@misc{1981, abstract = {Variation in mitochondrial DNA is often assumed to be neutral and is used to construct the genealogical relationships among populations and species. However, if extant variation is the result of episodes of positive selection, these genealogies may be incorrect, although this information itself may provide biologically and evolutionary meaningful information. In fact, positive Darwinian selection has been detected in the mitochondrial-encoded subunits that comprise complex I from diverse taxa with seemingly dissimilar bioenergetic life histories, but the functional implications of the selected sites are unknown. Complex I produces roughly 40% of the proton flux that is used to synthesize ATP from ADP, and a functional model based on the high-resolution structure of complex I described a unique biomechanical apparatus for proton translocation. We reported positive selection at sites in this apparatus during the evolution of Pacific salmon, and it appeared this was also the case in published reports from other taxa, but a comparison among studies was difficult because different statistical tests were used to detect selection and oftentimes, specific sites were not reported. Here we review the literature of positive selection in mitochondrial genomes, the statistical tests used to detect selection, and the structural and functional models that are currently available to study the physiological implications of selection. We then search for signatures of positive selection among the coding mitochondrial genomes of 237 species with a common set of tests and verify that the ND5 subunit of complex I is a repeated target of positive Darwinian selection in diverse taxa. We propose a novel hypothesis to explain the results based on their bioenergetic life histories and provide a guide for laboratory and field studies to test this hypothesis.}, author = {Garvin, Michael R and Bielawski, Joseph P and Leonid Sazanov and Gharrett, Anthony J}, booktitle = {Journal of Zoological Systematics and Evolutionary Research}, number = {1}, pages = {1 -- 17}, publisher = {Wiley-Blackwell}, title = {{Review and meta-analysis of natural selection in mitochondrial complex I in metazoans}}, doi = {10.1111/jzs.12079}, volume = {53}, year = {2014}, } @article{1989, abstract = {During animal cell division, the cleavage furrow is positioned by microtubules that signal to the actin cortex at the cell midplane. We developed a cell-free system to recapitulate cytokinesis signaling using cytoplasmic extract from Xenopus eggs. Microtubules grew out as asters from artificial centrosomes and met to organize antiparallel overlap zones. These zones blocked the interpenetration of neighboring asters and recruited cytokinesis midzone proteins, including the chromosomal passenger complex (CPC) and centralspindlin. The CPC was transported to overlap zones, which required two motor proteins, Kif4A and a Kif20A paralog. Using supported lipid bilayers to mimic the plasma membrane, we observed the recruitment of cleavage furrow markers, including an active RhoA reporter, at microtubule overlaps. This system opens further approaches to understanding the biophysics of cytokinesis signaling.}, author = {Nguyen, Phuong A and Groen, Aaron C and Martin Loose and Ishihara, Keisuke and Wühr, Martin and Field, Christine M and Mitchison, Timothy J}, journal = {Science}, number = {6206}, pages = {244 -- 247}, publisher = {American Association for the Advancement of Science}, title = {{Spatial organization of cytokinesis signaling reconstituted in a cell-free system}}, doi = {10.1126/science.1256773}, volume = {346}, year = {2014}, } @article{1990, abstract = {Bacterial cytokinesis is commonly initiated by the Z-ring, a cytoskeletal structure that assembles at the site of division. Its primary component is FtsZ, a tubulin superfamily GTPase, which is recruited to the membrane by the actin-related protein FtsA. Both proteins are required for the formation of the Z-ring, but if and how they influence each other's assembly dynamics is not known. Here, we reconstituted FtsA-dependent recruitment of FtsZ polymers to supported membranes, where both proteins self-organize into complex patterns, such as fast-moving filament bundles and chirally rotating rings. Using fluorescence microscopy and biochemical perturbations, we found that these large-scale rearrangements of FtsZ emerge from its polymerization dynamics and a dual, antagonistic role of FtsA: recruitment of FtsZ filaments to the membrane and negative regulation of FtsZ organization. Our findings provide a model for the initial steps of bacterial cell division and illustrate how dynamic polymers can self-organize into large-scale structures.