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  • 101.
    Eichhorn, Ralf
    et al.
    KTH, Centra, Nordic Institute for Theoretical Physics NORDITA.
    Aurell, Erik
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB. KTH, Skolan för elektro- och systemteknik (EES), Centra, ACCESS Linnaeus Centre.
    Stochastic thermodynamics2014Ingår i: Physica Scripta, ISSN 0031-8949, E-ISSN 1402-4896, Vol. 89, nr 4, s. 048001-Artikel i tidskrift (Refereegranskat)
  • 102. Ekdahl, Y.
    et al.
    Shahrabi Farahani, Hossein
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Behm, M.
    Lagergren, Jens
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Öhman, M.
    A-to-I editing of microRNAs in the mammalian brain increases during development2012Ingår i: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 22, nr 8, s. 1477-1487Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Adenosine-to-inosine (A-to-I) RNA editing targets double-stranded RNA stem-loop structures in the mammalian brain. It has previously been shown that miRNAs are substrates for A-to-I editing. For the first time, we show that for several definitions of edited miRNA, the level of editing increases with development, thereby indicating a regulatory role for editing during brain maturation. We use high-throughput RNA sequencing to determine editing levels in mature miRNA, from the mouse transcriptome, and compare these with the levels of editing in pri-miRNA. We show that increased editing during development gradually changes the proportions of the two miR-376a isoforms, which previously have been shown to have different targets. Several other miRNAs that also are edited in the seed sequence show an increased level of editing through development. By comparing editing of pri-miRNA with editing and expression of the corresponding mature miRNA, we also show an editing-induced developmental regulation of miRNA expression. Taken together, our results imply that RNA editing influences the miRNA repertoire during brain maturation.

  • 103.
    Ekeberg, Magnus
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Hartonen, Tuomo
    Aurell, Erik
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB. Aalto University, Finland.
    Fast pseudolikelihood maximization for direct-coupling analysis of protein structure from many homologous amino-acid sequences2014Ingår i: Journal of Computational Physics, ISSN 0021-9991, E-ISSN 1090-2716, Vol. 276, s. 341-356Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Direct-coupling analysis is a group of methods to harvest information about coevolving residues in a protein family by learning a generative model in an exponential family from data. In protein families of realistic size, this learning can only be done approximately, and there is a trade-off between inference precision and computational speed. We here show that an earlier introduced l(2)-regularized pseudolikelihood maximization method called plmDCA can be modified as to be easily parallelizable, as well as inherently faster on a single processor, at negligible difference in accuracy. We test the new incarnation of the method on 143 protein family/structure-pairs from the Protein Families database (PFAM), one of the larger tests of this class of algorithms to date.

  • 104.
    Ekeberg, Magnus
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC).
    Lövkvist, Cecilia
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Lan, Y.
    Weigt, M.
    Aurell, Erik
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB. KTH, Skolan för elektro- och systemteknik (EES), Centra, ACCESS Linnaeus Centre.
    Improved contact prediction in proteins: Using pseudolikelihoods to infer Potts models2013Ingår i: Physical Review E. Statistical, Nonlinear, and Soft Matter Physics, ISSN 1539-3755, E-ISSN 1550-2376, Vol. 87, nr 1, s. 012707-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Spatially proximate amino acids in a protein tend to coevolve. A protein's three-dimensional (3D) structure hence leaves an echo of correlations in the evolutionary record. Reverse engineering 3D structures from such correlations is an open problem in structural biology, pursued with increasing vigor as more and more protein sequences continue to fill the data banks. Within this task lies a statistical inference problem, rooted in the following: correlation between two sites in a protein sequence can arise from firsthand interaction but can also be network-propagated via intermediate sites; observed correlation is not enough to guarantee proximity. To separate direct from indirect interactions is an instance of the general problem of inverse statistical mechanics, where the task is to learn model parameters (fields, couplings) from observables (magnetizations, correlations, samples) in large systems. In the context of protein sequences, the approach has been referred to as direct-coupling analysis. Here we show that the pseudolikelihood method, applied to 21-state Potts models describing the statistical properties of families of evolutionarily related proteins, significantly outperforms existing approaches to the direct-coupling analysis, the latter being based on standard mean-field techniques. This improved performance also relies on a modified score for the coupling strength. The results are verified using known crystal structures of specific sequence instances of various protein families. Code implementing the new method can be found at http://plmdca.csc.kth.se/.

  • 105.
    Ekeberg, Örjan
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Pearson, Keir
    Univ of Alberta.
    Computer simulation of stepping in the hind legs of the cat: An examination of mechanisms regulating the stance-to-swing transition2005Ingår i: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 94, nr 6, s. 4256-4268Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Physiological studies in walking cats have indicated that two sensory signals are involved in terminating stance in the hind legs: one related to unloading of the leg and the other to hip extension. To study the relative importance of these two signals, we developed a three- dimensional computer simulation of the cat hind legs in which the timing of the swing- to- stance transition was controlled by signals related to the force in ankle extensor muscles, the angle at the hip joint, or a combination of both. Even in the absence of direct coupling between the controllers for each leg, stable stepping was easily obtained using either a combination of ankle force and hip position signals or the ankle force signal alone. Stable walking did not occur when the hip position signal was used alone. Coupling the two controllers by mutual inhibition restored stability, but it did not restore the correct timing of stepping of the two hind legs. Small perturbations applied during the swing phase altered the movement of the contralateral leg in a manner that tended to maintain alternating stepping when the ankle force signal was included but tended to shift coordination away from alternating when the hip position signal was used alone. We conclude that coordination of stepping of the hind legs depends critically on load- sensitive signals from each leg and that mechanical linkages between the legs, mediated by these signals, play a significant role in establishing the alternating gait.

  • 106.
    Ensterö, Mats
    et al.
    Department of Molecular Biology and Functional Genomics, Stockholm University.
    Åkerborg, Örjan
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Lundin, Daniel
    Department of Molecular Biology and Functional Genomics, Stockholm University.
    Wang, Bei
    Department of Computer Science, Duke University, Durham, United States.
    Furey, Terrence S.
    Department of Computer Science, Duke University, Durham, United States.
    Öhman, Marie
    Department of Molecular Biology and Functional Genomics, Stockholm University.
    Lagergren, Jens
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    A computational screen for site selective A-to-I editing detects novel sites in neuron specific Hu proteins2010Ingår i: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 11Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Several bioinformatic approaches have previously been used to find novel sites of ADAR mediated A-to-I RNA editing in human. These studies have discovered thousands of genes that are hyper-edited in their non-coding intronic regions, especially in alu retrotransposable elements, but very few substrates that are site-selectively edited in coding regions. Known RNA edited substrates suggest, however, that site selective A-to-I editing is particularly important for normal brain development in mammals. Results: We have compiled a screen that enables the identification of new sites of site-selective editing, primarily in coding sequences. To avoid hyper-edited repeat regions, we applied our screen to the alu-free mouse genome. Focusing on the mouse also facilitated better experimental verification. To identify candidate sites of RNA editing, we first performed an explorative screen based on RNA structure and genomic sequence conservation. We further evaluated the results of the explorative screen by determining which transcripts were enriched for A-G mismatches between the genomic template and the expressed sequence since the editing product, inosine (I), is read as guanosine (G) by the translational machinery. For expressed sequences, we only considered coding regions to focus entirely on re-coding events. Lastly, we refined the results from the explorative screen using a novel scoring scheme based on characteristics for known A-to-I edited sites. The extent of editing in the final candidate genes was verified using total RNA from mouse brain and 454 sequencing. Conclusions: Using this method, we identified and confirmed efficient editing at one site in the Gabra3 gene. Editing was also verified at several other novel sites within candidates predicted to be edited. Five of these sites are situated in genes coding for the neuron-specific RNA binding proteins HuB and HuD.

