TY - JOUR
AB - Some mutations in human mitochondrial tRNAs are severely pathogenic. The available computational methods have a poor record of predicting the impact of a tRNA mutation on the phenotype and fitness. Here patterns of evolution at tRNA sites that harbor pathogenic mutations and at sites that harbor phenotypically cryptic polymorphisms were compared. Mutations that are pathogenic to humans occupy more conservative sites, are only rarely fixed in closely related species, and, when located in stem structures, often disrupt Watson-Crick pairing and display signs of compensatory evolution. These observations make it possible to classify ∼90% of all known pathogenic mutations as deleterious together with only ∼30% of polymorphisms. These polymorphisms segregate at frequencies that are more than two times lower than frequencies of polymorphisms classified as benign, indicating that at least ∼30% of known polymorphisms in mitochondrial tRNAs affect fitness negatively.
AU - Fyodor Kondrashov
ID - 882
IS - 16
JF - Human Molecular Genetics
TI - Prediction of pathogenic mutations in mitochondrially encoded human tRNAs
VL - 14
ER -
TY - JOUR
AB - Amino acid composition of proteins varies substantially between taxa and, thus, can evolve. For example, proteins from organisms with (G+C)-rich (or (A+T)-rich) genomes contain more (or fewer) amino acids encoded by (G+C)-rich codons. However, no universal trends in ongoing changes of amino acid frequencies have been reported. We compared sets of orthologous proteins encoded by triplets of closely related genomes from 15 taxa representing all three domains of life (Bacteria, Archaea and Eukaryota), and used phylogenies to polarize amino acid substitutions. Cys, Met, His, Ser and Phe accrue in at least 14 taxa, whereas Pro, Ala, Glu and Gly are consistently lost. The same nine amino acids are currently accrued or lost in human proteins, as shown by analysis of non-synonymous single-nucleotide polymorphisms. All amino acids with declining frequencies are thought to be among the first incorporated into the genetic code; conversely, all amino acids with increasing frequencies, except Ser, were probably recruited late. Thus, expansion of initially under-represented amino acids, which began over 3,400 million years ago, apparently continues to this day.
AU - Jordan, Ingo K
AU - Fyodor Kondrashov
AU - Adzhubeǐ, Ivan A
AU - Wolf, Yuri I
AU - Koonin, Eugene V
AU - Kondrashov, Alexey S
AU - Sunyaev, Shamil R
ID - 893
IS - 7026
JF - Nature
TI - A universal trend of amino acid gain and loss in protein evolution
VL - 433
ER -
TY - JOUR
AB - Genetically encoded fluorescent probes of neural activity represent new promising tools for systems neuroscience. Here, we present a comparative in vivo analysis of 10 different genetically encoded calcium indicators, as well as the pH-sensitive synapto-pHluorin. We analyzed their fluorescence changes in presynaptic boutons of the Drosophila larval neuromuscular junction. Robust neural activity did not result in any or noteworthy fluorescence changes when Flash-Pericam, Camgaroo-1, and Camgaroo-2 were expressed. However, calculated on the raw data, fractional fluorescence changes up to 18% were reported by synapto-pHluorin, Yellow Cameleon 2.0, 2.3, and 3.3, Inverse-Pericam, GCaMP1.3, GCaMP1.6, and the troponin C-based calcium sensor TN-L15. The response characteristics of all of these indicators differed considerably from each other, with GCaMP1.6 reporting high rates of neural activity with the largest and fastest fluorescence changes. However, GCaMP1.6 suffered from photobleaching, whereas the fluorescence signals of the double-chromophore indicators were in general smaller but more photostable and reproducible, with TN-L15 showing the fastest rise of the signals at lower activity rates. We show for GCaMP1.3 and YC3.3 that an expanded range of neural activity evoked fairly linear fluorescence changes and a corresponding linear increase in the signal-to-noise ratio (SNR). The expression level of the indicator biased the signal kinetics and SNR, whereas the signal amplitude was independent. The presented data will be useful for in vivo experiments with respect to the selection of an appropriate indicator, as well as for the correct interpretation of the optical signals.
