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Type VI secretion system baseplate.

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Type VI secretion system baseplate.

Nat Microbiol. 2018 Dec;3(12):1330-1331

Authors: Davidson AR, Maxwell KL

Abstract

PMID: 30478386 [PubMed - in process]



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Dual embryonic origin of the mammalian enteric nervous system.

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Dual embryonic origin of the mammalian enteric nervous system.

Dev Biol. 2018 Nov 22;:

Authors: Brokhman I, Xu J, Coles BLK, Razavi R, Engert S, Lickert H, Babona-Pilipos R, Morshead CM, Sibley E, Chen C, van der Kooy D

Abstract
The enteric nervous system is thought to originate solely from the neural crest. Transgenic lineage tracing revealed a novel population of clonal pancreatic duodenal homeobox-1 (Pdx1)-Cre lineage progenitor cells in the tunica muscularis of the gut that produced pancreatic descendants as well as neurons upon differentiation in vitro. Additionally, an in vivo subpopulation of endoderm lineage enteric neurons, but not glial cells, was seen especially in the proximal gut. Analysis of early transgenic embryos revealed Pdx1-Cre progeny (as well as Sox-17-Cre and Foxa2-Cre progeny) migrating from the developing pancreas and duodenum at E11.5 and contributing to the enteric nervous system. These results show that the mammalian enteric nervous system arises from both the neural crest and the endoderm. Moreover, in adult mice there are separate Wnt1-Cre neural crest stem cells and Pdx1-Cre pancreatic progenitors within the muscle layer of the gut.

PMID: 30472119 [PubMed - as supplied by publisher]



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Human Oligodendrogenic Neural Progenitor Cells Delivered with Chondroitinase ABC Facilitate Functional Repair of Chronic Spinal Cord Injury.

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Human Oligodendrogenic Neural Progenitor Cells Delivered with Chondroitinase ABC Facilitate Functional Repair of Chronic Spinal Cord Injury.

Stem Cell Reports. 2018 Nov 09;:

Authors: Nori S, Khazaei M, Ahuja CS, Yokota K, Ahlfors JE, Liu Y, Wang J, Shibata S, Chio J, Hettiaratchi MH, Führmann T, Shoichet MS, Fehlings MG

Abstract
Treatment of chronic spinal cord injury (SCI) is challenging due to cell loss, cyst formation, and the glial scar. Previously, we reported on the therapeutic potential of a neural progenitor cell (NPC) and chondroitinase ABC (ChABC) combinatorial therapy for chronic SCI. However, the source of NPCs and delivery system required for ChABC remained barriers to clinical application. Here, we investigated directly reprogrammed human NPCs biased toward an oligodendrogenic fate (oNPCs) in combination with sustained delivery of ChABC using an innovative affinity release strategy in a crosslinked methylcellulose biomaterial for the treatment of chronic SCI in an immunodeficient rat model. This combinatorial therapy increased long-term survival of oNPCs around the lesion epicenter, facilitated greater oligodendrocyte differentiation, remyelination of the spared axons by engrafted oNPCs, enhanced synaptic connectivity with anterior horn cells and neurobehavioral recovery. This combinatorial therapy is a promising strategy to regenerate the chronically injured spinal cord.

PMID: 30472009 [PubMed - as supplied by publisher]



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Allosteric Modulation of Binding Specificity by Alternative Packing of Protein Cores.

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Allosteric Modulation of Binding Specificity by Alternative Packing of Protein Cores.

J Mol Biol. 2018 Nov 21;:

Authors: Ben-David M, Huang H, Sun MGF, Corbi-Verge C, Petsalaki E, Liu K, Gfeller D, Garg P, Tempel W, Sochirca I, Shifman JM, Davidson A, Min J, Kim PM, Sidhu SS

Abstract
Hydrophobic cores are often viewed as tightly packed and rigid, but they do show some plasticity and could thus be attractive targets for protein design. Here we explored the role of different functional pressures on the core packing and ligand recognition of the SH3 domain from human Fyn tyrosine kinase. We randomized the hydrophobic core and used phage display to select variants that bound to each of three distinct ligands. The three evolved groups showed remarkable differences in core composition, illustrating the effect of different selective pressures on the core. Changes in the core did not significantly alter protein stability, but were linked closely to changes in binding affinity and specificity. Structural analysis and molecular dynamics simulations revealed the structural basis for altered specificity. The evolved domains had significantly reduced core volumes, which in turn induced increased backbone flexibility. These motions were propagated from the core to the binding surface and induced significant conformational changes. These results show that alternative core packing and consequent allosteric modulation of binding interfaces could be used to engineer proteins with novel functions.

PMID: 30471255 [PubMed - as supplied by publisher]



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Initial cell maturity changes following transplantation in a hyaluronan-based hydrogel and impacts therapeutic success in the stroke-injured rodent brain.

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Initial cell maturity changes following transplantation in a hyaluronan-based hydrogel and impacts therapeutic success in the stroke-injured rodent brain.

Biomaterials. 2018 Nov 15;192:309-322

Authors: Payne SL, Tuladhar A, Obermeyer JM, Varga BV, Teal CJ, Morshead CM, Nagy A, Shoichet MS

Abstract
Ischemic stroke results in a loss of neurons for which there are no available clinical strategies to stimulate regeneration. While preclinical studies have demonstrated that functional recovery can be obtained by transplanting an exogenous source of neural progenitors into the brain, it remains unknown at which stage of neuronal maturity cells will provide the most benefit. We investigated the role of neuronal maturity on cell survival, differentiation, and long-term sensorimotor recovery in stroke-injured rats using a population of human cortically-specified neuroepithelial progenitor cells (cNEPs) delivered in a biocompatible, bioresorbable hyaluronan/methylcellulose hydrogel. We demonstrate that transplantation of immature cNEPs result in the greatest tissue and functional repair, relative to transplantation of more mature neurons. The transplantation process itself resulted in the least cell death and phenotypic changes in the immature cNEPs, and the greatest acute cell death in the mature cells. The latter negatively impacted host tissue and negated any potential positive effects associated with cell maturity and the hydrogel vehicle, which itself showed some functional and tissue benefit. Moreover, we show that more mature cell populations are drastically altered during the transplantation process itself. The phenotype of the cells before and after transplantation had an enormous impact on their survival and the consequent tissue and behavioral response, emphasizing the importance of characterizing injected cells in transplantation studies more broadly.

PMID: 30468998 [PubMed - as supplied by publisher]



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Protocadherin-1 is essential for cell entry by New World hantaviruses.

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Protocadherin-1 is essential for cell entry by New World hantaviruses.

Nature. 2018 Nov;563(7732):559-563

Authors: Jangra RK, Herbert AS, Li R, Jae LT, Kleinfelter LM, Slough MM, Barker SL, Guardado-Calvo P, Román-Sosa G, Dieterle ME, Kuehne AI, Muena NA, Wirchnianski AS, Nyakatura EK, Fels JM, Ng M, Mittler E, Pan J, Bharrhan S, Wec AZ, Lai JR, Sidhu SS, Tischler ND, Rey FA, Moffat J, Brummelkamp TR, Wang Z, Dye JM, Chandran K

Abstract
The zoonotic transmission of hantaviruses from their rodent hosts to humans in North and South America is associated with a severe and frequently fatal respiratory disease, hantavirus pulmonary syndrome (HPS)1,2. No specific antiviral treatments for HPS are available, and no molecular determinants of in vivo susceptibility to hantavirus infection and HPS are known. Here we identify the human asthma-associated gene protocadherin-1 (PCDH1)3-6 as an essential determinant of entry and infection in pulmonary endothelial cells by two hantaviruses that cause HPS, Andes virus (ANDV) and Sin Nombre virus (SNV). In vitro, we show that the surface glycoproteins of ANDV and SNV directly recognize the outermost extracellular repeat domain of PCDH1-a member of the cadherin superfamily7,8-to exploit PCDH1 for entry. In vivo, genetic ablation of PCDH1 renders Syrian golden hamsters highly resistant to a usually lethal ANDV challenge. Targeting PCDH1 could provide strategies to reduce infection and disease caused by New World hantaviruses.

