@phdthesis{6825, abstract = {The solving of complex tasks requires the functions of more than one brain area and their interaction. Whilst spatial navigation and memory is dependent on the hippocampus, flexible behavior relies on the medial prefrontal cortex (mPFC). To further examine the roles of the hippocampus and mPFC, we recorded their neural activity during a task that depends on both of these brain regions. With tetrodes, we recorded the extracellular activity of dorsal hippocampal CA1 (HPC) and mPFC neurons in Long-Evans rats performing a rule-switching task on the plus-maze. The plus-maze task had a spatial component since it required navigation along one of the two start arms and at the maze center a choice between one of the two goal arms. Which goal contained a reward depended on the rule currently in place. After an uncued rule change the animal had to abandon the old strategy and switch to the new rule, testing cognitive flexibility. Investigating the coordination of activity between the HPC and mPFC allows determination during which task stages their interaction is required. Additionally, comparing neural activity patterns in these two brain regions allows delineation of the specialized functions of the HPC and mPFC in this task. We analyzed neural activity in the HPC and mPFC in terms of oscillatory interactions, rule coding and replay. We found that theta coherence between the HPC and mPFC is increased at the center and goals of the maze, both when the rule was stable or has changed. Similar results were found for locking of HPC and mPFC neurons to HPC theta oscillations. However, no differences in HPC-mPFC theta coordination were observed between the spatially- and cue-guided rule. Phase locking of HPC and mPFC neurons to HPC gamma oscillations was not modulated by maze position or rule type. We found that the HPC coded for the two different rules with cofiring relationships between cell pairs. However, we could not find conclusive evidence for rule coding in the mPFC. Spatially-selective firing in the mPFC generalized between the two start and two goal arms. With Bayesian positional decoding, we found that the mPFC reactivated non-local positions during awake immobility periods. Replay of these non-local positions could represent entire behavioral trajectories resembling trajectory replay of the HPC. Furthermore, mPFC trajectory-replay at the goal positively correlated with rule-switching performance. Finally, HPC and mPFC trajectory replay occurred independently of each other. These results show that the mPFC can replay ordered patterns of activity during awake immobility, possibly underlying its role in flexible behavior. }, author = {Käfer, Karola}, issn = {2663-337X}, pages = {89}, publisher = {Institute of Science and Technology Austria}, title = {{The hippocampus and medial prefrontal cortex during flexible behavior}}, doi = {10.15479/AT:ISTA:6825}, year = {2019}, } @article{5949, abstract = {Aberrant proteostasis of protein aggregation may lead to behavior disorders including chronic mental illnesses (CMI). Furthermore, the neuronal activity alterations that underlie CMI are not well understood. We recorded the local field potential and single-unit activity of the hippocampal CA1 region in vivo in rats transgenically overexpressing the Disrupted-in-Schizophrenia 1 (DISC1) gene (tgDISC1), modeling sporadic CMI. These tgDISC1 rats have previously been shown to exhibit DISC1 protein aggregation, disturbances in the dopaminergic system and attention-related deficits. Recordings were performed during exploration of familiar and novel open field environments and during sleep, allowing investigation of neuronal abnormalities in unconstrained behavior. Compared to controls, tgDISC1 place cells exhibited smaller place fields and decreased speed-modulation of their firing rates, demonstrating altered spatial coding and deficits in encoding location-independent sensory inputs. Oscillation analyses showed that tgDISC1 pyramidal neurons had higher theta phase locking strength during novelty, limiting their phase coding ability. However, their mean theta phases were more variable at the population level, reducing oscillatory network synchronization. Finally, tgDISC1 pyramidal neurons showed a lack of novelty-induced shift in their preferred theta and gamma firing phases, indicating deficits in coding of novel environments with oscillatory firing. By combining single cell and neuronal population analyses, we link DISC1 protein pathology with abnormal hippocampal neural coding and network synchrony, and thereby gain a more comprehensive understanding of CMI mechanisms.