AU - Reiff, Dierk F
AU - Ihring, Alexandra
AU - Guerrero, Giovanna
AU - Isacoff, Ehud Y
AU - Maximilian Jösch
AU - Nakai, Junichi
AU - Borst, Alexander
ID - 1298
IS - 19
JF - Journal of Neuroscience
TI - In vivo performance of genetically encoded indicators of neural activity in flies
VL - 25
ER -
TY - CHAP
AB - The paper surveys the mirror symmetry conjectures of Hausel-Thaddeus and Hausel-Rodriguez-Villegas concerning the equality of certain Hodge numbers of SL(n, ℂ) vs. PGL(n, ℂ) flat connections and character varieties for curves, respectively. Several new results and conjectures and their relations to works of Hitchin, Gothen, Garsia-Haiman and Earl-Kirwan are explained. These use the representation theory of finite groups of Lie-type via the arithmetic of character varieties and lead to an unexpected conjecture for a Hard Lefschetz theorem for their cohomology.
AU - Tamas Hausel
ID - 1444
T2 - Geometric Methods in Algebra and Number Theory
TI - Mirror symmetry and Langlands duality in the non-Abelian Hodge theory of a curve
VL - 235
ER -
TY - JOUR
AB - Building on a recent paper [8], here we argue that the combinatorics of matroids are intimately related to the geometry and topology of toric hyperkähler varieties. We show that just like toric varieties occupy a central role in Stanley’s proof for the necessity of McMullen’s conjecture (or g-inequalities) about the classification of face vectors of simplicial polytopes, the topology of toric hyperkähler varieties leads to new restrictions on face vectors of matroid complexes. Namely in this paper we will give two proofs that the injectivity part of the Hard Lefschetz theorem survives for toric hyperkähler varieties. We explain how this implies the g-inequalities for rationally representable matroids. We show how the geometrical intuition in the first proof, coupled with results of Chari [3], leads to a proof of the g-inequalities for general matroid complexes, which is a recent result of Swartz [20]. The geometrical idea in the second proof will show that a pure O-sequence should satisfy the g-inequalities, thus showing that our result is in fact a consequence of a long-standing conjecture of Stanley.
AU - Tamas Hausel
ID - 1447
IS - 1
JF - Open Mathematics
TI - Quaternionic geometry of matroids
VL - 3
ER -
TY - JOUR
AB - We study an integration theory in circle equivariant cohomology in order to prove a theorem relating the cohomology ring of a hyperkähler quotient to the cohomology ring of the quotient by a maximal abelian subgroup, analogous to a theorem of Martin for symplectic quotients. We discuss applications of this theorem to quiver varieties, and compute as an example the ordinary and equivariant cohomology rings of a hyperpolygon space.
AU - Tamas Hausel
AU - Proudfoot, Nicholas J
ID - 1463
IS - 1
JF - Topology
TI - Abelianization for hyperkähler quotients
VL - 44
ER -
TY - CONF
AB - This paper addresses the novel problem of automatically synthesizing an output image from a large collection of different input images. The synthesized image, called a digital tapestry, can be viewed as a visual summary or a virtual 'thumbnail' of all the images in the input collection. The problem of creating the tapestry is cast as a multi-class labeling problem such that each region in the tapestry is constructed from input image blocks that are salient and such that neighboring blocks satisfy spatial compatibility. This is formulated using a Markov Random Field and optimized via the graph cut based expansion move algorithm. The standard expansion move algorithm can only handle energies with metric terms, while our energy contains non-metric (soft and hard) constraints. Therefore we propose two novel contributions. First, we extend the expansion move algorithm for energy functions with non-metric hard constraints. Secondly, we modify it for functions with "almost" metric soft terms, and show that it gives good results in practice. The proposed framework was tested on several consumer photograph collections, and the results are presented.
