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  • 1
    Publication Date: 2012-01-25
    Description: A requisite component of nervous system development is the achievement of cellular recognition and spatial segregation through competition-based refinement mechanisms. Competition for available axon space by myelinating oligodendrocytes ensures that all relevant CNS axons are myelinated properly. To ascertain the nature of this competition, we generated a transgenic mouse with sparsely labeled oligodendrocytes and establish that individual oligodendrocytes occupying similar axon tracts can greatly vary the number and lengths of their myelin internodes. Here we show that intercellular interactions between competing oligodendroglia influence the number and length of myelin internodes, referred to as myelinogenic potential, and identify the amino-terminal region of Nogo-A, expressed by oligodendroglia, as necessary and sufficient to inhibit this process. Exuberant and expansive myelination/remyelination is detected in the absence of Nogo during development and after demyelination, suggesting that spatial segregation and myelin extent is limited by microenvironmental inhibition. We demonstrate a unique physiological role for Nogo-A in the precise myelination of the developing CNS. Maximizing the myelinogenic potential of oligodendrocytes may offer an effective strategy for repair in future therapies for demyelination.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 2
    Publication Date: 2014-08-22
    Description: Senataxin, encoded by the SETX gene, contributes to multiple aspects of gene expression, including transcription and RNA processing. Mutations in SETX cause the recessive disorder ataxia with oculomotor apraxia type 2 (AOA2) and a dominant juvenile form of amyotrophic lateral sclerosis (ALS4). To assess the functional role of senataxin in disease, we examined differential gene expression in AOA2 patient fibroblasts, identifying a core set of genes showing altered expression by microarray and RNA-sequencing. To determine whether AOA2 and ALS4 mutations differentially affect gene expression, we overexpressed disease-specific SETX mutations in senataxin-haploinsufficient fibroblasts and observed changes in distinct sets of genes. This implicates mutation-specific alterations of senataxin function in disease pathogenesis and provides a novel example of allelic neurogenetic disorders with differing gene expression profiles. Weighted gene co-expression network analysis (WGCNA) demonstrated these senataxin-associated genes to be involved in both mutation-specific and shared functional gene networks. To assess this in vivo, we performed gene expression analysis on peripheral blood from members of 12 different AOA2 families and identified an AOA2-specific transcriptional signature. WGCNA identified two gene modules highly enriched for this transcriptional signature in the peripheral blood of all AOA2 patients studied. These modules were disease-specific and preserved in patient fibroblasts and in the cerebellum of Setx knockout mice demonstrating conservation across species and cell types, including neurons. These results identify novel genes and cellular pathways related to senataxin function in normal and disease states, and implicate alterations in gene expression as underlying the phenotypic differences between AOA2 and ALS4.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
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  • 3
    Publication Date: 1985
    Keywords: Reflection seismics
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  • 4
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    Geol. Landesamt NW
    In:  Fortschr. Geol. Rheinland u. Westf., Krefeld, Geol. Landesamt NW , vol. 10, no. GL-TR-89-0230, pp. 387-394, (ISBN 3-933346-037)
    Publication Date: 1971
    Keywords: Geomagnetics
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  • 5
    Publication Date: 2013-05-24