}, author = {Käfer, Karola and Malagon-Vina, Hugo and Dickerson, Desiree and O'Neill, Joseph and Trossbach, Svenja V. and Korth, Carsten and Csicsvari, Jozsef L}, journal = {Hippocampus}, number = {9}, pages = {802--816}, publisher = {Wiley}, title = {{Disrupted-in-schizophrenia 1 overexpression disrupts hippocampal coding and oscillatory synchronization}}, doi = {10.1002/hipo.23076}, volume = {29}, year = {2019}, } @article{6187, abstract = {Aberrant display of the truncated core1 O-glycan T-antigen is a common feature of human cancer cells that correlates with metastasis. Here we show that T-antigen in Drosophila melanogaster macrophages is involved in their developmentally programmed tissue invasion. Higher macrophage T-antigen levels require an atypical major facilitator superfamily (MFS) member that we named Minerva which enables macrophage dissemination and invasion. We characterize for the first time the T and Tn glycoform O-glycoproteome of the Drosophila melanogaster embryo, and determine that Minerva increases the presence of T-antigen on proteins in pathways previously linked to cancer, most strongly on the sulfhydryl oxidase Qsox1 which we show is required for macrophage tissue entry. Minerva’s vertebrate ortholog, MFSD1, rescues the minerva mutant’s migration and T-antigen glycosylation defects. We thus identify a key conserved regulator that orchestrates O-glycosylation on a protein subset to activate a program governing migration steps important for both development and cancer metastasis.}, author = {Valosková, Katarina and Biebl, Julia and Roblek, Marko and Emtenani, Shamsi and György, Attila and Misova, Michaela and Ratheesh, Aparna and Dos Reis Rodrigues, Patricia and Shkarina, Katerina and Larsen, Ida Signe Bohse and Vakhrushev, Sergey Y and Clausen, Henrik and Siekhaus, Daria E}, issn = {2050-084X}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{A conserved major facilitator superfamily member orchestrates a subset of O-glycosylation to aid macrophage tissue invasion}}, doi = {10.7554/elife.41801}, volume = {8}, year = {2019}, } @phdthesis{6546, abstract = {Invasive migration plays a crucial role not only during development and homeostasis but also in pathological states, such as tumor metastasis. Drosophila macrophage migration into the extended germband is an interesting system to study invasive migration. It carries similarities to immune cell transmigration and cancer cell invasion, therefore studying this process could also bring new understanding of invasion in higher organisms. In our work, we uncover a highly conserved member of the major facilitator family that plays a role in tissue invasion through regulation of glycosylation on a subgroup of proteins and/or by aiding the precise timing of DN-Cadherin downregulation. Aberrant display of the truncated core1 O-glycan T-antigen is a common feature of human cancer cells that correlates with metastasis. Here we show that T-antigen in Drosophila melanogaster macrophages is involved in their developmentally programmed tissue invasion. Higher macrophage T-antigen levels require an atypical major facilitator superfamily (MFS) member that we named Minerva which enables macrophage dissemination and invasion. We characterize for the first time the T and Tn glycoform O-glycoproteome of the Drosophila melanogaster embryo, and determine that Minerva increases the presence of T-antigen on proteins in pathways previously linked to cancer, most strongly on the sulfhydryl oxidase Qsox1 which we show is required for macrophage tissue entry. Minerva’s vertebrate ortholog, MFSD1, rescues the minerva mutant’s migration and T-antigen glycosylation defects. We thus identify a key conserved regulator that orchestrates O-glycosylation on a protein subset to activate a program governing migration steps important for both development and cancer metastasis. }, author = {Valosková, Katarina}, issn = {2663-337X}, pages = {141}, publisher = {Institute of Science and Technology Austria}, title = {{The role of a highly conserved major facilitator superfamily member in Drosophila embryonic macrophage migration}}, doi = {10.15479/AT:ISTA:6546}, year = {2019}, } @phdthesis{7132, abstract = {A major challenge in neuroscience research is to dissect the circuits that orchestrate behavior in health and disease. Proteins from a wide range of non-mammalian species, such as microbial opsins, have been successfully transplanted to specific neuronal targets to override their natural communication patterns. The goal of our work is to manipulate synaptic communication in a manner that closely incorporates the functional intricacies of synapses by preserving temporal encoding (i.e. the firing pattern of the presynaptic neuron) and connectivity (i.e. target specific synapses rather than specific neurons). Our strategy to achieve this goal builds on the use of non-mammalian transplants to create a synthetic synapse. The mode of modulation comes from pre-synaptic uptake of a synthetic neurotransmitter (SN) into synaptic vesicles by means of a genetically targeted transporter selective for the SN. Upon natural vesicular release, exposure of the SN to the synaptic cleft will modify the post-synaptic potential through