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  • 1
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    LZTR1 is a regulator of RAS ubiquitination and signaling (2018)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2018
    Description: 〈p〉In genetic screens aimed at understanding drug resistance mechanisms in chronic myeloid leukemia cells, inactivation of the cullin 3 adapter protein-encoding leucine zipper like transcription regulator 1 (〈i〉LZTR1〈/i〉) gene led to enhanced mitogen-activated protein kinase pathway activity and reduced sensitivity to tyrosine kinase inhibitors. Knockdown of the 〈i〉Drosophila LZTR1〈/i〉 ortholog 〈i〉CG3711〈/i〉 resulted in a RAS-dependent gain of function phenotype. Endogenous human LZTR1 associates with the main RAS isoforms. Inactivation of 〈i〉LZTR1〈/i〉 led to decreased ubiquitination and enhanced plasma membrane localization of endogenous KRAS. We propose that LZTR1 acts as a conserved regulator of RAS ubiquitination and MAPK pathway activation. As 〈i〉LZTR1〈/i〉 disease mutations failed to revert loss-of-function phenotypes, our findings provide a molecular rationale for 〈i〉LZTR1〈/i〉 involvement in a variety of inherited and acquired human disorders.〈/p〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Natural Sciences in General
    Published by American Association for the Advancement of Science (AAAS)
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  • 2
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    Structure of Arp2/3 complex in its activated state and in actin filament branch junctions (2001)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2001-09-05
    Description: The seven-subunit Arp2/3 complex choreographs the formation of branched actin networks at the leading edge of migrating cells. When activated by Wiskott-Aldrich Syndrome protein (WASp), the Arp2/3 complex initiates actin filament branches from the sides of existing filaments. Electron cryomicroscopy and three-dimensional reconstruction of Acanthamoeba castellanii and Saccharomyces cerevisiae Arp2/3 complexes bound to the WASp carboxy-terminal domain reveal asymmetric, oblate ellipsoids. Image analysis of actin branches indicates that the complex binds the side of the mother filament, and Arp2 and Arp3 (for actin-related protein) are the first two subunits of the daughter filament. Comparison to the actin-free, WASp-activated complexes suggests that branch initiation involves large-scale structural rearrangements within Arp2/3.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Volkmann, N -- Amann, K J -- Stoilova-McPhie, S -- Egile, C -- Winter, D C -- Hazelwood, L -- Heuser, J E -- Li, R -- Pollard, T D -- Hanein, D -- New York, N.Y. -- Science. 2001 Sep 28;293(5539):2456-9. Epub 2001 Aug 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Burnham Institute, La Jolla, CA 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11533442" target="_blank"〉PubMed〈/a〉
    Keywords: Acanthamoeba ; Actin Cytoskeleton/*metabolism/ultrastructure ; Actin-Related Protein 2 ; Actin-Related Protein 3 ; Actins/*chemistry/*metabolism ; Animals ; Cryoelectron Microscopy ; *Cytoskeletal Proteins ; Fourier Analysis ; Image Processing, Computer-Assisted ; Microscopy, Electron ; Models, Molecular ; Proteins/metabolism ; Saccharomyces cerevisiae ; Wiskott-Aldrich Syndrome Protein
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
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    Stress in puberty unmasks latent neuropathological consequences of prenatal immune activation in mice (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-03-02
    Description: Prenatal infection and exposure to traumatizing experiences during peripuberty have each been associated with increased risk for neuropsychiatric disorders. Evidence is lacking for the cumulative impact of such prenatal and postnatal environmental challenges on brain functions and vulnerability to psychiatric disease. Here, we show in a translational mouse model that combined exposure to prenatal immune challenge and peripubertal stress induces synergistic pathological effects on adult behavioral functions and neurochemistry. We further demonstrate that the prenatal insult markedly increases the vulnerability of the pubescent offspring to brain immune changes in response to stress. Our findings reveal interactions between two adverse environmental factors that have individually been associated with neuropsychiatric disease and support theories that mental illnesses with delayed onsets involve multiple environmental hits.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Giovanoli, Sandra -- Engler, Harald -- Engler, Andrea -- Richetto, Juliet -- Voget, Mareike -- Willi, Roman -- Winter, Christine -- Riva, Marco A -- Mortensen, Preben B -- Feldon, Joram -- Schedlowski, Manfred -- Meyer, Urs -- New York, N.Y. -- Science. 2013 Mar 1;339(6123):1095-9. doi: 10.1126/science.1228261.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Physiology and Behavior Laboratory, Swiss Federal Institute of Technology (ETH) Zurich, 8603 Schwerzenbach, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23449593" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cytokines/immunology ; Disease Models, Animal ; Female ; Humans ; Mental Disorders/*immunology ; Mice ; Mice, Inbred C57BL ; Poly I-C/immunology/pharmacology ; Pregnancy ; Prenatal Exposure Delayed Effects/*immunology/virology ; Puberty/*immunology ; Stress, Physiological/*immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
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    LZTR1 is a regulator of RAS ubiquitination and signaling (2018)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2018