AU - Rother, Carsten
AU - Kumar, Sanjiv
AU - Vladimir Kolmogorov
AU - Blake, Andrew
ID - 3175
TI - Digital tapestry
VL - 1
ER -
TY - CONF
AB - This paper demonstrates the high quality, real-time segmentation techniques. We achieve real-time segmentation of foreground from background layers in stereo video sequences. Automatic separation of layers from colour/contrast or from stereo alone is known to be error-prone. Here, colour, contrast and stereo matching information are fused to infer layers accurately and efficiently. The first algorithm, layered dynamic programming (LDP), solves stereo in an extended 6-state space that represents both foreground/background layers and occluded regions. The stereo-match likelihood is then fused with a contrast-sensitive colour model that is learned on the fly, and stereo disparities are obtained by dynamic programming. The second algorithm, layered graph cut (LGC), does not directly solve stereo. Instead the stereo match likelihood is marginalised over foreground and background hypotheses, and fused with a contrast-sensitive colour model like the one used in LDP. Segmentation is solved efficiently by ternary graph cut. Both algorithms are evaluated with respect to ground truth data and found to have similar performance, substantially better than stereo or colour/contrast alone. However, their characteristics with respect to computational efficiency are rather different. The algorithms are demonstrated in the application of background substitution and shown to give good quality composite video output.
AU - Vladimir Kolmogorov
AU - Criminisi, Antonio
AU - Blake, Andrew
AU - Cross, Geoffrey
AU - Rother, Carsten
ID - 3176
TI - Bi-layer segmentation of binocular stereo video
ER -
TY - CONF
AB - Tree-reweighted max-product (TRW) message passing [9] is a modified form of the ordinary max-product algorithm for attempting to find minimal energy configurations in Markov random field with cycles. For a TRW fixed point satisfying the strong tree agreement condition, the algorithm outputs a configuration that is provably optimal. In this paper, we focus on the case of binary variables with pairwise couplings, and establish stronger properties of TRW fixed points that satisfy only the milder condition of weak tree agreement (WTA). First, we demonstrate how it is possible to identify part of the optimal solution - i.e., a provably optimal solution for a subset of nodes - without knowing a complete solution. Second, we show that for submodular functions, a WTA fixed point always yields a globally optimal solution. We establish that for binary variables, any WTA fixed point always achieves the global maximum of the linear programming relaxation underlying the TRW method.
AU - Vladimir Kolmogorov
AU - Wainwright, Martin J
ID - 3181
TI - On the optimality of tree reweighted max product message passing
ER -
TY - CONF
AB - In the work of the authors (2003), we showed that graph cuts can find hypersurfaces of globally minimal length (or area) under any Riemannian metric. Here we show that graph cuts on directed regular grids can approximate a significantly more general class of continuous non-symmetric metrics. Using submodularity condition (Boros and Hammer, 2002 and Kolmogorov and Zabih, 2004), we obtain a tight characterization of graph-representable metrics. Such "submodular" metrics have an elegant geometric interpretation via hypersurface functionals combining length/area and flux. Practically speaking, we attend 'geo-cuts' algorithm to a wider class of geometrically motivated hypersurface functionals and show how to globally optimize any combination of length/area and flux of a given vector field. The concept of flux was recently introduced into computer vision by Vasilevskiy and Siddiqi (2002) but it was mainly studied within variational framework so far. We are first to show that flux can be integrated into graph cuts as well. Combining geometric concepts of flux and length/area within the global optimization framework of graph cuts allows principled discrete segmentation models and advances the slate of the art for the graph cuts methods in vision. In particular we address the "shrinking" problem of graph cuts, improve segmentation of long thin objects, and introduce useful shape constraints.