  • 107. Ericsson, J.
    et al.
    Stephenson-Jones, M.R.
    Samuelsson, E.
    Robertson, B.
    Hill, R.H.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Grillner, S.
    The lamprey provides a vertebrate blueprint of the mammalian basal ganglia2010Konferensbidrag (Refereegranskat)
    Abstract [en]

    The basal ganglia are a group of subcortical nuclei that play a prominent role in motor function in mammals as well as in lamprey. The aim of the present study was to characterize the different components of the lamprey basal ganglia, and determine to what extent they correspond to those found in the mammalian basal ganglia. Anatomical tract tracing, immunohistochemistry and acute brain slice patch clamp recordings were employed to address this question.Two pallidal regions were identified in the lamprey; one region, considered homologous to the mammalian globus pallidus, was located ventral to the ementia thalami on the telencephalic/diencephalic border. It receives striatal input from inwardly rectifying neurons (IRNs) and contains GABAergic projection neurons, of which those projecting to the tectum were shown to be tonically active. It also contains neurons immunoreactive for parvalbumin. Separate subpopulations of pallidal neurons project to the optic tectum, the diencephalic and mesencephalic locomotor regions (MLR).Another region, in the midbrain, considered homologous to the substantia nigra pars reticulata receives input from a different subset of IRNs and sends GABAergic projections to the tectum and the diencephalic locomotor region. This midbrain region also contains parvalbumin immunoreactive neurons. The main population of striatal neurons, IRNs, displays the anatomical and electrophysiological hallmarks of mammalian medium spiny neurons, including inward rectification and ramping responses to first spike. It also contains neurons with properties similar to fast-spiking neurons. The striatum receives pallial and thalamic input as well as ascending dopaminergic, serotonergic and histaminergic inputs, similar to that in mammals.Our results suggest that the basic features of the basal ganglia with regard to both structure and function are conserved throughout the vertebrate phylogeny, including striatal/pallidal subdivisions.

  • 108. Eriksson, Johan
    et al.
    Vogel, Edward K.
    Lansner, Anders B.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB. Department of Numerical Analysis and Computer Science, Stockholm University, Sweden.
    Bergstrom, Fredrik
    Nyberg, Lars
    Neurocognitive Architecture of Working Memory2015Ingår i: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 88, nr 1, s. 33-46Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    A crucial role for working memory in temporary information processing and guidance of complex behavior has been recognized for many decades. There is emerging consensus that working-memory maintenance results from the interactions among long-term memory representations and basic processes, including attention, that are instantiated as reentrant loops between frontal and posterior cortical areas, as well as sub-cortical structures. The nature of such interactions can account for capacity limitations, lifespan changes, and restricted transfer after working-memory training. Recent data and models indicate that working memory may also be based on synaptic plasticity and that working memory can operate on non-consciously perceived information.

  • 109. Evans, R.C.
    et al.
    Du, K.
    Sheehan, T.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Blackwell, K.T.
    Effects of NMDA receptor NR2 subunit on calcium concentration2009Konferensbidrag (Refereegranskat)
  • 110. Fagerstedt, P
    et al.
    Kozlov, Alexander
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Ullén, F
    Aurell, E
    Lansner, A
    Grillner, S
    computational modeling of turning behavior in lamprey2000Konferensbidrag (Refereegranskat)
  • 111.
    Farahini, Nasim
    et al.
    KTH, Skolan för informations- och kommunikationsteknik (ICT), Elektroniksystem.
    Hemani, Ahmed
    KTH, Skolan för informations- och kommunikationsteknik (ICT), Elektroniksystem.
    Lansner, Anders
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Clermidy, F.
    Svensson, C.
    A scalable custom simulation machine for the Bayesian Confidence Propagation Neural Network model of the brain2014Ingår i: 2014 19th Asia and South Pacific Design Automation Conference (ASP-DAC), IEEE , 2014, s. 578-585Konferensbidrag (Refereegranskat)
    Abstract [en]

    A multi-chip custom digital super-computer called eBrain for simulating Bayesian Confidence Propagation Neural Network (BCPNN) model of the human brain has been proposed. It uses Hybrid Memory Cube (HMC), the 3D stacked DRAM memories for storing synaptic weights that are integrated with a custom designed logic chip that implements the BCPNN model. In 22nm node, eBrain executes BCPNN in real time with 740 TFlops/s while accessing 30 TBs synaptic weights with a bandwidth of 112 TBs/s while consuming less than 6 kWs power for the typical case. This efficiency is three orders better than general purpose supercomputers in the same technology node.

  • 112. Feinauer, Christoph
    et al.
    Skwark, Marcin J.
    Pagnani, Andrea
    Aurell, Erik
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB. Aalto University, Finland.
    Improving Contact Prediction along Three Dimensions2014Ingår i: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 10, nr 10, s. e1003847-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Correlation patterns in multiple sequence alignments of homologous proteins can be exploited to infer information on the three-dimensional structure of their members. The typical pipeline to address this task, which we in this paper refer to as the three dimensions of contact prediction, is to (i) filter and align the raw sequence data representing the evolutionarily related proteins; (ii) choose a predictive model to describe a sequence alignment; (iii) infer the model parameters and interpret them in terms of structural properties, such as an accurate contact map. We show here that all three dimensions are important for overall prediction success. In particular, we show that it is possible to improve significantly along the second dimension by going beyond the pair-wise Potts models from statistical physics, which have hitherto been the focus of the field. These (simple) extensions are motivated by multiple sequence alignments often containing long stretches of gaps which, as a data feature, would be rather untypical for independent samples drawn from a Potts model. Using a large test set of proteins we show that the combined improvements along the three dimensions are as large as any reported to date.

  • 113.
    Ferreira, Tiago
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB. Aalto, School of Science.
    Catch the dream Wave: Propagation of Cortical Slow Oscillation to the Striatum in anaesthetised mice2014Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Under anaesthesia or in deep sleep, different parts of the brain have a distinctive slow oscillatory activity, characterised by states of high membrane potential and intensive spiking activity, the Up-states; followed by hyperpolarisation and quiescence, the Down-states. This activity has been previously described in vitro and in vivo in the cortex and the striatum, across several species. Here, we look into it, during anaesthesia, in the mouse brain. Using whole-cell patch-clamp recordings of cortical cells, it was possible to compare different signal processing methods used to extract the Up-and- Down states in extracellular recordings of the cortex. Our results show that the method based on the Multi-Unit Activity (> 200Hz) have better ac- curacy than High-Gamma Range (20 100Hz) or wavelet decomposition (< 2Hz band).

    After establishing the most robust method, this was used to compare the intracellular recordings of striatal cells to different parts of the cortex. The results obtained here support a functional connection between the dorsolateral striatal neurons and the ipsilateral barrel field. They also support a functional connection between dorsomedial striatal cells and the primary visual cortex.

    The analysis of delay between recordings allowed to establish temporal relationships between the contralateral barrel field, the ipsilateral barrel field, and the dorsolateral striatum; and between the ipsilateral barrel field, the ipsilateral primary visual field and the dorsomedial striatum. 

  • 114.
    Fiebig, Florian
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Lansner, Anders
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Memory consolidation from seconds to weeks: a three-stage neural network model with autonomous reinstatement dynamics2014Ingår i: Frontiers in Computational Neuroscience, ISSN 1662-5188, E-ISSN 1662-5188, Vol. 8, s. 64-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Declarative long-term memories are not created in an instant. Gradual stabilization and temporally shifting dependence of acquired declarative memories in different brain regions called systems consolidation- can be tracked in time by lesion experiments. The observation of temporally graded retrograde amnesia(RA) following hippocampal lesions points to a gradual transfer of memory from hippocampus to neocortical long-term memory. Spontaneous reactivations of hippocampal memories, asobserved in place cell reactivations during slow wave- sleep, are supposed to driven eocortical reinstatements and facilitate this process. We proposea functional neural network implementation of these ideas and further more suggest anextended three-state framework that includes the prefrontal cortex( PFC). It bridges the temporal chasm between working memory percepts on the scale of seconds and consolidated long-term memory on the scale of weeks or months. Wes how that our three-stage model can autonomously produce the necessary stochastic reactivation dynamics for successful episodic memory consolidation. There sulting learning system is shown to exhibit classical memory effects seen in experimental studies, such as retrograde and anterograde amnesia(AA) after simulated hippocampal lesioning; further more the model reproduces peculiar biological findings on memory modulation, such as retrograde facilitation of memory after suppressed acquisition of new longterm memories- similar to the effects of benzodiazepines on memory.