    Description: 〈p〉In genetic screens aimed at understanding drug resistance mechanisms in chronic myeloid leukemia cells, inactivation of the cullin 3 adapter protein-encoding leucine zipper-like transcription regulator 1 (〈i〉LZTR1〈/i〉) gene led to enhanced mitogen-activated protein kinase (MAPK) pathway activity and reduced sensitivity to tyrosine kinase inhibitors. Knockdown of the 〈i〉Drosophila LZTR1〈/i〉 ortholog 〈i〉CG3711〈/i〉 resulted in a Ras-dependent gain-of-function phenotype. Endogenous human LZTR1 associates with the main RAS isoforms. Inactivation of 〈i〉LZTR1〈/i〉 led to decreased ubiquitination and enhanced plasma membrane localization of endogenous KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog). We propose that LZTR1 acts as a conserved regulator of RAS ubiquitination and MAPK pathway activation. Because 〈i〉LZTR1〈/i〉 disease mutations failed to revert loss-of-function phenotypes, our findings provide a molecular rationale for 〈i〉LZTR1〈/i〉 involvement in a variety of inherited and acquired human disorders.〈/p〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 5
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    LZTR1 is a regulator of RAS ubiquitination and signaling (2018)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2018-12-07
    Description: In genetic screens aimed at understanding drug resistance mechanisms in chronic myeloid leukemia cells, inactivation of the cullin 3 adapter protein-encoding leucine zipper-like transcription regulator 1 ( LZTR1 ) gene led to enhanced mitogen-activated protein kinase (MAPK) pathway activity and reduced sensitivity to tyrosine kinase inhibitors. Knockdown of the Drosophila LZTR1 ortholog CG3711 resulted in a Ras-dependent gain-of-function phenotype. Endogenous human LZTR1 associates with the main RAS isoforms. Inactivation of LZTR1 led to decreased ubiquitination and enhanced plasma membrane localization of endogenous KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog). We propose that LZTR1 acts as a conserved regulator of RAS ubiquitination and MAPK pathway activation. Because LZTR1 disease mutations failed to revert loss-of-function phenotypes, our findings provide a molecular rationale for LZTR1 involvement in a variety of inherited and acquired human disorders.
    Keywords: Cell Biology, Medicine, Diseases
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 6
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    Delaney reform (1995)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1995-06-30
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cohen, S M -- Clydesdale, F M -- Winter, C -- Graham, J D -- Weil, W B Jr -- Kroger, M -- Pariza, M W -- Crawford, L M -- Avery, D -- Scheuplein, R J -- New York, N.Y. -- Science. 1995 Jun 30;268(5219):1829-30.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/7604249" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Carcinogens/*analysis ; Food Additives/*adverse effects ; Food Contamination/*legislation & jurisprudence ; Humans ; *Legislation, Food ; Pesticide Residues/*adverse effects ; United States
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 7
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    Spatiotemporal expansion of primary progenitor zones in the developing human cerebellum (2019)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2019
    Description: 〈p〉We present histological and molecular analyses of the developing human cerebellum from 30 days after conception to 9 months after birth. Differences in developmental patterns between humans and mice include spatiotemporal expansion of both ventricular and rhombic lip primary progenitor zones to include subventricular zones containing basal progenitors. The human rhombic lip persists longer through cerebellar development than in the mouse and undergoes morphological changes to form a progenitor pool in the posterior lobule, which is not seen in other organisms, not even in the nonhuman primate, the macaque. Disruptions in human rhombic lip development are associated with posterior cerebellar vermis hypoplasia and Dandy-Walker malformation. The presence of these species-specific neural progenitor populations refines our insight into human cerebellar developmental disorders.〈/p〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Natural Sciences in General
    Published by American Association for the Advancement of Science (AAAS)
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  • 8
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    Spatiotemporal expansion of primary progenitor zones in the developing human cerebellum (2019)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2019
    Description: 〈p〉We present histological and molecular analyses of the developing human cerebellum from 30 days after conception to 9 months after birth. Differences in developmental patterns between humans and mice include spatiotemporal expansion of both ventricular and rhombic lip primary progenitor zones to include subventricular zones containing basal progenitors. The human rhombic lip persists longer through cerebellar development than in the mouse and undergoes morphological changes to form a progenitor pool in the posterior lobule, which is not seen in other organisms, not even in the nonhuman primate the macaque. Disruptions in human rhombic lip development are associated with posterior cerebellar vermis hypoplasia and Dandy-Walker malformation. The presence of these species-specific neural progenitor populations refines our insight into human cerebellar developmental disorders.〈/p〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 9
