@article{2011, abstract = {The protection of privacy of individual-level information in genome-wide association study (GWAS) databases has been a major concern of researchers following the publication of “an attack” on GWAS data by Homer et al. (2008). Traditional statistical methods for confidentiality and privacy protection of statistical databases do not scale well to deal with GWAS data, especially in terms of guarantees regarding protection from linkage to external information. The more recent concept of differential privacy, introduced by the cryptographic community, is an approach that provides a rigorous definition of privacy with meaningful privacy guarantees in the presence of arbitrary external information, although the guarantees may come at a serious price in terms of data utility. Building on such notions, Uhler et al. (2013) proposed new methods to release aggregate GWAS data without compromising an individual’s privacy. We extend the methods developed in Uhler et al. (2013) for releasing differentially-private χ2χ2-statistics by allowing for arbitrary number of cases and controls, and for releasing differentially-private allelic test statistics. We also provide a new interpretation by assuming the controls’ data are known, which is a realistic assumption because some GWAS use publicly available data as controls. We assess the performance of the proposed methods through a risk-utility analysis on a real data set consisting of DNA samples collected by the Wellcome Trust Case Control Consortium and compare the methods with the differentially-private release mechanism proposed by Johnson and Shmatikov (2013).}, author = {Yu, Fei and Fienberg, Stephen and Slaković, Alexandra and Uhler, Caroline}, journal = {Journal of Biomedical Informatics}, pages = {133 -- 141}, publisher = {Elsevier}, title = {{Scalable privacy-preserving data sharing methodology for genome-wide association studies}}, doi = {10.1016/j.jbi.2014.01.008}, volume = {50}, year = {2014}, } @inproceedings{2012, abstract = {The classical sphere packing problem asks for the best (infinite) arrangement of non-overlapping unit balls which cover as much space as possible. We define a generalized version of the problem, where we allow each ball a limited amount of overlap with other balls. We study two natural choices of overlap measures and obtain the optimal lattice packings in a parameterized family of lattices which contains the FCC, BCC, and integer lattice.}, author = {Iglesias Ham, Mabel and Kerber, Michael and Uhler, Caroline}, booktitle = {26th Canadian Conference on Computational Geometry}, location = {Halifax, Canada}, pages = {155--161}, publisher = {Canadian Conference on Computational Geometry}, title = {{Sphere packing with limited overlap}}, year = {2014}, } @article{2013, abstract = {An asymptotic theory is developed for computing volumes of regions in the parameter space of a directed Gaussian graphical model that are obtained by bounding partial correlations. We study these volumes using the method of real log canonical thresholds from algebraic geometry. Our analysis involves the computation of the singular loci of correlation hypersurfaces. Statistical applications include the strong-faithfulness assumption for the PC algorithm and the quantification of confounder bias in causal inference. A detailed analysis is presented for trees, bow ties, tripartite graphs, and complete graphs. }, author = {Lin, Shaowei and Uhler, Caroline and Sturmfels, Bernd and Bühlmann, Peter}, journal = {Foundations of Computational Mathematics}, number = {5}, pages = {1079 -- 1116}, publisher = {Springer}, title = {{Hypersurfaces and their singularities in partial correlation testing}}, doi = {10.1007/s10208-014-9205-0}, volume = {14}, year = {2014}, } @article{2018, abstract = {Synaptic cell adhesion molecules are increasingly gaining attention for conferring specific properties to individual synapses. Netrin-G1 and netrin-G2 are trans-synaptic adhesion molecules that distribute on distinct axons, and their presence restricts the expression of their cognate receptors, NGL1 and NGL2, respectively, to specific subdendritic segments of target neurons. However, the neural circuits and functional roles of netrin-G isoform complexes remain unclear. Here, we use netrin-G-KO and NGL-KO mice to reveal that netrin-G1/NGL1 and netrin-G2/NGL2 interactions specify excitatory synapses in independent hippocampal pathways. In the hippocampal CA1 area, netrin-G1/NGL1 and netrin-G2/NGL2 were expressed in the temporoammonic and Schaffer collateral pathways, respectively. The lack of presynaptic netrin-Gs led to the dispersion of NGLs from postsynaptic membranes. In accord, netrin-G mutant synapses displayed opposing phenotypes in long-term and short-term plasticity through discrete biochemical pathways. The plasticity phenotypes in netrin-G-KOs were phenocopied in NGL-KOs, with a corresponding loss of netrin-Gs from presynaptic membranes. Our findings show that netrin-G/NGL interactions differentially control synaptic plasticity in distinct circuits via retrograde signaling mechanisms and explain how synaptic inputs are diversified to control neuronal activity.