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  1. Article ; Online: Teaching Health as a Human Right in the Undergraduate Context

    Bisan A. Salhi / Peter J. Brown

    Health and Human Rights, Vol 21, Iss 1, Pp 191-

    Challenges and Opportunities

    2019  Volume 202

    Abstract: This paper explores the possibility of a pedagogy about health and human rights that is understandable and persuasive to undergraduate students yet does not succumb to a reductive dualism of optimism and pessimism. In 2014, we presented the topic of ... ...

    Abstract This paper explores the possibility of a pedagogy about health and human rights that is understandable and persuasive to undergraduate students yet does not succumb to a reductive dualism of optimism and pessimism. In 2014, we presented the topic of health and human rights in an introductory undergraduate global health course in conjunction with the exhibit “Health is a Human Right: Race and Place in America” at the Centers for Disease Control in Atlanta, Georgia. The exhibition highlighted the United States’ complicated legacy and failures of health and human rights, with an emphasis on ongoing racial and socioeconomic inequities. In conjunction with class lectures, students viewed the exhibit and submitted a survey and a reflective essay about human rights abuses, as well as possibilities for realizing the right to health in the United States. Contrary to our expectations, the human rights issues surrounding the AIDS epidemic raised very little interest among our students, for whom AIDS is a preventable and treatable chronic disease. Instead, students were most interested in exhibits on eugenics and forced sterilization, deficits in water and sanitation, racism, and contradictions of American exceptionalism. We conclude that an emphasis on the violations of human rights and their health effects using domestic examples from relatively recent history can be an effective pedagogical strategy. This approach represents an opportunity to counter students’ presumptions that the United States exists outside of the human rights discourse. Moreover, this approach may reinforce the idea that the domestic race- and class-based inequalities can and should be understood as human rights violations.
    Keywords Public aspects of medicine ; RA1-1270 ; Social history and conditions. Social problems. Social reform ; HN1-995
    Subject code 170
    Language English
    Publishing date 2019-06-01T00:00:00Z
    Publisher Harvard FXB Center for Health and Human Rights
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Hyperplastic and fibrosing gastropathy resembling Ménétrier disease in a cat

    Emi N Barker / Andrew S Holdsworth / Angie Hibbert / Peter J Brown / Nicolette J Hayward

    Journal of Feline Medicine and Surgery Open Reports, Vol

    2019  Volume 5

    Abstract: Case summary A 3.5-year-old domestic shorthair cat presented with a 6 month history of weight loss and polyphagia. Clinical examination revealed a markedly reduced body condition score (2/9) and a quiet demeanour. Laboratory abnormalities comprised a ... ...

    Abstract Case summary A 3.5-year-old domestic shorthair cat presented with a 6 month history of weight loss and polyphagia. Clinical examination revealed a markedly reduced body condition score (2/9) and a quiet demeanour. Laboratory abnormalities comprised a mild non-regenerative anaemia, stress leukogram, hypoproteinaemia due to hypoalbuminaemia, azotaemia, hypokalaemia, total hypocalcaemia and sub-maximally concentrated urine (specific gravity 1.020). Abdominal ultrasonography revealed marked thickening of the gastric mucosa within the fundus, body and pylorus; the most dorsal portion of the fundus was spared. The thickened mucosa contained multiple small, anechoic cyst-like structures. The gastric submucosa, muscularis and serosa appeared normal. Histopathology, performed on a full-thickness gastric biopsy, revealed mucosal hypertrophy and markedly dilated gastric glands in areas; not all gastric glands were affected, with some appearing normal or atrophic. Focal interstitial fibrosis was present in some areas. The findings of hypoproteinaemia, gastric ultrasonographic changes and histopathology results share several similarities to those reported with Ménétrier disease. Relevance and novel information Ménétrier disease is a rare condition of the stomach in humans. A similar condition, giant hypertrophic gastritis (or Ménétrier-like disease), has also been described rarely in dogs. To our knowledge, Ménétrier-like disease has not been previously described cats. This case shares features of Ménétrier-like disease, raising the suspicion of a similar aetiopathogenesis.
    Keywords Veterinary medicine ; SF600-1100
    Subject code 630
    Language English
    Publishing date 2019-07-01T00:00:00Z
    Publisher SAGE Publishing
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Discovery of selective activators of PRC2 mutant EED-I363M

