of energy losses at world scale. The nature of turbulent friction and techniques aimed at reducing it have been subject of extensive research over the last century, but no definite answer has been found yet. In this thesis we show that in pipes at moderate turbulent Reynolds numbers friction is better described by the power law first introduced by Blasius and not by the Prandtl–von Kármán formula. At higher Reynolds numbers, large scale motions gradually become more important in the flow and can be related to the change in scaling of friction. Next, we present a series of new techniques that can relaminarize turbulence by suppressing a key mechanism that regenerates it at walls, the lift–up effect. In addition, we investigate the process of turbulence decay in several experiments and discuss the drag reduction potential. Finally, we examine the behavior of friction under pulsating conditions inspired by the human heart cycle and we show that under such circumstances turbulent friction can be reduced to produce energy savings.}, author = {Scarselli, Davide}, issn = {2663-337X}, pages = {174}, publisher = {Institute of Science and Technology Austria}, title = {{New approaches to reduce friction in turbulent pipe flow}}, doi = {10.15479/AT:ISTA:7258}, year = {2020}, }