Viral sovereignty

In the mid-2000s, Indonesia became ‘ground zero’ for an outbreak of highly pathogenic avian influenza, the H5N1 strain, which global health experts feared would cause a devastating pandemic. When asked to participate in global health measures, Indonesia’s minister of health argued that the country had ‘viral sovereignty’ and refused to share samples with the World Health Organization’s Global Influenza Surveillance and Response System. The global health community claimed, in response, that such refusal put all humanity at risk. Both sides of the debate expressed paranoia, resentment, and mistrust as their different ideas of security came into play. In the midst of these accusations and counteraccusations, little attention was paid to the larger social and ecological context in which the virus had emerged and flourished. I argue that when vital matter gets taken up within frameworks of security, human and animal bodies, narratives, and politics get scripted through concerns for biological and political vulnerability. Paranoia, resentment, and mistrust resonate as the multiple vulnerabilities of bodies and their social positioning frame uncertain futures

The Viral Creep Elephants and Herpes in Times of Extinction

Across the world, elephant endotheliotropic herpesvirus is increasingly killing elephant calves and threatening the long-term survival of the Asian elephant, a species that is currently facing extinction. This article presents three open-ended stories of elephant care in times of death and loss: at places of confinement and elephant suffering like the zoos in Seattle and Zurich as well as in the conflict-ridden landscapes of South India, where the country's last free-ranging elephants live. Our stories of deadly viral-elephant-human becomings remind us that neither human care, love, and attentiveness nor techniques of control and creative management are sufficient to fully secure elephant survival. The article introduces the concept of "viral creep" to explore the ability of a creeping, only partially knowable virus to rearrange relations among people, animals, and objects despite multiple experimental human regimes of elephant care, governance, and organization. The viral creep exceeds the physical and intellectual contexts of human interpretation and control. It reminds us that uncertainty and modes of imaging are always involved when we make sense of the world around us

Face-to-face and online collaboration: appreciating rules and adding complexity

This paper reports how 6-8 year-old children build, play and share video-games in an animated programming environment. Children program their games using rules as creative tools in the construction process. While working both face-to-face and remotely on their games, we describe how they can collaboratively come to explain phenomena arising from programmed or 'system' rules. Focusing on one illustrative case study of two children, we propose two conjectures. First, we claim that in face-to-face collaboration, the children centre their attention on narrative, and address the problem of translating the narrative into system rules which can be =programmed‘ into the computer. This allowed the children to debug any conflicts between system rules in order to maintain the flow of the game narrative. A second conjecture is that over the Internet children were encouraged to add complexity and innovative elements to their games, not by the addition of socially-constructed or 'player' rules but rather through additional system rules which elaborate the mini-formalism in which they engaged. This shift of attention to system rules occurred at the same time, and perhaps as a result of, a loosening of the game narrative that was a consequence of the remoteness of the interaction

A CellAgeClock for expedited discovery of anti-ageing compounds

We aim to improve anti-ageing drug discovery, currently achieved through laborious and lengthy longevity analysis. Recent studies demonstrated that the most accurate molecular method to measure human age is based on CpG methylation profiles, as exemplified by several epigenetics clocks that can accurately predict an individual’s age. Here, we developed CellAgeClock, a new epigenetic clock that measures subtle ageing changes in primary human cells in vitro . As such, it provides a unique tool to measure effects of relatively short pharmacological treatments on ageing. We validated the CellAgeClock against known longevity drugs such as rapamycin and trametinib. Moreover, we uncovered novel anti-ageing drugs, torin2 and Dactolisib (BEZ-235), demonstrating the value of our approach as a screening and discovery platform for anti-ageing strategies. The CellAgeClock outperforms other epigenetic clocks in measuring subtle ageing changes in primary human cells in culture. The tested drug treatments reduced senescence and other ageing markers, further consolidating our approach as a screening platform. Finally, we show that the novel anti-ageing drugs we uncovered in vitro , indeed increased longevity in vivo . Our method expands the scope of CpG methylation profiling from measuring human chronological and biological age from human samples in years, to accurately and rapidly detecting anti-ageing potential of drugs using human cells in vitro , providing a novel accelerated discovery platform to test sought after geroprotectors

Analysis of the expression patterns, subcellular localisations and interaction partners of Drosophila proteins using a pigP protein trap library.

