A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson's disease.

in Science translational medicine (2020), 12(560),

Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder with monogenic forms representing prototypes of the underlying molecular pathology and reproducing to variable degrees the sporadic ... [more ▼]

Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder with monogenic forms representing prototypes of the underlying molecular pathology and reproducing to variable degrees the sporadic forms of the disease. Using a patient-based in vitro model of PARK7-linked PD, we identified a U1-dependent splicing defect causing a drastic reduction in DJ-1 protein and, consequently, mitochondrial dysfunction. Targeting defective exon skipping with genetically engineered U1-snRNA recovered DJ-1 protein expression in neuronal precursor cells and differentiated neurons. After prioritization of candidate drugs, we identified and validated a combinatorial treatment with the small-molecule compounds rectifier of aberrant splicing (RECTAS) and phenylbutyric acid, which restored DJ-1 protein and mitochondrial dysfunction in patient-derived fibroblasts as well as dopaminergic neuronal cell loss in mutant midbrain organoids. Our analysis of a large number of exomes revealed that U1 splice-site mutations were enriched in sporadic PD patients. Therefore, our study suggests an alternative strategy to restore cellular abnormalities in in vitro models of PD and provides a proof of concept for neuroprotection based on precision medicine strategies in PD. [less ▲]

Body weight and high-fat diet are associated with epigenetic aging in female members of the BXD murine family.

in Aging cell (2020), 19(9), 13207

DNA methylation (DNAm) is shaped by genetic and environmental factors and modulated by aging. Here, we examine interrelations between epigenetic aging, body weight (BW), and life span in 12 isogenic ... [more ▼]

DNA methylation (DNAm) is shaped by genetic and environmental factors and modulated by aging. Here, we examine interrelations between epigenetic aging, body weight (BW), and life span in 12 isogenic strains from the BXD family of mice that exhibit over twofold variation in longevity. Genome-wide DNAm was assayed in 70 liver specimens from predominantly female cases, 6-25 months old, that were maintained on normal chow or high-fat diet (HFD). We defined subsets of CpG regions associated with age, BW at young adulthood, and strain-by-diet-dependent life span. These age-associated differentially methylated CpG regions (age-DMRs) featured distinct genomic characteristics, with DNAm gains over time occurring in sites such as promoters and exons that have high CpG density and low average methylation. CpG regions associated with BW were enriched in introns, tended to have lower methylation in mice with higher BW, and were inversely correlated with gene expression (i.e., higher mRNA levels in mice with higher BW). CpG regions associated with life span were linked to genes involved in life span modulation, including the telomerase reverse transcriptase gene, Tert, which had both lower methylation and higher expression in long-lived strains. An epigenetic clock defined from age-DMRs revealed accelerated aging in mice belonging to strains with shorter life spans. Both higher BW and the HFD were associated with accelerated epigenetic aging. Our results highlight the age-accelerating effect of heavier BW. Furthermore, we demonstrate that the measure of epigenetic aging derived from age-DMRs can predict genotype and diet-induced differences in life span among female BXD members. [less ▲]

Introduction: The ITU as Actor, Arena, and Antenna of Techno-Diplomacy

in Fickers, Andreas; Balbi, Gabriele (Eds.) History of the International Telecoommunication Union (ITU): Transnational Techno-Diplomacy from the Telegraph to the Internet (2020)

This book focuses on the history of the International Telecommunication Union (ITU), from its origins in the mid-19th century to nowadays. ITU was the fi rst international organization ever and still ... [more ▼]

This book focuses on the history of the International Telecommunication Union (ITU), from its origins in the mid-19th century to nowadays. ITU was the fi rst international organization ever and still plays a crucial role in managing global telecommunications today. Putting together some of the most relevant scholars in the fi eld of transnational communications, the book covers the history of ITU from 1865 to digital times in a truly global perspective, taking into account several technologies like the telegraph, the telephone, cables, wireless, radio, television, satellites, mobile phone, the internet and others. The main goal is to identify the long-term strategies of regulation and the techno-diplomatic manoeuvres taken inside ITU, from convincing the majority of the nations to establish the offi cial seat of the Telegraph Union bureau in Switzerland in the 1860s, to contrasting the multi-stakeholder model of Internet governance (supported by US and ICANN). History of the International Telecommunication Union is a trans-disciplinary text and can be interesting for scholars and students in the fi elds of telecommunications, media, international organizations, transnational communication, diplomacy, political economy of communication, STS, and others. It has the ambition to become a reference point in the history of ITU and, at the same time, just the fi rst comprehensive step towards a longer, inter-technological, political and cultural history of transnational communications to be written in the future. [less ▲]

History of the International Telecommunication Union (ITU). Transnational Techno-Diplomacy from the Telegraph to the Internet.

