Civil society roles in transition: towards sustainable food?

Civil society organisations (CSOs) are often conspicuously absent in policy discussions and strategic planning about food security and the environmental sustainability of food systems. However, findings from a recent study of UK-based CSOs indicate that these groups make a variety of important contributions towards innovation in both policy and practice. This briefing paper draws attention to the disconnection between the narrowly constrained treatment of CSOs within policy circles, and the broad range of different ways that they actually engage with and influence policy and market conditions. Its purpose is to provoke new ways of thinking about civil society and provide CSOs with a new logic (and evidence) to underpin their efforts to leverage resources. Key messages are as follows: - UK-based CSOs have historically made significant contributions to the innovation trajectories of our food and agriculture systems - In contrast to markets, which tend towards homogeneity and are fuelled by competition, characteristics of civil society that crucially underpin these contributions are diversity and collaboration - Policy ignorance of civil society – its purposes, how it operates and its contributions to the development of agro-food systems – must be addressed, e.g. by incentivising and creating spaces for exchange of ideas and practices between CSOs, policy-makers and academics - Established ways of engaging CSOs in the governance of agro-food systems must be re-thought and more appropriate modes and levels of intervention in and support for civil society must be sough

Autophagy, citrullination and cancer

A cell needs to maintain a balance between biosynthesis and degradation of cellular components to maintain homeostasis. There are 2 pathways, the proteasome, which degrades short-lived proteins, and the autophagy/lysosomal pathway, which degrades long-lived proteins and organelles. Both of these pathways are also involved in antigen presentation or the effective delivery of peptides to MHC molecules for presentation to T cells. Autophagy (macroautophagy) is a key player in providing substantial sources of citrullinated peptides for loading onto MHC-II molecules to stimulate CD4(+) T cell responses. Stressful conditions in the tumor microenvironment induce autophagy in cancer cells as a mechanism to promote their survival. We therefore investigated if citrullinated peptides could stimulate CD4(+) T cell responses that would recognize these modifications produced during autophagy within tumor cells. Focusing on the intermediate filament protein VIM (vimentin), we generated citrullinated VIM peptides for immunization experiments in mice. Immunization with these peptides induced CD4(+) T cells in response to autophagic tumor targets. Remarkably, a single immunization with modified peptide, up to 14 d after tumor implant, resulted in long-term survival in 60% to 90% of animals with no associated toxicity. These results show how CD4(+) cells can mediate potent antitumor responses against modified self-epitopes presented on tumor cells, and they illustrate for the first time how the citrullinated peptides produced during autophagy may offer especially attractive vaccine targets for cancer therapy

CSO – academic collaboration: theory and practice

The Food Research Collaboration has at its heart the bringing together of academics and civil society organisations with a common interest in food policy. Over the last three years it has striven to encourage collaboration between organisations on joint ventures including a workshop in October 2016 on CSO-academic collaboration and the potential for pursuing this in the face of increasingly challenging economic and political circumstances. This Briefing Paper stems from this workshop and offers a review of the literature on collaboration as well as a summary of the four case studies presented on the day

Can Pay-As-You-Go, digitally enabled business models support sustainability transformations in developing countries? Outstanding questions and a theoretical basis for future research

This paper examines the rapidly emerging and rapidly changing phenomenon of pay-as-you-go (PAYG) digitally enabled business models, which have had significant early success in providing poor people with access to SDG relevant technologies (e.g. for electricity access, water and sanitation and agricultural irrigation). Data is analysed based on literature review, two stakeholder workshops (or “transformation labs”) and stakeholder interviews (engaging 41 stakeholders in total). This demonstrates the existing literature on PAYG is patchy at best, with no comprehensive or longitudinal, and very little theoretically grounded, research to date. The paper contributes to existing research on PAYG and sustainability transformations more broadly in two key ways. Firstly, it articulates a range of questions that remain to be answered in order to understand and deliver against the current and potential contribution of PAYG to effecting sustainability transformations (the latter we define as achieving environmental sustainability and social justice). These questions focus at three levels: national contexts for fostering innovation and technology uptake; the daily lives of poor and marginalised women and men, and; global political economies and value accumulation. Secondly, the paper articulates three areas of theory (based on emerging critical social science research on sustainable energy access) that have potential to support future research that might answer these questions, namely: socio-technical innovation system building; social practice, and; global political economy and value chain analysis. Whilst recognising existing tensions between these three areas of theory, we argue that rapid sustainability transformations demand a level of epistemic pragmatism. Such pragmatism, we argue, can be achieved by situating research using any of the above areas of theory within the broader context of Leach et al.’s (2010) Pathways Approach. This allows for exactly the kind of interdisciplinary approach, based on a commitment to pluralism and the co-production of knowledge, and firmly rooted in a commitment to environmental sustainability and social justice, that the SDGs demand