an orthogonal ligand gated ion channel. To achieve this goal we have functionally characterized a mixed cationic methionine-gated ion channel from Arabidopsis thaliana, designed a method to functionally characterize a synthetic transporter in isolated synaptic vesicles without the need for transgenic animals, identified and extracted multiple prokaryotic uptake systems that are substrate specific for methionine (Met), and established a primary/cell line co-culture system that would allow future combinatorial testing of this orthogonal transmitter-transporter-channel trifecta. Synthetic synapses will provide a unique opportunity to manipulate synaptic communication while maintaining the electrophysiological integrity of the pre-synaptic cell. In this way, information may be preserved that was generated in upstream circuits and that could be essential for concerted function and information processing.}, author = {Mckenzie, Catherine}, issn = {2663-337X}, pages = {95}, publisher = {Institute of Science and Technology Austria}, title = {{Design and characterization of methods and biological components to realize synthetic neurotransmission}}, doi = {10.15479/at:ista:7132}, year = {2019}, } @phdthesis{6849, abstract = {Brain function is mediated by complex dynamical interactions between excitatory and inhibitory cell types. The Cholecystokinin-expressing inhibitory cells (CCK-interneurons) are one of the least studied types, despite being suspected to play important roles in cognitive processes. We studied the network effects of optogenetic silencing of CCK-interneurons in the CA1 hippocampal area during exploration and sleep states. The cell firing pattern in response to light pulses allowed us to classify the recorded neurons in 5 classes, including disinhibited and non-responsive pyramidal cell and interneurons, and the inhibited interneurons corresponding to the CCK group. The light application, which inhibited the activity of CCK interneurons triggered wider changes in the firing dynamics of cells. We observed rate changes (i.e. remapping) of pyramidal cells during the exploration session in which the light was applied relative to the previous control session that was not restricted neither in time nor space to the light delivery. Also, the disinhibited pyramidal cells had higher increase in bursting than in single spike firing rate as a result of CCK silencing. In addition, the firing activity patterns during exploratory periods were more weakly reactivated in sleep for those periods in which CCK-interneuron were silenced than in the unaffected periods. Furthermore, light pulses during sleep disrupted the reactivation of recent waking patterns. Hence, silencing CCK neurons during exploration suppressed the reactivation of waking firing patterns in sleep and CCK interneuron activity was also required during sleep for the normal reactivation of waking patterns. These findings demonstrate the involvement of CCK cells in reactivation-related memory consolidation. An important part of our analysis was to test the relationship of the identified CCKinterneurons to brain oscillations. Our findings showed that these cells exhibited different oscillatory behaviour during anaesthesia and natural waking and sleep conditions. We showed that: 1) Contrary to the past studies performed under anaesthesia, the identified CCKinterneurons fired on the descending portion of the theta phase in waking exploration. 2) CCKinterneuron preferred phases around the trough of gamma oscillations. 3) Contrary to anaesthesia conditions, the average firing rate of the CCK-interneurons increased around the peak activity of the sharp-wave ripple (SWR) events in natural sleep, which is congruent with new reports about their functional connectivity. We also found that light driven CCK-interneuron silencing altered the dynamics on the CA1 network oscillatory activity: 1) Pyramidal cells negatively shifted their preferred theta phases when the light was applied, while interneurons responses were less consistent. 2) As a population, pyramidal cells negatively shifted their preferred activity during gamma oscillations, albeit we did not find gamma modulation differences related to the light application when pyramidal cells were subdivided into the disinhibited and unaffected groups. 3) During the peak of SWR events, all but the CCK-interneurons had a reduction in their relative firing rate change during the light application as compared to the change observed at SWR initiation. Finally, regarding to the place field activity of the recorded pyramidal neurons, we showed that the disinhibited pyramidal cells had reduced place field similarity, coherence and spatial information, but only during the light application. The mechanisms behind such observed behaviours might involve eCB signalling and plastic changes in CCK-interneuron synapses. In conclusion, the observed changes related to the light-mediated silencing of CCKinterneurons have unravelled characteristics of this interneuron subpopulation that might change the understanding not only of their particular network interactions, but also of the current theories about the emergence of certain cognitive processes such as place coding needed for navigation or hippocampus-dependent memory consolidation. }, author = {Rangel Guerrero, Dámaris K}, isbn = {978-3-99078-003-9}, issn = {2663-337X}, pages = {97}, publisher = {Institute of Science and Technology Austria}, title = {{The role of CCK-interneurons in regulating hippocampal network dynamics}}, doi = {10.15479/AT:ISTA:6849}, year = {2019}, } @inbook{10864, abstract = {We prove that every congruence distributive variety has directed Jónsson terms, and every congruence modular variety has directed Gumm terms. The directed terms we construct witness every case of absorption witnessed by the original Jónsson or Gumm terms. This result is equivalent to a pair of claims about absorption for admissible preorders in congruence distributive and congruence modular varieties, respectively. For finite algebras, these absorption theorems have already seen significant applications, but until now, it was not clear if the theorems hold for general algebras as well. Our method also yields a novel proof of a result by P. Lipparini about the existence of a chain of terms (which we call Pixley terms) in varieties that are at the same time congruence distributive and k-permutable for some k.}, author = {Kazda, Alexandr and Kozik, Marcin and McKenzie, Ralph and Moore, Matthew}, booktitle = {Don Pigozzi on Abstract Algebraic Logic, Universal Algebra, and Computer Science}, editor = {Czelakowski, J}, isbn = {9783319747712}, issn = {2211-2766}, pages = {203--220}, publisher = {Springer Nature}, title = {{Absorption and directed Jónsson terms}}, doi = {10.1007/978-3-319-74772-9_7}, volume = {16}, year = {2018}, } @article{10880, abstract = {Acquisition of evolutionary novelties is a fundamental process for adapting to the external environment and invading new niches and results in the diversification of life, which we can see in the world today. How such novel phenotypic traits are acquired in the course of evolution and are built up in developing embryos has been a central question in biology. Whole-genome duplication (WGD) is a process of genome doubling that supplies raw genetic materials and increases genome complexity. Recently, it has been gradually revealed that WGD and subsequent fate changes of duplicated genes can facilitate phenotypic evolution. Here, we review the current understanding of the relationship between WGD and the acquisition of evolutionary novelties. We show some examples of this link and discuss how WGD and subsequent duplicated genes can facilitate phenotypic evolution as well as when such genomic doubling can be advantageous for adaptation.}, author = {Yuuta, Moriyama and Koshiba-Takeuchi, Kazuko}, issn = {2041-2657}, journal = {Briefings in Functional Genomics}, keywords = {Genetics, Molecular Biology, Biochemistry, General Medicine}, number = {5}, pages = {329--338}, publisher = {Oxford University Press}, title = {{Significance of whole-genome duplications on the emergence of evolutionary novelties}}, doi = {10.1093/bfgp/ely007}, volume = {17}, year = {2018}, } @article{10881, abstract = {Strigolactones (SLs) are a relatively recent addition to the list of plant hormones that control different aspects of plant development. SL signalling is perceived by an α/β hydrolase, DWARF 14 (D14). A close homolog of D14, KARRIKIN INSENSTIVE2 (KAI2), is involved in perception of an uncharacterized molecule called karrikin (KAR). Recent studies in Arabidopsis identified the SUPPRESSOR OF MAX2 1 (SMAX1) and SMAX1-LIKE 7 (SMXL7) to be potential SCF–MAX2 complex-mediated proteasome targets of KAI2 and D14, respectively. Genetic studies on SMXL7 and SMAX1 demonstrated distinct developmental roles for each, but very little is known about these repressors in terms of their sequence features. In this study, we performed an extensive comparative analysis of SMXLs and determined their phylogenetic and evolutionary history in the plant lineage. Our results show that SMXL family members can be sub-divided into four distinct phylogenetic clades/classes, with an ancient SMAX1. Further, we identified the clade-specific motifs that have evolved and that might act as determinants of SL-KAR signalling specificity. These specificities resulted from functional diversities among the clades. Our results suggest that a gradual co-evolution of SMXL members with their upstream receptors D14/KAI2 provided an increased specificity to both the SL perception and response in land plants.