AU - Vladimir Kolmogorov
AU - Boykov, Yuri
ID - 3182
TI - What metrics can be approximated by geo cuts or global optimization of length area and flux
VL - 1
ER -
TY - CONF
AB - This paper describes two algorithms capable of real-time segmentation of foreground from background layers in stereo video sequences. Automatic separation of layers from colour/contrast or from stereo alone is known to be error-prone. Here, colour, contrast and stereo matching information are fused to infer layers accurately and efficiently. The first algorithm, Layered Dynamic Programming (LDP), solves stereo in an extended 6-state space that represents both foreground/background layers and occluded regions. The stereo-match likelihood is then fused with a contrast-sensitive colour model that is learned on the fly, and stereo disparities are obtained by dynamic programming. The second algorithm, Layered Graph Cut (LGC), does not directly solve stereo. Instead the stereo match likelihood is marginalised over foreground and background hypotheses, and fused with a contrast-sensitive colour model like the one used in LDP. Segmentation is solved efficiently by ternary graph cut. Both algorithms are evaluated with respect to ground truth data and found to have similar perfomance, substantially better than stereo or colour/contrast alone. However, their characteristics with respect to computational efficiency are rather different. The algorithms are demonstrated in the application of background substitution and shown to give good quality composite video output.
AU - Vladimir Kolmogorov
AU - Criminisi, Antonio
AU - Blake, Andrew
AU - Cross, Geoffrey
AU - Rother, Carsten
ID - 3183
TI - Bi-layer segmentation of binocular stereo video
VL - 2
ER -
TY - CONF
AB - We present an improved bound on the advantage of any q-query adversary at distinguishing between the CBC MAC over a random n-bit permutation and a random function outputting n bits. The result assumes that no message queried is a prefix of any other, as is the case when all messages to be MACed have the same length. We go on to give an improved analysis of the encrypted CBC MAC, where there is no restriction on queried messages. Letting m be the block length of the longest query, our bounds are about mq2/2n for the basic CBC MAC and mo(1)q2/2n for the encrypted CBC MAC, improving prior bounds of m2q2/2n. The new bounds translate into improved guarantees on the probability of forging these MACs.
AU - Bellare, Mihir
AU - Krzysztof Pietrzak
AU - Rogaway, Phillip
ID - 3211
TI - Improved security analyses for CBC MACs
VL - 3621
ER -
TY - CONF
AB - The Full-Domain Hash (FDH) signature scheme [3] forms one the most basic usages of random oracles. It works with a family F of trapdoor permutations (TDP), where the signature of m is computed as f−1(h(m)) (here f ∈R F and h is modelled as a random oracle). It is known to be existentially unforgeable for any TDP family F [3], although a much tighter security reduction is known for a restrictive class of TDP’s [10,14] — namely, those induced by a family of claw-free permutations (CFP) pairs. The latter result was shown [11] to match the best possible “black-box” security reduction in the random oracle model, irrespective of the TDP family F (e.g., RSA) one might use.
In this work we investigate the question if it is possible to instantiate the random oracle h with a “real” family of hash functions H such that the corresponding schemes can be proven secure in the standard model, under some natural assumption on the family F. Our main result rules out the existence of such instantiations for any assumption on F which (1) is satisfied by a family of random permutations; and (2) does not allow the attacker to invert f ∈R F on an a-priori unbounded number of points. Moreover, this holds even if the choice of H can arbitrarily depend on f. As an immediate corollary, we rule out instantiating FDH based on general claw-free permutations, which shows that in order to prove the security of FDH in the standard model one must utilize significantly more structure on F than what is sufficient for the best proof of security in the random oracle model.
AU - Dodis, Yevgeniy
AU - Oliveira, Roberto
AU - Krzysztof Pietrzak
ID - 3212
TI - On the generic insecurity of the full domain hash
VL - 3621
ER -
TY - CONF
AB - We study the question whether the sequential or parallel composition of two functions, each indistinguishable from a random function by non-adaptive distinguishers is secure against adaptive distinguishers. The sequential composition of F and G is the function G(F()), the parallel composition is F G where ⋆ is some group operation. It has been shown that composition indeed gives adaptive security in the information theoretic setting, but unfortunately the proof does not translate into the more interesting computational case.