  • 115.
    Fiebig, Florian
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB. Stockholm Univ, Sweden.
    Lansner, Anders
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB. Stockholm University, Sweden.
    Memory Consolidation from Seconds to Weeks Through Autonomous Reinstatement Dynamics in a Three-Stage Neural Network Model2015Ingår i: ADVANCES IN COGNITIVE NEURODYNAMICS (IV), SPRINGER , 2015, s. 47-53Konferensbidrag (Refereegranskat)
    Abstract [en]

    Long-term memories for facts and events are not created at an instant. Rather, memories stabilize gradually over time and involve various brain regions. The shifting dependence of acquired declarative memories on different brain regions - called systems consolidation - can be tracked in time by lesion experiments and has led to the development of the Complementary Learning Systems framework, which focuses on hippocampal-cortical interaction. Observations of temporally graded retrograde amnesia following hippocampal lesions, point to a gradual transfer from hippocampus to cortical long-term memory. Spontaneous reactivations of hippocampal memories, as observed in place cell reactivations during slow-wave-sleep, are supposed to drive cortical reinstatements and facilitate this process. We propose a functional neural network implementation of these ideas and furthermore suggest an extended three-stage framework that also includes the prefrontal cortex and bridges the temporal chasm between working memory percepts on the scale of seconds and consolidated long-term memory on the scale of weeks or months. We show that our three-stage model can autonomously produce the necessary stochastic reactivation dynamics for successful episodic memory consolidation. The resulting learning system is shown to exhibit classical memory effects seen in experimental studies, such as retrograde and anterograde amnesia after simulated hippocampal lesioning.

  • 116. Fino, E
    et al.
    Paille, V
    Du, K
    Morera Herreras, T
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Venance, L
    GABA operates as a Hebbian/anti-Hebbian switch for spike-timing-dependent plasticity 2011Konferensbidrag (Refereegranskat)
  • 117. Fonollosa, J.
    et al.
    Gutierrez-Galvez, A.
    Lansner, Anders
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Martinez, D.
    Rospars, J. P.
    Beccherelli, R.
    Perera, A.
    Pearce, T.
    Vershure, P.
    Persaud, K.
    Marco, S.
    Biologically inspired computation for chemical sensing2011Ingår i: Procedia Comput. Sci., 2011, s. 226-227Konferensbidrag (Refereegranskat)
    Abstract [en]

    In this paper, we present how the achievements related to NEUROCHEM project (FP7, Bio-ICT, Grant number 216916) have increased the understanding of the olfactory system and helped to develop novel computing architectures and models for chemical sensing. We present the developed computational models of the olfactory pathway of vertebrates and insects to capture the mechanisms that underlie their chemical information processing abilities. To mimic the biological olfactory epithelium a large scale chemical sensor array has been developed.We also present a robot that demonstrates the chemical search task as a direct application of the computing paradigms extracted.

  • 118.
    Fouquier d'Herouel, Aymeric
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Statistical models of TF/DNA interaction2008Licentiatavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Gene expression is regulated in response to metabolic necessities and environmental changes throughout the life of a cell.

    A major part of this regulation is governed at the level of transcription, deciding whether messengers to specific genes are produced or not.

    This decision is triggered by the action of transcription factors, proteins which interact with specific sites on DNA and thus influence the rate of transcription of proximal genes.

    Mapping the organisation of these transcription factor binding sites sheds light on potential causal relations between genes and is the key to establishing networks of genetic interactions, which determine how the cell adapts to external changes.

    In this work I review briefly the basics of genetics and summarise popular approaches to describe transcription factor binding sites, from the most straight forward to finally discuss a biophysically motivated representation based on the estimation of free energies of molecular interactions.

    Two articles on transcription factors are contained in this thesis, one published (Aurell, Fouquier d'Hérouël, Malmnäs and Vergassola, 2007) and one submitted (Fouquier d'Hérouël, 2008).

    Both rely strongly on the representation of binding sites by matrices accounting for the affinity of the proteins to specific nucleotides at the different positions of the binding sites.

    The importance of non-specific binding of transcription factors to DNA is briefly addressed in the text and extensively discussed in the first appended article:

    In a study on the affinity of yeast transcription factors for their binding sites, we conclude that measured in vivo protein concentrations are marginally sufficient to guarantee the occupation of functional sites, as opposed to unspecific emplacements on the genomic sequence.

    A common task being the inference of binding site motifs, the most common statistical method is reviewed in detail, upon which I constructed an alternative biophysically motivated approach, exemplified in the second appended article.

  • 119.
    Fouquier D´Hérouel, Aymeric
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Autocorrelation maps of masked sequences reveal novel repeatsManuskript (preprint) (Övrigt vetenskapligt)
  • 120.
    Fouquier D´Hérouel, Aymeric
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    On diverse biophysical aspects of genetics: from the action of regulators to the characterization of transcripts2011Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Genetics is among the most rewarding fields of biology for the theoretically inclined, offering both room and need for modeling approaches in the light of an abundance of experimental data of different kinds. Many aspects of the field are today understood in terms of physical and chemical models, joined by information theoretical descriptions. This thesis discusses different mechanisms and phenomena related to genetics, employing tools from statistical physics along with experimental biomolecular methods. Five articles support this work.

    Two articles deal with interactions between proteins and DNA. The first one reports on the properties of non-specific binding of transcription factors proteins in the yeast Saccharomyces cerevisiae, due to an effective background free energy which describes the affinity of a single protein for random locations on DNA. We argue that a background pool of non-specific binding sites is filled up before specific binding sites can be occupied with high probability, thus presenting a natural filter for genetic responses to spurious transcription factor productions. The second article describes an algorithm for the inference of transcription factor binding sites for proteins using a realistic physical model. The functionality of the method is verified on a set of known binding sequences for Escherichia coli transcription factors.

    The third article describes a possible genetic feedback mechanism between human cells and the ubiquitous Epstein-Barr virus (EBV). 40 binding regions for the major EBV transcription factor EBNA1 are identified in human DNA. Several of these are located nearby genes of particular relevance in the context of EBV infection and the most interesting ones are discussed.

    The fourth article describes results obtained from a positional autocorrelation analysis of the human genome, a simple technique to visualize and classify sequence repeats, constituting large parts of eukaryotic genomes. Applying this analysis to genome sequences in which previously known repeats have been removed gives rise to signals corroborating the existence of yet unclassified repeats of surprisingly long periods.

    The fifth article combines computational predictions with a novel molecular biological method based on the rapid amplification of cDNA ends (RACE), coined 5’tagRACE. The first search for non-coding RNAs encoded in the genome of the opportunistic bacterium Enterococcus faecalis is performed here. Applying 5’tagRACE allows us to discover and map 29 novel ncRNAs, 10 putative novelm RNAs and 16 antisense transcriptional organizations.

    Further studies, which are not included as articles, on the monitoring of secondary structure formation of nucleic acids during thermal renaturation and the inference of genetic couplings of various kinds from massive gene expression data and computational predictions, are outlined in the central chapters.

  • 121.
    Fouquier d'Hérouel, Aymeric
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Wessner, Françoise
    Halpern, David
    Ly-Vu, Joseph
    Kennedy, Sean P
    Serror, Pascale
    Aurell, Erik
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Repoila, Francis
    A simple and efficient method to search for selected primary transcripts: non-coding and antisense RNAs in the human pathogen Enterococcus faecalis2011Ingår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 39, nr 7, s. E46-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Enterococcus faecalis is a commensal bacterium and a major opportunistic human pathogen. In this study, we combined in silico predictions with a novel 5'RACE-derivative method coined '5'tagRACE', to perform the first search for non-coding RNAs (ncRNAs) encoded on the E. faecalis chromosome. We used the 5'tagRACE to simultaneously probe and characterize primary transcripts, and demonstrate here the simplicity, the reliability and the sensitivity of the method. The 5'tagRACE is complementary to tiling arrays or RNA-sequencing methods, and is also directly applicable to deep RNA sequencing and should significantly improve functional studies of bacterial RNA landscapes. From 45 selected loci of the E. faecalis chromosome, we discovered and mapped 29 novel ncRNAs, 10 putative novel mRNAs and 16 antisense transcriptional organizations. We describe in more detail the oxygen-dependent expression of one ncRNA located in an E. faecalis pathogenicity island, the existence of an ncRNA that is antisense to the ncRNA modulator of the RNA polymerase, SsrS and provide evidences for the functional interplay between two distinct toxin-antitoxin modules.