}, author = {Moturu, Taraka Ramji and Thula, Sravankumar and Singh, Ravi Kumar and Nodzyński, Tomasz and Vařeková, Radka Svobodová and Friml, Jiří and Simon, Sibu}, issn = {1460-2431}, journal = {Journal of Experimental Botany}, keywords = {Plant Science, Physiology}, number = {9}, pages = {2367--2378}, publisher = {Oxford University Press}, title = {{Molecular evolution and diversification of the SMXL gene family}}, doi = {10.1093/jxb/ery097}, volume = {69}, year = {2018}, } @inproceedings{10882, abstract = {We introduce Intelligent Annotation Dialogs for bounding box annotation. We train an agent to automatically choose a sequence of actions for a human annotator to produce a bounding box in a minimal amount of time. Specifically, we consider two actions: box verification [34], where the annotator verifies a box generated by an object detector, and manual box drawing. We explore two kinds of agents, one based on predicting the probability that a box will be positively verified, and the other based on reinforcement learning. We demonstrate that (1) our agents are able to learn efficient annotation strategies in several scenarios, automatically adapting to the image difficulty, the desired quality of the boxes, and the detector strength; (2) in all scenarios the resulting annotation dialogs speed up annotation compared to manual box drawing alone and box verification alone, while also outperforming any fixed combination of verification and drawing in most scenarios; (3) in a realistic scenario where the detector is iteratively re-trained, our agents evolve a series of strategies that reflect the shifting trade-off between verification and drawing as the detector grows stronger.}, author = {Uijlings, Jasper and Konyushkova, Ksenia and Lampert, Christoph and Ferrari, Vittorio}, booktitle = {2018 IEEE/CVF Conference on Computer Vision and Pattern Recognition}, isbn = {9781538664209}, issn = {2575-7075}, location = {Salt Lake City, UT, United States}, pages = {9175--9184}, publisher = {IEEE}, title = {{Learning intelligent dialogs for bounding box annotation}}, doi = {10.1109/cvpr.2018.00956}, year = {2018}, } @inproceedings{10883, abstract = {Solving parity games, which are equivalent to modal μ-calculus model checking, is a central algorithmic problem in formal methods, with applications in reactive synthesis, program repair, verification of branching-time properties, etc. Besides the standard compu- tation model with the explicit representation of games, another important theoretical model of computation is that of set-based symbolic algorithms. Set-based symbolic algorithms use basic set operations and one-step predecessor operations on the implicit description of games, rather than the explicit representation. The significance of symbolic algorithms is that they provide scalable algorithms for large finite-state systems, as well as for infinite-state systems with finite quotient. Consider parity games on graphs with n vertices and parity conditions with d priorities. While there is a rich literature of explicit algorithms for parity games, the main results for set-based symbolic algorithms are as follows: (a) the basic algorithm that requires O(nd) symbolic operations and O(d) symbolic space; and (b) an improved algorithm that requires O(nd/3+1) symbolic operations and O(n) symbolic space. In this work, our contributions are as follows: (1) We present a black-box set-based symbolic algorithm based on the explicit progress measure algorithm. Two important consequences of our algorithm are as follows: (a) a set-based symbolic algorithm for parity games that requires quasi-polynomially many symbolic operations and O(n) symbolic space; and (b) any future improvement in progress measure based explicit algorithms immediately imply an efficiency improvement in our set-based symbolic algorithm for parity games. (2) We present a set-based symbolic algorithm that requires quasi-polynomially many symbolic operations and O(d · log n) symbolic space. Moreover, for the important special case of d ≤ log n, our algorithm requires only polynomially many symbolic operations and poly-logarithmic symbolic space.}, author = {Chatterjee, Krishnendu and Dvořák, Wolfgang and Henzinger, Monika H and Svozil, Alexander}, booktitle = {22nd International Conference on Logic for Programming, Artificial Intelligence and Reasoning}, issn = {2398-7340}, location = {Awassa, Ethiopia}, pages = {233--253}, publisher = {EasyChair}, title = {{Quasipolynomial set-based symbolic algorithms for parity games}}, doi = {10.29007/5z5k}, volume = {57}, year = {2018}, } @inproceedings{11, abstract = {We report on a novel strategy to derive mean-field limits of quantum mechanical systems in which a large number of particles weakly couple to a second-quantized radiation field. The technique combines the method of counting and the coherent state approach to study the growth of the correlations among the particles and in the radiation field. As an instructional example, we derive the Schrödinger–Klein–Gordon system of equations from the Nelson model with ultraviolet cutoff and possibly massless scalar field. In particular, we prove the convergence of the reduced density matrices (of the nonrelativistic particles and the field bosons) associated with the exact time evolution to the projectors onto the solutions of the Schrödinger–Klein–Gordon equations in trace norm. Furthermore, we derive explicit bounds on the rate of convergence of the one-particle reduced density matrix of the nonrelativistic particles in Sobolev norm.