226 research outputs found

    'Word from the street' : when non-electoral representative claims meet electoral representation in the United Kingdom

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    Taking the specific case of street protests in the UK – the ‘word from the street’– this article examines recent (re)conceptualizations of political representation, most particularly Saward’s notion of ‘representative claim’. The specific example of nonelectoral claims articulated by protestors and demonstrators in the UK is used to illustrate: the processes of making, constituting, evaluating and accepting claims for and by constituencies and audiences; and the continuing distinctiveness of claims based upon electoral representation. Two basic questions structure the analysis: first, why would the political representative claims of elected representatives trump the nonelectoral claims of mass demonstrators and, second, in what ways does the ‘perceived legitimacy’ of the former differ from the latter

    Characterization of IXINITY (Trenonacog Alfa), a Recombinant Factor IX with Primary Sequence Corresponding to the Threonine-148 Polymorph

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    The goal of these studies was to extensively characterize the first recombinant FIX therapeutic corresponding to the threonine-148 (Thr-148) polymorph, IXINITY (trenonacog alfa [coagulation factor IX (recombinant)]). Gel electrophoresis, circular dichroism, and gel filtration were used to determine purity and confirm structure. Chromatographic and mass spectrometry techniques were used to identify and quantify posttranslationalmodifications. Activity was assessed as the ability to activate factor X (FX) both with and without factor VIIIa (FVIIIa) and in a standard clotting assay. All results were consistent across multiple lots. Trenonacog alfa migrated as a single band onCoomassie-stained gels; activity assayswere normal and showed97% -carboxylation and underwent the appropriate structural change upon binding calcium ions. Trenonacog alfa was activated normally with factor XIa (FXIa); once activated it bound to FVIIIa and FXa. When activated to FIXa, it was inhibited efficiently by antithrombin. Glycosylation patterns were similar to plasma-derived FIX with sialic acid content consistent with the literature reports of good pharmacokinetic performance. These studies have shown that trenonacog alfa is a highly pure product with a primary sequence and posttranslational modifications consistent with the common Thr-148 polymorphism of plasma-derived FIX

    Characterization of IXINITY (Trenonacog Alfa), a Recombinant Factor IX with Primary Sequence Corresponding to the Threonine-148 Polymorph

    Get PDF
    The goal of these studies was to extensively characterize the first recombinant FIX therapeutic corresponding to the threonine-148 (Thr-148) polymorph, IXINITY (trenonacog alfa [coagulation factor IX (recombinant)]). Gel electrophoresis, circular dichroism, and gel filtration were used to determine purity and confirm structure. Chromatographic and mass spectrometry techniques were used to identify and quantify posttranslationalmodifications. Activity was assessed as the ability to activate factor X (FX) both with and without factor VIIIa (FVIIIa) and in a standard clotting assay. All results were consistent across multiple lots. Trenonacog alfa migrated as a single band onCoomassie-stained gels; activity assayswere normal and showed97% -carboxylation and underwent the appropriate structural change upon binding calcium ions. Trenonacog alfa was activated normally with factor XIa (FXIa); once activated it bound to FVIIIa and FXa. When activated to FIXa, it was inhibited efficiently by antithrombin. Glycosylation patterns were similar to plasma-derived FIX with sialic acid content consistent with the literature reports of good pharmacokinetic performance. These studies have shown that trenonacog alfa is a highly pure product with a primary sequence and posttranslational modifications consistent with the common Thr-148 polymorphism of plasma-derived FIX

    Bioluminescence imaging of chronic Trypanosoma cruzi infections reveals tissue-specific parasite dynamics and heart disease in the absence of locally persistent infection.

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    Chronic Trypanosoma cruzi infections lead to cardiomyopathy in 20-30% of cases. A causal link between cardiac infection and pathology has been difficult to establish because of a lack of robust methods to detect scarce, focally distributed parasites within tissues. We developed a highly sensitive bioluminescence imaging system based on T. cruzi expressing a novel luciferase that emits tissue-penetrating orange-red light. This enabled long-term serial evaluation of parasite burdens in individual mice with an in vivo limit of detection of significantly less than 1000 parasites. Parasite distributions during chronic infections were highly focal and spatiotemporally dynamic, but did not localize to the heart. End-point ex vivo bioluminescence imaging allowed tissue-specific quantification of parasite loads with minimal sampling bias. During chronic infections, the gastro-intestinal tract, specifically the colon and stomach, was the only site where T. cruzi infection was consistently observed. Quantitative PCR-inferred parasite loads correlated with ex vivo bioluminescence and confirmed the gut as the parasite reservoir. Chronically infected mice developed myocarditis and cardiac fibrosis, despite the absence of locally persistent parasites. These data identify the gut as a permissive niche for long-term T. cruzi infection and show that canonical features of Chagas disease can occur without continual myocardium-specific infection

    Synthesis and antitrypanosomal activities of novel pyridylchalcones

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    Collaboration with the London School of Hygiene and Tropical Medicine. The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.A library of novel pyridylchalcones were synthesised and screened against Trypanosoma brucei rhodesiense. Eight were shown to have good activity with the most potent 8 having an IC50 value of 0.29 M. Cytotoxicity testing with human KB cells showed a good selectivity profile for this compound with a selectivity index of 47. Little activity was seen when the library was tested against Leishmania donovani. In conclusion, pyridylchalcones are promising leads in the development of novel compounds for the treatment of human African trypanosomiasis (HAT)

    Growth or decline in the Church of England during the decade of Evangelism: did the Churchmanship of the Bishop matter?

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    The Decade of Evangelism occupied the attention of the Church of England throughout the 1990s. The present study employs the statistics routinely published by the Church of England in order to assess two matters: the extent to which these statistics suggest that the 43 individual dioceses finished the decade in a stronger or weaker position than they had entered it and the extent to which, according to these statistics, the performance of dioceses led by bishops shaped in the Evangelical tradition differed from the performance of dioceses led by bishops shaped in the Catholic tradition. The data demonstrated that the majority of dioceses were performing less effectively at the end of the decade than at the beginning, in terms of a range of membership statistics, and that the rate of decline varied considerably from one diocese to another. The only exception to the trend was provided by the diocese of London, which experienced some growth. The data also demonstrated that little depended on the churchmanship of the diocesan bishop in shaping diocesan outcomes on the performance indicators employed in the study
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