Although we now have a wealth of information on the transcription patterns of all the genes in the Drosophila genome, much less is known about the properties of the encoded proteins. To provide information on the expression patterns and subcellular localisations of many proteins in parallel, we have performed a large-scale protein trap screen using a hybrid piggyBac vector carrying an artificial exon encoding yellow fluorescent protein (YFP) and protein affinity tags. From screening 41 million embryos, we recovered 616 verified independent YFP-positive lines representing protein traps in 374 genes, two-thirds of which had not been tagged in previous P element protein trap screens. Over 20 different research groups then characterized the expression patterns of the tagged proteins in a variety of tissues and at several developmental stages. In parallel, we purified many of the tagged proteins from embryos using the affinity tags and identified co-purifying proteins by mass spectrometry. The fly stocks are publicly available through the Kyoto Drosophila Genetics Resource Center. All our data are available via an open access database (Flannotator), which provides comprehensive information on the expression patterns, subcellular localisations and in vivo interaction partners of the trapped proteins. Our resource substantially increases the number of available protein traps in Drosophila and identifies new markers for cellular organelles and structures.This work was supported by a project grant from the Wellcome Trust [076739], by a Wellcome Trust Principal Research Fellowship to D.StJ. [049818 and 080007], and by core support from the Wellcome Trust [092096] and Cancer Research UK [A14492].This is the final version of the article. It was first available from The Company of Biologists via http://dx.doi.org/10.1242/dev.11105

Tracking the impacts of climate change on human health via indicators: lessons from the Lancet Countdown

Background: In the past decades, climate change has been impacting human lives and health via extreme weather and climate events and alterations in labour capacity, food security, and the prevalence and geographical distribution of infectious diseases across the globe. Climate change and health indicators (CCHIs) are workable tools designed to capture the complex set of interdependent interactions through which climate change is affecting human health. Since 2015, a novel sub-set of CCHIs, focusing on climate change impacts, exposures, and vulnerability indicators (CCIEVIs) has been developed, refined, and integrated by Working Group 1 of the “Lancet Countdown: Tracking Progress on Health and Climate Change”, an international collaboration across disciplines that include climate, geography, epidemiology, occupation health, and economics. / Discussion: This research in practice article is a reflective narrative documenting how we have developed CCIEVIs as a discrete set of quantifiable indicators that are updated annually to provide the most recent picture of climate change’s impacts on human health. In our experience, the main challenge was to define globally relevant indicators that also have local relevance and as such can support decision making across multiple spatial scales. We found a hazard, exposure, and vulnerability framework to be effective in this regard. We here describe how we used such a framework to define CCIEVIs based on both data availability and the indicators’ relevance to climate change and human health. We also report on how CCIEVIs have been improved and added to, detailing the underlying data and methods, and in doing so provide the defining quality criteria for Lancet Countdown CCIEVIs. / Conclusions: Our experience shows that CCIEVIs can effectively contribute to a world-wide monitoring system that aims to track, communicate, and harness evidence on climate-induced health impacts towards effective intervention strategies. An ongoing challenge is how to improve CCIEVIs so that the description of the linkages between climate change and human health can become more and more comprehensive

Tracking the impacts of climate change on human health via indicators: lessons from the Lancet Countdown

Background: In the past decades, climate change has been impacting human lives and health via extreme weather and climate events and alterations in labour capacity, food security, and the prevalence and geographical distribution of infectious diseases across the globe. Climate change and health indicators (CCHIs) are workable tools designed to capture the complex set of interdependent interactions through which climate change is affecting human health. Since 2015, a novel sub-set of CCHIs, focusing on climate change impacts, exposures, and vulnerability indicators (CCIEVIs) has been developed, refined, and integrated by Working Group 1 of the “Lancet Countdown: Tracking Progress on Health and Climate Change”, an international collaboration across disciplines that include climate, geography, epidemiology, occupation health, and economics. Discussion: This research in practice article is a reflective narrative documenting how we have developed CCIEVIs as a discrete set of quantifiable indicators that are updated annually to provide the most recent picture of climate change’s impacts on human health. In our experience, the main challenge was to define globally relevant indicators that also have local relevance and as such can support decision making across multiple spatial scales. We found a hazard, exposure, and vulnerability framework to be effective in this regard. We here describe how we used such a framework to define CCIEVIs based on both data availability and the indicators’ relevance to climate change and human health. We also report on how CCIEVIs have been improved and added to, detailing the underlying data and methods, and in doing so provide the defining quality criteria for Lancet Countdown CCIEVIs. Conclusions: Our experience shows that CCIEVIs can effectively contribute to a world-wide monitoring system that aims to track, communicate, and harness evidence on climate-induced health impacts towards effective intervention strategies. An ongoing challenge is how to improve CCIEVIs so that the description of the linkages between climate change and human health can become more and more comprehensive

Human Rights in the Context of Environmental Conservation on the US-Mexico Border

At Cabeza Priesta National Wildlife Refuge, a wilderness area on the US-Mexico border in Arizona, conflicting policies permit the provision of supplementary water for wildlife but not for undocumented immigrants passing through the area. Federal refuge environmental policy prioritizes active management of endangered and threatened species. Vast systems of water resources have been developed to support wildlife conservation in this extremely hot and dry environment. At the same time, humanitarian groups are not allowed to supply water to undocumented border crossers in the park. Human border-crossers must utilize non-potable wildlife water guzzlers for survival and face risk of illness or death by dehydration. This article analyzes human rights via an ethnographic lens. From this perspective, water policy at the wildlife refuge brings into question the value of human life in a border conservation context, especially for those entering the site illegally

Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. Video Abstract [Figure presented] Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology