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1416 Publications

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    03/25/19 | The mucin-selective protease StcE enables molecular and functional analysis of human cancer-associated mucins
    Malaker SA, Pedram K, Ferracane MJ, Bensing BA, Krishnan V, Pett C, Yu J, Woods EC, Kramer JR, Westerlind U, Dorigo O, Bertozzi CR
    Proceedings of the National Academy of Sciences. Sep-04-2019;116(15):7278 - 7287. doi: 10.1073/pnas.1813020116

    Mucin domains are densely O-glycosylated modular protein domains that are found in a wide variety of cell surface and secreted proteins. Mucin-domain glycoproteins are known to be key players in a host of human diseases, especially cancer, wherein mucin expression and glycosylation patterns are altered. Mucin biology has been difficult to study at the molecular level, in part, because methods to manipulate and structurally characterize mucin domains are lacking. Here, we demonstrate that secreted protease of C1 esterase inhibitor (StcE), a bacterial protease from Escherichia coli, cleaves mucin domains by recognizing a discrete peptide- and glycan-based motif. We exploited StcE's unique properties to improve sequence coverage, glycosite mapping, and glycoform analysis of recombinant human mucins by mass spectrometry. We also found that StcE digests cancer-associated mucins from cultured cells and from ascites fluid derived from patients with ovarian cancer. Finally, using StcE, we discovered that sialic acid-binding Ig-type lectin-7 (Siglec-7), a glycoimmune checkpoint receptor, selectively binds sialomucins as biological ligands, whereas the related receptor Siglec-9 does not. Mucin-selective proteolysis, as exemplified by StcE, is therefore a powerful tool for the study of mucin domain structure and function.


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    03/19/19 | Innexin expression in electrically coupled motor circuits
    Adriane G. Otopalik , Brian Lane , David J. Schulz , Eve Marder
    Neuroscience Letters. 2019 Mar 16;695:19-24. doi:

    The many roles of innexins, the molecules that form gap junctions in invertebrates, have been explored in numerous species. Here, we present a summary of innexin expression and function in two small, central pattern generating circuits found in crustaceans: the stomatogastric ganglion and the cardiac ganglion. The two ganglia express multiple innexin genes, exhibit varying combinations of symmetrical and rectifying gap junctions, as well as gap junctions within and across different cell types. Past studies have revealed correlations in ion channel and innexin expression in coupled neurons, as well as intriguing functional relationships between ion channel conductances and electrical coupling. Together, these studies suggest a putative role for innexins in correlating activity between coupled neurons at the levels of gene expression and physiological activity during development and in the adult animal.

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    Studies of perceptual decision-making have often assumed that the main role of sensory cortices is to provide sensory input to downstream processes that accumulate and drive behavioral decisions. We performed a systematic comparison of neural activity in primary visual (V1) to secondary visual and retrosplenial cortices, as mice performed a task where they should accumulate pulsatile visual cues through time to inform a navigational decision. Even in V1, only a small fraction of neurons had sensory-like responses to cues. Instead, in all areas neurons were sequentially active, and contained information ranging from sensory to cognitive, including cue timings, evidence, place/time, decision and reward outcome. Per-cue sensory responses were amplitude-modulated by various cognitive quantities, notably accumulated evidence. This inspired a multiplicative feedback-loop circuit hypothesis that proposes a more intricate role of sensory areas in the accumulation process, and furthermore explains a surprising observation that perceptual discrimination deviates from Weber-Fechner Law.Highlights / eTOC BlurbMice made navigational decisions based on accumulating pulsatile visual cuesThe bulk of neural activity in visual cortices was sequential and beyond-sensoryAccumulated pulse-counts modulated sensory (cue) responses, suggesting feedbackA feedback-loop neural circuit explains behavioral deviations from Weber’s LawHighlights / eTOC BlurbIn a task where navigation was informed by accumulated pulsatile visual evidence, neural activity in visual cortices predominantly coded for cognitive variables across multiple timescales, including outside of a visual processing context. Even sensory responses to visual pulses were amplitude-modulated by accumulated pulse counts and other variables, inspiring a multiplicative feedback-loop circuit hypothesis that in turn explained behavioral deviations from Weber-Fechner Law.