  • 122.
    Fouquier d'Hérouël, Aymeric
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    QPS - quadratic programming sampler: a motif finder using biophysical modeling2008Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    We present a Markov chain Monte Carlo algorithm for local alignments of nucleotide sequences aiming to infer putative transcription factor binding sites, referred to as the quadratic programming sampler. The new motif nder incorporates detailed biophysical modeling of the transcription factor binding site recognition which arises an intrinsic threshold discriminating putative binding sites from other/background sequences.

    We validate the principal functioning of the algorithm on a sample of four promoter regions from Escherichia coli. The resulting description of the motif can be readily evaluated on the whole genome to identify new putative binding sites.

  • 123.
    Fouquier d’Hérouël, Aymeric
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Birgersdotter, Anna
    Werner, Maria
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    FR-like EBNA1 binding repeats in the human genome2010Ingår i: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 405, nr 2, s. 524-529Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Epstein Barr Virus (EBV) is widely spread in the human population. EBV nuclear antigen 1 (EBNA1) is a transcription factor that activates viral genes and is necessary for viral replication and partitioning, which binds the EBV genome cooperatively. We identify similar EBNA1 repeat binding sites in the human genome using a nearest-neighbour positional weight matrix. Previously experimentally verified EBNA1 sites in the human genome are successfully recovered by our approach. Most importantly, 40 novel regions are identified in the human genome, constituted of tandemly repeated binding sites for EBNA1. Genes located in vicinity of these regions are presented as possible targets for EBNA1-mediated regulation. Among these, four are discussed in more detail: IQCB1, IMPG1, IRF2BP and TPO. Incorporating the cooperative actions of EBNA1 is essential when identifying regulatory regions in the human genome and we believe the findings presented here are highly valuable for the understanding of EBV-induced phenotypic changes.

  • 124.
    Franović, Tin
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Cortex Inspired Network Architectures For Spatio-Temporal Information Processing2013Självständigt arbete på avancerad nivå (masterexamen), 80 poäng / 120 hpStudentuppsats (Examensarbete)
    Abstract [en]

    The abundance of high-dimensional datasets providesscientists with a strong foundation in their research. With high-performancecomputing platforms becoming increasingly available and more powerful,large-scale data processing represents an important step toward modeling andunderstanding the underlying processes behind such data.

    In this thesis, we propose a general cortex-inspired information processingnetwork architecture capable of capturing spatio-temporal correlations in dataand forming distributed representations as cortical activation patterns. Theproposed architecture has a modular and multi-layered organization which isefficiently parallelized to allow large-scale computations. The network allowsunsupervised processing of multivariate stochastic time series, irregardless ofthe data source, producing a sparse de-correlated representation of the inputfeatures expanded by time delays.

    The features extracted by the architecture are then used for supervised learningwith Bayesian confidence propagation neural networks and evaluated on speechclassification and recognition tasks. Due to their rich temporal dynamics, weexploited auditory signals for speech recognition as an use case for performanceevaluation. In terms of classification performance, the proposed architectureoutperforms modern machine-learning methods such as support vector machines andobtains results comparable to other state-of-the-art speech recognition methods.The potential of the proposed scalable cortex-inspired approach to capturemeaningful multivariate temporal correlations and provide insight into themodel-free high- dimensional data decomposition basis is expected to be ofparticular use in the analysis of large brain signal datasets such as EEG orMEG.

  • 125.
    Fransén, Erik
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Ionic Mechanisms in Peripheral Pain2014Ingår i: Computational Neuroscience / [ed] Blackwell, K.T., Elsevier, 2014, s. 23-51Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    Chronic pain constitutes an important and growing problem in society with large unmet needs with respect to treatment and clear implications for quality of life. Computational modeling is used to complement experimental studies to elucidate mechanisms involved in pain states. Models representing the peripheral nerve ending often address questions related to sensitization or reduction in pain detection threshold. In models of the axon or the cell body of the unmyelinated C-fiber, a large body of work concerns the role of particular sodium channels and mutations of these. Furthermore, in central structures: spinal cord or higher structures, sensitization often refers not only to enhanced synaptic efficacy but also to elevated intrinsic neuronal excitability. One of the recent developments in computational neuroscience is the emergence of computational neuropharmacology. In this area, computational modeling is used to study mechanisms of pathology with the objective of finding the means of restoring healthy function. This research has received increased attention from the pharmaceutical industry as ion channels have gained increased interest as drug targets. Computational modeling has several advantages, notably the ability to provide mechanistic links between molecular and cellular levels on the one hand and functions at the systems level on the other hand. These characteristics make computational modeling an additional tool to be used in the process of selecting pharmaceutical targets. Furthermore, large-scale simulations can provide a framework to systematically study the effects of several interacting disease parameters or effects from combinations of drugs.

  • 126.
    Fransén, Erik
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Neural response profile design: Reducing epileptogenic activity by modifying neuron responses to synchronized input using novel potassium channels obtained by parameter search optimization2007Ingår i: Neurocomputing, ISSN 0925-2312, E-ISSN 1872-8286, Vol. 70, nr 10-12, s. 1630-1634Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Neurons obtain their dynamical electrical characteristics by a set of ion channels. These properties may not only affect the function of the neuron and the local network it forms part of, but it may also eventually affect behavior. We were interested to study whether epileptogenic activity could be reduced by adding an ion channel. In this work, we used computational search techniques to optimize ion channel properties for the goal of modifying neural response characteristics. Our results show that this type of parameter search is possible and reasonably efficient. Successful searches were generated using the direct method PRAXIS, and by systematic searches in low-dimensional sub-spaces. We also report on unsuccessful searches using a simplex-type method, a gradient-based method, and attempts to reduce goal function evaluation time. Importantly, using this search strategy, our study has shown that it is possible to change a neuron's characteristics selectively with regard to response to degree of synchronicity in synaptic input.

  • 127.
    Fransén, Erik A.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Mechanisms of Graded Persistent Activity: Implications for Epilepsy2008Ingår i: Computational Neuroscience in Epilepsy, Elsevier, 2008, s. 215-231Kapitel i bok, del av antologi (Övrigt vetenskapligt)
    Abstract [en]

    One major topic in epilepsy is factors contributing to neuronal excitability. This chapter considers depolarizing sources from cationic currents. These ion channels of the TRP-type are permeable to Na, K and sometimes Ca, and show a slow time dynamics. They can therefore provide the dendrites with integrative properties over seconds and perhaps even minutes. This makes them powerful as integrators of synaptic input. Further, their activation depends to a large degree on intracellular calcium. They may therefore during seizures become strongly activated and thereby further contribute to epileptogenic activity directly by depolarization and indirectly by their calcium permeability. Cationic currents are widely distributed throughout the nervous system, including cortical, cerebellar and subcortical neurons. This chapter describes the work in entorhinal cortex and, specifically, the plateau firing characteristics found in pyramidal cells of layer V. These cells show persistent action potential firing at plateaus, which may last over ten minutes. Intriguingly, these plateaus are graded in that input, synaptic or by current injection, can shift them up and down in frequency. After the original finding, graded plateaus have been found also in perirhinal cortex and amygdala. Functionally, cationic neuronal integrator capacity has been shown to be involved in sensory-motor integration. Finally, anticonvulsants like lamotrigine and phenytoin have been found to reduce depolarizations involving cationic currents. Cation currents may therefore be targets in treatments of epilepsy.