Antibiotic Treatment of Suspected and Confirmed Neonatal Sepsis Within 28 Days of Birth: A Retrospective Analysis

Neonatal sepsis causes significant mortality and morbidity worldwide. Diagnosis is usually confirmed via blood culture results. Blood culture sepsis confirmation can take days and suffer from contamination and false negatives. Empiric therapy with antibiotics is common. This study aims to retrospectively describe and compare treatments of blood culture-confirmed and unconfirmed, but suspected, sepsis within the University of Utah Hospital system. Electronic health records were obtained from 1,248 neonates from January 1, 2006, to December 31, 2017. Sepsis was categorized into early-onset (≤3 days of birth, EOS) and late-onset (\u3e3 and ≤28 days of birth, LOS) and categorized as culture-confirmed sepsis if a pathogen was cultured from the blood and unconfirmed if all blood cultures were negative with no potentially contaminated blood cultures. Of 1,010 neonates in the EOS cohort, 23 (2.3%) were culture-confirmed, most with Escherichia coli (42%). Treatment for unconfirmed EOS lasted an average of 6.1 days with primarily gentamicin and ampicillin while confirmed patients were treated for an average of 12.3 days with increased administration of cefotaxime. Of 311 neonates in the LOS cohort, 62 (20%) were culture-confirmed, most culturing coagulase negative staphylococci (46%). Treatment courses for unconfirmed LOS lasted an average of 7.8 days while confirmed patients were treated for an average of 11.4 days, these patients were primarily treated with vancomycin and gentamicin. The use of cefotaxime for unconfirmed EOS and LOS increased throughout the study period. Cefotaxime administration was associated with an increase in neonatal mortality, even when potential confounding factors were added to the logistic regression model (adjusted odds ratio 2.8, 95%CI [1.21, 6.88], p = 0.02). These results may not be generalized to all hospitals and the use of cefotaxime may be a surrogate for other factors. Given the low rate of blood culture positive diagnosis and the high exposure rate of empiric antibiotics, this patient population might benefit from improved diagnostics with reevaluation of antibiotic use guideline

The acceleration of transitions to urban sustainability: a case study of Brighton and Hove

Cities raise major challenges and opportunities for achieving sustainability. Much literature on urban sustainability focuses on specific aspects such as planning practices, urban policy or the diffusion of more sustainable technologies or practices. However, attempts at understanding the mechanisms of structural change towards sustainability have resulted in the emergence of an interdisciplinary field of sustainability transitions research. Transitions research has developed a phase model of transitions in which predevelopment, take-off, acceleration and stabilization phases are distinguished. However, the acceleration phase has received limited attention so far. This is a crucial gap as policy makers are keen to accelerate transitions. This paper aims to enhance our understanding of how local actions contribute towards accelerating urban sustainability transitions. It does so by testing an acceleration mechanisms framework through exploring the collective agency of local initiatives in urban sustainability transitions. Drawing on a case study of the city of Brighton & Hove (UK), the paper finds that despite favourable local political conditions, there is a lack of evidence of acceleration apart from in individual domains such as food or mobility. Progress is found to depend on the agency of initiatives to both scale up sustainable practices and embed these practices into local governance arrangements

T cell repertoire to citrullinated self-peptides in healthy humans is not confined to the HLA-DR SE alleles; targeting of citrullinated self-peptides presented by HLA-DP4 for tumour therapy

