183,913 research outputs found
Abstract 4025: New candidate therapy for BAP1-mutant cancer identified using novel screen
No full textAbstract Inactivation of the oncogene BAP1 is associated with poor prognosis in many cancers, including uveal melanoma (UM). Therapies for mediating the detrimental effects of BAP1 mutations have yet to be developed. Previously, we found that BAP1 depletion in Xenopus causes a striking developmental phenotype and a global dysregulation of differentiation markers across the genetic landscape. This was caused by impaired promoter assembly at commitment genes, marked by decreased H3K27ac levels. Inhibition of HDAC4 protein rescues the affected BAP1-depleted phenotype and genetic regulations, further emphasizing the role of H3K27ac in BAP1 function. Pairing these findings with a lab-devised multitiered screening process, we identified an epigenetic compound that successfully reverses the detrimental effects of the BAP1 deficient phenotype back to phenotypically normal conditions. This multitiered screening process tests prospective compounds for the ability to mediate transcriptional aberrations caused by BAP1 loss in UM cells (phase 1), rescue the BAP1 loss phenotype in Xenopus (phase 2), and provide significant inhibition of UM tumor growth in a mouse model (phase 3). These findings reveal a new application for a promising epigenetic compound as a therapeutic and reversing agent for BAP1 mutant UM. Furthermore, our streamlined process for the testing of promising therapeutic agents can accelerate the testing of such agents and getting them to clinical trials in a timely manner. Citation Format: DAWN A. OWENS, Jeffim N. Kuznetsov, Andy Lopez, Stefan Kurtenbach, Daniel Bilbao, Evan R. Roberts, Claude-Henry Volmar, Claes R. Wahlestedt, Shaun P. Brothers, J. William Harbour. New candidate therapy for BAP1-mutant cancer identified using novel screen [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4025
Appropriate Similarity Measures for Author Cocitation Analysis
No full textWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
"Closing the R&D Gap, Evaluating the Sources of R&D Spending"
No full textBoth spending and tax policies have been implemented in the United States with the goal of stimulating private sector research and development (R&D). Karier questions whether current R&D policy, especially the research and experimentation tax credit, can contribute to closing the gap between nondefense expenditures on R&D in the United States and such expenditures in other countries, such as Japan and Germany. He also explores possible changes to our current R&D policy to make it more effective.
Nordiska kulturfonden – En utvärdering och omvärldsanalys 2008 : Sammanfattning av Claes Lennartsson och Jan Nolins rapport
No full textNordiska kulturfonden – en utvärdering och omvärldsanalys 2008, av Claes Lennartsson och Jan Nolin, Högskolan i Borås, Centrum för kulturpolitisk forskning, ANP 2008:755, ISBN 978-92-893-1780-
Nordiska kulturfonden – En utvärdering och omvärldsanalys 2008 : Sammanfattning av Claes Lennartsson och Jan Nolins rapport
No full textNordiska kulturfonden – en utvärdering och omvärldsanalys 2008, av Claes Lennartsson och Jan Nolin, Högskolan i Borås, Centrum för kulturpolitisk forskning, ANP 2008:755, ISBN 978-92-893-1780-
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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DNA Hydroxymethylation in Non-coding Repeat Expansion Disorders
No full textHexanucleotide repeat expansion in C9ORF72 gene has recently been shown to cause familial amyotrophic lateral sclerosis, a neurodegenerative disease caused by global death of motor neurons. The expansion leads to partial heterochromatinization of the locus, yet mutant RNAs and dipeptide repeat proteins are still produced in sufficient quantities to confer neurotoxicity. So far several research groups have identified DNA hypermethylation at C9ORF72 promoter CpG sites in a fraction of patients, but the developmental timing and the reason of its occurrence only in a subset of individuals remains unknown. In order to model the acquisition of C9ORF72 hypermethylation, we generated induced pluripotent stem cells from an ALS patient with C9ORF72 promoter hypermethylation. Our data show that methylation levels are reduced by reprogramming and then re-acquired upon neuronal specification, while hydroxymethylation levels increase following reprogramming and are highest in iPSCs and motor neurons. We confirmed the presence of hydroxymethylation within the C9ORF72 promoter in post-mortem brain tissues of hypermethylated patients. Using iPSC neurons, we found