  • 128.
    Fransén, Erik
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Ahlström, Peter
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Ionic mechanisms of post spike excitability changes during high-frequency firing rates2014Ingår i: Scandinavian Journal of Pain, ISSN 1877-8860, E-ISSN 1877-8879, Vol. 5, nr 3, s. 208-Artikel i tidskrift (Refereegranskat)
  • 129.
    Fransén, Erik
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Petersson, Marcus E.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Tigerholm, Jenny
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Andersson, Sten
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Obreja, O
    Dept. of Anaesthesiology Mannheim, Heidelberg University, Mannheim, Germany.
    Lampert, A
    Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
    Carr, R
    Dept. of Anaesthesiology Mannheim, Heidelberg University, Mannheim, Germany.
    Schmelz, M
    Dept. of Anaesthesiology Mannheim, Heidelberg University, Mannheim, Germany.
    Differences in action potential propagation in mechanosensitive and insensitive C-nociceptors - a modeling approach2012Konferensbidrag (Refereegranskat)
    Abstract [en]

    C-fibers, unmyelinated afferent axons, convey information from the periphery of the nervous system to the spinal cord. They transmit signals originating from noxious stimulation evoking the sensations of itch and pain in the central nervous system. Different classes of C-fibers are characterized by functional, morphological and biochemical characteristics. In pain studies, a classification into mechano-insensitive (CMi) and mechano responsive fibers (CM) has proven useful as changes in proportions and response characteristics of these fibers have been observed in neuropathy patients (Weidner et al. 1999, 2000; Orstavik 2003, 2010). In this study, using computational modeling of a C-fiber, we have studied the possible contribution of different ion channel subtypes (Na-TTXs, Nav1.8, Nav1.9, Kdr, KA, KM, K(Na), h) as well as the Na/K-ATPase pump to conductive properties of C-fibers. In particular we investigated mechanisms that could generate the fiber-specific differences between CM and CMi fibers with regard to activity dependent slowing (ADS) and recovery cycles (RC). In our study we represent the axon by three cylindrical sections, one representing the peripheral thin end (branch, 2.5 cm), one the central part (parent, 10 cm) and a conical section between these (0.5 cm). In total 730 compartments are used. Temperature is set to 32 degrees C in branch and 37 degrees in parent sections. We represent variable ion concentrations of Na and K intra axonally, periaxonally and extracellularly, from which reversal potentials are calculated. We use ion channel models based on Hodgkin Huxley formalism. An ion pump (Na/K-ATPase) is included. We find that TTX-sensitive Na and Nav1.8 have the strongest influence on action potential conduction velocity as is expected since these are the major components of the rising phase of the action potential. Preliminary observations indicate that a small subset of Na and K currents play a key role in determining differences in activity dependent velocity changes (ADS) in the two fiber classes. We plan to also study contributions from morphological characteristics (superficial branch lengths) to activity dependent differences between the fiber classes (Schmidt et al. 2002). We further intend to investigate candidate ion channels which could play a role in changing the functional characteristics of a CMi fiber to that of a CM fiber. Our studies may provide insights into ionic changes underlying changes in the excitability of C-fibers associated with pain.

  • 130.
    Fransén, Erik
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Tahvildari, B.
    Egorov, A. V.
    Hasselmo, M. E.
    Alonso, A. A.
    Mechanism of graded persistent cellular activity of entorhinal cortex layer V neurons2006Ingår i: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 49, nr 5, s. 735-746Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Working memory is an emergent property of neuronal networks, but its cellular basis remains elusive. Recent data show that principal neurons of the entorhinal cortex display persistent firing at graded firing rates that can be shifted up or down in response to brief excitatory or inhibitory stimuli. Here, we present a model of a potential mechanism for graded firing. Our multicompartmental model provides stable plateau firing generated by a nonspecific calcium-sensitive cationic (CAN) current. Sustained firing is insensitive to small variations in Ca2+ concentration in a neutral zone. However, both high and low Ca2+ levels alter firing rates. Specifically, increases in persistent firing rate are triggered only during high levels of calcium, while decreases in rate occur in the presence of low levels of calcium. The model is consistent with detailed experimental observations and provides a mechanism for maintenance of memory-related activity in individual neurons.

  • 131.
    Fransén, Erik
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Tigerholm, Jenny
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Role of A-type potassium currents in excitability, network synchronicity, and epilepsy2010Ingår i: Hippocampus, ISSN 1050-9631, E-ISSN 1098-1063, Vol. 20, nr 7, s. 877-887Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A range of ionic currents have been suggested to be involved in distinct aspects of epileptogenesis. Based on pharmacological and genetic studies, potassium currents have been implicated, in particular the transient A-type potassium current (K-A). Epileptogenic activity comprises a rich repertoire of characteristics, one of which is synchronized activity of principal cells as revealed by occurrences of for instance fast ripples. Synchronized activity of this kind is particularly efficient in driving target cells into spiking. In the recipient cell, this synchronized input generates large brief compound excitatory postsynaptic potentials (EPSPs). The fast activation and inactivation of K-A lead us to hypothesize a potential role in suppression of such EPSPs. In this work, using computational modeling, we have studied the activation of K-A by synaptic inputs of different levels of synchronicity. We find that K-A participates particularly in suppressing inputs of high synchronicity. We also show that the selective suppression stems from the current's ability to become activated by potentials with high slopes. We further show that K-A suppresses input mimicking the activity of a fast ripple. Finally, we show that the degree of selectivity of K-A can be modified by changes to its kinetic parameters, changes of the type that are produced by the modulatory action of KChIPs and DPPs. We suggest that the wealth of modulators affecting K-A might be explained by a need to control cellular excitability in general and suppression of responses to synchronicity in particular. We also suggest that compounds changing K-A-kinetics may be used to pharmacologically improve epileptic status.

  • 132.
    Fransén, Erik
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Tigerholm, Jenny
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Petersson, Marcus E.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Carr, R
    Dept. of Anaesthesiology Mannheim, Heidelberg University, Mannheim, German.
    Obreja, O
    Dept. of Anaesthesiology Mannheim, Heidelberg University, Mannheim, Germany.
    Lampert, A
    Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
    Schmelz, M
    Dept. of Anaesthesiology Mannheim, Heidelberg University, Mannheim, Germany.
    Computational modeling of activity dependent velocity changes in peripheral C-fibers2011Konferensbidrag (Refereegranskat)
    Abstract [en]

    Initiation and propagation of action potentials along unmyelinated C-fibers are the first steps of the pain pathway. Propagation velocity and its fiber class-specific activity-dependent slowing (ADS) is intimately linked to fibre excitability. In chronic pain patients, ADS alterations have been suggested to reflect increased excitability, possibly underlying clinical pain. Due to their small diameter, peripheral axons of nociceptors in patients are not accessible for intraaxonal recordings of their ion channel properties. We have therefore constructed a model of a C-fibre to study the relationship between ion channel composition and velocity changes as well as excitability. Ion channels are modeled from data of DRG somata using a Hodgkin-Huxley formalism (Na currents: TTX-sensitive, Nav1.8, Nav1.9, K currents: Kdr, A-type, Kv7.3, non-specific cationic: HCN). Moreover, ion pumps (Na/K-ATPase) and concentrations of intra and extraaxonal sodium and potassium are also included. The geometry and temperature of the fibre represents a section of the superficial branch and the deeper parent and is represented by a multicompartmental structure where each compartment contains passive as well as ion channel and pump elements. Using parameter estimation techniques, we optimized ion channel and pump expression pattern such that basic electrophysiological characteristics of the action potential and its velocity matched the experimental data. Moreover, we have also replicated activity dependent slowing. In ongoing work, we extend optimization to also include recovery cycles. The model will be used to study hypothesis of the relationship between individual ion channel subtypes and axonal excitability related to pain, generating independent information on impact of selective neuronal targets.

  • 133. Frygelius, Jessica
    et al.
    Arvestad, Lars
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Wedell, Anna
    Tohonen, Virpi
    Evolution and human tissue expression of the Cres/Testatin subgroup genes, a reproductive tissue specific subgroup of the type 2 cystatins2010Ingår i: Evolution & Development, ISSN 1520-541X, E-ISSN 1525-142X, Vol. 12, nr 3, s. 329-342Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    P>The cystatin family comprises a group of generally broadly expressed protease inhibitors. The Cres/Testatin subgroup (CTES) genes within the type 2 cystatins differs from the classical type 2 cystatins in having a strikingly reproductive tissue-specific expression, and putative functions in reproduction have therefore been discussed. We have performed evolutionary studies of the CTES genes based on gene searches in genomes from 11 species. Ancestors of the cystatin family can be traced back to plants. We have localized the evolutionary origin of the CTES genes to the split of marsupial and placental mammals. A model for the evolution of these genes illustrates that they constitute a dynamic group of genes, which has undergone several gene expansions and we find indications of a high degree of positive selection, in striking contrast to what is seen for the classical cystatin C. We show with phylogenetic relations that the CTES genes are clustered into three original groups, a testatin, a Cres, and a CstL1 group. We have further characterized the expression patterns of all human members of the subfamily. Of a total of nine identified human genes, four express putative functional transcripts with a predominant expression in the male reproductive system. Our results are compatible with a function of this gene family in reproduction.