}, author = {Martin Loose and Mitchison, Timothy J}, journal = {Nature Cell Biology}, number = {1}, pages = {38 -- 46}, publisher = {Nature Publishing Group}, title = {{The bacterial cell division proteins ftsA and ftsZ self-organize into dynamic cytoskeletal patterns}}, doi = {10.1038/ncb2885}, volume = {16}, year = {2014}, } @article{1994, abstract = {The emergence and radiation of multicellular land plants was driven by crucial innovations to their body plans [1]. The directional transport of the phytohormone auxin represents a key, plant-specific mechanism for polarization and patterning in complex seed plants [2-5]. Here, we show that already in the early diverging land plant lineage, as exemplified by the moss Physcomitrella patens, auxin transport by PIN transporters is operational and diversified into ER-localized and plasma membrane-localized PIN proteins. Gain-of-function and loss-of-function analyses revealed that PIN-dependent intercellular auxin transport in Physcomitrella mediates crucial developmental transitions in tip-growing filaments and waves of polarization and differentiation in leaf-like structures. Plasma membrane PIN proteins localize in a polar manner to the tips of moss filaments, revealing an unexpected relation between polarization mechanisms in moss tip-growing cells and multicellular tissues of seed plants. Our results trace the origins of polarization and auxin-mediated patterning mechanisms and highlight the crucial role of polarized auxin transport during the evolution of multicellular land plants.}, author = {Viaene, Tom and Landberg, Katarina and Thelander, Mattias and Medvecka, Eva and Pederson, Eric and Feraru, Elena and Cooper, Endymion and Karimi, Mansour and Delwiche, Charles and Ljung, Karin and Geisler, Markus and Sundberg, Eva and Friml, Jirí}, journal = {Current Biology}, number = {23}, pages = {2786 -- 2791}, publisher = {Cell Press}, title = {{Directional auxin transport mechanisms in early diverging land plants}}, doi = {10.1016/j.cub.2014.09.056}, volume = {24}, year = {2014}, } @article{1995, abstract = {Optical transport represents a natural route towards fast communications, and it is currently used in large scale data transfer. The progressive miniaturization of devices for information processing calls for the microscopic tailoring of light transport and confinement at length scales appropriate for upcoming technologies. With this goal in mind, we present a theoretical analysis of a one-dimensional Fabry-Perot interferometer built with two highly saturable nonlinear mirrors: a pair of two-level systems. Our approach captures nonlinear and nonreciprocal effects of light transport that were not reported previously. Remarkably, we show that such an elementary device can operate as a microscopic integrated optical rectifier.}, author = {Fratini, Filippo and Mascarenhas, Eduardo and Safari, Laleh and Poizat, Jean and Valente, Daniel and Auffèves, Alexia and Gerace, Dario and Santos, Marcelo}, journal = {Physical Review Letters}, number = {24}, publisher = {American Physical Society}, title = {{Fabry-Perot interferometer with quantum mirrors: Nonlinear light transport and rectification}}, doi = {10.1103/PhysRevLett.113.243601}, volume = {113}, year = {2014}, } @article{1996, abstract = {Auxin polar transport, local maxima, and gradients have become an importantmodel system for studying self-organization. Auxin distribution is regulated by auxin-dependent positive feedback loops that are not well-understood at the molecular level. Previously, we showed the involvement of the RHO of Plants (ROP) effector INTERACTOR of CONSTITUTIVELY active ROP 1 (ICR1) in regulation of auxin transport and that ICR1 levels are posttranscriptionally repressed at the site of maximum auxin accumulation at the root tip. Here, we show that bimodal regulation of ICR1 levels by auxin is essential for regulating formation of auxin local maxima and gradients. ICR1 levels increase concomitant with increase in auxin response in lateral root primordia, cotyledon tips, and provascular tissues. However, in the embryo hypophysis and root meristem, when auxin exceeds critical levels, ICR1 is rapidly destabilized by an SCF(TIR1/AFB) [SKP, Cullin, F-box (transport inhibitor response 1/auxin signaling F-box protein)]-dependent auxin signaling mechanism. Furthermore, ectopic expression of ICR1 in the embryo hypophysis resulted in reduction of auxin accumulation and concomitant root growth arrest. ICR1 disappeared during root regeneration and lateral root initiation concomitantly with the formation of a local auxin maximum in response to external auxin treatments and transiently after gravitropic stimulation. Destabilization of ICR1 was impaired after inhibition of auxin transport and signaling, proteasome function, and protein synthesis. A mathematical model based on these findings shows that an in vivo-like auxin distribution, rootward auxin flux, and shootward reflux can be simulated without assuming preexisting tissue polarity. Our experimental results and mathematical modeling indicate that regulation of auxin distribution is tightly associated with auxin-dependent ICR1 levels.