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191 Publications

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    10/14/20 | The neuroanatomical ultrastructure and function of a biological ring attractor.
    Turner-Evans DB, Jensen KT, Ali S, Paterson T, Sheridan A, Ray RP, Wolff T, Lauritzen JS, Rubin GM, Bock DD, Jayaraman V
    Neuron. 2020 Oct 14;108(1):145-63. doi: 10.1016/j.neuron.2020.08.006

    Neural representations of head direction (HD) have been discovered in many species. Theoretical work has proposed that the dynamics associated with these representations are generated, maintained, and updated by recurrent network structures called ring attractors. We evaluated this theorized structure-function relationship by performing electron-microscopy-based circuit reconstruction and RNA profiling of identified cell types in the HD system of Drosophila melanogaster. We identified motifs that have been hypothesized to maintain the HD representation in darkness, update it when the animal turns, and tether it to visual cues. Functional studies provided support for the proposed roles of individual excitatory or inhibitory circuit elements in shaping activity. We also discovered recurrent connections between neuronal arbors with mixed pre- and postsynaptic specializations. Our results confirm that the Drosophila HD network contains the core components of a ring attractor while also revealing unpredicted structural features that might enhance the network's computational power.

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    08/01/20 | Sensing cellular biochemistry with fluorescent chemical–genetic hybrids
    Gautier A, Tebo AG
    Current Opinion in Chemical Biology. 08/2020;57:58–64. doi: 10.1016/j.cbpa.2020.04.005

    Fluorescent biosensors are powerful tools for the detection of biochemical events inside cells with high spatiotemporal resolution. Biosensors based on fluorescent proteins often suffer from issues with photostability and brightness. On the other hand, hybrid, chemical–genetic systems present unique opportunities to combine the strengths of synthetic, organic chemistry with biological macromolecules to generate exquisitely tailored semisynthetic sensors.

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    10/06/20 | Simultaneous computation of dynamical and equilibrium information using a weighted ensemble of trajectories
    Suarez E, Lettieri S, Stringer CA, Zwier MC, Subramanian SR, Chong LT, Zuckerman DM
    Journal of chemical theory and computation;10:2658–2667
    10/06/20 | Simultaneous computation of dynamical and equilibrium information using a weighted ensemble of trajectories
    Suarez E, Lettieri S, Stringer CA, Zwier MC, Subramanian SR, Chong LT, Zuckerman DM
    Journal of chemical theory and computation;10:2658–2667
    10/06/20 | Simultaneous computation of dynamical and equilibrium information using a weighted ensemble of trajectories
    Suarez E, Lettieri S, Stringer CA, Zwier MC, Subramanian SR, Chong LT, Zuckerman DM
    Journal of chemical theory and computation;10:2658–2667
    10/06/20 | The mTORC1/S6K/PDCD4/eIF4A axis determines outcome of mitotic arrest.
    Moustafa-Kamal M, Kucharski TJ, El-Assaad W, Abbas YM, Gandin V, Nagar B, Pelletier J, Topisirovic I, Teodoro JG
    Cell Reports. 2020 Oct 06;33(1):108230. doi: 10.1016/j.celrep.2020.108230

    mTOR is a serine/threonine kinase and a master regulator of cell growth and proliferation. Raptor, a scaffolding protein that recruits substrates to mTOR complex 1 (mTORC1), is known to be phosphorylated during mitosis, but the significance of this phosphorylation remains largely unknown. Here we show that raptor expression and mTORC1 activity are dramatically reduced in cells arrested in mitosis. Expression of a non-phosphorylatable raptor mutant reactivates mTORC1 and significantly reduces cytotoxicity of the mitotic poison Taxol. This effect is mediated via degradation of PDCD4, a tumor suppressor protein that inhibits eIF4A activity and is negatively regulated by the mTORC1/S6K pathway. Moreover, pharmacological inhibition of eIF4A is able to enhance the effects of Taxol and restore sensitivity in Taxol-resistant cancer cells. These findings indicate that the mTORC1/S6K/PDCD4/eIF4A axis has a pivotal role in the death versus slippage decision during mitotic arrest and may be exploited clinically to treat tumors resistant to anti-mitotic agents.