PMID: 30464266 [PubMed - in process]



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Direct interaction between the PRDM3 and PRDM16 tumor suppressors and the NuRD chromatin remodeling complex.

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Direct interaction between the PRDM3 and PRDM16 tumor suppressors and the NuRD chromatin remodeling complex.

Nucleic Acids Res. 2018 Nov 20;:

Authors: Ivanochko D, Halabelian L, Henderson E, Savitsky P, Jain H, Marcon E, Duan S, Hutchinson A, Seitova A, Barsyte-Lovejoy D, Filippakopoulos P, Greenblatt J, Lima-Fernandes E, Arrowsmith CH

Abstract
Aberrant isoform expression of chromatin-associated proteins can induce epigenetic programs related to disease. The MDS1 and EVI1 complex locus (MECOM) encodes PRDM3, a protein with an N-terminal PR-SET domain, as well as a shorter isoform, EVI1, lacking the N-terminus containing the PR-SET domain (ΔPR). Imbalanced expression of MECOM isoforms is observed in multiple malignancies, implicating EVI1 as an oncogene, while PRDM3 has been suggested to function as a tumor suppressor through an unknown mechanism. To elucidate functional characteristics of these N-terminal residues, we compared the protein interactomes of the full-length and ΔPR isoforms of PRDM3 and its closely related paralog, PRDM16. Unlike the ΔPR isoforms, both full-length isoforms exhibited a significantly enriched association with components of the NuRD chromatin remodeling complex, especially RBBP4. Typically, RBBP4 facilitates chromatin association of the NuRD complex by binding to histone H3 tails. We show that RBBP4 binds to the N-terminal amino acid residues of PRDM3 and PRDM16, with a dissociation constant of 3.0 μM, as measured by isothermal titration calorimetry. Furthermore, high-resolution X-ray crystal structures of PRDM3 and PRDM16 N-terminal peptides in complex with RBBP4 revealed binding to RBBP4 within the conserved histone H3-binding groove. These data support a mechanism of isoform-specific interaction of PRDM3 and PRDM16 with the NuRD chromatin remodeling complex.

PMID: 30462309 [PubMed - as supplied by publisher]



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A PxL motif promotes timely cell cycle substrate dephosphorylation by the Cdc14 phosphatase.

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A PxL motif promotes timely cell cycle substrate dephosphorylation by the Cdc14 phosphatase.

Nat Struct Mol Biol. 2018 Nov 19;:

Authors: Kataria M, Mouilleron S, Seo MH, Corbi-Verge C, Kim PM, Uhlmann F

Abstract
The cell division cycle consists of a series of temporally ordered events. Cell cycle kinases and phosphatases provide key regulatory input, but how the correct substrate phosphorylation and dephosphorylation timing is achieved is incompletely understood. Here we identify a PxL substrate recognition motif that instructs dephosphorylation by the budding yeast Cdc14 phosphatase during mitotic exit. The PxL motif was prevalent in Cdc14-binding peptides enriched in a phage display screen of native disordered protein regions. PxL motif removal from the Cdc14 substrate Cbk1 delays its dephosphorylation, whereas addition of the motif advances dephosphorylation of otherwise late Cdc14 substrates. Crystal structures of Cdc14 bound to three PxL motif substrate peptides provide a molecular explanation for PxL motif recognition on the phosphatase surface. Our results illustrate the sophistication of phosphatase-substrate interactions and identify them as an important determinant of ordered cell cycle progression.

