In vitro activation of the interferon-induced, double-stranded RNA-dependent protein kinase PKR by RNA from the 3' untranslated regions of human alpha-tropomyosin.

The cellular kinase known as PKR (protein kinase RNA-activated) is induced by interferon and activated by RNA. PKR is known to have antiviral properties due to its role in translational control. Active PKR phosphorylates eukaryotic initiation factor 2 alpha and leads to inhibition of translation, including viral translation. PKR is also known to function as a tumor suppressor, presumably by limiting the rate of tumor-cell translation and growth. Recent research has shown that RNA from the 3' untranslated region (3'UTR) of human alpha-tropomyosin has tumor-suppressor properties in vivo [Rastinejad, F., Conboy, M. J., Rando, T. A. & Blau, H. M. (1993) Cell 75, 1107-1117]. Here we report that purified RNA from the 3'UTR of human alpha-tropomyosin can inhibit in vitro translation in a manner consistent with activation of PKR. Inhibition of translation by tropomyosin 3'UTR RNA was observed in a rabbit reticulocyte lysate system, which is known to contain endogenous PKR but was not seen in wheat germ lysate, which is not responsive to a known activator of PKR. A control RNA purified in the same manner as the 3'UTR RNA did not inhibit translation in either system. The inhibition of translation observed in reticulocyte lysates was prevented by the addition of adenovirus virus-associated RNA1 (VA RNAI), an inhibitor of PKR activation. Tropomyosin 3'UTR RNA was bound by immunoprecipitated PKR and activated the enzyme in an in vitro kinase assay. These data suggest that activation of PKR could be the mechanism by which tropomyosin 3'UTR RNA exerts its tumor-suppression activity in vivo.

Physical mapping of the minimal region of loss in 5q- chromosome.

Acquired interstitial loss of all or part of the long arm of human chromosome 5 (5q-) is an anomaly that is seen frequently in patients with preleukemic myelodysplasia and acute myelogenous leukemia. Loss of a critical region of overlap at band 5q31.1 in all of these cases, with various cytogenetic breaks, signifies the existence of a key negative regulator of leukemogenesis. Previous studies have defined the proximal and distal ends of the critical region to reside between the genes for IL9 and EGR1, respectively. In this report, we describe a yeast artificial chromosome contig spanning this myeloid tumor suppressor locus. The combined order of the polymorphic loci is centromere-IL9-(D5S525-D5S558-D5S89-D5S526 -D5S393)-D5S399-D5S396-D5S414-EGR1 and telomere. The physical distance between the IL9 and EGR1 genes is estimated to be < 2.4 Mb. Here we report the utility of these polymorphic loci by detecting a submicroscopic deletion of 5q31; an acute myelogenous leukemia patient with a three-way translocation, t(5;18;17)(q31;p11;q11), as the sole anomaly revealed allele loss of the D5S399 and D5S396 loci.

The European Court of Justice blocks the EU’s accession to the ECHR. CEPS Commentary, 8 January 2015

The goal of accession to the European Convention of Human Rights (ECHR) is to place the EU under the external oversight of the specialised court in Strasbourg. But in its Opinion of 18 December 2014 the Luxembourg-based European Court of Justice ruled that the draft accession agreement is not compatible with the EU treaties. In this commentary the authors argue that this would force EU member states to renegotiate the terms of accession to the ECHR. But meeting the demands made by the Court of Justice will prove to be very difficult.

Technicians of Human Dignity : Bodies, Souls, and the Making of Intrinsic Worth /

Tracks the development of the concept of human dignity in post-war ethics and politics, focusing on the Vatican, the United Nations, and U.S. Federal Bioethics. This title was made Open Access by libraries from around the world through Knowledge Unlatched.

Evocations of Nature in the Piano Music of Franz Liszt and the Seeds of Impressionism

Thesis (D.M.A.)--University of Washington, 2016-06

The chemistry and biology of human relaxin-3

A novel member of the human relaxin subclass of the insulin superfamily was recently discovered during a genomics database search and named relaxin-3. Like human relaxin-1 and relaxin-2, relaxin-3 is predicted to consist of a two-chain structure and three disulfide bonds in a disposition identical to that of insulin. To undertake detailed biophysical and biological characterization of the peptide, its chemical synthesis was undertaken. In contrast to human relaxin-1 and relaxin-2, however, relaxin-3 could not be successfully prepared by simple combination of the individual chains, thus necessitating recourse to the use of a regioselective disulfide bond formation strategy. Solid phase synthesis of the separate, selectively S-protected A and B chains followed by their purification and the subsequent stepwise formation of each of the three disulfides led to the successful acquisition of human relaxin-3. Comprehensive chemical characterization confirmed both the correct chain orientation and the integrity of the synthetic product. Relaxin-3 was found to bind to and activate native relaxin receptors in vitro and stimulate water drinking through central relaxin receptors in vivo. Recent studies have demonstrated that relaxin-3 will bind to and activate human LGR7, but not LGR8, in vitro. Secondary structural analysis showed it to adopt a less ordered confirmation than either relaxin-1 or relaxin-2, reflecting the presence in the former of a greater percentage of nonhelical forming amino acids. NMR spectroscopy and simulated annealing calculations were used to determine the three-dimensional structure of relaxin-3 and to identify key structural differences between the human relaxins.