}, author = {Leopold, Nikolai K and Pickl, Peter}, location = {Munich, Germany}, pages = {185 -- 214}, publisher = {Springer}, title = {{Mean-field limits of particles in interaction with quantised radiation fields}}, doi = {10.1007/978-3-030-01602-9_9}, volume = {270}, year = {2018}, } @article{23, abstract = {The strong atomistic spin–orbit coupling of holes makes single-shot spin readout measurements difficult because it reduces the spin lifetimes. By integrating the charge sensor into a high bandwidth radio frequency reflectometry setup, we were able to demonstrate single-shot readout of a germanium quantum dot hole spin and measure the spin lifetime. Hole spin relaxation times of about 90 μs at 500 mT are reported, with a total readout visibility of about 70%. By analyzing separately the spin-to-charge conversion and charge readout fidelities, we have obtained insight into the processes limiting the visibilities of hole spins. The analyses suggest that high hole visibilities are feasible at realistic experimental conditions, underlying the potential of hole spins for the realization of viable qubit devices.}, author = {Vukušić, Lada and Kukucka, Josip and Watzinger, Hannes and Milem, Joshua M and Schäffler, Friedrich and Katsaros, Georgios}, issn = {1530-6984}, journal = {Nano Letters}, number = {11}, pages = {7141 -- 7145}, publisher = {American Chemical Society}, title = {{Single-shot readout of hole spins in Ge}}, doi = {10.1021/acs.nanolett.8b03217}, volume = {18}, year = {2018}, } @inproceedings{24, abstract = {Partially-observable Markov decision processes (POMDPs) with discounted-sum payoff are a standard framework to model a wide range of problems related to decision making under uncertainty. Traditionally, the goal has been to obtain policies that optimize the expectation of the discounted-sum payoff. A key drawback of the expectation measure is that even low probability events with extreme payoff can significantly affect the expectation, and thus the obtained policies are not necessarily risk-averse. An alternate approach is to optimize the probability that the payoff is above a certain threshold, which allows obtaining risk-averse policies, but ignores optimization of the expectation. We consider the expectation optimization with probabilistic guarantee (EOPG) problem, where the goal is to optimize the expectation ensuring that the payoff is above a given threshold with at least a specified probability. We present several results on the EOPG problem, including the first algorithm to solve it.}, author = {Chatterjee, Krishnendu and Elgyütt, Adrian and Novotny, Petr and Rouillé, Owen}, location = {Stockholm, Sweden}, pages = {4692 -- 4699}, publisher = {IJCAI}, title = {{Expectation optimization with probabilistic guarantees in POMDPs with discounted-sum objectives}}, doi = {10.24963/ijcai.2018/652}, volume = {2018}, year = {2018}, } @inproceedings{25, abstract = {Partially observable Markov decision processes (POMDPs) are the standard models for planning under uncertainty with both finite and infinite horizon. Besides the well-known discounted-sum objective, indefinite-horizon objective (aka Goal-POMDPs) is another classical objective for POMDPs. In this case, given a set of target states and a positive cost for each transition, the optimization objective is to minimize the expected total cost until a target state is reached. In the literature, RTDP-Bel or heuristic search value iteration (HSVI) have been used for solving Goal-POMDPs. Neither of these algorithms has theoretical convergence guarantees, and HSVI may even fail to terminate its trials. We give the following contributions: (1) We discuss the challenges introduced in Goal-POMDPs and illustrate how they prevent the original HSVI from converging. (2) We present a novel algorithm inspired by HSVI, termed Goal-HSVI, and show that our algorithm has convergence guarantees. (3) We show that Goal-HSVI outperforms RTDP-Bel on a set of well-known examples.