}, author = {Matsukawa, Hiroshi and Akiyoshi Nishimura, Sachiko and Zhang, Qi and Luján, Rafael and Yamaguchi, Kazuhiko and Goto, Hiromichi and Yaguchi, Kunio and Hashikawa, Tsutomu and Sano, Chie and Shigemoto, Ryuichi and Nakashiba, Toshiaki and Itohara, Shigeyoshi}, issn = {1529-2401}, journal = {Journal of Neuroscience}, number = {47}, pages = {15779 -- 15792}, publisher = {Society for Neuroscience}, title = {{Netrin-G/NGL complexes encode functional synaptic diversification}}, doi = {10.1523/JNEUROSCI.1141-14.2014}, volume = {34}, year = {2014}, } @article{2019, abstract = {We prove that the empirical density of states of quantum spin glasses on arbitrary graphs converges to a normal distribution as long as the maximal degree is negligible compared with the total number of edges. This extends the recent results of Keating et al. (2014) that were proved for graphs with bounded chromatic number and with symmetric coupling distribution. Furthermore, we generalise the result to arbitrary hypergraphs. We test the optimality of our condition on the maximal degree for p-uniform hypergraphs that correspond to p-spin glass Hamiltonians acting on n distinguishable spin- 1/2 particles. At the critical threshold p = n1/2 we find a sharp classical-quantum phase transition between the normal distribution and the Wigner semicircle law. The former is characteristic to classical systems with commuting variables, while the latter is a signature of noncommutative random matrix theory.}, author = {Erdös, László and Schröder, Dominik J}, journal = {Mathematical Physics, Analysis and Geometry}, number = {3-4}, pages = {441 -- 464}, publisher = {Springer}, title = {{Phase transition in the density of states of quantum spin glasses}}, doi = {10.1007/s11040-014-9164-3}, volume = {17}, year = {2014}, } @article{2020, abstract = {The mammalian heart has long been considered a postmitotic organ, implying that the total number of cardiomyocytes is set at birth. Analysis of cell division in the mammalian heart is complicated by cardiomyocyte binucleation shortly after birth, which makes it challenging to interpret traditional assays of cell turnover [Laflamme MA, Murray CE (2011) Nature 473(7347):326–335; Bergmann O, et al. (2009) Science 324(5923):98–102]. An elegant multi-isotope imaging-mass spectrometry technique recently calculated the low, discrete rate of cardiomyocyte generation in mice [Senyo SE, et al. (2013) Nature 493(7432):433–436], yet our cellular-level understanding of postnatal cardiomyogenesis remains limited. Herein, we provide a new line of evidence for the differentiated α-myosin heavy chain-expressing cardiomyocyte as the cell of origin of postnatal cardiomyogenesis using the “mosaic analysis with double markers” mouse model. We show limited, life-long, symmetric division of cardiomyocytes as a rare event that is evident in utero but significantly diminishes after the first month of life in mice; daughter cardiomyocytes divide very seldom, which this study is the first to demonstrate, to our knowledge. Furthermore, ligation of the left anterior descending coronary artery, which causes a myocardial infarction in the mosaic analysis with double-marker mice, did not increase the rate of cardiomyocyte division above the basal level for up to 4 wk after the injury. The clonal analysis described here provides direct evidence of postnatal mammalian cardiomyogenesis.}, author = {Ali, Shah and Hippenmeyer, Simon and Saadat, Lily and Luo, Liqun and Weissman, Irving and Ardehali, Reza}, journal = {PNAS}, number = {24}, pages = {8850 -- 8855}, publisher = {National Academy of Sciences}, title = {{Existing cardiomyocytes generate cardiomyocytes at a low rate after birth in mice}}, doi = {10.1073/pnas.1408233111}, volume = {111}, year = {2014}, } @article{2021, abstract = {Neurotrophins regulate diverse aspects of neuronal development and plasticity, but their precise in vivo functions during neural circuit assembly in the central brain remain unclear. We show that the neurotrophin receptor tropomyosin-related kinase C (TrkC) is required for dendritic growth and branching of mouse cerebellar Purkinje cells. Sparse TrkC knockout reduced dendrite complexity, but global Purkinje cell knockout had no effect. Removal of the TrkC ligand neurotrophin-3 (NT-3) from cerebellar granule cells, which provide major afferent input to developing Purkinje cell dendrites, rescued the dendrite defects caused by sparse TrkC disruption in Purkinje cells. Our data demonstrate that NT-3 from presynaptic neurons (granule cells) is required for TrkC-dependent competitive dendrite morphogenesis in postsynaptic neurons (Purkinje cells)—a previously unknown mechanism of neural circuit development.