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    02/07/19 | Deterministic Somatic Cell Reprogramming Involves Continuous Transcriptional Changes Governed by Myc and Epigenetic-Driven Modules.
    Zviran A, Mor N, Rais Y, Gingold H, Peles S, Chomsky E, Viukov S, Buenrostro JD, Scognamiglio R, Weinberger L, Manor YS, Krupalnik V, Zerbib M, Hezroni H, Jaitin DA, Larastiaso D, Gilad S, Benjamin S, Gafni O, Mousa A, Ayyash M, Sheban D, Bayerl J, Aguilera-Castrejon A, Massarwa R, Maza I, Hanna S, Stelzer Y, Ulitsky I, Greenleaf WJ, Tanay A, Trumpp A, Amit I, Pilpel Y, Novershtern N, Hanna JH
    Cell Stem Cell. 02/2019;24(2):328-341.e9. doi: 10.1016/j.stem.2018.11.014

    The epigenetic dynamics of induced pluripotent stem cell (iPSC) reprogramming in correctly reprogrammed cells at high resolution and throughout the entire process remain largely undefined. Here, we characterize conversion of mouse fibroblasts into iPSCs using Gatad2a-Mbd3/NuRD-depleted and highly efficient reprogramming systems. Unbiased high-resolution profiling of dynamic changes in levels of gene expression, chromatin engagement, DNA accessibility, and DNA methylation were obtained. We identified two distinct and synergistic transcriptional modules that dominate successful reprogramming, which are associated with cell identity and biosynthetic genes. The pluripotency module is governed by dynamic alterations in epigenetic modifications to promoters and binding by Oct4, Sox2, and Klf4, but not Myc. Early DNA demethylation at certain enhancers prospectively marks cells fated to reprogram. Myc activity drives expression of the essential biosynthetic module and is associated with optimized changes in tRNA codon usage. Our functional validations highlight interweaved epigenetic- and Myc-governed essential reconfigurations that rapidly commission and propel deterministic reprogramming toward naive pluripotency.

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    Darshan Lab
    02/01/19 | Neuronal activity and learning in local cortical networks are modulated by the action-perception state
    Ben Engelhard , Ran Darshan , Nofar Ozeri-Engelhard , Zvi Israel , Uri Werner-Reiss , David Hansel , Hagai Bergman , Eilon Vaadia
    bioRxiv. 2019 Feb 01:. doi: 10.1101/537613

    During sensorimotor learning, neuronal networks change to optimize the associations between action and perception. In this study, we examine how the brain harnesses neuronal patterns that correspond to the current action-perception state during learning. To this end, we recorded activity from motor cortex while monkeys either performed a familiar motor task (movement-state) or learned to control the firing rate of a target neuron using a brain-machine interface (BMI-state). Before learning, monkeys were placed in an observation-state, where no action was required. We found that neuronal patterns during the BMI-state were markedly different from the movement-state patterns. BMI-state patterns were initially similar to those in the observation-state and evolved to produce an increase in the firing rate of the target neuron. The overall activity of the non-target neurons remained similar after learning, suggesting that excitatory-inhibitory balance was maintained. Indeed, a novel neural-level reinforcement-learning network model operating in a chaotic regime of balanced excitation and inhibition predicts our results in detail. We conclude that during BMI learning, the brain can adapt patterns corresponding to the current action-perception state to gain rewards. Moreover, our results show that we can predict activity changes that occur during learning based on the pre-learning activity. This new finding may serve as a key step toward clinical brain-machine interface applications to modify impaired brain activity.

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    01/19/19 | Neuronal morphologies built for reliable physiology in a rhythmic motor circuit
    Otopalik AG, Pipkin J, Marder E, Slutsky I, Calabrese RL
    eLife. 2019 Jan 19;8:e41728. doi: 10.7554/eLife.41728

    It is often assumed that highly-branched neuronal structures perform compartmentalized computations. However, previously we showed that the Gastric Mill (GM) neuron in the crustacean stomatogastric ganglion (STG) operates like a single electrotonic compartment, despite having thousands of branch points and total cable length >10 mm (Otopalik et al., 2017a; 2017b). Here we show that compact electrotonic architecture is generalizable to other STG neuron types, and that these neurons present direction-insensitive, linear voltage integration, suggesting they pool synaptic inputs across their neuronal structures. We also show, using simulations of 720 cable models spanning a broad range of geometries and passive properties, that compact electrotonus, linear integration, and directional insensitivity in STG neurons arise from their neurite geometries (diameters tapering from 10-20 µm to \uline< 2 µm at their terminal tips). A broad parameter search reveals multiple morphological and biophysical solutions for achieving different degrees of passive electrotonic decrement and computational strategies in the absence of active properties.