In this work we show that in the computational setting composition does not imply adaptive security: If there is a prime order cyclic group where the decisional Diffie-Hellman assumption holds, then there are functions F and G which are indistinguishable by non-adaptive polynomially time-bounded adversaries, but whose parallel composition can be completely broken (i.e. we recover the key) with only three adaptive queries. We give a similar result for sequential composition. Interestingly, we need a standard assumption from the asymmetric (aka. public-key) world to prove a negative result for symmetric (aka. private-key) systems.
AU - Krzysztof Pietrzak
ID - 3213
TI - Composition does not imply adaptive security
VL - 3621
ER -
TY - JOUR
AB - In the last decade atomic force microscopy has been used to measure the mechanical stability of single proteins. These force spectroscopy experiments have shown that many water-soluble and membrane proteins unfold via one or more intermediates. Recently, Li and co-workers found a linear correlation between the unfolding force of the native state and the intermediate in fibronectin, which they suggested indicated the presence of a molecular memory or multiple unfolding pathways (1). Here, we apply two independent methods in combination with Monte Carlo simulations to analyze the unfolding of α-helices E and D of bacteriorhodopsin (BR). We show that correlation analysis of unfolding forces is very sensitive to errors in force calibration of the instrument. In contrast, a comparison of relative forces provides a robust measure for the stability of unfolding intermediates. The proposed approach detects three energetically different states of α-helices E and D in trimeric BR. These states are not observed for monomeric BR and indicate that substantial information is hidden in forced unfolding experiments of single proteins.
AU - Harald Janovjak
AU - Sapra, Tanuj K
AU - Mueller, Daniel J
ID - 3416
IS - 5
JF - Biophysical Journal
TI - Complex stability of single proteins explored by forced unfolding experiments
VL - 88
ER -
TY - JOUR
AB - Recently, direct measurements of forces stabilizing single proteins or individual receptor–ligand bonds became possible with ultra-sensitive force probe methods like the atomic force microscope (AFM). In force spectroscopy experiments using AFM, a single molecule or receptor–ligand pair is tethered between the tip of a micromachined cantilever and a supporting surface. While the molecule is stretched, forces are measured by the deflection of the cantilever and plotted against extension, yielding a force spectrum characteristic for each biomolecular system. In order to obtain statistically relevant results, several hundred to thousand single-molecule experiments have to be performed, each resulting in a unique force spectrum. We developed software and algorithms to analyse large numbers of force spectra. Our algorithms include the fitting polymer extension models to force peaks as well as the automatic alignment of spectra. The aligned spectra allowed recognition of patterns of peaks across different spectra. We demonstrate the capabilities of our software by analysing force spectra that were recorded by unfolding single transmembrane proteins such as bacteriorhodopsin and NhaA. Different unfolding pathways were detected by classifying peak patterns. Deviant spectra, e.g. those with no attachment or erratic peaks, can be easily identified. The software is based on the programming language C++, the GNU Scientific Library (GSL), the software WaveMetrics IGOR Pro and available open-source at http://bioinformatics.org/fskit/.
AU - Kuhn, Michael
AU - Harald Janovjak
AU - Hubain, Maurice
AU - Mueller, Daniel J
ID - 3417
IS - 2
JF - Journal of Microscopy
TI - Automated alignment and pattern recognition of single-molecule force spectroscopy data
VL - 218
ER -
TY - JOUR
AB - Atomic force microscopy (AFM) allows the critical forces that unfold single proteins and rupture individual receptor–ligand bonds to be measured. To derive the shape of the energy landscape, the dynamic strength of the system is probed at different force loading rates. This is usually achieved by varying the pulling speed between a few nm/s and a few mgrm/s, although for a more complete investigation of the kinetic properties higher speeds are desirable. Above 10 mgrm/s, the hydrodynamic drag force acting on the AFM cantilever reaches the same order of magnitude as the molecular forces. This has limited the maximum pulling speed in AFM single-molecule force spectroscopy experiments. Here, we present an approach for considering these hydrodynamic effects, thereby allowing a correct evaluation of AFM force measurements recorded over an extended range of pulling speeds (and thus loading rates). To support and illustrate our theoretical considerations, we experimentally evaluated the mechanical unfolding of a multi-domain protein recorded at 30 mgrm/s pulling speed.