}, author = {William, Joo and Hippenmeyer, Simon and Luo, Liqun}, journal = {Science}, number = {6209}, pages = {626 -- 629}, publisher = {American Association for the Advancement of Science}, title = {{Dendrite morphogenesis depends on relative levels of NT-3/TrkC signaling}}, doi = {10.1126/science.1258996}, volume = {346}, year = {2014}, } @article{2022, abstract = {Radial glial progenitors (RGPs) are responsible for producing nearly all neocortical neurons. To gain insight into the patterns of RGP division and neuron production, we quantitatively analyzed excitatory neuron genesis in the mouse neocortex using Mosaic Analysis with Double Markers, which provides single-cell resolution of progenitor division patterns and potential in vivo. We found that RGPs progress through a coherent program in which their proliferative potential diminishes in a predictable manner. Upon entry into the neurogenic phase, individual RGPs produce ∼8–9 neurons distributed in both deep and superficial layers, indicating a unitary output in neuronal production. Removal of OTX1, a transcription factor transiently expressed in RGPs, results in both deep- and superficial-layer neuron loss and a reduction in neuronal unit size. Moreover, ∼1/6 of neurogenic RGPs proceed to produce glia. These results suggest that progenitor behavior and histogenesis in the mammalian neocortex conform to a remarkably orderly and deterministic program.}, author = {Gao, Peng and Postiglione, Maria P and Krieger, Teresa and Hernandez, Luisirene and Wang, Chao and Han, Zhi and Streicher, Carmen and Papusheva, Ekaterina and Insolera, Ryan and Chugh, Kritika and Kodish, Oren and Huang, Kun and Simons, Benjamin and Luo, Liqun and Hippenmeyer, Simon and Shi, Song}, journal = {Cell}, number = {4}, pages = {775 -- 788}, publisher = {Cell Press}, title = {{Deterministic progenitor behavior and unitary production of neurons in the neocortex}}, doi = {10.1016/j.cell.2014.10.027}, volume = {159}, year = {2014}, } @article{2024, abstract = {The yeast Rab5 homologue, Vps21p, is known to be involved both in the vacuolar protein sorting (VPS) pathway from the trans-Golgi network to the vacuole, and in the endocytic pathway from the plasma membrane to the vacuole. However, the intracellular location at which these two pathways converge remains unclear. In addition, the endocytic pathway is not completely blocked in yeast cells lacking all Rab5 genes, suggesting the existence of an unidentified route that bypasses the Rab5-dependent endocytic pathway. Here we show that convergence of the endocytic and VPS pathways occurs upstream of the requirement for Vps21p in these pathways. We also identify a previously unidentified endocytic pathway mediated by the AP-3 complex. Importantly, the AP-3-mediated pathway appears mostly intact in Rab5-disrupted cells, and thus works as an alternative route to the vacuole/lysosome. We propose that the endocytic traffic branches into two routes to reach the vacuole: a Rab5-dependent VPS pathway and a Rab5-independent AP-3-mediated pathway.}, author = {Toshima, Junko and Nishinoaki, Show and Sato, Yoshifumi and Yamamoto, Wataru and Furukawa, Daiki and Siekhaus, Daria E and Sawaguchi, Akira and Toshima, Jiro}, journal = {Nature Communications}, publisher = {Nature Publishing Group}, title = {{Bifurcation of the endocytic pathway into Rab5-dependent and -independent transport to the vacuole}}, doi = {10.1038/ncomms4498}, volume = {5}, year = {2014}, } @inproceedings{2026, abstract = {We present a tool for translating LTL formulae into deterministic ω-automata. It is the first tool that covers the whole LTL that does not use Safra’s determinization or any of its variants. This leads to smaller automata. There are several outputs of the tool: firstly, deterministic Rabin automata, which are the standard input for probabilistic model checking, e.g. for the probabilistic model-checker PRISM; secondly, deterministic generalized Rabin automata, which can also be used for probabilistic model checking and are sometimes by orders of magnitude smaller. We also link our tool to PRISM and show that this leads to a significant speed-up of probabilistic LTL model checking, especially with the generalized Rabin automata.}, author = {Komárková, Zuzana and Kretinsky, Jan}, booktitle = {Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics)}, editor = {Cassez, Franck and Raskin, Jean-François}, location = {Sydney, Australia}, pages = {235 -- 241}, publisher = {Springer}, title = {{Rabinizer 3: Safraless translation of ltl to small deterministic automata}}, doi = {10.1007/978-3-319-11936-6_17}, volume = {8837}, year = {2014}, } @article{2029, abstract = {Spin-wave theory is a key ingredient in our comprehension of quantum spin systems, and is used successfully for understanding a wide range of magnetic phenomena, including magnon condensation and stability of patterns in dipolar systems. Nevertheless, several decades of research failed to establish the validity of spin-wave theory rigorously, even for the simplest models of quantum spins. A rigorous justification of the method for the three-dimensional quantum Heisenberg ferromagnet at low temperatures is presented here. We derive sharp bounds on its free energy by combining a bosonic formulation of the model introduced by Holstein and Primakoff with probabilistic estimates and operator inequalities.}, author = {Correggi, Michele and Giuliani, Alessandro and Seiringer, Robert}, journal = {EPL}, number = {2}, publisher = {IOP Publishing}, title = {{Validity of spin-wave theory for the quantum Heisenberg model}}, doi = {10.1209/0295-5075/108/20003}, volume = {108}, year = {2014}, } @article{2031, abstract = {A puzzling property of synaptic transmission, originally established at the neuromuscular junction, is that the time course of transmitter release is independent of the extracellular Ca2+ concentration ([Ca2+]o), whereas the rate of release is highly [Ca2+]o-dependent. Here, we examine the time course of release at inhibitory basket cell-Purkinje cell synapses and show that it is independent of [Ca2+]o. Modeling of Ca2+-dependent transmitter release suggests that the invariant time course of release critically depends on tight coupling between Ca2+ channels and release sensors. Experiments with exogenous Ca2+ chelators reveal that channel-sensor coupling at basket cell-Purkinje cell synapses is very tight, with a mean distance of 10–20 nm. Thus, tight channel-sensor coupling provides a mechanistic explanation for the apparent [Ca2+]o independence of the time course of release.}, author = {Arai, Itaru and Jonas, Peter M}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{Nanodomain coupling explains Ca^2+ independence of transmitter release time course at a fast central synapse}}, doi = {10.7554/eLife.04057}, volume = {3}, year = {2014}, } @article{2032, abstract = {As light-based control of fundamental signaling pathways is becoming a reality, the field of optogenetics is rapidly moving beyond neuroscience. We have recently developed receptor tyrosine kinases that are activated by light and control cell proliferation, epithelial–mesenchymal transition, and angiogenic sprouting—cell behaviors central to cancer progression.}, author = {Inglés Prieto, Álvaro and Gschaider-Reichhart, Eva and Schelch, Karin and Janovjak, Harald L and Grusch, Michael}, issn = {2372-3556}, journal = {Molecular and Cellular Oncology}, number = {4}, publisher = {Taylor & Francis}, title = {{The optogenetic promise for oncology: Episode I}}, doi = {10.4161/23723548.2014.964045}, volume = {1}, year = {2014}, } @inproceedings{2033, abstract = {The learning with privileged information setting has recently attracted a lot of attention within the machine learning community, as it allows the integration of additional knowledge into the training process of a classifier, even when this comes in the form of a data modality that is not available at test time. Here, we show that privileged information can naturally be treated as noise in the latent function of a Gaussian process classifier (GPC). That is, in contrast to the standard GPC setting, the latent function is not just a nuisance but a feature: it becomes a natural measure of confidence about the training data by modulating the slope of the GPC probit likelihood function. Extensive experiments on public datasets show that the proposed GPC method using privileged noise, called GPC+, improves over a standard GPC without privileged knowledge, and also over the current state-of-the-art SVM-based method, SVM+. Moreover, we show that advanced neural networks and deep learning methods can be compressed as privileged information.