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    Nonlinear effects of locally heterogeneous hydraulic conductivity fields on regional stream–aquifer exchanges (2015)
    Copernicus
    Details
    Publication Date: 2015-11-12
    Description: Computational experiments are performed to evaluate the effects of locally heterogeneous conductivity fields on regional exchanges of water between stream and aquifer systems in the Middle Heihe River basin (MHRB) of northwestern China. The effects are found to be nonlinear in the sense that simulated discharges from aquifers to streams are systematically lower than discharges produced by a base model parameterized with relatively coarse effective conductivity. A similar, but weaker, effect is observed for stream leakage. The study is organized around three hypotheses: (H1) small-scale spatial variations of conductivity significantly affect regional exchanges of water between streams and aquifers in river basins, (H2) aggregating small-scale heterogeneities into regional effective parameters systematically biases estimates of stream–aquifer exchanges, and (H3) the biases result from slow paths in groundwater flow that emerge due to small-scale heterogeneities. The hypotheses are evaluated by comparing stream–aquifer fluxes produced by the base model to fluxes simulated using realizations of the MHRB characterized by local (grid-scale) heterogeneity. Levels of local heterogeneity are manipulated as control variables by adjusting coefficients of variation. All models are implemented using the MODFLOW (Modular Three-dimensional Finite-difference Groundwater Flow Model) simulation environment, and the PEST (parameter estimation) tool is used to calibrate effective conductivities defined over 16 zones within the MHRB. The effective parameters are also used as expected values to develop lognormally distributed conductivity (K) fields on local grid scales. Stream–aquifer exchanges are simulated with K fields at both scales and then compared. Results show that the effects of small-scale heterogeneities significantly influence exchanges with simulations based on local-scale heterogeneities always producing discharges that are less than those produced by the base model. Although aquifer heterogeneities are uncorrelated at local scales, they appear to induce coherent slow paths in groundwater fluxes that in turn reduce aquifer–stream exchanges. Since surface water–groundwater exchanges are critical hydrologic processes in basin-scale water budgets, these results also have implications for water resources management.
    Print ISSN: 1027-5606
    Electronic ISSN: 1607-7938
    Topics: Geography , Geosciences
    Published by Copernicus on behalf of European Geosciences Union.
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  • 10
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    Nonlinear effects of locally heterogeneous hydraulic conductivity fields on regional stream–aquifer exchanges (2015)
    Copernicus
    Details
    Publication Date: 2015-08-10
    Description: Computational experiments are performed to evaluate the effects of locally heterogeneous conductivity fields on regional exchanges of water between stream and aquifer systems in the Middle Heihe River Basin (MHRB) of northwestern China. The effects are found to be nonlinear in the sense that simulated discharges from aquifers to streams are systematically lower than discharges produced by a base model parameterized with relatively coarse effective conductivity. A similar, but weaker, effect is observed for stream leakage. The study is organized around three hypotheses: (H1) small-scale spatial variations of conductivity significantly affect regional exchanges of water between streams and aquifers in river basins, (H2) aggregating small-scale heterogeneities into regional effective parameters systematically biases estimates of stream–aquifer exchanges, and (H3) the biases result from slow-paths in groundwater flow that emerge due to small-scale heterogeneities. The hypotheses are evaluated by comparing stream–aquifer fluxes produced by the base model to fluxes simulated using realizations of the MHRB characterized by local (grid-scale) heterogeneity. Levels of local heterogeneity are manipulated as control variables by adjusting coefficients of variation. All models are implemented using the MODFLOW simulation environment, and the PEST tool is used to calibrate effective conductivities defined over 16 zones within the MHRB. The effective parameters are also used as expected values to develop log-normally distributed conductivity (K) fields on local grid scales. Stream-aquifer exchanges are simulated with K fields at both scales and then compared. Results show that the effects of small-scale heterogeneities significantly influence exchanges with simulations based on local-scale heterogeneities always producing discharges that are less than those produced by the base model. Although aquifer heterogeneities are uncorrelated at local scales, they appear to induce coherent slow-paths in groundwater fluxes that in turn reduce aquifer–stream exchanges. Since surface water–groundwater exchanges are critical hydrologic processes in basin-scale water budgets, these results also have implications for water resources management.
    Print ISSN: 1812-2108
    Electronic ISSN: 1812-2116
    Topics: Geography , Geosciences
    Published by Copernicus on behalf of European Geosciences Union.
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