}, author = {Hazak, Ora and Obolski, Uri and Prat, Tomas and Friml, Jiří and Hadany, Lilach and Yalovsky, Shaul}, journal = {PNAS}, number = {50}, pages = {E5471 -- E5479}, publisher = {National Academy of Sciences}, title = {{Bimodal regulation of ICR1 levels generates self-organizing auxin distribution}}, doi = {10.1073/pnas.1413918111}, volume = {111}, year = {2014}, } @article{1998, abstract = {Immune systems are able to protect the body against secondary infection with the same parasite. In insect colonies, this protection is not restricted to the level of the individual organism, but also occurs at the societal level. Here, we review recent evidence for and insights into the mechanisms underlying individual and social immunisation in insects. We disentangle general immune-protective effects from specific immune memory (priming), and examine immunisation in the context of the lifetime of an individual and that of a colony, and of transgenerational immunisation that benefits offspring. When appropriate, we discuss parallels with disease defence strategies in human societies. We propose that recurrent parasitic threats have shaped the evolution of both the individual immune systems and colony-level social immunity in insects.}, author = {El Masri, Leila and Cremer, Sylvia}, journal = {Trends in Immunology}, number = {10}, pages = {471 -- 482}, publisher = {Elsevier}, title = {{Individual and social immunisation in insects}}, doi = {10.1016/j.it.2014.08.005}, volume = {35}, year = {2014}, } @article{1999, abstract = {Selection for disease control is believed to have contributed to shape the organisation of insect societies — leading to interaction patterns that mitigate disease transmission risk within colonies, conferring them ‘organisational immunity’. Recent studies combining epidemiological models with social network analysis have identified general properties of interaction networks that may hinder propagation of infection within groups. These can be prophylactic and/or induced upon pathogen exposure. Here we review empirical evidence for these two types of organisational immunity in social insects and describe the individual-level behaviours that underlie it. We highlight areas requiring further investigation, and emphasise the need for tighter links between theory and empirical research and between individual-level and collective-level analyses.}, author = {Stroeymeyt, Nathalie and Casillas Perez, Barbara E and Cremer, Sylvia}, journal = {Current Opinion in Insect Science}, number = {1}, pages = {1 -- 15}, publisher = {Elsevier}, title = {{Organisational immunity in social insects}}, doi = {10.1016/j.cois.2014.09.001}, volume = {5}, year = {2014}, } @article{2001, abstract = {Antibiotics affect bacterial cell physiology at many levels. Rather than just compensating for the direct cellular defects caused by the drug, bacteria respond to antibiotics by changing their morphology, macromolecular composition, metabolism, gene expression and possibly even their mutation rate. Inevitably, these processes affect each other, resulting in a complex response with changes in the expression of numerous genes. Genome‐wide approaches can thus help in gaining a comprehensive understanding of bacterial responses to antibiotics. In addition, a combination of experimental and theoretical approaches is needed for identifying general principles that underlie these responses. Here, we review recent progress in our understanding of bacterial responses to antibiotics and their combinations, focusing on effects at the levels of growth rate and gene expression. We concentrate on studies performed in controlled laboratory conditions, which combine promising experimental techniques with quantitative data analysis and mathematical modeling. While these basic research approaches are not immediately applicable in the clinic, uncovering the principles and mechanisms underlying bacterial responses to antibiotics may, in the long term, contribute to the development of new treatment strategies to cope with and prevent the rise of resistant pathogenic bacteria.}, author = {Mitosch, Karin and Bollenbach, Tobias}, journal = {Environmental Microbiology Reports}, number = {6}, pages = {545 -- 557}, publisher = {Wiley}, title = {{Bacterial responses to antibiotics and their combinations}}, doi = {10.1111/1758-2229.12190}, volume = {6}, year = {2014}, } @article{2002, abstract = {Oriens-lacunosum moleculare (O-LM) interneurons in the CA1 region of the hippocampus play a key role in feedback inhibition and in the control of network activity. However, how these cells are efficiently activated in the network remains unclear. To address this question, I performed recordings from CA1 pyramidal neuron axons, the presynaptic fibers that provide feedback innervation of these interneurons. Two forms of axonal action potential (AP) modulation were identified. First, repetitive stimulation resulted in activity-dependent AP broadening. Broadening showed fast onset, with marked changes in AP shape following a single AP. Second, tonic depolarization in CA1 pyramidal neuron somata induced AP broadening in the axon, and depolarization-induced broadening summated with activity-dependent broadening. Outsideout patch recordings from CA1 pyramidal neuron axons revealed a high density of a-dendrotoxin (α-DTX)-sensitive, inactivating K+ channels, suggesting that K+ channel inactivation mechanistically contributes to AP broadening. To examine the functional consequences of axonal AP modulation for synaptic transmission, I performed paired recordings between synaptically connected CA1 pyramidal neurons and O-LM interneurons. CA1 pyramidal neuron-O-LM interneuron excitatory postsynaptic currents (EPSCs) showed facilitation during both repetitive stimulation and tonic depolarization of the presynaptic neuron. Both effects were mimicked and occluded by α-DTX, suggesting that they were mediated by K+ channel inactivation. Therefore, axonal AP modulation can greatly facilitate the activation of O-LM interneurons. In conclusion, modulation of AP shape in CA1 pyramidal neuron axons substantially enhances the efficacy of principal neuron-interneuron synapses, promoting the activation of O-LM interneurons in recurrent inhibitory microcircuits.