    Description: The KRAS oncogene product is considered a major target in anticancer drug discovery. However, direct interference with KRAS signalling has not yet led to clinically useful drugs. Correct localization and signalling by farnesylated KRAS is regulated by the prenyl-binding protein PDEdelta, which sustains the spatial organization of KRAS by facilitating its diffusion in the cytoplasm. Here we report that interfering with binding of mammalian PDEdelta to KRAS by means of small molecules provides a novel opportunity to suppress oncogenic RAS signalling by altering its localization to endomembranes. Biochemical screening and subsequent structure-based hit optimization yielded inhibitors of the KRAS-PDEdelta interaction that selectively bind to the prenyl-binding pocket of PDEdelta with nanomolar affinity, inhibit oncogenic RAS signalling and suppress in vitro and in vivo proliferation of human pancreatic ductal adenocarcinoma cells that are dependent on oncogenic KRAS. Our findings may inspire novel drug discovery efforts aimed at the development of drugs targeting oncogenic RAS.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zimmermann, Gunther -- Papke, Bjorn -- Ismail, Shehab -- Vartak, Nachiket -- Chandra, Anchal -- Hoffmann, Maike -- Hahn, Stephan A -- Triola, Gemma -- Wittinghofer, Alfred -- Bastiaens, Philippe I H -- Waldmann, Herbert -- England -- Nature. 2013 May 30;497(7451):638-42. doi: 10.1038/nature12205. Epub 2013 May 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemical Biology, Max Planck Institute of Molecular Physiology, D-44227 Dortmund, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23698361" target="_blank"〉PubMed〈/a〉
    Keywords: Adenocarcinoma/drug therapy/genetics/metabolism ; Animals ; Benzimidazoles/*chemistry/metabolism/*pharmacology/therapeutic use ; Binding Sites ; Carcinoma, Pancreatic Ductal/drug therapy/genetics/metabolism ; Cell Line ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cyclic Nucleotide Phosphodiesterases, Type 6/antagonists & ; inhibitors/chemistry/*metabolism ; Dogs ; Humans ; Hydrogen Bonding ; MAP Kinase Signaling System/drug effects ; Mice ; Mice, Nude ; Mitogen-Activated Protein Kinases/metabolism ; Models, Molecular ; Molecular Conformation ; Neoplasm Transplantation ; Oncogene Protein p21(ras)/*antagonists & inhibitors/genetics/*metabolism ; Protein Binding/drug effects ; Signal Transduction/*drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2015-03-29
    Description: We study the angular-momentum (AM) buildup in high- z massive galaxies using high-resolution cosmological simulations. The AM originates in co-planar streams of cold gas and merging galaxies tracing cosmic-web filaments, and it undergoes four phases of evolution. (I) Outside the halo virial radius ( R v  ~ 100 kpc), the elongated streams gain AM by tidal torques with a specific AM (sAM) ~1.7 times the dark matter (DM) spin due to the gas’ higher quadrupole moment. This AM is expressed as stream impact parameters, from ~0.3 R v to counter rotation. (II) In the outer halo, while the incoming DM mixes with the existing halo of lower sAM to a spin dm  ~ 0.04, the cold streams transport the AM to the inner halo such that their spin in the halo is ~3 dm . (III) Near pericentre, the streams dissipate into an irregular rotating ring extending to ~0.3 R v and tilted relative to the inner disc. Torques exerted partly by the disc make the ring gas lose AM, spiral in, and settle into the disc within one orbit. The ring is observable with 30 per cent probability as a damped Lyman α absorber. (IV) Within the disc, 〈0.1 R v , torques associated with violent disc instability drive AM out and baryons into a central bulge, while outflows remove low-spin gas, introducing certain sensitivity to feedback strength. Despite the different AM histories of gas and DM, the disc spin is comparable to the DM-halo spin. Counter rotation can strongly affect disc evolution.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
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  • 7
    Publication Date: 2015-10-07
    Description: Enterohemorrhagic Escherichia coli (EHEC) is one of the leading causes of bacterial enteric infections worldwide, causing ∼100,000 illnesses, 3,000 hospitalizations, and 90 deaths annually in the United States alone. These illnesses have been linked to consumption of contaminated animal products and vegetables. Currently, other than thermal inactivation, there are no...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 8
    Publication Date: 2018-05-19