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    10/06/20 | Nuclear crowding and nonlinear diffusion during interkinetic nuclear migration in the zebrafish retina.
    Azizi A, Herrmann A, Wan Y, Buse SJ, Keller PJ, Goldstein RE, Harris WA
    eLife. 2020 Oct 06;9:. doi: 10.7554/eLife.58635

    An important question in early neural development is the origin of stochastic nuclear movement between apical and basal surfaces of neuroepithelia during interkinetic nuclear migration. Tracking of nuclear subpopulations has shown evidence of diffusion - mean squared displacements growing linearly in time - and suggested crowding from cell division at the apical surface drives basalward motion. Yet, this hypothesis has not yet been tested, and the forces involved not quantified. We employ long-term, rapid light-sheet and two-photon imaging of early zebrafish retinogenesis to track entire populations of nuclei within the tissue. The time-varying concentration profiles show clear evidence of crowding as nuclei reach close-packing and are quantitatively described by a nonlinear diffusion model. Considerations of nuclear motion constrained inside the enveloping cell membrane show that concentration-dependent stochastic forces inside cells, compatible in magnitude to those found in cytoskeletal transport, can explain the observed magnitude of the diffusion constant.

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    10/05/20 | Circuit and behavioral mechanisms of sexual rejection by drosophila females.
    Wang F, Wang K, Forknall N, Parekh R, Dickson BJ
    Current Biology. 2020 Oct 05;30(19):. doi: 10.1016/j.cub.2020.07.083

    The mating decisions of Drosophila melanogaster females are primarily revealed through either of two discrete actions: opening of the vaginal plates to allow copulation, or extrusion of the ovipositor to reject the male. Both actions are triggered by the male courtship song, and both are dependent upon the female's mating status. Virgin females are more likely to open their vaginal plates in response to song; mated females are more likely to extrude their ovipositor. Here, we examine the neural cause and behavioral consequence of ovipositor extrusion. We show that the DNp13 descending neurons act as command-type neurons for ovipositor extrusion, and that ovipositor extrusion is an effective deterrent only when performed by females that have previously mated. The DNp13 neurons respond to male song via direct synaptic input from the pC2l auditory neurons. Mating status does not modulate the song responses of DNp13 neurons, but rather how effectively they can engage the motor circuits for ovipositor extrusion. We present evidence that mating status information is mediated by ppk sensory neurons in the uterus, which are activated upon ovulation. Vaginal plate opening and ovipositor extrusion are thus controlled by anatomically and functionally distinct circuits, highlighting the diversity of neural decision-making circuits even in the context of closely related behaviors with shared exteroceptive and interoceptive inputs.

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    10/01/20 | A genetically defined compartmentalized striatal direct pathway for negative reinforcement.
    Xiao X, Deng H, Furlan A, Yang T, Zhang X, Hwang G, Tucciarone J, Wu P, He M, Palaniswamy R, Ramakrishnan C, Ritola K, Hantman A, Deisseroth K, Osten P, Huang ZJ, Li B
    Cell. 2020 Oct 1;181(1):211. doi: 10.1016/j.cell.2020.08.032

    The striosome compartment within the dorsal striatum has been implicated in reinforcement learning and regulation of motivation, but how striosomal neurons contribute to these functions remains elusive. Here, we show that a genetically identified striosomal population, which expresses the Teashirt family zinc finger 1 (Tshz1) and belongs to the direct pathway, drives negative reinforcement and is essential for aversive learning in mice. Contrasting a "conventional" striosomal direct pathway, the Tshz1 neurons cause aversion, movement suppression, and negative reinforcement once activated, and they receive a distinct set of synaptic inputs. These neurons are predominantly excited by punishment rather than reward and represent the anticipation of punishment or the motivation for avoidance. Furthermore, inhibiting these neurons impairs punishment-based learning without affecting reward learning or movement. These results establish a major role of striosomal neurons in behaviors reinforced by punishment and moreover uncover functions of the direct pathway unaccounted for in classic models.

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    09/30/20 | Structural insight into the ATP-driven exporter of virulent peptide toxins.
    Zeytuni N, Dickey SW, Hu J, Chou HT, Worrall LJ, Alexander JA, Carlson ML, Nosella M, Duong F, Yu Z, Otto M, Strynadka NC
    Science Advances. 2020 Sep 30;6(40):. doi: 10.1126/sciadv.abb8219

    is a major human pathogen that has acquired alarming broad-spectrum antibiotic resistance. One group of secreted toxins with key roles during infection is the phenol-soluble modulins (PSMs). PSMs are amphipathic, membrane-destructive cytolytic peptides that are exported to the host-cell environment by a designated adenosine 5'-triphosphate (ATP)-binding cassette (ABC) transporter, the PSM transporter (PmtABCD). Here, we demonstrate that the minimal Pmt unit necessary for PSM export is PmtCD and provide its first atomic characterization by single-particle cryo-EM and x-ray crystallography. We have captured the transporter in the ATP-bound state at near atomic resolution, revealing a type II ABC exporter fold, with an additional cytosolic domain. Comparison to a lower-resolution nucleotide-free map displaying an "open" conformation and putative hydrophobic inner chamber of a size able to accommodate the binding of two PSM peptides provides mechanistic insight and sets the foundation for therapeutic design.

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