Book published by De Gruyter (2020)

This book focuses on the history of the International Telecommunication Union (ITU), from its origins in the mid-19th century to nowadays. ITU was the fi rst international organization ever and still ... [more ▼]

This book focuses on the history of the International Telecommunication Union (ITU), from its origins in the mid-19th century to nowadays. ITU was the fi rst international organization ever and still plays a crucial role in managing global telecommunications today. Putting together some of the most relevant scholars in the fi eld of transnational communications, the book covers the history of ITU from 1865 to digital times in a truly global perspective, taking into account several technologies like the telegraph, the telephone, cables, wireless, radio, television, satellites, mobile phone, the internet and others. The main goal is to identify the long-term strategies of regulation and the techno-diplomatic manoeuvres taken inside ITU, from convincing the majority of the nations to establish the offi cial seat of the Telegraph Union bureau in Switzerland in the 1860s, to contrasting the multi-stakeholder model of Internet governance (supported by US and ICANN). History of the International Telecommunication Union is a trans-disciplinary text and can be interesting for scholars and students in the fi elds of telecommunications, media, international organizations, transnational communication, diplomacy, political economy of communication, STS, and others. It has the ambition to become a reference point in the history of ITU and, at the same time, just the fi rst comprehensive step towards a longer, inter-technological, political and cultural history of transnational communications to be written in the future. [less ▲]

Power-sharing and democratization in Africa: the Kenyan experience

in Journal of International Relations and Development (2020), 23(3), 607-635

Review of Elizabeth Guffey (2018): Designing Disability: Symbols, Space and Society. London: Bloomsbury.

in Design Issues (2020), 36(1), 100-101

In her pathbreaking book Designing Disability: Symbols, Space and Society, Elizabeth Guffey provides vital insights into decades of social and design processes that ultimately produced the most ubiquitous ... [more ▼]