}, author = {Hernandez Lobato, Daniel and Sharmanska, Viktoriia and Kersting, Kristian and Lampert, Christoph and Quadrianto, Novi}, booktitle = {Advances in Neural Information Processing Systems}, location = {Montreal, Canada}, number = {January}, pages = {837--845}, publisher = {Neural Information Processing Systems Foundation}, title = {{Mind the nuisance: Gaussian process classification using privileged noise}}, volume = {1}, year = {2014}, } @article{2039, abstract = {A fundamental question in biology is the following: what is the time scale that is needed for evolutionary innovations? There are many results that characterize single steps in terms of the fixation time of new mutants arising in populations of certain size and structure. But here we ask a different question, which is concerned with the much longer time scale of evolutionary trajectories: how long does it take for a population exploring a fitness landscape to find target sequences that encode new biological functions? Our key variable is the length, (Formula presented.) of the genetic sequence that undergoes adaptation. In computer science there is a crucial distinction between problems that require algorithms which take polynomial or exponential time. The latter are considered to be intractable. Here we develop a theoretical approach that allows us to estimate the time of evolution as function of (Formula presented.) We show that adaptation on many fitness landscapes takes time that is exponential in (Formula presented.) even if there are broad selection gradients and many targets uniformly distributed in sequence space. These negative results lead us to search for specific mechanisms that allow evolution to work on polynomial time scales. We study a regeneration process and show that it enables evolution to work in polynomial time.}, author = {Chatterjee, Krishnendu and Pavlogiannis, Andreas and Adlam, Ben and Nowak, Martin}, journal = {PLoS Computational Biology}, number = {9}, publisher = {Public Library of Science}, title = {{The time scale of evolutionary innovation}}, doi = {10.1371/journal.pcbi.1003818}, volume = {10}, year = {2014}, } @article{2040, abstract = {Development requires tissue growth as well as cell diversification. To address how these processes are coordinated, we analyzed the development of molecularly distinct domains of neural progenitors in the mouse and chick neural tube. We show that during development, these domains undergo changes in size that do not scale with changes in overall tissue size. Our data show that domain proportions are first established by opposing morphogen gradients and subsequently controlled by domain-specific regulation of differentiation rate but not differences in proliferation rate. Regulation of differentiation rate is key to maintaining domain proportions while accommodating both intra- and interspecies variations in size. Thus, the sequential control of progenitor specification and differentiation elaborates pattern without requiring that signaling gradients grow as tissues expand. }, author = {Kicheva, Anna and Bollenbach, Mark Tobias and Ribeiro, Ana and Pérez Valle, Helena and Lovell Badge, Robin and Episkopou, Vasso and Briscoe, James}, journal = {Science}, number = {6204}, publisher = {American Association for the Advancement of Science}, title = {{Coordination of progenitor specification and growth in mouse and chick spinal cord}}, doi = {10.1126/science.1254927}, volume = {345}, year = {2014}, } @article{2041, abstract = {The hippocampus mediates several higher brain functions, such as learning, memory, and spatial coding. The input region of the hippocampus, the dentate gyrus, plays a critical role in these processes. Several lines of evidence suggest that the dentate gyrus acts as a preprocessor of incoming information, preparing it for subsequent processing in CA3. For example, the dentate gyrus converts input from the entorhinal cortex, where cells have multiple spatial fields, into the spatially more specific place cell activity characteristic of the CA3 region. Furthermore, the dentate gyrus is involved in pattern separation, transforming relatively similar input patterns into substantially different output patterns. Finally, the dentate gyrus produces a very sparse coding scheme in which only a very small fraction of neurons are active at any one time.