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157 Publications

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    Svoboda Lab
    09/01/09 | Experience-dependent structural synaptic plasticity in the mammalian brain.
    Holtmaat A, Svoboda K
    Nature Reviews Neuroscience. 2009 Sep;10(9):647-58. doi: 10.1038/nrn2699

    Synaptic plasticity in adult neural circuits may involve the strengthening or weakening of existing synapses as well as structural plasticity, including synapse formation and elimination. Indeed, long-term in vivo imaging studies are beginning to reveal the structural dynamics of neocortical neurons in the normal and injured adult brain. Although the overall cell-specific morphology of axons and dendrites, as well as of a subpopulation of small synaptic structures, are remarkably stable, there is increasing evidence that experience-dependent plasticity of specific circuits in the somatosensory and visual cortex involves cell type-specific structural plasticity: some boutons and dendritic spines appear and disappear, accompanied by synapse formation and elimination, respectively. This Review focuses on recent evidence for such structural forms of synaptic plasticity in the mammalian cortex and outlines open questions.

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    09/01/09 | Flight dynamics and control of evasive maneuvers: the fruit fly’s takeoff.
    Zabala FA, Card GM, Fontaine EI, Dickinson MH, Murray RM
    IEEE Transactions on Bio-Medical Engineering. 2009 Sep;56(9):2295-8. doi: 10.1109/TBME.2009.2027606

    We have approached the problem of reverse-engineering the flight control mechanism of the fruit fly by studying the dynamics of the responses to a visual stimulus during takeoff. Building upon a prior framework [G. Card and M. Dickinson, J. Exp. Biol., vol. 211, pp. 341-353, 2008], we seek to understand the strategies employed by the animal to stabilize attitude and orientation during these evasive, highly dynamical maneuvers. As a first step, we consider the dynamics from a gray-box perspective: examining lumped forces produced by the insect’s legs and wings. The reconstruction of the flight initiation dynamics, based on the unconstrained motion formulation for a rigid body, allows us to assess the fly’s responses to a variety of initial conditions induced by its jump. Such assessment permits refinement by using a visual tracking algorithm to extract the kinematic envelope of the wings [E. I. Fontaine, F. Zabala, M. Dickinson, and J. Burdick, "Wing and body motion during flight initiation in Drosophila revealed by automated visual tracking," submitted for publication] in order to estimate lift and drag forces [F. Zabala, M. Dickinson, and R. Murray, "Control and stability of insect flight during highly dynamical maneuvers," submitted for publication], and recording actual leg-joint kinematics and using them to estimate jump forces [F. Zabala, "A bio-inspired model for directionality control of flight initiation," to be published.]. In this paper, we present the details of our approach in a comprehensive manner, including the salient results.

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    09/01/09 | Genetic aspects of behavioral neurotoxicology.
    Levin ED, Aschner M, Heberlein U, Ruden D, Welsh-Bohmer KA, Bartlett S, Berger K, Chen L, Corl AB, Eddins D, French R, Hayden KM, Helmcke K, Hirsch HV, Linney E, Lnenicka G, Page GP, Possidente D, Possidente B, Kirshner A
    Neurotoxicology. 2009 Sep;30(5):741-53. doi: 10.1016/j.neuro.2009.07.014

    Considerable progress has been made over the past couple of decades concerning the molecular bases of neurobehavioral function and dysfunction. The field of neurobehavioral genetics is becoming mature. Genetic factors contributing to neurologic diseases such as Alzheimer's disease have been found and evidence for genetic factors contributing to other diseases such as schizophrenia and autism are likely. This genetic approach can also benefit the field of behavioral neurotoxicology. It is clear that there is substantial heterogeneity of response with behavioral impairments resulting from neurotoxicants. Many factors contribute to differential sensitivity, but it is likely that genetic variability plays a prominent role. Important discoveries concerning genetics and behavioral neurotoxicity are being made on a broad front from work with invertebrate and piscine mutant models to classic mouse knockout models and human epidemiologic studies of polymorphisms. Discovering genetic factors of susceptibility to neurobehavioral toxicity not only helps identify those at special risk, it also advances our understanding of the mechanisms by which toxicants impair neurobehavioral function in the larger population. This symposium organized by Edward Levin and Annette Kirshner, brought together researchers from the laboratories of Michael Aschner, Douglas Ruden, Ulrike Heberlein, Edward Levin and Kathleen Welsh-Bohmer conducting studies with Caenorhabditis elegans, Drosophila, fish, rodents and humans studies to determine the role of genetic factors in susceptibility to behavioral impairment from neurotoxic exposure.