AU - Harald Janovjak
AU - Struckmeier, Jens
AU - Mueller, Daniel J
ID - 3418
IS - 1
JF - European Biophysics Journal
TI - Hydrodynamic effects in fast AFM single molecule force measurements
VL - 34
ER -
TY - CHAP
AU - Jonathan Bollback
ED - Nielsen, Rasmus
ID - 3433
T2 - Statistical methods in Molecular Evolution
TI - Posterior mapping and posterior predictive distributions
ER -
TY - JOUR
AB - In the hippocampal CA1 area, a relatively homogenous population of pyramidal cells is accompanied by a diversity of GABAergic interneurons. Previously, we found that parvalbumin-expressing basket, axo-axonic, bistratified, and oriens-lacunosum moleculare cells, innervating different domains of pyramidal cells, have distinct firing patterns during network oscillations in vivo. A second family of interneurons, expressing cholecystokinin but not parvalbumin, is known to target the same domains of pyramidal cells as do the parvalbumin cells. To test the temporal activity of these independent and parallel GABAergic inputs, we recorded the precise spike timing of identified cholecystokinin interneurons during hippocampal network oscillations in anesthetized rats and determined their molecular expression profiles and synaptic targets. The cells were cannabinoid receptor type 1 immunopositive. Contrary to the stereotyped firing of parvalbumin interneurons, cholecystokinin-expressing basket and dendrite-innervating cells discharge, on average, with 1.7 ± 2.0 Hz during high-frequency ripple oscillations in an episode-dependent manner. During theta oscillations, cholecystokinin- expressing interneurons fire with 8.8 ± 3.3 Hz at a characteristic time on the ascending phase of theta waves (155 ± 81°), when place cells start firing in freely moving animals. The firing patterns of some interneurons recorded in drug-free behaving rats were similar to cholecystokinin cells in anesthetized animals. Our results demonstrate that cholecystokinin- and parvalbumin-expressing interneurons make different contributions to network oscillations and play distinct roles in different brain states. We suggest that the specific spike timing of cholecystokinin interneurons and their sensitivity to endocannabinoids might contribute to differentiate subgroups of pyramidal cells forming neuronal assemblies, whereas parvalbumin interneurons contribute to synchronizing the entire network. Copyright © 2005 Society for Neuroscience.
AU - Klausberger,Thomas
AU - Marton,Laszlo F
AU - Joseph O'Neill
AU - Huck, Jojanneke H
AU - Dalezios, Yannis
AU - Fuentealba,Pablo
AU - Suen, Wai Yee
AU - Papp, Edit Cs
AU - Kaneko, Takeshi
AU - Watanabe, Masahiko
AU - Jozsef Csicsvari
AU - Somogyi, Péter
ID - 3443
IS - 42
JF - Journal of Neuroscience
TI - Complementary roles of cholecystokinin- and parvalbumin-expressing GABAergic neurons in hippocampal network oscillations
VL - 25
ER -
TY - GEN
AB - Methods, apparatus and computer program products can generate light weight but highly realistic and accurate colored models of three-dimensional colored objects. The colored model may be generated from a second plurality of points that define a coarse digital representation of the surface and at least one texture map containing information derived from a first plurality of colored points that define a fine digital representation of the surface. This derivation is achieved by mapping points within the texture map to the fine digital representation of the three-dimensional surface. Colored scan data may be used to construct the fine digital representation as a triangulated surface (i.e., triangulation) using a wrapping operation.
AU - Williams, Steven P
AU - Herbert Edelsbrunner
AU - Fu, Ping
ID - 3509
TI - Methods, apparatus and computer program products for modeling three-dimensional colored objects
ER -