Post-translational modifications are induced in stressed cells which cause them to be recognised by the immune system. One such modification is citrullination where the positive charged arginine is modified to a neutral citrulline. We demonstrate most healthy donors show an oligoclonal CD4 response in vitro to at least one citrullinated vimentin or enolase peptide. Unlike rheumatoid arthritis patients, these T cell responses were not restricted by HLA-DRB1 shared epitope (SE) alleles, suggesting they could be presented by other MHC-II alleles. As HLA-DP is less polymorphic than HLA-DR, we investigated whether the common allele, HLA-DP4 could present citrullinated epitopes. The modification of arginine to citrulline enhanced binding of the peptides to HLA-DP4 and induced high frequency CD4 responses in HLA-DP4 transgenic mouse models. Our previous studies have shown that tumours present citrullinated peptides restricted through HLA-DR4 which are good targets for anti-tumour immunity. In this study we show that citrullinated vimentin and enolase peptides also induced strong anti-tumour immunity (100% survival,

Citrullinated α-enolase is an effective target for anti-cancer immunity

Targeting post-translationally modified epitopes may provide a new strategy for generating tumor specific immune responses. Citrullination is the post-translational modification of arginine to citrulline catalyzed by peptidylarginine deaminase (PAD) enzymes. Presentation of citrullinated peptides on MHC-II has been associated with autophagy. Tumors upregulate autophagy and present citrullinated peptides in response to stresses including nutrient deprivation, oxygen deprivation, redox stress and DNA damage, making them good targets for immune attack. The ubiquitous glycolytic enzyme α-enolase (ENO1) is often citrullinated and degraded during autophagy. Immunization of mice with two citrullinated ENO1 peptides (ENO1 241-260cit253 or 11-25cit15) induced strong Th1 responses that recognize the post-translationally modified, but not the wild type unmodified epitope. ENO1 11-25cit15 induced tumor therapy of melanoma cells in C57Bl/6 (B16F1 50% survival p = 0.0026) and ENO1 241-260cit253 in HLA-DR4 transgenic mice (B16-DR4 50% survival p = 0.0048). In addition, ENO1 241-260cit253 induced therapy of pancreatic (Pan02-DR4 50% survival p = 0.0076) and lung (LLC/2-DR4 40% survival p = 0.0142) tumors in HLA-DR4 transgenic mice. The unmodified epitope induced no anti-tumor response. Minimal regression of class II negative B16 or LLC/2 tumor was seen, confirming direct recognition of MHC-II was required. Most tumors only express MHC-II in the presence of IFNγ; an IFNγ inducible model showed strong responses, with rejection of tumors in up to 90% of animals (p = 0.0001). In humans, a repertoire to ENO1 241-260cit253 was observed in healthy donors. This response was CD4 mediated and seen in people with a variety of HLA types suggesting a broad application for this vaccine in human cancer therapy

Citrullinated vimentin presented on MHC-II in tumor cells is a target for CD4+ T-cell-mediated antitumor immunity

Stressful conditions in the harsh tumor microenvironment induce autophagy in cancer cells as a mechanism to promote their survival. However, autophagy also causes post-translational modification of proteins that are recognized by the immune system. In particular, modified self-antigens can trigger CD4(+) T-cell responses that might be exploited to boost antitumor immune defenses. In this study, we investigated the ability of CD4 cells to target tumor-specific self-antigens modified by citrullination, which converts arginine residues in proteins to citrulline. Focusing on the intermediate filament protein vimentin, which is frequently citrullinated in cells during epithelial-to-mesenchymal transition of metastasizing epithelial tumors, we generated citrullinated vimentin peptides for immunization experiments in mice. Immunization with these peptides induced IFN?- and granzyme B-secreting CD4 T cells in response to autophagic tumor targets. Remarkably, a single immunization with modified peptide, up to 14 days after tumor implant, resulted in long-term survival in 60% to 90% of animals with no associated toxicity. This antitumor response was dependent on CD4 cells and not CD8(+) T cells. These results show how CD4 cells can mediate potent antitumor responses against modified self-epitopes presented on tumor cells, and they illustrate for the first time how the citrullinated peptides may offer especially attractive vaccine targets for cancer therapy