    Description: Genes, Vol. 9, Pages 262: Genomic Differentiation during Speciation-with-Gene-Flow: Comparing Geographic and Host-Related Variation in Divergent Life History Adaptation in Rhagoletis pomonella Genes doi: 10.3390/genes9050262 Authors: Meredith M. Doellman Gregory J. Ragland Glen R. Hood Peter J. Meyers Scott P. Egan Thomas H. Q. Powell Peter Lazorchak Mary M. Glover Cheyenne Tait Hannes Schuler Daniel A. Hahn Stewart H. Berlocher James J. Smith Patrik Nosil Jeffrey L. Feder A major goal of evolutionary biology is to understand how variation within populations gets partitioned into differences between reproductively isolated species. Here, we examine the degree to which diapause life history timing, a critical adaptation promoting population divergence, explains geographic and host-related genetic variation in ancestral hawthorn and recently derived apple-infesting races of Rhagoletis pomonella. Our strategy involved combining experiments on two different aspects of diapause (initial diapause intensity and adult eclosion time) with a geographic survey of genomic variation across four sites where apple and hawthorn flies co-occur from north to south in the Midwestern USA. The results demonstrated that the majority of the genome showing significant geographic and host-related variation can be accounted for by initial diapause intensity and eclosion time. Local genomic differences between sympatric apple and hawthorn flies were subsumed within broader geographic clines; allele frequency differences within the races across the Midwest were two to three-fold greater than those between the races in sympatry. As a result, sympatric apple and hawthorn populations displayed more limited genomic clustering compared to geographic populations within the races. The findings suggest that with reduced gene flow and increased selection on diapause equivalent to that seen between geographic sites, the host races may be recognized as different genotypic entities in sympatry, and perhaps species, a hypothesis requiring future genomic analysis of related sibling species to R. pomonella to test. Our findings concerning the way selection and geography interplay could be of broad significance for many cases of earlier stages of divergence-with-gene flow, including (1) where only modest increases in geographic isolation and the strength of selection may greatly impact genetic coupling and (2) the dynamics of how spatial and temporal standing variation is extracted by selection to generate differences between new and discrete units of biodiversity.
    Electronic ISSN: 2073-4425
    Topics: Biology
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  • 9
    Publication Date: 2018-06-13
    Description: Achieving the upper limits of face identification accuracy in forensic applications can minimize errors that have profound social and personal consequences. Although forensic examiners identify faces in these applications, systematic tests of their accuracy are rare. How can we achieve the most accurate face identification: using people and/or machines working...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 10
    Publication Date: 1996-01-19
    Description: About 90 percent of human pancreatic carcinomas show allelic loss at chromosome 18q. To identify candidate tumor suppressor genes on 18q, a panel of pancreatic carcinomas were analyzed for convergent sites of homozygous deletion. Twenty-five of 84 tumors had homozygous deletions at 18q21.1, a site that excludes DCC (a candidate suppressor gene for colorectal cancer) and includes DPC4, a gene similar in sequence to a Drosophila melanogaster gene (Mad) implicated in a transforming growth factor-beta (TGF-beta)-like signaling pathway. Potentially inactivating mutations in DPC4 were identified in six of 27 pancreatic carcinomas that did not have homozygous deletions at 18q21.1. These results identify DPC4 as a candidate tumor suppressor gene whose inactivation may play a role in pancreatic and possibly other human cancers.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hahn, S A -- Schutte, M -- Hoque, A T -- Moskaluk, C A -- da Costa, L T -- Rozenblum, E -- Weinstein, C L -- Fischer, A -- Yeo, C J -- Hruban, R H -- Kern, S E -- CA62924/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 1996 Jan 19;271(5247):350-3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8553070" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Amino Acid Sequence ; Animals ; Base Sequence ; Cell Division ; Chromosome Mapping ; *Chromosomes, Human, Pair 18 ; *DNA-Binding Proteins ; Gene Deletion ; Gene Expression ; *Genes, Tumor Suppressor ; Genetic Markers ; Humans ; Mice ; Molecular Sequence Data ; Mutation ; Neoplasm Transplantation ; Pancreatic Neoplasms/*genetics/pathology ; Proteins/chemistry/*genetics/physiology ; Signal Transduction ; Smad4 Protein ; *Trans-Activators ; Transforming Growth Factor beta/physiology ; Transplantation, Heterologous ; Tumor Cells, Cultured
    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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