    Junghyun L. Suh / Kimberly D. Barnash / Tigran M. Abramyan / Fengling Li / Juliana The / Isabelle A. Engelberg / Masoud Vedadi / Peter J. Brown / Dmitri B. Kireev / Cheryl H. Arrowsmith / Lindsey I. James / Stephen V. Frye

    Scientific Reports, Vol 9, Iss 1, Pp 1-

    2019  Volume 10

    Abstract: Abstract Many common disease-causing mutations result in loss-of-function (LOF) of the proteins in which they occur. LOF mutations have proven recalcitrant to pharmacologic intervention, presenting a challenge for the development of targeted therapeutics. ...

    Abstract Abstract Many common disease-causing mutations result in loss-of-function (LOF) of the proteins in which they occur. LOF mutations have proven recalcitrant to pharmacologic intervention, presenting a challenge for the development of targeted therapeutics. Polycomb repressive complex 2 (PRC2), which contains core subunits (EZH2, EED, and SUZ12), regulates gene activity by trimethylation of histone 3 lysine 27. The dysregulation of PRC2 catalytic activity by mutations has been implicated in cancer and other diseases. Among the mutations that cause PRC2 malfunction, an I363M LOF mutation of EED has been identified in myeloid disorders, where it prevents allosteric activation of EZH2 catalysis. We describe structure-based design and computational simulations of ligands created to ameliorate this LOF. Notably, these compounds selectively stimulate the catalytic activity of PRC2-EED-I363M over wildtype-PRC2. Overall, this work demonstrates the feasibility of developing targeted therapeutics for PRC2-EED-I363M that act as allosteric agonists, potentially correcting this LOF mutant phenotype.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2019-04-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article: A scintillation proximity assay for histone demethylases

    Yu, Wenyu / Aleksandra Szykowska / Masoud Vedadi / Mohammad S. Eram / Nicola Burgess-Brown / Peter J. Brown / Taraneh Hajian

    Analytical biochemistry. 2014 Oct. 15, v. 463

    2014  

    Abstract: Covalent modifications, such as methylation and demethylation of lysine residues in histones, play important roles in chromatin dynamics and the regulation of gene expression. The lysine demethylases (KDMs) catalyze the demethylation of lysine residues ... ...

    Abstract Covalent modifications, such as methylation and demethylation of lysine residues in histones, play important roles in chromatin dynamics and the regulation of gene expression. The lysine demethylases (KDMs) catalyze the demethylation of lysine residues on histone tails and are associated with diverse human diseases, including cancer, and are therefore proposed as targets for the therapeutic modulation of gene transcription. High-throughput assays have been developed to find inhibitors of KDMs, most of which are fluorescence-based assays. Here we report the development of a coupled scintillation proximity assay (SPA) for 3 KDMs: KDM1A (LSD1), KDM3A (JMJD1A), and KDM4A (JMJD2A). In this assay methylated peptides are first demethylated by a KDM, and a protein methyltransferase (PMT) is added to methylate the resulting peptide with tritiated S-(5′-adenosyl)-l-methionine. The enzyme activities were optimized and kinetic parameters were determined. These robust coupled assays are suitable for screening KDMs in 384-well format (Z′ factors of 0.70–0.80), facilitating discovery of inhibitors in the quest for cancer therapeutics.
    Keywords chromatin ; enzyme activity ; gene expression regulation ; histones ; human diseases ; lysine ; methylation ; neoplasms ; peptides ; screening ; therapeutics ; transcription (genetics) ; tritium
    Language English
    Dates of publication 2014-1015
    Size p. 54-60.
    Publishing place Elsevier Inc.
    Document type Article
    ZDB-ID 1110-1
    ISSN 1096-0309 ; 0003-2697
    ISSN (online) 1096-0309
    ISSN 0003-2697
    DOI 10.1016/j.ab.2014.06.023
    Database NAL-Catalogue (AGRICOLA)

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  5. Article ; Online: SET9-Mediated Regulation of TGF-β Signaling Links Protein Methylation to Pulmonary Fibrosis

    Maximilianos Elkouris / Haroula Kontaki / Athanasios Stavropoulos / Anastasia Antonoglou / Kostas C. Nikolaou / Martina Samiotaki / Eszter Szantai / Dimitra Saviolaki / Peter J. Brown / Paschalis Sideras / George Panayotou / Iannis Talianidis

    Cell Reports, Vol 15, Iss 12, Pp 2733-

    2016  Volume 2744

    Abstract: TGF-β signaling regulates a variety of cellular processes, including proliferation, apoptosis, differentiation, immune responses, and fibrogenesis. Here, we describe a lysine methylation-mediated mechanism that controls the pro-fibrogenic activity of TGF- ...

