Lentiviral gene therapy reverts GPIX expression and phenotype in Bernard-Soulier syndrome type C

Bernard-Soulier syndrome (BSS) is a rare congenital disease characterized by macrothrombocytopenia and frequent bleeding. It is caused by pathogenic variants in three genes (GP1BA, GP1BB, or GP9) that encode for the GPIbα, GPIbβ, and GPIX subunits of the GPIb-V-IX complex, the main platelet surface receptor for von Willebrand factor, being essential for platelet adhesion and aggregation. According to the affected gene, we distinguish BSS type A1 (GP1BA), type B (GP1BB), or type C (GP9). Pathogenic variants in these genes cause absent, incomplete, or dysfunctional GPIb-V-IX receptor and, consequently, a hemorrhagic phenotype. Using gene-editing tools, we generated knockout (KO) human cellular models that helped us to better understand GPIb-V-IX complex assembly. Furthermore, we developed novel lentiviral vectors capable of correcting GPIX expression, localization, and functionality in human GP9-KO megakaryoblastic cell lines. Generated GP9-KO induced pluripotent stem cells produced platelets that recapitulated the BSS phenotype: absence of GPIX on the membrane surface and large size. Importantly, gene therapy tools reverted both characteristics. Finally, hematopoietic stem cells from two unrelated BSS type C patients were transduced with the gene therapy vectors and differentiated to produce GPIX-expressing megakaryocytes and platelets with a reduced size. These results demonstrate the potential of lentiviral-based gene therapy to rescue BSS type C

How Did the West Usurp the Rest? Origins of the Great Divergence over the Longue Durée

Traditional explanations of the “rise of the West” have located the sources of Western supremacy in structural or long-term developmental factors internal to Europe. By contrast, revisionist accounts have emphasized the conjunctural and contingent aspects of Europe's ascendancy, while highlighting intersocietal conditions that shaped this trajectory to global dominance. While sharing the revisionist focus on the non-Western sources of European development, we challenge their conjunctural explanation, which denies differences between “West” and “East” and within Europe. We do so by deploying the idea of uneven and combined development (UCD), which redresses the shortcomings found on both sides of the debate: the traditional Eurocentric focus on the structural and immanent characteristics of European development and the revisionists’ emphasis on contingency and the homogeneity of Eurasian societies. UCD resolves these problems by integrating structural and contingent factors into a unified explanation: unevenness makes sense of the sociological differences that revisionists miss, while combination captures the aleatory processes of interactive and multilinear development overlooked by Eurocentric approaches. From this perspective, the article examines the sociologically generative interactions between European and Asian societies’ development over the longue durée and traces how the breakdown of feudalism and the rise of capitalism in Europe were fundamentally rooted in and conditioned by extra-European structures and agents. This then sets up our conjunctural analysis of a central yet underappreciated factor explaining Europe rise to global dominance: the disintegration of the Mughal Empire and Britain's colonization of India

Expressive free speech, the state, and the public sphere: A Bakhtinian–Deleuzian analysis of ‘public address’ at Hyde Park

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2008 Taylor & Francis.In this paper I explore how struggles around free speech between social movements and the state are often underpinned by a deeper struggle around expressive images of what counts as either ‘decent’ or ‘indecent’ discussion. These points are developed by exploring what is arguably the most famous populist place for free speech in Britain, namely Hyde Park. In 1872 the state introduced the Parks Regulation Act in order to regulate, amongst other things, populist uses of free speech at Hyde Park. However, although the 1872 Act designated a site in Hyde Park for public meetings, it did not mention ‘free speech’. Rather, the 1872 Act legally enforced the liberty to make a ‘public address’ and this was implicitly contrasted by the state of an expressive image of ‘indecent’ speakers exercising their ‘right’ of free speech at Hyde Park. Once constructed, the humiliating image of ‘indecent’ free speech could then be used by the state to regulate actual utterances of public speakers at Hyde Park. But the paper shows how in the years immediately following 1872 a battle was fought out in Hyde Park over the expressive image of public address between the state and regulars using Hyde Park as a public sphere to exercise free speech. For its part the state had to engage in meaningful deliberative forms of discussion within its own regulatory framework and with the public sphere at Hyde Park in order to maintain the legal form, content and expression of the 1872 Act. To draw out the implications of these points I employ some of the theoretical ideas of the Bakhtin Circle and Gilles Deleuze. Each set of thinkers in their own way make valuable contributions for understanding the relationship between the state, public sphere and expressive images

War Memorial: the Calling Blighty films and remembrance

The Calling Blighty series of nearly 400 films were messages from servicemen in India and Burma to be shown to families in local cinemas at the end of the Second World War. They are remarkable because of their cinematic quality and the men’s direct address to camera, and the 64 remaining films reveal much about family memories, public remembrance and representation of the Northern voice on screen. Along with Marion Hewitt of the North West Film Archive, the author has been engaged in an ongoing project to find the relatives of the men of the ‘Forgotten Army’ in the films and recreate the screenings. These ritual ceremonies of remembrance have been augmented by a media memorial, a Channel 4 TV documentary about the project and creative critical reflection through an experimental artist’s film, drawing on the archive material. This analysis of the project looks at the relationship of the Blighty films to wartime film and documentary, in particular, as well as soldier self-representation, and their implications for both family and communal remembrance

De Statuis: christian sources on the “Riot of statues”

La información sobre la “Revuelta de las estatuas” acontecida en Antioquía en el año 387 d. C. transmitida por autores cristianos contemporáneos a la asonada y del siglo V d. C. relata los acontecimientos desde diversos géneros literarios pero con unas líneas directrices comunes. La decisiva intervención del sector meleciano de la Iglesia antioquena para conseguir el perdón del emperador Teodosio y el retrato de éste como un monarca obediente a las figuras cristianas son las pautas comunes en los relatos de Juan Crisóstomo, Ambrosio de Milán, Sozómeno y Teodoreto de Ciro.The historical account of the “Riot of the Statues” of A.D. 387 Antioch found in Christian authors coetaneous to the event and from the Vth century A.D. is provided from different literary genres but approached with common narrative lines. The decisive intervention of the Meletian group of the Antiochene Church in order to obtain the emperor Theodosius’ forgiveness and his portrait as a submissive ruler to Christian figures are the main leitmotifs in the accounts of John Chrysostom, Ambrose of Milan, Sozomenus and Theodoretus of Cyr.Este trabajo se enmarca en el proyecto de investigación FFI2012-32012 “La teatralización de la retórica y el establecimiento de un canon en la literatura griega y latina en la Antigüedad tardía (s. III-V)”, del Ministerio de Economía, Industria y Competitividad

St. Ambrose and ecclesiastical politics in Milan, 374-397

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