In her pathbreaking book Designing Disability: Symbols, Space and Society, Elizabeth Guffey provides vital insights into decades of social and design processes that ultimately produced the most ubiquitous symbol of disability—and accessibility—worldwide: The International Symbol of Access (ISA). Building on existing scholarship from a range of disciplines coupled with original historical research, this book uncovers the origins and evolving (largely transatlantic) architectural and design discourse, and several moments of serendipity, that led to its creation. The ISA has since diffused to become part of the built environment in all corners of the world. Richly illustrated and charting at times vitriolic debates, protest activities, and artistic interventions up to the contemporary era, Guffey weaves together activist and aesthetic perspectives into a tapestry of social and design history relating to disability and accessibility. Structured in historical phases, the book’s chapters progress across larger and shorter stretches over more than a century of wheelchair design, social and welfare policies and programs (mostly in the US, UK, and Scandinavia), architectural standards, and symbols relating to barriers and accessibility measures. Guffey engages the reader in what is necessarily a multidisciplinary, multilevel investigation, with unexpected twists and turns. On one level, the book focuses on the politics of highest office, with US Presidents Franklin D. Roosevelt and Dwight D. Eisenhower (who permanently or temporarily used wheelchairs) sketched against the backdrop of the lack of accessible government buildings in Washington, DC, and the social consensus then to hide impairment for fear of stigmatization (shifted marginally by disabled Veterans). On another level, welfare state provisions in the US, UK, and Scandinavia are discussed in light of progressive legislation and the persistent challenges of implementation. Finally, at ground level, the utmost significance of individuals devoted to universal design writ large becomes manifestly evident. Guffey recounts how, in US universities, inspirational figures such as Timothy Nugent (at Illinois), Ron Mace (at North Carolina State), and Viktor Papanek (at Purdue, CalArts, Kansas, etc.), campus planners, and students designed and constructed new worlds on the drawing board and poured in concrete. We follow design professionals, such as architect Selwyn Goldsmith in the UK, who was a strident arbiter of accessibility. Academic initiatives went hand-in-fist with advocacy activities in organizations and protest and artistic actions in the streets. Indeed, to raise general awareness of the ever-present attitudinal and structural barriers—institutionalized discrimination—that disabled people face daily and to secure disability rights, disability protests and cross-national organizing have repeatedly been necessary. The long and bumpy road to universal design extends into the future. Integral to this history of design development, revision, and critiques of various symbols of disability have been international events (world expositions, Olympics & Paralympics) and organizations (Rehabilitation International), artistic inspiration, design competitions, and guerilla art interventions. Tracing the convoluted process of designing what would become the ISA—fifty years ago now—leads to Susanne Koefoed, a Danish design student, and Karl Montan, leader of the Swedish Institute for the Handicapped, but also to international negotiations and chance. The on-going questioning of the official ISA, especially, its “misfit” nature as an amalgam of technical aid and person, emphasizes the shift from invisibility to ubiquity of disability via social change and political activism as well as cultural representations and the need for signs of identity. In the new century, newer initiatives in the US, such as Brendan Murphy’s and the Accessible Icon Project (developed by Sara Hendren and Brian Glenney), have challenged the official ISA, revealing both persistence and change in understandings of disability and accessibility. When integrated into signage, the ISA designates accessible spaces and facilities. If the ISA has become present in public buildings and spaces everywhere, cultural notions of disability and access remain understudied across the social sciences, with especially the Global South remaining a blank page. Research is needed to chart the diverse local interpretations that mirror shifts from exclusion to inclusion of disabled people as the human rights revolution witnessed since the end of WWII continues, but also suffers backlash, even in the Global North. Paradoxically, this global icon refers simultaneously to disability, and its ameliorating factor, accessibility. Yet, the ambivalence and debate surrounding the ISA persist, as Guffey emphasizes especially in the later chapters, focusing on proposed alternatives to the existing ISA, codified as it is in law and conforming to the guidelines of the International Organization for Standardization (ISO). Until universal design (and the universalizing social policies likely needed to support it) succeeds in reducing the barriers in environments and in attitudes and in maximizing the usefulness of products and services during the design stage, identity formation processes are among the most positive aspects of the ISA. The icon’s influence and implementation extend far beyond marking modifications to the built environment. Whether taken-for-granted, modified or critiqued, the current ISA has spread globally. It can now be found wherever people move in physical space, finding their way. The symbol testifies to the on-going shift from exclusion, along a slow and winding road, to social inclusion and full participation of disabled people. In sum, Guffey brings scholarship on the ISA to the next stage. It complements studies that chart the influence of disabled peoples’ organizations and of international organizations as they facilitated remarkable shifts in disability paradigms. Yet institutionalized discrimination abounds, with the ISA marking that accessibility and universal design are far from achieved. If a few imprecisions tarnish the literature list, this historical work reconstructing a largely Western process cannot be faulted for not providing a complete global analysis of ISA implementation and adjustment. In that vein, with contributions from Guffey herself, the current exhibition “Viktor Papanek: The Politics of Design” (Kries, Klein & Clarke, 2018) indeed extends the discussion to the Global South and across further disciplines, rightfully embedding the dialogue about symbols of disability and enhancing access within broader contexts. Footnote: Kries, Matteo, Amelie Klein & Alison J. Clarke (eds.) (2018). Viktor Papanek: The Politics of Design. Weil am Rhein, Germany: Vitra Design Museum. ISBN: 978-3-945852-26-2. The exhibition is currently on view at Germany’s Vitra Design Museum (20 September 2018–10 March 2019), then at Barcelona Design Museum (20 October 2019–2 February 2020). [less ▲]

The exposome and health: Where chemistry meets biology

in Science (2020), 367(6476), 392--396

Despite extensive evidence showing that exposure to specific chemicals can lead to disease, current research approaches and regulatory policies fail to address the chemical complexity of our world. To ... [more ▼]

Despite extensive evidence showing that exposure to specific chemicals can lead to disease, current research approaches and regulatory policies fail to address the chemical complexity of our world. To safeguard current and future generations from the increasing number of chemicals polluting our environment, a systematic and agnostic approach is needed. The \textquotedblleftexposome\textquotedblright concept strives to capture the diversity and range of exposures to synthetic chemicals, dietary constituents, psychosocial stressors, and physical factors, as well as their corresponding biological responses. Technological advances such as high-resolution mass spectrometry and network science have allowed us to take the first steps toward a comprehensive assessment of the exposome. Given the increased recognition of the dominant role that nongenetic factors play in disease, an effort to characterize the exposome at a scale comparable to that of the human genome is warranted. [less ▲]

La disparition de la cause du contrat

in Prüm, André; Ancel, Pascal (Eds.) Réformer le droit des contrats ? Analyse comparée autour du droit luxembourgeois (2020)

réflexions sur l'utilité des concept traditionnel de cause des contrats et discussion des arguments pour le maintien ou la suppression de la cause comme condition de validité des contrats

On the long run sustainability of small jurisdictions

in Journal of Industrial and Business Economics (2020)

"Heldentod" - "Soldatenfriedhof" in Großes Lexikon der Bestattungs- und Friedhofskultur. Wörterbuch zur Sepulkralkultur, Medienkultureller Teil

in Janz, Nina (Ed.) Großes Lexikon der Bestattungs- und Friedhofskultur. Wörterbuch zur Sepulkralkultur, Medienkultureller Teil: Von Absurdes Theater bis Zombie (2020)