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    Fetter Lab
    09/01/09 | Negative regulation of active zone assembly by a newly identified SR protein kinase.
    Johnson EL, Fetter RD, Davis GW
    PLoS Biology. 2009 Sep;7(9):e1000193. doi: 10.1371/journal.pbio.1000193

    Presynaptic, electron-dense, cytoplasmic protrusions such as the T-bar (Drosophila) or ribbon (vertebrates) are believed to facilitate vesicle movement to the active zone (AZ) of synapses throughout the nervous system. The molecular composition of these structures including the T-bar and ribbon are largely unknown, as are the mechanisms that specify their synapse-specific assembly and distribution. In a large-scale, forward genetic screen, we have identified a mutation termed air traffic controller (atc) that causes T-bar-like protein aggregates to form abnormally in motoneuron axons. This mutation disrupts a gene that encodes for a serine-arginine protein kinase (SRPK79D). This mutant phenotype is specific to SRPK79D and is not secondary to impaired kinesin-dependent axonal transport. The srpk79D gene is neuronally expressed, and transgenic rescue experiments are consistent with SRPK79D kinase activity being necessary in neurons. The SRPK79D protein colocalizes with the T-bar-associated protein Bruchpilot (Brp) in both the axon and synapse. We propose that SRPK79D is a novel T-bar-associated protein kinase that represses T-bar assembly in peripheral axons, and that SRPK79D-dependent repression must be relieved to facilitate site-specific AZ assembly. Consistent with this model, overexpression of SRPK79D disrupts AZ-specific Brp organization and significantly impairs presynaptic neurotransmitter release. These data identify a novel AZ-associated protein kinase and reveal a new mechanism of negative regulation involved in AZ assembly. This mechanism could contribute to the speed and specificity with which AZs are assembled throughout the nervous system.

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    Kainmueller Lab
    08/28/09 | Comparison and evaluation of methods for liver segmentation from CT datasets.
    Heimann T, van Ginneken B, Styner MA, Arzhaeva Y, Aurich V, Bauer C, Beck A, Becker C, Beichel R, Bekes G, Bello F, Binnig G, Bischof H, Bornik A, Cashman PM, Chi Y, Cordova A, Dawant BM, Fidrich M, Furst JD, Furukawa D, Grenacher L, Hornegger J, Kainmüller D, Kitney RI, Kobatake H, Lamecker H, Lange T, Lee J, Lennon B, Li R, Li S, Meinzer H, Nemeth G, Raicu DS, Rau A, van Rikxoort EM, Rousson M, Rusko L, Saddi KA, Schmidt G, Seghers D, Shimizu A, Slagmolen P, Sorantin E, Soza G, Susomboon R, Waite JM, Wimmer A, Wolf I
    IEEE transactions on medical imaging. 2009 Aug;28(8):1251-65. doi: 10.1109/TMI.2009.2013851

    This paper presents a comparison study between 10 automatic and six interactive methods for liver segmentation from contrast-enhanced CT images. It is based on results from the "MICCAI 2007 Grand Challenge" workshop, where 16 teams evaluated their algorithms on a common database. A collection of 20 clinical images with reference segmentations was provided to train and tune algorithms in advance. Participants were also allowed to use additional proprietary training data for that purpose. All teams then had to apply their methods to 10 test datasets and submit the obtained results. Employed algorithms include statistical shape models, atlas registration, level-sets, graph-cuts and rule-based systems. All results were compared to reference segmentations five error measures that highlight different aspects of segmentation accuracy. All measures were combined according to a specific scoring system relating the obtained values to human expert variability. In general, interactive methods reached higher average scores than automatic approaches and featured a better consistency of segmentation quality. However, the best automatic methods (mainly based on statistical shape models with some additional free deformation) could compete well on the majority of test images. The study provides an insight in performance of different segmentation approaches under real-world conditions and highlights achievements and limitations of current image analysis techniques.

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    08/25/09 | Olfactory information processing in Drosophila.
    Masse NY, Turner GC, Jeffers GS
    Current Biology : CB. 2009 Aug 25;19(16):R700-13. doi: 10.1016/j.cub.2009.06.026

    In both insect and vertebrate olfactory systems only two synapses separate the sensory periphery from brain areas required for memory formation and the organisation of behaviour. In the Drosophila olfactory system, which is anatomically very similar to its vertebrate counterpart, there has been substantial recent progress in understanding the flow of information from experiments using molecular genetic, electrophysiological and optical imaging techniques. In this review, we shall focus on how olfactory information is processed and transformed in order to extract behaviourally relevant information. We follow the progress from olfactory receptor neurons, through the first processing area, the antennal lobe, to higher olfactory centres. We address both the underlying anatomy and mechanisms that govern the transformation of neural activity. We emphasise our emerging understanding of how different elementary computations, including signal averaging, gain control, decorrelation and integration, may be mapped onto different circuit elements.

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    08/21/09 | A divergent approach to the synthesis of 3-substituted-2-pyrazolines: Suzuki cross-coupling of 3-sulfonyloxy-2-pyrazolines.
    Grimm JB, Wilson KJ, Witter DJ
    The Journal of Organic Chemistry. 2009 Aug 21;74(16):6390-3. doi: 10.1021/jo9011859

    The efficient Suzuki cross-coupling of pyrazoline nonaflates with organoboron reagents was achieved to afford diverse 3-substituted-2-pyrazolines in excellent yield. The nonaflates displayed improved reactivity over the corresponding triflates and smoothly coupled to a variety of aryl- and heteroarylboronic acids. This process and its broad scope constitute a rapid, divergent strategy for the synthesis of elaborated 2-pyrazolines that are not readily obtained via conventional methods.