  • 134. Frånberg, Mattias
    et al.
    Gertow, Karl
    Hamsten, Anders
    Lagergren, Jens
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB. KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Centra, SeRC - Swedish e-Science Research Centre.
    Sennblad, Bengt
    Discovering Genetic Interactions in Large-Scale Association Studies by Stage-wise Likelihood Ratio Tests2015Ingår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, nr 9, artikel-id e1005502Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Despite the success of genome-wide association studies in medical genetics, the underlying genetics of many complex diseases remains enigmatic. One plausible reason for this could be the failure to account for the presence of genetic interactions in current analyses. Exhaustive investigations of interactions are typically infeasible because the vast number of possible interactions impose hard statistical and computational challenges. There is, therefore, a need for computationally efficient methods that build on models appropriately capturing interaction. We introduce a new methodology where we augment the interaction hypothesis with a set of simpler hypotheses that are tested, in order of their complexity, against a saturated alternative hypothesis representing interaction. This sequential testing provides an efficient way to reduce the number of non-interacting variant pairs before the final interaction test. We devise two different methods, one that relies on a priori estimated numbers of marginally associated variants to correct for multiple tests, and a second that does this adaptively. We show that our methodology in general has an improved statistical power in comparison to seven other methods, and, using the idea of closed testing, that it controls the family-wise error rate. We apply our methodology to genetic data from the PRO-CARDIS coronary artery disease case/control cohort and discover three distinct interactions. While analyses on simulated data suggest that the statistical power may suffice for an exhaustive search of all variant pairs in ideal cases, we explore strategies for a priori selecting subsets of variant pairs to test. Our new methodology facilitates identification of new disease-relevant interactions from existing and future genome-wide association data, which may involve genes with previously unknown association to the disease. Moreover, it enables construction of interaction networks that provide a systems biology view of complex diseases, serving as a basis for more comprehensive understanding of disease pathophysiology and its clinical consequences.

  • 135.
    Fugelstad, Johanna
    et al.
    KTH, Skolan för bioteknologi (BIO), Glykovetenskap.
    Bouzenzana, Jamel
    Djerbi, Soraya
    Guerriero, Gea
    KTH, Skolan för bioteknologi (BIO), Glykovetenskap.
    Ezcurra, Inés
    KTH, Skolan för bioteknologi (BIO), Glykovetenskap.
    Teeri, Tuula T.
    KTH, Skolan för bioteknologi (BIO), Glykovetenskap.
    Arvestad, Lars
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Bulone, Vincent
    KTH, Skolan för bioteknologi (BIO), Glykovetenskap.
    Identification of the cellulose synthase genes from the Oomycete Saprolegnia monoica and effect of cellulose synthesis inhibitors on gene expression and enzyme activity2009Ingår i: Fungal Genetics and Biology, ISSN 1087-1845, E-ISSN 1096-0937, Vol. 46, nr 10, s. 759-767Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cellulose biosynthesis is a vital but yet poorly understood biochemical process in Oomycetes. Here, we report the identification and characterization of the cellulose synthase genes (CesA) from Saprolegnia monoica. Southern blot experiments revealed the occurrence of three CesA homologues in this species and phylogenetic analyses confirmed that Oomycete CesAs form a clade of their own. All gene products contained the D,D,D,QXXRW signature of most processive glycosyltransferases, including cellulose synthases. However, their N-terminal ends exhibited Oomycete-specific domains, i.e. Pleckstrin Homology domains, or conserved domains of an unknown function together with additional putative transmembrane domains. Mycelial growth was inhibited in the presence of the cellulose biosynthesis inhibitors 2,6-dichlorobenzonitrile or Congo Red. This inhibition was accompanied by a higher expression of all CesA genes in the mycelium and increased in vitro glucan synthase activities. Altogether, our data strongly suggest a direct involvement of the identified CesA genes in cellulose biosynthesis.

  • 136.
    Gao, Chen-Yi
    et al.
    Chinese Acad Sci, Inst Theoret Phys, Key Lab Theoret Phys, Beijing 100190, Peoples R China.;Univ Chinese Acad Sci, Sch Phys Sci, Beijing 100049, Peoples R China..
    Zhou, Hai-Jun
    Chinese Acad Sci, Inst Theoret Phys, Key Lab Theoret Phys, Beijing 100190, Peoples R China.;Univ Chinese Acad Sci, Sch Phys Sci, Beijing 100049, Peoples R China.;Hunan Normal Univ, Synerget Innovat Ctr Quantum Effects & Applicat, Changsha 410081, Hunan, Peoples R China..
    Aurell, Erik
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB. Aalto Univ, Dept Appl Phys, Aalto 00076, Finland.;Aalto Univ, Dept Comp Sci, Aalto 00076, Finland..
    Correlation-compressed direct-coupling analysis2018Ingår i: Physical review. E, ISSN 2470-0045, E-ISSN 2470-0053, Vol. 98, nr 3, artikel-id 032407Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Learning Ising or Potts models from data has become an important topic in statistical physics and computational biology, with applications to predictions of structural contacts in proteins and other areas of biological data analysis. The corresponding inference problems are challenging since the normalization constant (partition function) of the Ising or Potts distribution cannot be computed efficiently on large instances. Different ways to address this issue have resulted in a substantial amount of methodological literature. In this paper we investigate how these methods could be used on much larger data sets than studied previously. We focus on a central aspect, that in practice these inference problems are almost always severely under-sampled, and the operational result is almost always a small set of leading predictions. We therefore explore an approach where the data are prefiltered based on empirical correlations, which can be computed directly even for very large problems. Inference is only used on the much smaller instance in a subsequent step of the analysis. We show that in several relevant model classes such a combined approach gives results of almost the same quality as inference on the whole data set. It can therefore provide a potentially very large computational speedup at the price of only marginal decrease in prediction quality. We also show that the results on whole-genome epistatic couplings that were obtained in a recent computation-intensive study can be retrieved by our approach. The method of this paper hence opens up the possibility to learn parameters describing pairwise dependences among whole genomes in a computationally feasible and expedient manner.

  • 137.
    Gillblad, Daniel
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    On practical machine learning and data analysis2008Doktorsavhandling, monografi (Övrigt vetenskapligt)
    Abstract [en]

    This thesis discusses and addresses some of the difficulties associated with practical machine learning and data analysis. Introducing data driven meth- ods in e. g. industrial and business applications can lead to large gains in productivity and efficiency, but the cost and complexity are often overwhelm- ing. Creating machine learning applications in practise often involves a large amount of manual labour, which often needs to be performed by an experi- enced analyst without significant experience with the application area. We will here discuss some of the hurdles faced in a typical analysis project and suggest measures and methods to simplify the process.

    One of the most important issues when applying machine learning meth- ods to complex data, such as e. g. industrial applications, is that the processes generating the data are modelled in an appropriate way. Relevant aspects have to be formalised and represented in a way that allow us to perform our calculations in an efficient manner. We present a statistical modelling framework, Hierarchical Graph Mixtures, based on a combination of graphi- cal models and mixture models. It allows us to create consistent, expressive statistical models that simplify the modelling of complex systems. Using a Bayesian approach, we allow for encoding of prior knowledge and make the models applicable in situations when relatively little data are available.

    Detecting structures in data, such as clusters and dependency structure, is very important both for understanding an application area and for speci- fying the structure of e. g. a hierarchical graph mixture. We will discuss how this structure can be extracted for sequential data. By using the inherent de- pendency structure of sequential data we construct an information theoretical measure of correlation that does not suffer from the problems most common correlation measures have with this type of data.