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    01/17/19 | CaImAn an open source tool for scalable calcium imaging data analysis
    Giovannucci A, Friedrich J, Gunn P, Kalfon J, Brown BL, Koay SA, Taxidis J, Najafi F, Gauthier JL, Zhou P, Khakh BS, Tank DW, Chklovskii DB, Pnevmatikakis EA
    eLife. 01/2019;8:. doi: 10.7554/eLife.38173

    Advances in fluorescence microscopy enable monitoring larger brain areas in-vivo with finer time resolution. The resulting data rates require reproducible analysis pipelines that are reliable, fully automated, and scalable to datasets generated over the course of months. We present CaImAn, an open-source library for calcium imaging data analysis. CaImAn provides automatic and scalable methods to address problems common to pre-processing, including motion correction, neural activity identification, and registration across different sessions of data collection. It does this while requiring minimal user intervention, with good scalability on computers ranging from laptops to high-performance computing clusters. CaImAn is suitable for two-photon and one-photon imaging, and also enables real-time analysis on streaming data. To benchmark the performance of CaImAn we collected and combined a corpus of manual annotations from multiple labelers on nine mouse two-photon datasets. We demonstrate that CaImAn achieves near-human performance in detecting locations of active neurons

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    01/07/19 | Quantitative Super-Resolution Microscopy of the Mammalian Glycocalyx
    Möckl L, Pedram K, Roy AR, Krishnan V, Gustavsson A, Dorigo O, Bertozzi CR, Moerner W
    Developmental Cell. Jan-07-2019;50(1):57 - 72.e6. doi: 10.1016/j.devcel.2019.04.035

    The mammalian glycocalyx is a heavily glycosylated extramembrane compartment found on nearly every cell. Despite its relevance in both health and disease, studies of the glycocalyx remain hampered by a paucity of methods to spatially classify its components. We combine metabolic labeling, bioorthogonal chemistry, and super-resolution localization microscopy to image two constituents of cell-surface glycans, N-acetylgalactosamine (GalNAc) and sialic acid, with 10–20 nm precision in 2D and 3D. This approach enables two measurements: glycocalyx height and the distribution of individual sugars distal from the membrane. These measurements show that the glycocalyx exhibits nanoscale organization on both cell lines and primary human tumor cells. Additionally, we observe enhanced glycocalyx height in response to epithelial-to-mesenchymal transition and to oncogenic KRAS activation. In the latter case, we trace increased height to an effector gene, GALNT7. These data highlight the power of advanced imaging methods to provide molecular and functional insights into glycocalyx biology.

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    01/06/19 | Physical Principles of Membrane Shape Regulation by the Glycocalyx
    Shurer CR, Kuo JC, Roberts LM, Gandhi JG, Colville MJ, Enoki TA, Pan H, Su J, Noble JM, Hollander MJ, O’Donnell JP, Yin R, Pedram K, Möckl L, Kourkoutis LF, Moerner W, Bertozzi CR, Feigenson GW, Reesink HL, Paszek MJ
    Cell. Jan-06-2019;177(7):1757 - 1770.e21. doi: 10.1016/j.cell.2019.04.017

    Cells bend their plasma membranes into highly curved forms to interact with the local environment, but how shape generation is regulated is not fully resolved. Here, we report a synergy between shape-generating processes in the cell interior and the external organization and composition of the cell-surface glycocalyxMucin biopolymers and long-chain polysaccharides within the glycocalyx can generate entropic forces that favor or disfavor the projection of spherical and finger-like extensions from the cell surface. A polymer brush model of the glycocalyx successfully predicts the effects of polymer size and cell-surface density on membrane morphologies. Specific glycocalyx compositions can also induce plasma membrane instabilities to generate more exotic undulating and pearled membrane structures and drive secretion of extracellular vesicles. Together, our results suggest a fundamental role for the glycocalyx in regulating curved membrane features that serve in communication between cells and with the extracellular matrix.

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    01/01/19 | Neural Correlates of Cognition in Primary Visual versus Downstream Posterior Cortices During Evidence Accumulation
    Koay SA, Tank D, Brody C
    APS March Meeting Abstracts. 01/2019:

    The ability of animals to accumulate sensory information across time is fundamental to decision-making. Using a mouse behavioral paradigm where navigational decisions are based on accumulating pulses of visual cues, I compared neural activity in primary visual (V1) to secondary visual and retrosplenial cortices. Even in V1, only a small fraction of neurons had sensory-like responses to cues. Instead, all areas were grossly similar in how neural populations contained a large variety of task-related information from sensory to cognitive, including cue timings, accumulated counts, place/time, decision and reward outcome. Across-trial influences were prevalent, possibly relevant to how animal behavior incorporates past contexts. Intriguingly, all these variables also modulated the amplitudes of sensory responses. While previous work often modeled the accumulation process as integration, the observed scaling of sensory responses by accumulated counts instead suggests a recursive process where sensory responses are gradually amplified. I show that such a multiplicative feedback-loop algorithm better explains psychophysical data than integration, particularly in how the performance transitions into following Weber-Fechner's Law only at high counts.



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