    Abstract TGF-β signaling regulates a variety of cellular processes, including proliferation, apoptosis, differentiation, immune responses, and fibrogenesis. Here, we describe a lysine methylation-mediated mechanism that controls the pro-fibrogenic activity of TGF-β. We find that the methyltransferase Set9 potentiates TGF-β signaling by targeting Smad7, an inhibitory downstream effector. Smad7 methylation promotes interaction with the E3 ligase Arkadia and, thus, ubiquitination-dependent degradation. Depletion or pharmacological inhibition of Set9 results in elevated Smad7 protein levels and inhibits TGF-β-dependent expression of genes encoding extracellular matrix components. The inhibitory effect of Set9 on TGF-β-mediated extracellular matrix production is further demonstrated in mouse models of pulmonary fibrosis. Lung fibrosis induced by bleomycin or Ad-TGF-β treatment was highly compromised in Set9-deficient mice. These results uncover a complex regulatory interplay among multiple Smad7 modifications and highlight the possibility that protein methyltransferases may represent promising therapeutic targets for treating lung fibrosis.
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2016-06-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: The dynamic conformational landscape of the protein methyltransferase SETD8

    Shi Chen / Rafal P Wiewiora / Fanwang Meng / Nicolas Babault / Anqi Ma / Wenyu Yu / Kun Qian / Hao Hu / Hua Zou / Junyi Wang / Shijie Fan / Gil Blum / Fabio Pittella-Silva / Kyle A Beauchamp / Wolfram Tempel / Hualiang Jiang / Kaixian Chen / Robert J Skene / Yujun George Zheng /
    Peter J Brown / Jian Jin / Cheng Luo / John D Chodera / Minkui Luo

    eLife, Vol

    2019  Volume 8

    Abstract: Elucidating the conformational heterogeneity of proteins is essential for understanding protein function and developing exogenous ligands. With the rapid development of experimental and computational methods, it is of great interest to integrate these ... ...

    Abstract Elucidating the conformational heterogeneity of proteins is essential for understanding protein function and developing exogenous ligands. With the rapid development of experimental and computational methods, it is of great interest to integrate these approaches to illuminate the conformational landscapes of target proteins. SETD8 is a protein lysine methyltransferase (PKMT), which functions in vivo via the methylation of histone and nonhistone targets. Utilizing covalent inhibitors and depleting native ligands to trap hidden conformational states, we obtained diverse X-ray structures of SETD8. These structures were used to seed distributed atomistic molecular dynamics simulations that generated a total of six milliseconds of trajectory data. Markov state models, built via an automated machine learning approach and corroborated experimentally, reveal how slow conformational motions and conformational states are relevant to catalysis. These findings provide molecular insight on enzymatic catalysis and allosteric mechanisms of a PKMT via its detailed conformational landscape.
    Keywords epigenetics ; posttranslational modification ; enzymology ; computational chemistry ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 612
    Language English
    Publishing date 2019-05-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Assay interference and off-target liabilities of reported histone acetyltransferase inhibitors

    Jayme L. Dahlin / Kathryn M. Nelson / Jessica M. Strasser / Dalia Barsyte-Lovejoy / Magdalena M. Szewczyk / Shawna Organ / Matthew Cuellar / Gurpreet Singh / Jonathan H. Shrimp / Nghi Nguyen / Jordan L. Meier / Cheryl H. Arrowsmith / Peter J. Brown / Jonathan B. Baell / Michael A. Walters

    Nature Communications, Vol 8, Iss 1, Pp 1-

    2017  Volume 14

    Abstract: A substantial obstacle in basic research is the use of poorly validated tool compounds with purported useful biological functions. Here, the authors systematically profile widely used histone acetyltransferase inhibitors and find that the majority are ... ...