    In many diagnosis situations it is desirable to perform a classification in an iterative and interactive manner. The matter is often complicated by very limited amounts of knowledge and examples when a new system to be diag- nosed is initially brought into use. We describe how to create an incremental classification system based on a statistical model that is trained from empiri- cal data, and show how the limited available background information can still be used initially for a functioning diagnosis system.

    To minimise the effort with which results are achieved within data anal- ysis projects, we need to address not only the models used, but also the methodology and applications that can help simplify the process. We present a methodology for data preparation and a software library intended for rapid analysis, prototyping, and deployment.

    Finally, we will study a few example applications, presenting tasks within classification, prediction and anomaly detection. The examples include de- mand prediction for supply chain management, approximating complex simu- lators for increased speed in parameter optimisation, and fraud detection and classification within a media-on-demand system.

  • 138. Giocomo, Lisa M.
    et al.
    Zilli, Eric A.
    Fransén, Erik
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Hasselmo, Michael E.
    Temporal frequency of subthreshold oscillations scales with entorhinal grid cell field spacing2007Ingår i: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 315, nr 5819, s. 1719-1722Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Grid cells in layer II of rat entorhinal cortex fire to spatial locations in a repeating hexagonal grid, with smaller spacing between grid fields for neurons in more dorsal anatomical locations. Data from in vitro whole-cell patch recordings showed differences in frequency of subthreshold membrane potential oscillations in entorhinal neurons that correspond to different positions along the dorsal-to-ventral axis, supporting a model of physiological mechanisms for grid cell responses.

  • 139.
    Golumbeanu, Monica
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Applying Hidden Markov Models to RNA-seq data2013Rapport (Övrigt vetenskapligt)
    Abstract [en]

    Enterococcus faecalis is one of the most controversial commensal bacteria of the human intestinal flora that is also responsible for lethal nosocomial infections. Determining the factors that influence its pathogenicity is at present a great challenge. Cutting-edge approaches analyze the E. faecalis bacterium trough the next generation RNA-sequencing technology. Since next generation sequencing is recent and yields a large amount of data, there is a continuous need for appropriate statistical methods to interpret its output. We propose an approach based on hidden Markov models to explore RNA-seq data and show an example of how we can apply this statistical tool to detect transcription start sites. We compare this application with a previously developed method based on signal processing.

  • 140.
    Golumbeanu, Monica
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Statistical Analysis of PAR-CLIP data2013Självständigt arbete på avancerad nivå (masterexamen), 80 poäng / 120 hpStudentuppsats (Examensarbete)
    Abstract [en]

    From creation to its degradation, the RNA molecule is the action field of many binding proteins with different roles in regulation and RNA metabolism. Since these proteins are involved in a large number of processes, a variety of diseases are related to abnormalities occurring within the binding mechanisms. One of the experimental methods for detecting the binding sites of these proteins is PAR-CLIP built on the next generation sequencing technology. Due to its size and intrinsic noise, PAR-CLIP data analysis requires appropriate pre-processing and thorough statistical analysis.

    The present work has two main goals. First, to develop a modular pipeline for preprocessing PAR-CLIP data and extracting necessary signals for further analysis. Second, to devise a novel statistical model in order to carry out inference about presence of protein binding sites based on the signals extracted in the pre-processing step. 

  • 141.
    Golumbeanu, Monica
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Statistical Analysis of PAR-CLIP data2013Självständigt arbete på avancerad nivå (masterexamen), 60 poäng / 90 hpStudentuppsats (Examensarbete)
    Abstract [en]

    From creation to its degradation, the RNA molecule is the action field of many binding proteins with different roles in regulation and RNA metabolism. Since these proteins are involved in a large number of processes, a variety of diseases are related to abnormalities occurring within the binding mechanisms. One of the experimental methods for detecting the binding sites of these proteins is PAR-CLIP built on the next generation sequencing technology. Due to its size and intrinsic noise, PAR-CLIP data analysis requires appropriate pre-processing and thorough statistical analysis.

    The present work has two main goals. First, to develop a modular pipeline for preprocessing PAR-CLIP data and extracting necessary signals for further analysis. Second, to devise a novel statistical model in order to carry out inference about presence of protein binding sites based on the signals extracted in the pre-processing step.

  • 142. Grillner, Sten
    et al.
    Kozlov, Alexander
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Dario, Paolo
    Stefanini, Cesare
    Menciassi, Arianna
    Lansner, Anders
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Modeling a vertebrate motor system: pattern generation, steering and control of body orientation2007Ingår i: Progress in Brain Research, ISSN 0079-6123, E-ISSN 1875-7855, Vol. 165, s. 221-234Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The lamprey is one of the few vertebrates in which the neural control system for goal-directed locomotion including steering and control of body orientation is well described at a cellular level. In this report we review the modeling of the central pattern-generating network, which has been carried out based on detailed experimentation. In the same way the modeling of the control system for steering and control of body orientation is reviewed, including neuromechanical simulations and robotic devices.

  • 143. Grönlund, Andreas
    et al.
    Holme, Petter
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Minnhagen, Petter
    Dynamic scaling regimes of collective decision making2008Ingår i: Europhysics letters, ISSN 0295-5075, E-ISSN 1286-4854, Vol. 81, nr 2, s. 28003-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We investigate a social system of agents faced with a binary choice. We assume there is a correct, or beneficial, outcome of this choice. Furthermore, we assume agents are influenced by others in making their decision, and that the agents can obtain information that may guide them towards making a correct decision. The dynamic model we propose is of nonequilibrium type, converging to a final decision. We run it on random graphs and scale-free networks. On random graphs, we find two distinct regions in terms of the finalizing time-the time until all agents have finalized their decisions. On scale-free networks, on the other hand, there do not seem to be such distinct scaling regions.

  • 144.
    Gutierrez-Arenas, Omar
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Handling and Analyzing Meshed Rendering of Segmented Structures From 3D Image Stacks in Blender2015Ingår i: Neuroinformatics, ISSN 1539-2791, E-ISSN 1559-0089, Vol. 13, nr 2, s. 151-152Artikel i tidskrift (Övrigt vetenskapligt)
  • 145.
    Gutierrez-Arenas, Omar
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Eriksson, O.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Segregation and Crosstalk of D1 Receptor-Mediated Activation of ERK in Striatal Medium Spiny Neurons upon Acute Administration of Psychostimulants2014Ingår i: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 10, nr 1, s. e1003445-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The convergence of corticostriatal glutamate and dopamine from the midbrain in the striatal medium spiny neurons (MSN) triggers synaptic plasticity that underlies reinforcement learning and pathological conditions such as psychostimulant addiction. The increase in striatal dopamine produced by the acute administration of psychostimulants has been found to activate not only effectors of the AC5/cAMP/PKA signaling cascade such as GluR1, but also effectors of the NMDAR/Ca2+/RAS cascade such as ERK. The dopamine-triggered effects on both these cascades are mediated by D1R coupled to Golf but while the phosphorylation of GluR1 is affected by reductions in the available amount of Golf but not of D1R, the activation of ERK follows the opposite pattern. This segregation is puzzling considering that D1R-induced Golf activation monotonically increases with DA and that there is crosstalk from the AC5/cAMP/PKA cascade to the NMDAR/Ca2+/RAS cascade via a STEP (a tyrosine phosphatase). In this work, we developed a signaling model which accounts for this segregation based on the assumption that a common pool of D1R and Golf is distributed in two D1R/Golf signaling compartments. This model integrates a relatively large amount of experimental data for neurons in vivo and in vitro. We used it to explore the crosstalk topologies under which the sensitivities of the AC5/cAMP/PKA signaling cascade to reductions in D1R or Golf are transferred or not to the activation of ERK. We found that the sequestration of STEP by its substrate ERK together with the insensitivity of STEP activity on targets upstream of ERK (i.e. Fyn and NR2B) to PKA phosphorylation are able to explain the experimentally observed segregation. This model provides a quantitative framework for simulation based experiments to study signaling required for long term potentiation in MSNs.