}, author = {Horák, Karel and Bošanský, Branislav and Chatterjee, Krishnendu}, booktitle = {Proceedings of the Twenty-Seventh International Joint Conference on Artificial Intelligence}, location = {Stockholm, Sweden}, pages = {4764 -- 4770}, publisher = {IJCAI}, title = {{Goal-HSVI: Heuristic search value iteration for goal-POMDPs}}, doi = {10.24963/ijcai.2018/662}, volume = {2018-July}, year = {2018}, } @inproceedings{273, abstract = {The accuracy of information retrieval systems is often measured using complex loss functions such as the average precision (AP) or the normalized discounted cumulative gain (NDCG). Given a set of positive and negative samples, the parameters of a retrieval system can be estimated by minimizing these loss functions. However, the non-differentiability and non-decomposability of these loss functions does not allow for simple gradient based optimization algorithms. This issue is generally circumvented by either optimizing a structured hinge-loss upper bound to the loss function or by using asymptotic methods like the direct-loss minimization framework. Yet, the high computational complexity of loss-augmented inference, which is necessary for both the frameworks, prohibits its use in large training data sets. To alleviate this deficiency, we present a novel quicksort flavored algorithm for a large class of non-decomposable loss functions. We provide a complete characterization of the loss functions that are amenable to our algorithm, and show that it includes both AP and NDCG based loss functions. Furthermore, we prove that no comparison based algorithm can improve upon the computational complexity of our approach asymptotically. We demonstrate the effectiveness of our approach in the context of optimizing the structured hinge loss upper bound of AP and NDCG loss for learning models for a variety of vision tasks. We show that our approach provides significantly better results than simpler decomposable loss functions, while requiring a comparable training time.}, author = {Mohapatra, Pritish and Rolinek, Michal and Jawahar, C V and Kolmogorov, Vladimir and Kumar, M Pawan}, booktitle = {2018 IEEE/CVF Conference on Computer Vision and Pattern Recognition}, isbn = {9781538664209}, location = {Salt Lake City, UT, USA}, pages = {3693--3701}, publisher = {IEEE}, title = {{Efficient optimization for rank-based loss functions}}, doi = {10.1109/cvpr.2018.00389}, year = {2018}, } @article{275, abstract = {Lymphatic endothelial cells (LECs) release extracellular chemokines to guide the migration of dendritic cells. In this study, we report that LECs also release basolateral exosome-rich endothelial vesicles (EEVs) that are secreted in greater numbers in the presence of inflammatory cytokines and accumulate in the perivascular stroma of small lymphatic vessels in human chronic inflammatory diseases. Proteomic analyses of EEV fractions identified > 1,700 cargo proteins and revealed a dominant motility-promoting protein signature. In vitro and ex vivo EEV fractions augmented cellular protrusion formation in a CX3CL1/fractalkine-dependent fashion and enhanced the directional migratory response of human dendritic cells along guidance cues. We conclude that perilymphatic LEC exosomes enhance exploratory behavior and thus promote directional migration of CX3CR1-expressing cells in complex tissue environments.}, author = {Brown, Markus and Johnson, Louise and Leone, Dario and Májek, Peter and Vaahtomeri, Kari and Senfter, Daniel and Bukosza, Nora and Schachner, Helga and Asfour, Gabriele and Langer, Brigitte and Hauschild, Robert and Parapatics, Katja and Hong, Young and Bennett, Keiryn and Kain, Renate and Detmar, Michael and Sixt, Michael K and Jackson, David and Kerjaschki, Dontscho}, journal = {Journal of Cell Biology}, number = {6}, pages = {2205 -- 2221}, publisher = {Rockefeller University Press}, title = {{Lymphatic exosomes promote dendritic cell migration along guidance cues}}, doi = {10.1083/jcb.201612051}, volume = {217}, year = {2018}, } @article{276, abstract = {Directed migration of cells relies on their ability to sense directional guidance cues and to interact with pericellular structures in order to transduce contractile cytoskeletal- into mechanical forces. These biomechanical processes depend highly on microenvironmental factors such as exposure to 2D surfaces or 3D matrices. In vivo, the majority of cells are exposed to 3D environments. Data on 3D cell migration are mostly derived from intravital microscopy or collagen-based in vitro assays. Both approaches offer only limited controlla-bility of experimental conditions. Here, we developed an automated microfluidic system that allows positioning of cells in 3D microenvironments containing highly controlled diffusion-based chemokine gradients. Tracking migration in such gradients was feasible in real time at the single cell level. Moreover, the setup allowed on-chip immunocytochemistry and thus linking of functional with phenotypical properties in individual cells. Spatially defined retrieval of cells from the device allows down-stream off-chip analysis. Using dendritic cells as a model, our setup specifically allowed us for the first time to quantitate key migration characteristics of cells exposed to identical gradients of the chemokine CCL19 yet placed on 2D vs in 3D environments. Migration properties between 2D and 3D migration were distinct. Morphological features of cells migrating in an in vitro 3D environment were similar to those of cells migrating in animal tissues, but different from cells migrating on a surface. Our system thus offers a highly controllable in vitro-mimic of a 3D environment that cells traffic in vivo.