PMID: 30455435 [PubMed - as supplied by publisher]



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Induction of rod versus cone photoreceptor-specific progenitors from retinal precursor cells.

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Induction of rod versus cone photoreceptor-specific progenitors from retinal precursor cells.

Stem Cell Res. 2018 Nov 13;33:215-227

Authors: Khalili S, Ballios BG, Belair-Hickey J, Donaldson L, Liu J, Coles BLK, Grisé KN, Baakdhah T, Bader GD, Wallace VA, Bernier G, Shoichet MS, van der Kooy D

Abstract
During development, multipotent progenitors undergo temporally-restricted differentiation into post-mitotic retinal cells; however, the mechanisms of progenitor division that occurs during retinogenesis remain controversial. Using clonal analyses (lineage tracing and single cell cultures), we identify rod versus cone lineage-specific progenitors derived from both adult retinal stem cells and embryonic neural retinal precursors. Taurine and retinoic acid are shown to act in an instructive and lineage-restricted manner early in the progenitor lineage hierarchy to produce rod-restricted progenitors from stem cell progeny. We also identify an instructive, but lineage-independent, mechanism for the specification of cone-restricted progenitors through the suppression of multiple differentiation signaling pathways. These data indicate that exogenous signals play critical roles in directing lineage decisions and resulting in fate-restricted rod or cone photoreceptor progenitors in culture. Additional factors may be involved in governing photoreceptor fates in vivo.

PMID: 30453152 [PubMed - as supplied by publisher]



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The Relative Contributions of Cell-Dependent Cortical Microcircuit Aging to Cognition and Anxiety.

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The Relative Contributions of Cell-Dependent Cortical Microcircuit Aging to Cognition and Anxiety.

Biol Psychiatry. 2018 Oct 05;:

Authors: Shukla R, Prevot TD, French L, Isserlin R, Rocco BR, Banasr M, Bader GD, Sibille E

Abstract
BACKGROUND: Aging is accompanied by altered thinking (cognition) and feeling (mood), functions that depend on information processing by brain cortical cell microcircuits. We hypothesized that age-associated long-term functional and biological changes are mediated by gene transcriptomic changes within neuronal cell types forming cortical microcircuits, namely excitatory pyramidal cells (PYCs) and inhibitory gamma-aminobutyric acidergic neurons expressing vasoactive intestinal peptide (Vip), somatostatin (Sst), and parvalbumin (Pvalb).
METHODS: To test this hypothesis, we assessed locomotor, anxiety-like, and cognitive behavioral changes between young (2 months of age, n = 9) and old (22 months of age, n = 12) male C57BL/6 mice, and performed frontal cortex cell type-specific molecular profiling, using laser capture microscopy and RNA sequencing. Results were analyzed by neuroinformatics and validated by fluorescent in situ hybridization.
RESULTS: Old mice displayed increased anxiety and reduced working memory. The four cell types displayed distinct age-related transcriptomes and biological pathway profiles, affecting metabolic and cell signaling pathways, and selective markers of neuronal vulnerability (Ryr3), resilience (Oxr1), and mitochondrial dynamics (Opa1), suggesting high age-related vulnerability of PYCs, and variable degree of adaptation in gamma-aminobutyric acidergic neurons. Correlations between gene expression and behaviors suggest that changes in cognition and anxiety associated with age are partly mediated by normal age-related cell changes, and that additional age-independent decreases in synaptic and signaling pathways, notably in PYCs and somatostatin neurons, further contribute to behavioral changes.
CONCLUSIONS: Our study demonstrates cell-dependent differential vulnerability and coordinated cell-specific cortical microcircuit molecular changes with age. Collectively, the results suggest intrinsic molecular links among aging, cognition, and mood-related behaviors, with somatostatin neurons contributing evenly to both behavioral conditions.

PMID: 30446205 [PubMed - as supplied by publisher]



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