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    Pavlopoulos Lab
    08/18/09 | Knockdown of parhyale ultrabithorax recapitulates evolutionary changes in crustacean appendage morphology.
    Liubicich DM, Serano JM, Pavlopoulos A, Kontarakis Z, Protas ME, Kwan E, Chatterjee S, Tran KD, Averof M, Patel NH
    Proceedings of the National Academy of Sciences of the United States of America. 2009 Aug 18;106:13892-6. doi: 10.1073/pnas.0903105106

    Crustaceans possess remarkably diverse appendages, both between segments of a single individual as well as between species. Previous studies in a wide range of crustaceans have demonstrated a correlation between the anterior expression boundary of the homeotic (Hox) gene Ultrabithorax (Ubx) and the location and number of specialized thoracic feeding appendages, called maxillipeds. Given that Hox genes regulate regional identity in organisms as diverse as mice and flies, these observations in crustaceans led to the hypothesis that Ubx expression regulates the number of maxillipeds and that evolutionary changes in Ubx expression have generated various aspects of crustacean appendage diversity. Specifically, evolutionary changes in the expression boundary of Ubx have resulted in crustacean species with either 0, 1, 2, or 3 pairs of thoracic maxillipeds. Here we test this hypothesis by altering the expression of Ubx in Parhyale hawaiensis, a crustacean that normally possesses a single pair of maxillipeds. By reducing Ubx expression, we can generate Parhyale with additional maxillipeds in a pattern reminiscent of that seen in other crustacean species, and these morphological alterations are maintained as the animals molt and mature. These results provide critical evidence supporting the proposition that changes in Ubx expression have played a role in generating crustacean appendage diversity and lend general insights into the mechanisms of morphological evolution.

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    Pavlopoulos Lab
    08/18/09 | Probing the evolution of appendage specialization by Hox gene misexpression in an emerging model crustacean.
    Pavlopoulos A, Kontarakis Z, Liubicich DM, Serano JM, Akam M, Patel NH, Averof M
    Proceedings of the National Academy of Sciences of the United States of America. 2009 Aug 18;106(33):13897-902. doi: 10.1073/pnas.0902804106

    Changes in the expression of Hox genes have been widely linked to the evolution of animal body plans, but functional demonstrations of this relationship have been impeded by the lack of suitable model organisms. A classic case study involves the repeated evolution of specialized feeding appendages, called maxillipeds, from anterior thoracic legs, in many crustacean lineages. These leg-to-maxilliped transformations correlate with the loss of Ultrabithorax (Ubx) expression from corresponding segments, which is proposed to be the underlying genetic cause. To functionally test this hypothesis, we establish tools for conditional misexpression and use these to misexpress Ubx in the crustacean Parhyale hawaiensis. Ectopic Ubx leads to homeotic transformations of anterior appendages toward more posterior thoracic fates, including maxilliped-to-leg transformations, confirming the capacity of Ubx to control thoracic (leg) versus gnathal (feeding) segmental identities. We find that maxillipeds not only are specified in the absence of Ubx, but also can develop in the presence of low/transient Ubx expression. Our findings suggest a path for the gradual evolutionary transition from thoracic legs to maxillipeds, in which stepwise changes in Hox gene expression have brought about this striking morphological and functional transformation.

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    08/15/09 | Correlated mutation analyses on super-family alignments reveal functionally important residues.
    Kuipers RK, Joosten H, Verwiel E, Paans S, Akerboom J, van der Oost J, Leferink NG, van Berkel WJ, Vriend G, Schaap PJ
    Proteins. 2009 Aug 15;76(3):608-16. doi: 10.1002/prot.22374

    Correlated mutation analyses (CMA) on multiple sequence alignments are widely used for the prediction of the function of amino acids. The accuracy of CMA-based predictions is mainly determined by the number of sequences, by their evolutionary distances, and by the quality of the alignments. These criteria are best met in structure-based sequence alignments of large super-families. So far, CMA-techniques have mainly been employed to study the receptor interactions. The present work shows how a novel CMA tool, called Comulator, can be used to determine networks of functionally related residues in enzymes. These analyses provide leads for protein engineering studies that are directed towards modification of enzyme specificity or activity. As proof of concept, Comulator has been applied to four enzyme super-families: the isocitrate lyase/phoshoenol-pyruvate mutase super-family, the hexokinase super-family, the RmlC-like cupin super-family, and the FAD-linked oxidases super-family. In each of those cases networks of functionally related residue positions were discovered that upon mutation influenced enzyme specificity and/or activity as predicted. We conclude that CMA is a powerful tool for redesigning enzyme activity and selectivity.

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