}, author = {Jonas, Peter M and Lisman, John}, journal = {Frontiers in Neural Circuits}, publisher = {Frontiers Research Foundation}, title = {{Structure, function and plasticity of hippocampal dentate gyrus microcircuits}}, doi = {10.3389/fncir.2014.00107}, volume = {8}, year = {2014}, } @article{2042, abstract = {Background: CRISPR is a microbial immune system likely to be involved in host-parasite coevolution. It functions using target sequences encoded by the bacterial genome, which interfere with invading nucleic acids using a homology-dependent system. The system also requires protospacer associated motifs (PAMs), short motifs close to the target sequence that are required for interference in CRISPR types I and II. Here, we investigate whether PAMs are depleted in phage genomes due to selection pressure to escape recognition.Results: To this end, we analyzed two data sets. Phages infecting all bacterial hosts were analyzed first, followed by a detailed analysis of phages infecting the genus Streptococcus, where PAMs are best understood. We use two different measures of motif underrepresentation that control for codon bias and the frequency of submotifs. We compare phages infecting species with a particular CRISPR type to those infecting species without that type. Since only known PAMs were investigated, the analysis is restricted to CRISPR types I-C and I-E and in Streptococcus to types I-C and II. We found evidence for PAM depletion in Streptococcus phages infecting hosts with CRISPR type I-C, in Vibrio phages infecting hosts with CRISPR type I-E and in Streptococcus thermopilus phages infecting hosts with type II-A, known as CRISPR3.Conclusions: The observed motif depletion in phages with hosts having CRISPR can be attributed to selection rather than to mutational bias, as mutational bias should affect the phages of all hosts. This observation implies that the CRISPR system has been efficient in the groups discussed here.}, author = {Kupczok, Anne and Bollback, Jonathan P}, journal = {BMC Genomics}, number = {1}, publisher = {BioMed Central}, title = {{Motif depletion in bacteriophages infecting hosts with CRISPR systems}}, doi = {10.1186/1471-2164-15-663}, volume = {15}, year = {2014}, } @inproceedings{2043, abstract = {Persistent homology is a popular and powerful tool for capturing topological features of data. Advances in algorithms for computing persistent homology have reduced the computation time drastically – as long as the algorithm does not exhaust the available memory. Following up on a recently presented parallel method for persistence computation on shared memory systems [1], we demonstrate that a simple adaption of the standard reduction algorithm leads to a variant for distributed systems. Our algorithmic design ensures that the data is distributed over the nodes without redundancy; this permits the computation of much larger instances than on a single machine. Moreover, we observe that the parallelism at least compensates for the overhead caused by communication between nodes, and often even speeds up the computation compared to sequential and even parallel shared memory algorithms. In our experiments, we were able to compute the persistent homology of filtrations with more than a billion (109) elements within seconds on a cluster with 32 nodes using less than 6GB of memory per node.}, author = {Bauer, Ulrich and Kerber, Michael and Reininghaus, Jan}, booktitle = {Proceedings of the Workshop on Algorithm Engineering and Experiments}, editor = { McGeoch, Catherine and Meyer, Ulrich}, location = {Portland, USA}, pages = {31 -- 38}, publisher = {Society for Industrial and Applied Mathematics}, title = {{Distributed computation of persistent homology}}, doi = {10.1137/1.9781611973198.4}, year = {2014}, } @inbook{2044, abstract = {We present a parallel algorithm for computing the persistent homology of a filtered chain complex. Our approach differs from the commonly used reduction algorithm by first computing persistence pairs within local chunks, then simplifying the unpaired columns, and finally applying standard reduction on the simplified matrix. The approach generalizes a technique by Günther et al., which uses discrete Morse Theory to compute persistence; we derive the same worst-case complexity bound in a more general context. The algorithm employs several practical optimization techniques, which are of independent interest. Our sequential implementation of the algorithm is competitive with state-of-the-art methods, and we further improve the performance through parallel computation.}, author = {Bauer, Ulrich and Kerber, Michael and Reininghaus, Jan}, booktitle = {Topological Methods in Data Analysis and Visualization III}, editor = {Bremer, Peer-Timo and Hotz, Ingrid and Pascucci, Valerio and Peikert, Ronald}, pages = {103 -- 117}, publisher = {Springer}, title = {{Clear and Compress: Computing Persistent Homology in Chunks}}, doi = {10.1007/978-3-319-04099-8_7}, year = {2014}, }