}, author = {Frick, Corina and Dettinger, Philip and Renkawitz, Jörg and Jauch, Annaïse and Berger, Christoph and Recher, Mike and Schroeder, Timm and Mehling, Matthias}, journal = {PLoS One}, number = {6}, publisher = {Public Library of Science}, title = {{Nano-scale microfluidics to study 3D chemotaxis at the single cell level}}, doi = {10.1371/journal.pone.0198330}, volume = {13}, year = {2018}, } @article{277, abstract = {Arabidopsis and human ARM protein interact with telomerase. Deregulated mRNA levels of DNA repair and ribosomal protein genes in an Arabidopsis arm mutant suggest non-telomeric ARM function. The human homolog ARMC6 interacts with hTRF2. Abstract: Telomerase maintains telomeres and has proposed non-telomeric functions. We previously identified interaction of the C-terminal domain of Arabidopsis telomerase reverse transcriptase (AtTERT) with an armadillo/β-catenin-like repeat (ARM) containing protein. Here we explore protein–protein interactions of the ARM protein, AtTERT domains, POT1a, TRF-like family and SMH family proteins, and the chromatin remodeling protein CHR19 using bimolecular fluorescence complementation (BiFC), yeast two-hybrid (Y2H) analysis, and co-immunoprecipitation. The ARM protein interacts with both the N- and C-terminal domains of AtTERT in different cellular compartments. ARM interacts with CHR19 and TRF-like I family proteins that also bind AtTERT directly or through interaction with POT1a. The putative human ARM homolog co-precipitates telomerase activity and interacts with hTRF2 protein in vitro. Analysis of Arabidopsis arm mutants shows no obvious changes in telomere length or telomerase activity, suggesting that ARM is not essential for telomere maintenance. The observed interactions with telomerase and Myb-like domain proteins (TRF-like family I) may therefore reflect possible non-telomeric functions. Transcript levels of several DNA repair and ribosomal genes are affected in arm mutants, and ARM, likely in association with other proteins, suppressed expression of XRCC3 and RPSAA promoter constructs in luciferase reporter assays. In conclusion, ARM can participate in non-telomeric functions of telomerase, and can also perform its own telomerase-independent functions.}, author = {Dokládal, Ladislav and Benková, Eva and Honys, David and Dupláková, Nikoleta and Lee, Lan and Gelvin, Stanton and Sýkorová, Eva}, journal = {Plant Molecular Biology}, number = {5}, pages = {407 -- 420}, publisher = {Springer}, title = {{An armadillo-domain protein participates in a telomerase interaction network}}, doi = {10.1007/s11103-018-0747-4}, volume = {97}, year = {2018}, } @article{279, abstract = {Background: Natural selection shapes cancer genomes. Previous studies used signatures of positive selection to identify genes driving malignant transformation. However, the contribution of negative selection against somatic mutations that affect essential tumor functions or specific domains remains a controversial topic. Results: Here, we analyze 7546 individual exomes from 26 tumor types from TCGA data to explore the portion of the cancer exome under negative selection. Although we find most of the genes neutrally evolving in a pan-cancer framework, we identify essential cancer genes and immune-exposed protein regions under significant negative selection. Moreover, our simulations suggest that the amount of negative selection is underestimated. We therefore choose an empirical approach to identify genes, functions, and protein regions under negative selection. We find that expression and mutation status of negatively selected genes is indicative of patient survival. Processes that are most strongly conserved are those that play fundamental cellular roles such as protein synthesis, glucose metabolism, and molecular transport. Intriguingly, we observe strong signals of selection in the immunopeptidome and proteins controlling peptide exposition, highlighting the importance of immune surveillance evasion. Additionally, tumor type-specific immune activity correlates with the strength of negative selection on human epitopes. Conclusions: In summary, our results show that negative selection is a hallmark of cell essentiality and immune response in cancer. The functional domains identified could be exploited therapeutically, ultimately allowing for the development of novel cancer treatments.}, author = {Zapata, Luis and Pich, Oriol and Serrano, Luis and Kondrashov, Fyodor and Ossowski, Stephan and Schaefer, Martin}, journal = {Genome Biology}, publisher = {BioMed Central}, title = {{Negative selection in tumor genome evolution acts on essential cellular functions and the immunopeptidome}}, doi = {10.1186/s13059-018-1434-0}, volume = {19}, year = {2018}, }