    Abstract A substantial obstacle in basic research is the use of poorly validated tool compounds with purported useful biological functions. Here, the authors systematically profile widely used histone acetyltransferase inhibitors and find that the majority are nonselective interference compounds.
    Keywords Science ; Q
    Language English
    Publishing date 2017-11-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Pharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress response

    Magdalena M. Szewczyk / Yoshinori Ishikawa / Shawna Organ / Nozomu Sakai / Fengling Li / Levon Halabelian / Suzanne Ackloo / Amber L. Couzens / Mohammad Eram / David Dilworth / Hideto Fukushi / Rachel Harding / Carlo C. dela Seña / Tsukasa Sugo / Kozo Hayashi / David McLeod / Carlos Zepeda / Ahmed Aman / Maria Sánchez-Osuna /
    Eric Bonneil / Shinji Takagi / Rima Al-Awar / Mike Tyers / Stephane Richard / Masayuki Takizawa / Anne-Claude Gingras / Cheryl H. Arrowsmith / Masoud Vedadi / Peter J. Brown / Hiroshi Nara / Dalia Barsyte-Lovejoy

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 15

    Abstract: Protein arginine methyltransferases (PRMTs) are increasingly recognized as potential therapeutic targets but PRMT7 remains an understudied member of this enzyme family. Here, the authors develop a chemical probe for PRMT7 and apply it to elucidate the ... ...

    Abstract Protein arginine methyltransferases (PRMTs) are increasingly recognized as potential therapeutic targets but PRMT7 remains an understudied member of this enzyme family. Here, the authors develop a chemical probe for PRMT7 and apply it to elucidate the role of PRMT7 in the cellular stress response.
    Keywords Science ; Q
    Language English
    Publishing date 2020-05-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Author Correction

    Magdalena M. Szewczyk / Yoshinori Ishikawa / Shawna Organ / Nozomu Sakai / Fengling Li / Levon Halabelian / Suzanne Ackloo / Amber L. Couzens / Mohammad Eram / David Dilworth / Hideto Fukushi / Rachel Harding / Carlo C. dela Seña / Tsukasa Sugo / Kozo Hayashi / David McLeod / Carlos Zepeda / Ahmed Aman / Maria Sánchez-Osuna /
    Eric Bonneil / Shinji Takagi / Rima Al-Awar / Mike Tyers / Stephane Richard / Masayuki Takizawa / Anne-Claude Gingras / Cheryl H. Arrowsmith / Masoud Vedadi / Peter J. Brown / Hiroshi Nara / Dalia Barsyte-Lovejoy

    Nature Communications, Vol 11, Iss 1, Pp 1-

    Pharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress response

    2020  Volume 1

    Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper. ...

    Abstract An amendment to this paper has been published and can be accessed via a link at the top of the paper.
    Keywords Science ; Q
    Language English
    Publishing date 2020-05-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Pharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress response

    Magdalena M. Szewczyk / Yoshinori Ishikawa / Shawna Organ / Nozomu Sakai / Fengling Li / Levon Halabelian / Suzanne Ackloo / Amber L. Couzens / Mohammad Eram / David Dilworth / Hideto Fukushi / Rachel Harding / Carlo C. dela Seña / Tsukasa Sugo / Kozo Hayashi / David McLeod / Carlos Zepeda / Ahmed Aman / Maria Sánchez-Osuna /
    Eric Bonneil / Shinji Takagi / Rima Al-Awar / Mike Tyers / Stephane Richard / Masayuki Takizawa / Anne-Claude Gingras / Cheryl H. Arrowsmith / Masoud Vedadi / Peter J. Brown / Hiroshi Nara / Dalia Barsyte-Lovejoy

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 15

    Abstract: Protein arginine methyltransferases (PRMTs) are increasingly recognized as potential therapeutic targets but PRMT7 remains an understudied member of this enzyme family. Here, the authors develop a chemical probe for PRMT7 and apply it to elucidate the ... ...

    Abstract Protein arginine methyltransferases (PRMTs) are increasingly recognized as potential therapeutic targets but PRMT7 remains an understudied member of this enzyme family. Here, the authors develop a chemical probe for PRMT7 and apply it to elucidate the role of PRMT7 in the cellular stress response.
    Keywords Science ; Q
    Language English
    Publishing date 2020-05-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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