that preventing R-loop formation did not impede heterochromatinization of the expanded locus. Moreover, we show that in C9-BAC mouse model of ALS, partial heterochromatinization of the C9ORF72 occurs during the first weeks of the lifespan, indicating that epigenetic repression is developmentally regulated. Taken together, these observations provide further insight into mechanism and developmental time-course of epigenetic perturbations conferred by the C9ORF72 repeat expansion. The Fragile X Syndrome (FXS) results from a repeat expansion mutation near the FMR1 gene promoter and is the most common form of heritable intellectual disability and autism. Mutations larger than 200 CGG repeats trigger FMR1 heterochromatinization and loss of gene expression, which is primarily responsible for the pathological features of FXS. While the role of 5-methylcytosine (5mC) in FMR1 gene silencing has been studied extensively, the role of 5-hydroxymethylation (5hmC), a newly discovered epigenetic mark produced through active DNA demethylation, has not been previously investigated in FXS neurons. Here, we used two complementary epigenetic assays, hydroxymethylation sensitive restriction digest and TET-assisted bisulfite pyrosequencing, to quantify FMR1 5mC and 5hmC levels. We observed increased levels of 5hmC at the FMR1 promoter in FXS patient brains with full-mutations relative to pre-mutation carriers and unaffected controls. In addition, we found that 5hmC enrichment at the FMR1 locus in FXS cells is specific to neurons by utilizing a nuclei sorting technique to separate neuronal and glial DNA fractions from post-mortem brain tissues. Future studies could investigate the potential to leverage this epigenetic pathway to restore FMR1 expression and discern whether levels of 5hmC correlate with phenotypic severity.</p
Letter from R. R. Zellick, Assistant Trust Officer, Anglo California National Bank of San Francisco, to Joseph R. Goodman, October 2, 1942
No full textLetter from R. R. Zellick, Assistant Trust Officer at The Anglo California National Bank of San Francisco, to Joseph R. Goodman, regarding property owned by Dave Tatsuno. Zellick mentions a dispute between current tenants and Tatsuno, and that Tatsuno has asked Goodman to help locate trustworthy tenants.Personal correspondence, organizational records, government documents, publications, and other papers created or collected by Joseph R. Goodman documenting the forced removal and incarceration of Japanese Americans during World War II, as well as organized resistance to incarceration. Included in the collection are records of the Japanese Young Men's Christian Association and the Japanese American Citizens' League in San Francisco, including papers of the Japanese YMCA's executive secretary Lincoln Kanai; Sakai family papers; Goodman's correspondence to and from Japanese American incarcerees, organizations opposing forced removal and incarceration of Japanese Americans, the War Relocation Authority, and others; publications, photographs, and ephemera from the Topaz Relocation Center, where Goodman taught high school; War Relocation Authority records and publications; and newspaper clippings, pamphlets, and reports about forced removal and incarceration created by various government, religious, and civic organizations, in California and nationwide
Behavioural analysis of melanin-concentrating hormone in rats: Evidence for orexigenic and anxiolytic properties
No full textMelanin-concentrating hormone (MCH) is a cyclic neuropeptide, predominantly expressed in hypothalamus, and recognized as a key regulator in feeding behaviour and energy balance. In this study, we examined the behavioural effects of intracerebroventricularly administered MCH on food intake, anxiety, exploratory behaviour and body core temperature in rats. MCH (0.15-10.0 μg, i.c.v.) acutely increased food intake in a dose-dependent manner. In addition, MCH (0.6-10.0 μg, i.c.v.) produced effects similar to anxiolytics in an animal model of anxiety, Vogel's punished drinking test. Thus, punished drinking episodes were significantly increased. We found no effects of MCH (5.0-20.0 μg, i.c.v.) on locomotor activity either in habituated or non-habituated animals. Furthermore, MCH did not produce any changes in body core temperature. Together, these observations further support a role for MCH as an orexigenic neuropeptide and also suggest anti-anxiety properties for MCH. © 2003 Elsevier Science B.V. All rights reserved
Dispelling the Myths Behind First-author Citation Counts
No full textWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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