}, author = {Kim, Sooyun}, journal = {PLoS One}, number = {11}, publisher = {Public Library of Science}, title = {{Action potential modulation in CA1 pyramidal neuron axons facilitates OLM interneuron activation in recurrent inhibitory microcircuits of rat hippocampus}}, doi = {10.1371/journal.pone.0113124}, volume = {9}, year = {2014}, } @article{2003, abstract = {Learning can be facilitated by previous knowledge when it is organized into relational representations forming schemas. In this issue of Neuron, McKenzie et al. (2014) demonstrate that the hippocampus rapidly forms interrelated, hierarchical memory representations to support schema-based learning.}, author = {O'Neill, Joseph and Csicsvari, Jozsef L}, journal = {Neuron}, number = {1}, pages = {8 -- 10}, publisher = {Elsevier}, title = {{Learning by example in the hippocampus}}, doi = {10.1016/j.neuron.2014.06.013}, volume = {83}, year = {2014}, } @article{2004, abstract = {We have assembled a network of cell-fate determining transcription factors that play a key role in the specification of the ventral neuronal subtypes of the spinal cord on the basis of published transcriptional interactions. Asynchronous Boolean modelling of the network was used to compare simulation results with reported experimental observations. Such comparison highlighted the need to include additional regulatory connections in order to obtain the fixed point attractors of the model associated with the five known progenitor cell types located in the ventral spinal cord. The revised gene regulatory network reproduced previously observed cell state switches between progenitor cells observed in knock-out animal models or in experiments where the transcription factors were overexpressed. Furthermore the network predicted the inhibition of Irx3 by Nkx2.2 and this prediction was tested experimentally. Our results provide evidence for the existence of an as yet undescribed inhibitory connection which could potentially have significance beyond the ventral spinal cord. The work presented in this paper demonstrates the strength of Boolean modelling for identifying gene regulatory networks.}, author = {Lovrics, Anna and Gao, Yu and Juhász, Bianka and Bock, István and Byrne, Helen and Dinnyés, András and Kovács, Krisztián}, journal = {PLoS One}, number = {11}, publisher = {Public Library of Science}, title = {{Boolean modelling reveals new regulatory connections between transcription factors orchestrating the development of the ventral spinal cord}}, doi = {10.1371/journal.pone.0111430}, volume = {9}, year = {2014}, } @article{2005, abstract = {By eliciting a natural exploratory behavior in rats, head scanning, a study reveals that hippocampal place cells form new, stable firing fields in those locations where the behavior has just occurred.}, author = {Dupret, David and Csicsvari, Jozsef L}, journal = {Nature Neuroscience}, number = {5}, pages = {643 -- 644}, publisher = {Nature Publishing Group}, title = {{Turning heads to remember places}}, doi = {10.1038/nn.3700}, volume = {17}, year = {2014}, } @misc{2007, abstract = {Maximum likelihood estimation under relational models, with or without the overall effect. For more information see the reference manual}, author = {Klimova, Anna and Rudas, Tamás}, publisher = {The Comprehensive R Archive Network}, title = {{gIPFrm: Generalized iterative proportional fitting for relational models}}, year = {2014}, } @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}, } @unpublished{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 = {arXiv}, title = {{Sphere packing with limited overlap}}, doi = {10.48550/arXiv.1401.0468}, 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}, } @unpublished{2017, abstract = { Gaussian graphical models have received considerable attention during the past four decades from the statistical and machine learning communities. In Bayesian treatments of this model, the G-Wishart distribution serves as the conjugate prior for inverse covariance matrices satisfying graphical constraints. While it is straightforward to posit the unnormalized densities, the normalizing constants of these distributions have been known only for graphs that are chordal, or decomposable. Up until now, it was unknown whether the normalizing constant for a general graph could be represented explicitly, and a considerable body of computational literature emerged that attempted to avoid this apparent intractability. We close this question by providing an explicit representation of the G-Wishart normalizing constant for general graphs.}, author = {Caroline Uhler and Lenkoski, Alex and Richards, Donald}, booktitle = {ArXiv}, publisher = {ArXiv}, title = {{ Exact formulas for the normalizing constants of Wishart distributions for graphical models}}, 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}, }