Comparison of the binding of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines with their isosteric sulfonamides to the active site of phenylethanolamine N-methyltransferase

3-Fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines (14, 16, and 18-22) are highly potent and selective inhibitors of phenylethanolamine N-methyltransferase (PNMT). Molecular modeling studies with 3-fluoromethyl-7-(N-alkyl aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines, such as 16, suggested that the sulfonamide -NH-could form a hydrogen bond with the side chain of Lys57. However, SAR studies and analysis of the crystal structure of human PNMT (hPNMT) in complex with 7 indicated that the sulfonamide oxygens, and not the sulfonamide -NH-, formed favorable interactions with the enzyme. Thus, we hypothesized that replacement of the sulfonamide -NH-with a methylene group could result in compounds that would retain potency at PNMT and that would have increased lipophilicity, thus increasing the likelihood they will cross the blood brain barrier. A series of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines (23-30) were synthesized and evaluated for their PNMT inhibitory potency and affinity for the R2-adrenoceptor. A comparison of these compounds with their isosteric sulfonamides (14, 16, and 18-22) showed that the sulfones were more lipophilic but less potent than their corresponding sulfonamides. Sulfone 24 (hPNMT K-i = 1.3 mu M) is the most potent compound in this series and is quite selective for PNMT versus the R2-adrenoceptor, but 24 is less potent than the corresponding sulfonamide, 16 (hPNMT K-i = 0.13 mu M). We also report the crystal structure of hPNMT in complex with sulfonamide 15, from which a potential hydrogen bond acceptor within the hPNMT active site has been identified, the main chain carbonyl oxygen of Asn39. The interaction of this residue with the sulfonamide -NH-is likely responsible for much of the enhanced inhibitory potency of the sulfonamides versus the sulfones.

The risky business of doctoral management

Universities are under no less pressure to adopt risk management strategies than other public and private organisations. The risk management of doctoral education is a particularly important issue given that a doctorate is the highest academic qualification a university offers and stakes are high in terms of assuring its quality. However, intense risk management can interfere with the intellectual and pedagogical work which are essentially part of doctoral education. This paper seeks to understand how the culture of risk meets the culture of doctoral education and with what effect. The authors draw on sociological understandings of risk in the work of Anthony Giddens (2002) and Ulrich Beck (1992), the anthropological focus on liminality in the work of Mary Douglas (1990), and the psychological theorising of human error in the work of James Reason (1990). The paper concludes that risk consciousness brings its own risks—in particular, the potential transformation of a culture based on intellect into a culture based on compliance.

Worker remittances and the global preconditions of ‘smart development’

With the growing environmental crisis affecting our globe, ideas to weigh economic or social progress by the ‘energy input’ necessary to achieve it are increasingly gaining acceptance. This question is intriguing and is being dealt with by a growing number of studies, focusing on the environmental price of human progress. Even more intriguing, however, is the question of which factors of social organization contribute to a responsible use of the resources of our planet to achieve a given social result (‘smart development’). In this essay, we present the first systematic study on how migration – or rather, more concretely, received worker remittances per GDP – helps the nations of our globe to enjoy social and economic progress at a relatively small environmental price. We look at the effects of migration on the balance sheets of societal accounting, based on the ‘ecological price’ of the combined performance of democracy, economic growth, gender equality, human development, research and development, and social cohesion. Feminism in power, economic freedom, population density, the UNDP education index as well as the receipt of worker remittances all significantly contribute towards a ‘smart overall development’, while high military expenditures and a high world economic openness are a bottleneck for ‘smart overall development’.

How relevant is the origin of human capital for immigrant wages? Evidence from Spain

The objective of this article is to analyse the role played by the different components of human capital in the wage determination of immigrants in the Spanish labour market. Using microdata from the Encuesta Nacional de Inmigrantes, we find that human capital of immigrants acquired in Spain presents higher returns than human capital obtained in home countries, reflecting the limited international transferability of the latter. This result is reinforced by the strong heterogeneity observed in wage returns to different kinds of human capital across immigrants from different origins and, in particular, by the fact that immigrants with the higher returns to human capital acquired in their home countries are those coming from other developed countries and Latin America, the two regions more similar to Spain in terms of development and/or culture.

Práticas corporais alternativas e educação física : entre a formação e a intervenção

Universidade Estadual de Campinas. Faculdade de Educação Física

Le silence des limites dans la littérature: Deux exemples :Michel de Montaigne et Marguerite Duras

The paper studies the concept of limit in literary discourse. Two aspects are discussed: 1) the limit as a necessary structuring element in the process of verbal nomination; 2) the limit as a verbal constraint which appeals to be defeated in case of extreme experience, as death, love, desire, Shoah. We analyse two examples dealing with the language restriction in the literary practice: Montaignes’ essays and Duras’ novels. Montaigne adopts a specific style of unlimited judgements and topics accumulation in a spontaneous order and logic with the purpose of revealing the deepest profile of human nature. Duras practices a minimalist writing that ruins the linear syntactic structure and the narrative model, achieving an effect of silence thus providing the possibility of unlimited meaning.

Studies in Christian worship /

"First published as the third part of Human nature a revelation of the divine, May, 1902."--verso of t.p.