  • 146.
    Gårding, Jonas
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Datorseende och robotik, CVAP.
    Lindeberg, Tony
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    CanApp: The Candela Application Library1989Rapport (Övrigt vetenskapligt)
    Abstract [en]

    This paper describes CanApp, the Candela Application Library. CanApp is a software package for image processing and image analysis. Most of the subroutines in CanApp are available both as stand-alone programs and C subroutines.

    CanApp currently comprises some 50 programs and 75 subroutines, and these numbers are expected to grow continuously as a result of joint efforts of the members of the CVAP group at the Royal Institute of Technology in Stockholm.

    CanApp is currently installed and running under UNIX on Sun workstations

  • 147. Göndör, Anita
    et al.
    Woodbridge, Alejandro Fernandez
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Shi, Chenxi
    Aurell, Erik
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB. KTH, Skolan för elektro- och systemteknik (EES), Centra, ACCESS Linnaeus Centre.
    Imreh, Marta
    Ohlsson, Rolf
    Window into the Complexities of Chromosome Interactomes2010Ingår i: Cold Spring Harbor Symposia on Quantitative Biology, ISSN 0091-7451, E-ISSN 1943-4456, Vol. 75, s. 493-500Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    DNA is folded into increasingly complex yet highly mobile structures to organize the chromosomes. In the interphase nucleus, chromosomes or part of the chromosomes encounter one another preferentially at the boundaries between chromosomal territories. Although this situation implies that the preferred chromosomal neighborhood is a key determinant of interactions between chromosomes, what this means in functional terms is currently not well understood. Using the H19 imprinting control region as a window, it has been demonstrated that epigenetic information of the primary chromatin fiber has dual functions. Thus, epigenetic marks not only influence the proximity between chromatin fibers but also transfer epigenetic states between chromatin fibers both in cis and in trans. High-throughput sequence and DNA fluorescence it situ hybridization (FISH) analyses reveal that these features require chromatin movements that are restricted in space and time. The mechanisms involved in the establishment of chromosome interactomes may provide insight of fundamental importance into pivotal regulatory processes in the nucleus, such as the coordination of transcriptional programs and replication timing.

  • 148.
    Hagen, Espen
    et al.
    Julich Res Ctr, Inst Neurosci & Med INM 6, D-52425 Julich, Germany.;Julich Res Ctr, Inst Adv Simulat IAS 6, D-52425 Julich, Germany.;Julich Res Ctr, JARA BRAIN Inst 1, D-52425 Julich, Germany.;Norwegian Univ Life Sci, Dept Math Sci & Technol, N-1403 As, Norway..
    Dahmen, David
    Julich Res Ctr, Inst Neurosci & Med INM 6, D-52425 Julich, Germany.;Julich Res Ctr, Inst Adv Simulat IAS 6, D-52425 Julich, Germany.;Julich Res Ctr, JARA BRAIN Inst 1, D-52425 Julich, Germany..
    Stavrinou, Maria L.
    Norwegian Univ Life Sci, Dept Math Sci & Technol, N-1403 As, Norway.;Univ Oslo, Dept Psychol, N-0373 Oslo, Norway..
    Lindén, Henrik
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB. Univ Copenhagen, Dept Neurosci & Pharmacol, DK-2200 Copenhagen, Denmark.;Royal Inst Technol, Sch Comp Sci & Commun, Dept Computat Biol, S-10044 Stockholm, Sweden..
    Tetzlaff, Tom
    Julich Res Ctr, Inst Neurosci & Med INM 6, D-52425 Julich, Germany.;Julich Res Ctr, Inst Adv Simulat IAS 6, D-52425 Julich, Germany.;Julich Res Ctr, JARA BRAIN Inst 1, D-52425 Julich, Germany..
    van Albada, Sacha J.
    Julich Res Ctr, Inst Neurosci & Med INM 6, D-52425 Julich, Germany.;Julich Res Ctr, Inst Adv Simulat IAS 6, D-52425 Julich, Germany.;Julich Res Ctr, JARA BRAIN Inst 1, D-52425 Julich, Germany..
    Gruen, Sonja
    Julich Res Ctr, Inst Neurosci & Med INM 6, D-52425 Julich, Germany.;Julich Res Ctr, Inst Adv Simulat IAS 6, D-52425 Julich, Germany.;Julich Res Ctr, JARA BRAIN Inst 1, D-52425 Julich, Germany.;Rhein Westfal TH Aachen, Theoret Syst Neurobiol, D-52056 Aachen, Germany..
    Diesmann, Markus
    Julich Res Ctr, Inst Neurosci & Med INM 6, D-52425 Julich, Germany.;Julich Res Ctr, Inst Adv Simulat IAS 6, D-52425 Julich, Germany.;Julich Res Ctr, JARA BRAIN Inst 1, D-52425 Julich, Germany.;Rhein Westfal TH Aachen, Fac Med, Dept Psychiat Psychotherapy & Psychosomat, D-52074 Aachen, Germany.;Rhein Westfal TH Aachen, Fac 1, Dept Phys, D-52062 Aachen, Germany..
    Einevoll, Gaute T.
    Norwegian Univ Life Sci, Dept Math Sci & Technol, N-1403 As, Norway.;Univ Oslo, Dept Phys, N-0316 Oslo, Norway..
    Hybrid Scheme for Modeling Local Field Potentials from Point-Neuron Networks2016Ingår i: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 26, nr 12, s. 4461-4496Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    With rapidly advancing multi-electrode recording technology, the local field potential (LFP) has again become a popular measure of neuronal activity in both research and clinical applications. Proper understanding of the LFP requires detailed mathematical modeling incorporating the anatomical and electrophysiological features of neurons near the recording electrode, as well as synaptic inputs from the entire network. Here we propose a hybrid modeling scheme combining efficient point-neuron network models with biophysical principles underlying LFP generation by real neurons. The LFP predictions rely on populations of network-equivalent multicompartment neuron models with layer-specific synaptic connectivity, can be used with an arbitrary number of point-neuron network populations, and allows for a full separation of simulated network dynamics and LFPs. We apply the scheme to a full-scale cortical network model for a similar to 1 mm(2) patch of primary visual cortex, predict laminar LFPs for different network states, assess the relative LFP contribution from different laminar populations, and investigate effects of input correlations and neuron density on the LFP. The generic nature of the hybrid scheme and its public implementation in hybridLFPy form the basis for LFP predictions from other and larger point-neuron network models, as well as extensions of the current application with additional biological detail.

  • 149.
    Halnes, Geir
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Ulfhielm, Erik
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Modeling of the receptor, G-protein and effector reactions in vertebrate olfactory receptor neurons2008Konferensbidrag (Refereegranskat)
    Abstract [en]

    A biochemical model is developed for the receptor, G-protein and effector (RGE) steps of olfactory signal transduction in the cilia of the vertebrate olfactory receptor neurons (ORNs). It describes the steps from odorant binding to activation of the effector enzyme, which catalyzes the conversion of ATP to cAMP. In the cilia of the olfactory receptor neurons (ORNs), cAMP regulates cyclic nucleotide gated channels, which in turn control Ca influx and Ca dependent activation of chloride conductances. As a result the cilia potential becomes depolarized.

  • 150.
    Halnes, Geir
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Ulfhielm, Erik
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Ljunggren, Emma Eklöf
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Rospars, Jean-Pierre
    Modelling and sensitivity analysis of the reactions involving receptor, G-protein and effector in vertebrate olfactory receptor neurons2009Ingår i: Journal of Computational Neuroscience, ISSN 0929-5313, E-ISSN 1573-6873, Vol. 27, nr 3, s. 471-491Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A biochemical model of the receptor, G-protein and effector (RGE) interactions during transduction in the cilia of vertebrate olfactory receptor neurons (ORNs) was developed and calibrated to experimental recordings of cAMP levels and the receptor current (RC). The model describes the steps from odorant binding to activation of the effector enzyme which catalyzes the conversion of ATP to cAMP, and shows how odorant stimulation is amplified and delayed by the RGE transduction cascade. A time-dependent sensitivity analysis was performed on the model. The model output-the cAMP production rate-is particularly sensitive to a few, dominant parameters. During odorant stimulation it depends mainly on the initial density of G-proteins and the catalytic constant for cAMP production.

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